Methods for preventing or treating tissue damage resulting from a disruption of homeostasis, and active principles for use in the same

Abstract

The present invention relates to a hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use in treating a patient having elevated serum lactate dehydrogenase (LDH) levels or at risk thereof following or during a traumatic event. The treatment comprises administering the hybrid protein to reduce the serum LDH levels of the patient to a target range of less than 280 U / L. The present invention also relates to means and methods for the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage, especially tissue damage associated with the occurrence and / or formation of thrombi in circulation.

Description

[0001] Methods for preventing or treating tissue damage resulting from a disruption of homeostasis, and active principles for use in the same. Priority This application claims priority to, and benefit from, U.S. provisional applications No. 63 / 663573, 63 / 663575 and 63 / 663576 filed on 24 June 2024, the contents of which are incorporated herein by reference in their entirety. Field of invention The present invention relates to the field of diseases or conditions that are caused by, that result in and / or that are associated with tissue damage. The present invention also relates to the field of diseases or conditions that are caused by and / or associated with vascular occlusions, such as vascular occlusion caused by thrombi (including large thrombi as well as micro-thrombi). The present invention also relates to the field of diseases or conditions that are caused by, that result in and / or that are associated with the presence and / or the formation of (micro-)thrombi in the circulation (and in particular micro-thrombi in the micro-vasculature). More in particular, the present invention relates to the field of diseases or conditions that are caused by, that result in and / or that are associated with the presence and / or the formation of thrombi in the circulation (and in particular micro-thrombi in the micro-vasculature), where the presence and / or the formation of micro-thrombi in the circulation (and in particular in the micro-vasculature) results in or can lead to tissue damage and / or where the presence and / or the formation of thrombi in the circulation (and in particular micro-thrombi in the micro- vasculature) results from and / or is associated with tissue damage (where the presence and / or the formation of micro-thrombi and / or the tissue damage may in turn be caused by and / or associated with another disease or disorder, such as an underlying disease or disorder). Background A hypoxic state refers to a condition in which there is insufficient oxygen reaching the tissues of the body. As oxygen is essential for normal cellular function, under hypoxic state the body’s tissues start to struggle to maintain hemostasis, leading to tissue damage. A hypoxic state (and / or associated tissue damage, the presence and / or formation of thrombi (in large and / or micro blood vessels), associated ischemic events and / or disruption of homeostasis) may result from and / or be associated with a multitude of diseases, disorders or events (including medical interventions) affecting the human body. The following discussion focuses on (micro)vascular thrombosis (occurred mainly in micro- vessels) as a particular example, but the concept of the present invention is equally applicable (and therefore the effects of the present invention are equally achievable) in macro-thrombosis (occurred mainly in large blood vessels). One specific cause of certain types of tissue damage (and / or a phenomenon that may be associated with certain types of tissue damage, in particular in their early stages), is the presence and / or the formation of micro-thrombi in the circulation (and in particular in the microvasculature, in which case it is also referred to by the general term microvascular thrombosis or “MVT”), which can occlude the vasculature (ischemia) and deplete the systemic circulation from platelets. This may lead to ischemic injury in the affected tissues and may in some cases be accompanied by a severe risk of bleeding (in particular in case of substantially lowered platelet counts). There are also a number of diseases and disorders that may cause, result in and / or are associated with the formation of such thrombi, and / or that have (micro)vascular thrombosis and / or the formation of (micro-)thrombi as one of their symptoms. (Micro)vascular thrombosis is a complex medical condition characterized by the formation of blood clots within the microvasculature. Understanding its origin requires a deep dive into the intricate interplay of various physiological factors and pathological conditions. The origin of microvascular thrombosis can be traced back to three primary factors: endothelial injury, abnormal blood flow, and hypercoagulability, collectively known as Virchow's triad. These factors contribute to the formation of thrombi, or blood clots, within vasculature. Endothelial injury is one of significant triggers for (micro)vascular thrombosis. The endothelium, the inner lining of blood vessels, plays a crucial role in maintaining vascular homeostasis. When the endothelium is damaged due to factors such as inflammation, infection, or trauma (including planned trauma, such as surgery), it may initiate hemostasis leading to plug formation that can escalate in to the formation of an occluding thrombi. Abnormal blood flow, or stasis, is another contributing factor. Under normal conditions, blood flow is laminar, meaning that it flows in parallel layers with minimal mixing. However, conditions that disrupt this flow, such as vessel narrowing or irregular heart rhythms, can lead to blood pooling and clot formation. Hypercoagulability, the third factor in Virchow's triad, refers to a state in which the blood has an increased tendency to clot. This can be due to genetic disorders, certain medications, or conditions like cancer or pregnancy. In addition to these primary factors, several secondary factors can contribute to the origin of (micro)vascular thrombosis. These include systemic conditions such as sepsis, autoimmune diseases like antiphospholipid syndrome, and metabolic disorders such as diabetes. (Micro)vascular thrombosis can also be a complication of certain medical procedures or treatments. For example, chemotherapy drugs can damage the endothelium and increase the risk of clot formation. Similarly, surgical procedures can lead to endothelial injury and stasis, contributing to thrombosis. Thus, it can be said that the origin of (micro)vascular thrombosis is multifactorial, involving a complex interplay of physiological and pathological factors. It is a dynamic process that begins with endothelial injury, abnormal blood flow, or hypercoagulability and can be exacerbated by various secondary factors. Understanding these origins is crucial for the development of effective prevention and treatment strategies. There is also a need for methods and means that can be applied in order to limit or slow the consequences of (and in particular the damage caused by) such a hypoxic state affecting one or more tissues in the human body. In this respect, it should be noted that the deleterious effects of such a hypoxic state (and / or, when or where such a hypoxic state occurs, worsen rapidly), often occur over the course of just a couple hours or even minutes. Thus, there is a particular need for treatments that can provide a acute or rapid intervention in case of a hypoxic state, tissue damage, MVT, the presence or formation of (micro-)thrombi and / or more generally diseases and disorders that can cause the same and / or are associated with the same. Some specific examples of such diseases and disorders will become clear to the skilled person based on the further disclosure herein. Based on the disclosure herein, it will be clear that there is a continuous need in the art for methods and means that can be applied to the prevention and treatment of the consequences of (and in particular the damage caused by) such a hypoxic state affecting one or more tissues in the human body. More particularly, but without limitation, it is an aim of the invention to provide means and methods that can be used for the purposes of such prevention in a subject showing signs (and in particular clinical signs, which clinical signs will be clear to the skilled person based on the disclosure herein and may involve the use of and / or the results from diagnostic methods or tools known per se) of one or more of tissue damage, thrombotic events, clot formation, the presence or formation of micro-thrombi, ischemic events (such as the presence or appearance of ischemic areas and / or signs of reduced / restricted blood flow, as determined using suitable technical means known per se) or similar signs showing that the supply of oxygen and / or oxygenated blood to certain tissues may be reduced or restricted (or that there is a risk of the same), in particular where the same affects homeostasis in the affected tissue(s) (or where these is risk of homeostasis in the affected tissue(s) being disturbed). Similarly, based on general experience and the further disclosure herein, it will be clear to the skilled person that there are diseases and disorders (as well as certain medical procedures / interventions) that come with a risk of homeostasis in one or more tissues being disturbed (in particular as a result of a hypoxic or ischemic event affecting said tissues and / or the flow of oxygen or oxygenated blood to said tissue(s)) with the concomitant risk of tissue damage occurring or arising said in one or more tissues; and some specific diseases for which this may be the case are mentioned in the further disclosure herein. Again, where it is generally envisaged that, based on his / her clinical expertise (optionally in combination with one or more other relevant clinical signs, such as those mentioned herein), the treating physician may decide to apply the means and methods described herein (for example, as a preventative measure to avoid tissue damage or prevent or reduce the risk of further tissue damage. Summary of Invention The following aspects A-1 to A-22 are specific, but non-limiting aspects of the invention: A-1. In a specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in cardiac tissue, and in particular such a hypoxic state in cardiac tissue that is caused by, results from and / or is associated with myocyte injury, hepatic congestion, a medical procedure or intervention (e.g. anastomosis of vascular grafts, atherectomy or arterial stenting, carotid endarterectomy or by-pass graft, or re-occlusion during and after thrombolytic therapy), thrombosis (such as thromboembolism, thromboembolic complications the formation of an occlusive thrombus, peripheral vascular disease, peripheral arterial occlusive disease, occlusive syndrome in a vascular system or lack of patency of diseased arteries, embolism, embolus formation, deep vein thrombosis, a non-occlusive thrombus, critical limb ischemia, arterial thrombus formation or arterial thrombosis), stenosis (such as carotid artery stenosis) restenosis (such as restenosis and disorders arising from coronary by- pass graft) and / or hemolysis (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi in cardiac tissue that are caused by, result from and / or are associated with myocyte injury, hepatic congestion, a medical procedure or intervention (e.g. anastomosis of vascular grafts, atherectomy or arterial stenting, carotid endarterectomy or by-pass graft, or re- occlusion during and after thrombolytic therapy), thrombosis (such as thromboembolism, thromboembolic complications the formation of an occlusive thrombus, peripheral vascular disease, peripheral arterial occlusive disease, occlusive syndrome in a vascular system or lack of patency of diseased arteries, embolism, embolus formation, deep vein thrombosis, a non-occlusive thrombus, critical limb ischemia, arterial thrombus formation or arterial thrombosis), stenosis (such as carotid artery stenosis) restenosis (such as restenosis and disorders arising from coronary by- pass graft) and / or hemolysis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) in cardiac tissue that is caused by, results from and / or is associated with myocyte injury, hepatic congestion, a medical procedure or intervention (e.g. anastomosis of vascular grafts, atherectomy or arterial stenting, carotid endarterectomy or by-pass graft, or re-occlusion during and after thrombolytic therapy), thrombosis (such as thromboembolism, thromboembolic complications the formation of an occlusive thrombus, peripheral vascular disease, peripheral arterial occlusive disease, occlusive syndrome in a vascular system or lack of patency of diseased arteries, embolism, embolus formation, deep vein thrombosis, a non-occlusive thrombus, critical limb ischemia, arterial thrombus formation or arterial thrombosis), stenosis (such as carotid artery stenosis) restenosis (such as restenosis and disorders arising from coronary by-pass graft) and / or hemolysis (and again, where the subject to be treated has an elevated LDH level (as defined herein)). A-2. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in cardiac tissue, and in particular such a hypoxic state in cardiac tissue that is caused by, results from and / or is associated with myocyte injury, in particular where such myocyte injury results from and / or is associated with one or more of demand ischemia, trauma, cadiovascular surgery, toxins, infection or infectious diseases (e.g. myocarditis, rheumatic fever or viral infections, with the latter being a possible cause of myocarditis), or the use, abuse and / or overdosing of controlled substances (e.g. alcohol or cocaine), prescription medicines (e.g. methysergide and / or chemotherapy) or other harmful or toxic substances causing myocyte injury (e.g. carbon monoxide) (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi in cardiac tissue that are caused by, result from and / or are associated with myocyte injury, in particular where such myocyte injury results from and / or is associated with one or more of demand ischemia, trauma, cadiovascular surgery, toxins, infection or infectious diseases (e.g. myocarditis, rheumatic fever or viral infections), or the use, abuse and / or overdosing of controlled substances (e.g. alcohol or cocaine), prescription medicines (e.g. methysergide and / or chemotherapy) or other harmful or toxic substances causing myocyte injury (e.g. carbon monoxide) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) in cardiac tissue that is caused by, results from and / or is associated with myocyte injury, in particular where such myocyte injury results from and / or is associated with one or more of demand ischemia, trauma, cadiovascular surgery, toxins infection or infectious diseases (e.g. myocarditis, rheumatic fever), or the use, abuse and / or overdosing of controlled substances (e.g. alcohol or cocaine), prescription medicines (e.g. methysergide and / or chemotherapy) or other harmful or toxic substances causing myocyte injury (e.g. carbon monoxide) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-3. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in cardiac tissue, and in particular such a hypoxic state in cardiac tissue that is caused by, results from and / or is associated with hepatic congestion, in particular where such hepatic congestion is caused by, results from and / or is associated with heart failure (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro- )thrombi in cardiac tissue that are caused by, result from and / or are associated with hepatic congestion, in particular where such hepatic congestion is caused by, results from and / or is associated with heart failure (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) in cardiac tissue that is caused by, results from and / or is associated with hepatic congestion, in particular where such hepatic congestion is caused by, results from and / or is associated with heart failure (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-4. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in cardiac tissue, and in particular such a hypoxic state in cardiac tissue that is caused by, results from and / or is associated with hemolysis, in particular where such hemolysis is caused by, results from and / or is associated with the use, presence and / or implantation of a prosthetic heart valve (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi in cardiac tissue that are caused by, result from and / or are associated with hemolysis, in particular where such hemolysis is caused by, results from and / or is associated with the use, presence and / or implantation of a prosthetic heart valve (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) in cardiac tissue that is caused by, results from and / or is associated with hemolysis, in particular where such hemolysis is caused by, results from and / or is associated with the use, presence and / or implantation of a prosthetic heart valve (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-5. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the nervous system (i.e. the central nervous system and / or the peripheral nervous system), and in particular such a hypoxic state that is caused by, results from and / or is associated with bacterial meningitis, cerebral venous thrombosis, cerebral infarction, transient cerebral ischemic attack, transient ischemic attacks and strokes or another disease, disorder or event that may cause a hypoxic state to occur in one or more cells, parts or tissues that form part of the nervous system (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi in one or more parts or tissues of the nervous system, and in particular such a hypoxic state that is caused by, results from and / or is associated with bacterial meningitis, cerebral venous thrombosis cerebral infarction, transient cerebral ischemic attack, transient ischemic attacks and strokes or another disease, disorder or event that may cause a hypoxic state to occur in one or more cells, parts or tissues that form part of the nervous system (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) in one or more cells, parts or tissues that form part of the nervous system, and in particular such a hypoxic state that is caused by, results from and / or is associated with bacterial meningitis, cerebral venous thrombosis cerebral infarction, transient cerebral ischemic attack, transient ischemic attacks and strokes or another disease, disorder or event that may cause a hypoxic state to occur in one or more cells, parts or tissues that form part of the nervous system (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-6. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with the use, abuse, overdosing and / or (where applicable) withdrawal from of recreational drugs and / or controlled substances, prescription medicines or other harmful or toxic substances causing such a hypoxic state (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with the use, abuse, overdosing and / or (where applicable) withdrawal from of recreational drugs and / or controlled substances, prescription medicines or other harmful or toxic substances causing such a hypoxic state (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with the use, abuse, overdosing and / or (where applicable) withdrawal from of recreational drugs and / or controlled substances, prescription medicines or other harmful or toxic substances causing such a hypoxic state. Some specific, but non-limiting examples of such recreational drugs, controlled substances, prescription medicines and / or other harmful or toxic substances include, but are not limited to, neuropleptic agents (e.g. as associated with neuroleptic malignant syndrome), withdrawal of L-Dope or a dopamine agonist, colchicine, antimalarials, chloesterol-lowering drugs, drugs causing malignant hyperthermia (such as some drugs used for anasthesia), cocaine, alcohol, and certain glucocorticoids (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-7. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a metabolic or endocrine disease or disorder, and in particular a metabolic or endocrine disease or disorder that is one of acromegaly, Cushing's syndrome or diabetic muscle infraction (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a metabolic or endocrine disease or disorder, and in particular a metabolic or endocrine disease or disorder that is one of acromegaly, Cushing's syndrome or diabetic muscle infraction (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a metabolic or endocrine disease or disorder, and in particular a metabolic or endocrine disease or disorder that is one of acromegaly, Cushing's syndrome or diabetic muscle infraction (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-8. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a gastro-intestinal disease or disorder, such as acute pancreatitis (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a gastro-intestinal disease or disorder, such as acute pancreatitis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a gastro-intestinal disease or disorder, such as acute pancreatitis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-9. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a hematological disease or disorder, such as hemolytic anemias (for example inherited hemolytic anemias as in the case of spherocytosis, sickle cell disease and / or an inherited deficiency of red blood cell enzymes or acquired hemolytic anemias as in the case of microangiopathic hemolytic anemia, PNH or immune hemolysis), antiphospholipid antibody syndrome, complement- mediated thrombotic microangiopathy or haemolytic uremic syndrome (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a hematological disease or disorder, such as hemolytic anemias (for example inherited hemolytic anemias as in the case of spherocytosis, sickle cell disease and / or an inherited deficiency of red blood cell enzymes or acquired hemolytic anemias as in the case of microangiopathic hemolytic anemia, PNH or immune hemolysis) antiphospholipid antibody syndrome, complement- mediated thrombotic microangiopathy or haemolytic uremic syndrome (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a hematological disease or disorder, such as hemolytic anemias (for example inherited hemolytic anemias as in the case of spherocytosis, sickle cell disease and / or an inherited deficiency of red blood cell enzymes or acquired hemolytic anemias as in the case of microangiopathic hemolytic anemia, PNH or immune hemolysis) antiphospholipid antibody syndrome, complement- mediated thrombotic microangiopathy or haemolytic uremic syndrome (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-10. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with an infectious disease (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with an infectious disease. This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with an infectious disease. In particular, in these aspects of the invention, the infectious disease may be one of pneumocystis pneumonia (late), a respiratory infectious disease (e.g. SARS or COVID-19), tuberculosis, malaria, a parasitic infection, legionnaires disease, histoplasmosis or disseminated intravascular coagulopathy (DIC) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-11. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with (the treatment of) a malignant disease or disorder, such as leukemias, lymphomas, solid tumors (for example testicular germ cell tumors) and tumor lysis syndrome (e.g. large tumor burden) (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a malignant disease or disorder, such as leukemias, lymphomas, solid tumors (for example testicular germ cell tumors) and tumor lysis syndrome (e.g. large tumor burden) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a malignant disease or disorder, such as leukemias, lymphomas, solid tumors (for example testicular germ cell tumors) and tumor lysis syndrome (e.g. large tumor burden) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-12. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a neuromuscular disease or disorder, and in particular (inherited, acquired or drug-related) myopathies (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a neuromuscular disease or disorder, and in particular (inherited, acquired or drug-related) myopathies (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a neuromuscular disease or disorder, and in particular (inherited, acquired or drug- related) myopathies (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-13. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with (a disease and disorder as may occur during) pregnancy, and in particular with preeclampsia, adnexal mass in pregnancy or HELLP syndrome (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with (a disease and disorder as may occur during) pregnancy, and in particular with preeclampsia, adnexal mass in pregnancy or HELLP syndrome (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with (a disease and disorder as may occur during) pregnancy, and in particular with preeclampsia, adnexal mass in pregnancy or HELLP syndrome (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-14. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body (and in particular of pulmonary tissue) where such a hypoxic state is caused by, results from and / or is associated with a pulmonary disease or disorder, and in particular pulmonary embolism or pulmonary infarction (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body (and in particular pulmonary tissue) where such a hypoxic state is caused by, results from and / or is associated with a pulmonary disease or disorder, and in particular pulmonary embolism or pulmonary infarction (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body (and in particular pulmonary tissue) where such a hypoxic state is caused by, results from and / or is associated with a pulmonary disease or disorder, and in particular pulmonary embolism or pulmonary infarction (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-15. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body (and in particular of renal tissue) where such a hypoxic state is caused by, results from and / or is associated with a disease or disorder of the kidneys, such as renal infarction or acute renal failure (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro- )thrombi that occurs in one or more parts or tissues of the human body (and in particular renal tissue) where such a hypoxic state is caused by, results from and / or is associated with a disease or disorder of the kidneys, such as renal infarction or acute renal failure. This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body (and in particular renal tissue) where such a hypoxic state is caused by, results from and / or is associated with a disease or disorder of the kidneys, such as renal infarction or acute renal failure (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-16. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a rheumatological disease or disorder, such as, in particular, one of dermatomyositis, MCTD or rheumatoid arthritis (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a rheumatological disease or disorder, such as, in particular, one of dermatomyositis, MCTD or rheumatoid arthritis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a rheumatological disease or disorder, such as, in particular, one of dermatomyositis, MCTD or rheumatoid arthritis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-17. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with trauma or injury (for example, in case of physical trauma or in case of rhabdomyolysis) or with a medical procedure or intervention (such as surgery) (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with trauma or injury (for example, in case of physical trauma or in case of rhabdomyolysis) or with a medical procedure or intervention (such as surgery) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with trauma or injury (for example, in case of physical trauma or in case of rhabdomyolysis) or with a medical procedure or intervention (such as surgery) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-18. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with vasculitis, for example in case of, in the context of and / or associated with one of the following diseases or disorders: polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis), granulomatosis with polyangiitis (Wegener's disease), Behçet's syndrome or sarcoidosis (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with vasculitis, for example in case of, in the context of and / or associated with one of the following diseases or disorders: polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis), granulomatosis with polyangiitis (Wegener's disease), Behçet's syndrome or sarcoidosis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with vasculitis, for example in case of, in the context of and / or associated with one of the following diseases or disorders: polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis), granulomatosis with polyangiitis (Wegener's disease), Behçet's syndrome or sarcoidosis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-19. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a traumatic event, for example in case of, in the context of and / or associated with one of the following traumatic events: a transplantation, a chemotherapy session, a radiotherapy session, a surgical intervention such as a stent insertion, a plasma exchange session, a stroke, an acute kidney injury, a myocardial infarction, a fluid imbalance, an ischemic event, and / or the result of: an autoimmune disease such as sclerosis, a hematologic disorder, a genetic disorder such as haemophilia, a viral infection such as COVID, a bacterial infection, a severe medical condition such as cancer, aHUS, st-HUS, or TMA, a pregnancy, a restenosis, or aging (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that occurs in one or more parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a traumatic event, for example in case of, in the context of and / or associated with one of the following traumatic events: a transplantation, a chemotherapy session, a radiotherapy session, a surgical intervention such as a stent insertion, a plasma exchange session, a stroke, an acute kidney injury, a myocardial infarction, a fluid imbalance, an ischemic event, and / or the result of: an autoimmune disease such as sclerosis, a hematologic disorder, a genetic disorder such as haemophilia, a viral infection such as COVID, a bacterial infection, a severe medical condition such as cancer, aHUS, st-HUS, or TMA, a pregnancy, a restenosis, or aging, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that occurs in one or more cells, parts or tissues of the human body where such a hypoxic state is caused by, results from and / or is associated with a traumatic event, for example in case of, in the context of and / or associated with one of the following traumatic events: a transplantation, a chemotherapy session, a radiotherapy session, a surgical intervention such as a stent insertion, a plasma exchange session, a stroke, an acute kidney injury, a myocardial infarction, a fluid imbalance, an ischemic event, and / or the result of: an autoimmune disease such as sclerosis, a hematologic disorder, a genetic disorder such as haemophilia, a viral infection such as COVID, a bacterial infection, a severe medical condition such as cancer, aHUS, st-HUS, or TMA, a pregnancy, a restenosis, or aging, in particular where the subject to be treated has an elevated LDH level (as defined herein)). A-20. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that is caused by, results from and / or is associated a medical procedure or intervention, such as anastomosis of vascular grafts, atherectomy or arterial stenting, carotid endarterectomy or by-pass graft, or re- occlusion during and after thrombolytic therapy (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that are caused by, result from and / or are associated with a medical procedure or intervention, such as anastomosis of vascular grafts, atherectomy or arterial stenting, carotid endarterectomy or by-pass graft, or re-occlusion during and after thrombolytic therapy (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that is caused by, results from and / or is associated with myocyte injury, hepatic congestion, a medical procedure or intervention (e.g. anastomosis of vascular grafts, atherectomy or arterial stenting, carotid endarterectomy or by-pass graft, or re-occlusion during and after thrombolytic therapy) (and again, where the subject to be treated has an elevated LDH level (as defined herein)). A-21. In a further specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that occurs, and in particular such a hypoxic state that is caused by, results from and / or is associated with thrombosis, such as thromboembolism, thromboembolic complications the formation of an occlusive thrombus, peripheral vascular disease, peripheral arterial occlusive disease, occlusive syndrome in a vascular system or lack of patency of diseased arteries, embolism, embolus formation, deep vein thrombosis, a non-occlusive thrombus, critical limb ischemia, arterial thrombus formation or arterial thrombosis (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that are caused by, result from and / or are associated with thrombosis, such as thromboembolism, thromboembolic complications the formation of an occlusive thrombus, peripheral vascular disease, peripheral arterial occlusive disease, occlusive syndrome in a vascular system or lack of patency of diseased arteries, embolism, embolus formation, deep vein thrombosis, a non-occlusive thrombus, critical limb ischemia, arterial thrombus formation or arterial thrombosis (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that is caused by thrombosis (such as thromboembolism, thromboembolic complications the formation of an occlusive thrombus, peripheral vascular disease, peripheral arterial occlusive disease, occlusive syndrome in a vascular system or lack of patency of diseased arteries, embolism, embolus formation, deep vein thrombosis, a non-occlusive thrombus, critical limb ischemia, arterial thrombus formation or arterial thrombosis (and again, where the subject to be treated has an elevated LDH level (as defined herein)). A-22. In a specific but non-limiting aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein), and in particular such a hypoxic state that is caused by, results from and / or is associated with stenosis (such as carotid artery stenosis) or restenosis (such as restenosis and disorders arising from coronary by-pass graft) (and in particular, as with the more general aspects of the invention described herein, where the subject to be treated has an elevated LDH level (as defined herein)). In particular, according to this specific aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that are caused by, result from and / or are associated with stenosis (such as carotid artery stenosis) or restenosis (such as restenosis and disorders arising from coronary by-pass graft) (and again, in particular where the subject to be treated has an elevated LDH level (as defined herein)). This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) stenosis (such as carotid artery stenosis) or restenosis (such as restenosis and disorders arising from coronary by-pass graft) (and again, where the subject to be treated has an elevated LDH level (as defined herein)). Definition of terms The term “hybrid protein” is defined as a complex of two or more polypeptide sequences or fragments thereof which would not normally be associated, but are coupled together either by fusing the genes (optionally with a peptide linker) which encode them or by chemically cross- linking the component parts. The term “chemically linked protein” is defined as understood by a person skilled in the art as a construct where two or more proteins are covalently attached to each other using chemical methods, including the use of cross-linking agents, such as bifunctional reagents, click chemistry, or enzymatic conjugation. The term "urokinase catalytic domain" refers to a specific region or segment of the urokinase- type plasminogen activator (uPA) protein. The terms “urokinase-type plasminogen activator” and “urokinase” are used interchangeably and refer to an enzyme that plays a role in the breakdown of blood clots, a process known as fibrinolysis. Both terms also encompass precursors or inactive forms of urokinase, such as pro-urokinase. In particular, the urokinase protein can facilitate the lysis of blood clots (i.e. microthrombi) by promoting the conversion of plasminogen to plasmin, which then degrades fibrin, the protein meshwork that forms blood clots, into smaller fragments. The urokinase protein is composed of several functional domains, each with its unique role in its enzymatic activity. The "catalytic domain" is the part of the urokinase protein responsible for its enzymatic function, specifically the ability to activate plasminogen into plasmin. In particular, urokinase is a serine protease that has the ability to catalyze the activation of plasmin via proteolytic cleavage of plasminogen. The term “residue” refers to a specific individual building block (i.e. an amino acid) within the polypeptide chain. Each amino acid in the chain is referred to as a residue. The term “position” refers to a specific position of a residue in the amino acid chain of a polypeptide. The number of the residue is assigned starting from the first amino acid at the N- terminus of the polypeptide. The first residue at the N-terminus is assigned number 1, the second residue is assigned number 2, et cetera. In this case, position 153 refers to the 153th amino acid in the polypeptide chain, counted from the N-terminus. The term “substitution” refers to a specific type of mutation that occurs when an amino acid residue in a polypeptide chain is replaced by a different amino acid residue. For instance, when an arginine residue is replaced with a glutamine residue. The terms “VHH” and “VHH antibody” are used interchangeably and refer to a single-domain antibody or nanobody, which is a type of antibody derived from camelids (camels, llamas, and alpacas) or cartilaginous fish (such as sharks and rays). Unlike conventional antibodies (IgG antibodies) found in humans and other mammals, which have two heavy chains and two light chains, VHH antibodies have a single polypeptide chain containing a single variable domain derived from the heavy chain. A VHH antibody has a framework region (FR) and a complementarity-determining region (CDR). The “framework region”, is typically comprised of framework regions 1-4 (FR1-FR4), and forms the scaffold of the VHH antibody's variable domain, providing structural support and maintaining the overall shape of the binding site. It comprises relatively conserved amino acid sequences that stabilize the antibody structure and contribute to its folding. The “complementarity-determining regions (CDRs)”, also known in the art as hypervariable regions, are short stretches of amino acids within the variable domain of an antibody. CDRs are highly diverse and responsible for antigen recognition and binding specificity. There are typically three CDRs in the variable domain of VHH antibodies, generally named CDR1, CDR2, and CDR3. The terms “humanization” and / or “deimmunization” refer to a modification wherein amino acids of an antibody derived from a non-human source (e.g., camelid, mouse, or other species) are modified to make them more similar to human antibodies. The goal of humanization is to reduce potential immunogenicity (the likelihood of eliciting an immune response) when the antibody is used in humans for therapeutic or diagnostic purposes. When an antibody is humanized, one or more amino acid residues are replaced by one or more of the amino acid residues that predominantly occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being. The hybrid protein, as set out above can be either a fusion protein or a chemically linked protein. Detailed Description Further aims, aspects, embodiments, applications, uses and advantages of the invention will become clear from the description below. In one specific but non-limiting aspect, the invention relates to the field of preventing or treating tissue damage, and in particular tissue damage that is caused by, is associated with and / or leads to the formation of thrombi such as microthrombi, where either the tissue damage and / or the formation of the (micro-)thrombi causing the tissue damage is the result of and ischemic injury (i.e. to the tissue itself and / or to surrounding tissues and / or to the blood vessels that supply blood and oxygen to said tissues) and / or an hypoxic state (i.e. of the affected tissue). In one even more specific but not-limiting aspect, said tissue damage and / or said formation of (micro-)thrombi is caused by reduced flow of blood (and in particular, of blood carrying oxygen) to the affected tissue, for example due to a partial or full blockage of the blood vessels (and in particular the artery or arteries) that carry blood (and in particular oxygenated blood) to the affected tissue, for example as a result of a blood clot or embolism that is blocking flow through said blood vessel(s), as a result of injury to said blood vessel(s), as a result of a medical procedure that disturbs or interrupts with the flow of blood to the affected tissues, and / or any other condition, event or state that results in and / or is associated with a reduced supply of oxygen and / or oxygenated blood to the affected tissue (and more generally an hypoxic state of the affected tissue or tissues, also known as ischemia or an ischemic event). The means and methods provided by the present invention may be used to reduce or to prevent the tissue damage that may result from and / or associated with a disease, disorder, procedure, injury or other condition or event that reduces or affects the supply of oxygen or blood to the affected tissue and / or otherwise leads to a hypoxic state in / of the affected tissues. Such diseases, disorders, procedures, injuries or other conditions or events will become clear to the skilled person based on the disclosure herein. One specific (and in the invention preferably used) sign of the foregoing may in particular be an increased LDH level (as defined herein) in the blood of the patient, and thus in a specific aspect the invention envisages the use of (increased) LDH levels as a marker for guiding the clinician in (the choice of) applying the means and methods described herein (optionally in combination with one of the other clinical signs mentioned herein and / or based on the judgement of the treating physician). LDH There are numerous diseases or disorders that lead to, cause and / or result in tissue damage, that are characterized by tissue damage and / or have tissue damage as one its symptoms, and / or that are associated with tissue damage. In addition to such diseases and disorders (which may be acute or chronic diseases), tissue damage by itself, for example as a result of trauma, injury, direct force, and wear and tear or overuse of tissues, can also itself be considered a medical condition and can in turn lead to further diseases and disorders. Tissue damage can also be the result of medical intervention, for example as a result of surgery. Reference is also made to the list of diseases and disorders given in Table 1 below. In the context of this application, the term “congenital” and “inherited” are used interchangeably. One known marker of tissue damage is (an elevated level in the bloodstream of) the enzyme lactate dehydrogenase or “LDH”, This is because, upon a tissue sustaining damage, the cells that are present in the damaged tissue release LDH into the bloodstream. Depending upon the type of tissue and the nature of the injury, after sustaining injury, LDH levels in the bloodstream can remain elevated for as long as the tissue damage sustains. For example, in patients with thrombotic thrombocytopenic purpura (TTP), the LDH level in the bloodstream is elevated for as long as (micro)thrombosis remains. For cancer patients, the LDH level in bloodstream may be elevated for a majority part or the whole duration of the cancer treatment. The elevated LDH in serum as a result of organ destruction occurs due to significant cell death that results in loss of cytoplasm. Also, when there is an hypoxic state (as defined herein) and / or an ischemic event in a particular tissue, LDH levels will generally also be elevated in and / or around the affected tissue(s), and such localized elevated LDH levels may also be used as a marker for damage to the affected tissues(s). However, in practice, it will usually be easier to determined LDH levels in the blood stream than locally in specific tissues. LDH is present in almost all the tissues in the human body, with the largest amounts of LDH being present in the muscles, liver, kidneys, and red blood cells. There are five different forms of the LDH enzyme (“LDH-1”to “LDH-5”), each of which are referred to as an “LDH isoenzyme”. These isoenzymes differ slightly in structure and generally can be said to be present in different / specific tissues in your body, with LDH-1 mainly being present in the heart and red blood cells; LDH-2 mainly being present in white blood cells (but also in the heart and in red blood cells, but in smaller amounts than LDH-1); LDH-3 being present in the lungs (with smaller amounts being present in other tissues); LDH-4 mainly being present in the kidneys and pancreas (and, in case of pregnancy, in the placenta); and LDH-5 mainly being present in the liver and in skeletal muscles. Claps et al., Nature Reviews Clinical Oncology, volume 19, pages 749–762 (2022) provide a review of the role of LDH and its use as a marker in various diseases and in particular in cancer. Reference is also made to the further references cited therein. Reference is for example also made to the review by Avdonin et al. (mentioned below). As is well known to the skilled person, various tests for measuring LDH level in blood samples and in samples of other bodily fluids are commercially available, and such tests are routinely used by medical professionals to look for signs of tissue damage. Such tests can either measure “total LDH” or the levels of specific LDH isoenzymes. Because each LDH isoenzyme is found in more than one type of tissue, such tests are sometimes also used in combination with other (and / or more specific) tests to accurately identify which tissue is damaged and the condition causing the damage. Measuring (changes in) levels of LDH (or of specific LDH isoenzymes) in samples obtained from a subject may also to be used to determine or monitor the status or progression of a disease or disorder that the subject is suffering from, to ascertain whether a treatment that is applied to a subject is having an effect and / or to monitor the course and / or effectiveness of such a treatment. Typically, for a healthy subject, the “total LDH” level (in blood or a blood sample, and determined in a manner known per se) will generally be in the range of 140 to 280 U / L (this range will also be referred to in the present description and claims as a “normal LDH level” or equivalent terms). Clinicians may also use slightly different internal reference values due to, for example, possible difference as a result of their geographical locations. The “normal LDH level” or the “Upper Limit of Normal” (ULN) value can also vary depending on the test performed (see for example, Stadler et al., J Immunother Cancer.2023; 11(5): e006456., who mention 120-246 U / L as a typical range in a healthy subject). An “elevated LDH level” (as this term is generally understood by clinicians and as this term is also used in the present description and claims) generally refers to a total LDH level (again, in blood or a blood sample, and determined in a manner known per se) of at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, more than the ULN determined by the clinicians. Putting it another way, an “elevated LDH level” may be at least 1.1 times, at least 1.3 times, at least 1.5 times, at least 1.7 times, at least 1.9 times, for example at least 2 times, of the ULN determined by the clinicians. For example, an elevated LDH level may be more than 280 U / L, in particular more than 300 U / L and will often be more than twice the ULN level (see for example Chin Keong Liam, Blood Res.2023 Mar 31; 58(1): 36–41) and may for some diseases or disorders reach levels of up to twenty times ULN level or more (see for example Avdonin et al., Biochemistry (Moscow), supplement series a: membrane and cell biology, vol.15 no.32021). vWF Von Willebrand Factor (vWF) is a complex multimeric glycoprotein that plays a crucial role in the process of hemostasis, the cessation of bleeding. This protein is particularly significant in the context of various forms of thrombosis, and in particular in case of microvascular thrombosis, a condition characterized by the formation of blood clots in the microvasculature (often in conjunction with essentially no or strongly reduced presence of fibrin; although in case of some conditions, it may also be possible that fibrin-mediated fibrinolysis may be less effective (or a combination of reduced fibrin and less effective fibrinolysis, in which case it may be difficult in practice to distinguish between the two)). The role of vWF in this pathological condition is multifaceted, involving aspects of platelet adhesion, aggregation, and thrombus formation (with aspects of inflammation sometimes also being mentioned in this context). vWF is primarily synthesized in endothelial cells and megakaryocytes, and stored in Weibel- Palade bodies in endothelial cells and alpha granules in platelets. Upon vascular injury, vWF is released into the bloodstream where it performs its primary function: mediating platelet adhesion to the subendothelial matrix. This is the first step in the formation of a platelet plug, a critical component of the hemostatic process. It has also been suggested that another important role of VWF is its binding to Factor VIII and the impact thereof on half-life. While both roles may have a major influence, and without being limited to any specific explanation, mechanism or hypothesis, it is assumed that in the context of the present invention, the platelet binding by VWF is one important (although potentially not the sole or only) mechanism. vWF achieves this by binding to specific receptors on the platelet surface, primarily glycoprotein Ib (GPIb). The shear stress conditions present in the microvasculature enhance this interaction, allowing vWF to tether platelets to the site of injury. This interaction is so crucial that defects in either vWF or GPIb can lead to bleeding disorders, such as von Willebrand disease and Bernard-Soulier syndrome, respectively. In addition to mediating platelet adhesion, vWF also plays a role in platelet aggregation, the clumping together of platelets to form a thrombus. It does this by binding to another platelet receptor, glycoprotein IIb / IIIa (GPIIb / IIIa), in a process that is dependent on the activation of the platelets and the presence of fibrinogen. This interaction further stabilizes the platelet plug and promotes the formation of a mature thrombus. In the context of (micro)vascular thrombosis, the role of vWF becomes particularly significant. Under pathological conditions, such as inflammation or infection, the endothelium can become activated, leading to an increased release of vWF (in particular, it leads to UL-vWF (Ultra Large vWF) secretion, with one side being anchored to the endothelial surface and the blood flow causing the VWF to “unroll” allowing ADAMTS13 to bind. ADAMTS13 will then start trimming down the UL-vWF into regular VWF sizes, which trimming "releases" vWF into circulation. Also, any UL-vWF that is directly released into the circulation – i.e. without being anchored to the endothelium- will also trimmed by ADAMTS13 in order to maintain normal multimer size distribution.). This can result in excessive platelet adhesion and aggregation leading to the formation of a thrombus. If this occurs in (micro)vasculature, it can lead to (micro)vascular thrombosis. Furthermore, certain conditions can lead to an increase in unusually large vWF multimers in circulation. These large multimers are particularly potent in promoting platelet adhesion and aggregation and are normally cleaved by a specific protease, ADAMTS13. However, in conditions such as thrombotic thrombocytopenic purpura (TTP), there is a deficiency of ADAMTS13, leading to an accumulation of large vWF multimers and a high risk of thrombosis. The role of vWF in (micro)vascular thrombosis is not limited to its interaction with platelets. It also interacts with other components of the coagulation system, such as factor VIII. vWF acts as a carrier protein for factor VIII, protecting it from degradation, improving its half-life and / or targeting it to sites of vascular injury (again, without the invention being limited to any specific explanation, hypothesis or mechanism). This interaction is crucial for the formation of a stable fibrin clot, the final step in the coagulation cascade. Thus, it can be said that vWF plays a multifaceted and crucial role in the process of hemostasis and, by extension, in the pathology of (micro)vascular thrombosis. It mediates platelet adhesion and aggregation, interacts with other components of the coagulation system, and its dysregulation can lead to pathological thrombus formation. Understanding the role of vWF in (micro)vascular thrombosis provides valuable insights into the mechanisms of this condition and can guide the development of therapeutic strategies. Von Willebrand Factor (vWF) activation is a crucial step in the process of hemostasis, the cessation of bleeding. The activation of vWF involves a series of steps that enable it to perform its primary functions: mediating platelet adhesion to the subendothelial matrix and carrying coagulation factor VIII, namely. - Synthesis and Storage: Ultra-large -vWF (UL-vWF) is synthesized in the endothelial cells,megakaryocytes and potentially platelets. In endothelial cells, it is stored in specialized storage organelles called Weibel-Palade bodies, while in platelets, it is stored in alpha granules. - Release: Upon vascular injury, hypoxia or endothelial stimulation by agonists like histamine or thrombin, UL-vWF will start to be released by these activated endothelial cells into the blood stream, a process known as exocytosis. The UL-vWF that is released is in an ultra-large multimeric form, is pro-thrombotic as it highly sensitive to shear stress conditions. This potentially enables the spontaneous binding of platelets to UL-vWF, leading to the spontaneous formation of thrombi. - UL-vWF is targeted by ADAMTS13 to cleaveing the ultra large multimers into smaller, normal vWFs multimers. This normalizes the interaction between VWF and platelets and prevents the spontenous formation of thrombi. - Upon injury of blood vessels, collagen becomes exposed. This allows for the binding of VWF, which in the presence of shear stress from the blood flow, will start to unrole. This unrolling / unfolding exposes the binding sites for platelet glycoprotein Ib (GPIb) receptors, allowing vWF to bind to platelets at the side of tissue injury This is the first step in the formation of a platelet plug, a crucial component of the hemostatic process. - Binding of platelets to VWF at sites of injury can lead to the activation of platelets via various pathways. Activation of platelets enables other process of hemostasis to progress such as the formation of coagulation. - Carrying Factor VIII: In addition to its role in platelet adhesion and aggregation, vWF also carries coagulation factor VIII in the circulation, thereby extending the relatively short half- life of Factor VIII. This results in a increasing blood concentration of Factor VIII towards normal endogenous levels. This protects factor VIII from elimination as well as targeting it to sites of vascular injury, where it participates in the coagulation cascade to form a stable fibrin clot. Typically, for a healthy subject (depending on several factors including for example blood type, see for example Gill et al., Blood, 1987 Jun;69(6):1691-5), the vWF level (in blood or a blood sample, and determined in a manner known per se, and often expressed as in units of VWF activity since VWF multimer size is important for its activity) will generally be in the range of 50-200 IU / dl, with a usual average of 100IU / dl which corresponds to about 10 microgram / ml of vWF, see for example the review by Avdonin cited herein) (this range will also be referred to in the present description and claims as a “normal vWF level” or equivalent terms). An “elevated vWF level” (as this term is generally understood by clinicians and as this term is also used in the present description and claims) generally refers to a vWF level (again, in blood or a blood sample, and determined in a manner known per se) of more than 200 IU / L or more (with highly elevated vWF levels often carrying a major risk of severe impact on the condition of the patient). vWF is thought to be involved in the pathogenesis of many diseases and / or in the thrombus formation that is causing, caused by and / or associated with the disease. Elevated vWF levels in blood may also be considered indicative of a disease, its state and / or its progress (and thus can for example be used as a diagnostic tool and / or a disease marker). For at least some diseases (as discussed in more detail in further description), vWF can be used as a marker to determine or monitor the effectiveness and / or progress of a treatment of the disease and its effects, including where such treatment is meant to prevent or treat the disease and / or meant to prevent or treat a hypoxic state (as defined) herein that is causing, caused by and / or associated with the disease (including preventing, reducing and / or limiting tissue damage caused by the disease and / or the hypoxic state). Applicability of the invention Table 1 below gives a non-limiting list of diseases and disorders in which vWF is known or assumed to play a role, such as how vWF is thought to be involved in the pathogenesis of the diseases and / or in the thrombus formation that is causing, caused by and / or associated with the disease and / or how elevated vWF levels in blood can be indicative of the disease, its state and / or its progress (and thus can for example be used as a diagnostic tool and / or a disease marker); as well as for example how, for at least some of the diseases mentioned, vWF and / or elevated LD level can be used as a marker to determine or monitor the effectiveness and / or progress of a treatment of the disease and its effects, including where such treatment is meant to prevent or treat the disease and / or meant to prevent or treat a hypoxic state (as defined) herein that is causing, caused by and / or associated with the disease (including preventing, reducing and / or limiting tissue damage caused by the disease and / or the hypoxic state), and therefore for which the hybrid protein described herein, would be useful for its treatment and / or prevention, on its own or in combination with other pharmaceutical composition(s). cri rc / e1sf ot.stF52fo slestn 6re,e f oci nW5roy, ve e1v siotnedeeitf 0 faV gt nao 1. r ol.J,,.L.novelH1.daweestxrptpahysis32otcois,.ivG,a90vd acD01 / rokirue nees tellae02 idyhL laf yl02 naesinL riof L.oceheo / d / evt dht ta utitht ehdnencne.r er p ,k sr ug,.neaeilc icia goeg ps ohtan átHroZ,gi or tcdgrciae tg napeednhi os tahca apev,.Baktn pidn ao.ded ni,e dnmoecla pera.jde ereJ,,.zsargnierFsla 7rpgni rumi ctntuht . / 6suhtC,.edZ, áh ot v pWnvru28 y dd ornaueodbr nno10 e.I ni Vnu iyor caaelytiootj2a2ltulcsed nsil ive7 na ni sirys esac ef kiraroitcr1.b0 naMrde,tóKnaka,.osPf vddc itnrocakh .nia.7w0cifi ,styllayraaeilneilo tcasf 1 / emefni gc etr HfaeciJl,zo np.eM,.uoP,aa.rbtca)f31L w1.nagi neci nr c nia fet l o.iD LruruTir .L e,lli dS wh ssvep orFesl yln aidod dlimili,sitZ, it naT / / a:s noiic yFait ocWresFe uno att Vvdoi tor roa / / etaf si afo oszc uWrbM pc:sav trFtrbsaéhksonoelA ptt talWdrWusiaf ran oyptt el ae Waemoparö nvf liD huVacVcaht oVsimimh 3 E hVhG P FáJ oWA(rae.hhpptres– ja y.j16unoit / 2 / 61z)so(lemcr -oa151110vc. -1 / rdovfinvi2l006.21m, / 1001vc / / 3ailgr 2, gr 9e ni 0s fdr at o. 12la o.5 -1.aeo aceio02siwo ye d / / .t i9e o 00.9rd / / 31 0001 / gDei yvemsd:s54 am:s .62,lrorfoniptt 00 uptt10a .islnaLh.tKh 2teoorsldie e e / / tn do^ ^lh:spneeeG mi tRtvhretnici / syrta ,yn43ere mugdru parobuehe raecs rh,toco e ra,l simerpsdauti eeaicsdrhdicgrnsiaas Dme vaoc ,eo lo syhrehc i yhs dam( otcl e) erdicro d,ass nAmeul(,ediiainamnd, mioitc)rs nixoftre uarx efegvuracnoaeOse D ToTnIefDocm HWsSaeUsi y8 dru0j4c2ae nip i no0 dyetciit2-1 raTyctaseSelCoypegnMbAaT.1M Hocnidd)1-nFdev31 e.se / r3 su51a .Hh n sun a.Wvevit ,) 54 uali stn18D.guoitbasK.( rece 13(0- c-laftet4Lsior cn m is.0Yroseps1 52laras82 / desyht uf orob8,tcrpor 010- ht ehsavtalo s shytnm5o-r3ouaf hter ,e2i h reo7 G,dtia ni 7g8 we ti n .-viehlms dlii20e ehobaielhT5...pnBaw re:)ci 2 taiwnan.0 ot rmoleorerp,,a bruFde1s / cstnm m0 / galrhht tnul)Bell liEp 6 os ei eln 6niuct od ati9af 0(,. iaWftFM. 81 str H( yd1.aoam.i10dp as -bc1. asaeestlvau nra edopr20M, no a n ut 01 ttUe 8n.01 4-ertc n miae1uVehoi sl / ghgC ht1 de / g 2vlnina nh,sciismi .lhtce22tiaran .ro.iuIo n nii0y2 r, mb o9.1i09av f aocnsioiasy.noatrs ku02,wstf ointa45odhtsyt lilla oh oo i naupod)0 citreetesytamal noime d .uJ, ne ovi it r8 / / es 9:sitHatr neng / / :s / / :s7(3hlop ta0tsma maF cniah b u tce2eptDotA Xapjebo.pthL moarptptP Gthth78or rmelfWmrPapHniVof1 4 3s285le1 / 3,.d v / ovgoP,oo.g nh. aM tihh rna&,la sif. in.w.m ms Ll.inarb n m .ilen.iedPca,Ass.e)Zb bgo 61mo-nc.n.aJ r:G02rf2de 12deee,.(. si000m2b2 m s C.Ns,o,su, biplbauw peiB namr / / u:s / t / / 6e :s / v2e,yrelmokrchept 3napt 1rooo aTMth26Yth47F C Mfost5f3argralucsseav sisvl fobaovsics moit orhehmtotstslaoraniretrO P AaWS U80s4siis20syob2-lomSmoMerhA H T1,5A .a)il65 s,aHrilAoja s80ih72ub.)i t0m8hNtmn .2 n(i po0. 0 npoOIn.rmenor0efoeit sih2irm T mk asoJo.tceao-p t(.l n . oei J.tc aA - Le sip nUcr ni etAs,afrdH.s56anSen rIAelA,afdH.s56Cyfialet ph sttn ygais3nr o1.ujoojni rtrenais31. 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By way of example, it is known that demand ischemia, trauma (e.g. cardiovascular surgery), toxins, infection and / or drugs can lead to myocyte injury via either one or more of hypoxia, inflammation, oxidative stress, calcium dysregulation or endothelial dysregulation. At the same time, these processes create a prothrombotic environment in which endothelial activation or injury has a central role. This can lead to vWF release and platelet-mediated thrombosis, similar to Myocardial infarction (MI). LDH elevation is a common characteristic of myocyte injury and can be increased due to ischemia after thrombosis. References show that vWF is present in the thrombus composition in acute myocardial infarction (Spiel et al., 2008) and elevated LDH can be used as predictor for heart failure after MI. vWF is also implicated in the pathophysiology of heart failure, indicating vWF mediated thrombosis, and elevated LDH increases mortality risk in heart failure patients (Zhang et al., 2024). vWF is also implicated in the pathophysiology of heart failure, indicating vWF mediated thrombosis, and elevated LDH increases mortality risk in heart failure patients. Increased vWF after coronary artery bypass grafting (CABG) is a risk factor for the development of Atrial fibrillation (AF), which can cause thrombosis and elevated LDH during CABG (Kaireviciute et al., 2011; Meng et al., 2008). Existing studies also suggest that vWF (of the increased level of vWF) is associated with various thrombosis or traumatic events, such as arterial thrombosis, atherectomy or arterial stenting, carotid artery stenosis, critical limb ischemia, deep vein thrombosis, embolism, non- occlusive thrombus, peripheral arterial occlusive disease, peripheral vascular disease, restenosis, thromboembolic complications, etc. Elevated LDH is often regarded as indicative of tissue damages and may be used as a biomarker to quantify the severity of the disease or trauma (Kolandaivelu et al., 2011; Bae et al, 2015; Hu et al., 2024). More details of the diseases, the role vWF is thought to have played in their pathology and prognosis, as well as how elevated LDH may be expected or used as a biomarker for monitoring the progress and / or development of the diseases or the relevant treatments, are given in the Table. By means and methods of the invention, the hybrid protein is capable of delivering the plasminogen activator to the site of thrombi or tissue damage by binding to vWF, thereby assisting lysis of blood clots, for example blood clots in macro and (micro)vascular, leading to the reduction of LDH level which may be indicative of reduction of tissue damage. The means and methods of the invention may therefore be useful in any disease or traumatic event that is associated with local vWF activities. In one aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) that is caused by, results from and / or is associated with one of the diseases, disorders or events that are listed in Table 1. In particular, according to this aspect of the invention, the means and methods of the invention are applied in the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of tissue damage and / or the occurrence and / or formation of (micro-)thrombi that are caused by, result from and / or are associated with one of the diseases, disorders or events that are listed in Table 1. This aspect of the invention further provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that is caused by, results from and / or is associated with one of the diseases, disorders or events that are listed in Table 1. As generally mentioned herein, it is in particular envisaged that, according to the invention and in case of a patient suffering from one of the diseases, disorders or events that are listed in Table 1, the treating physician will be guided in his choice about whether or not to apply the means and methods described herein for the purposes of prevention and / or treatment (as well as the manner in which such means and methods are applied for such a purpose) by the presence of an elevated LDH level (as defined herein) in the blood of the patient. Thus, in one specific aspect, the invention provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that is caused by, results from and / or is associated with one of the diseases, disorders or events that are listed in Table 1, where the subject to be treated has an elevated LDH level (as defined herein). It is also particularly envisaged that, according to the invention and in case of a patient suffering from one of the diseases, disorders or events that are listed in Table 1, the treating physician will be guided in his choice about whether or not to apply the means and methods described herein for the purposes of prevention and / or treatment (as well as the manner in which such e means and methods are applied for such a purpose) by the presence of an elevated vWF level (as defined herein) in the blood of the patient. Thus, in one specific aspect, the invention provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that is caused by, results from and / or is associated with one of the diseases, disorders or events that are listed in Table 1, where the subject to be treated has an elevated vWF level (as defined herein). Furthermore, it is also envisaged that, according to the invention and in case of a patient suffering from one of the diseases, disorders or events that are listed in Table 1, the treating physician will be guided in his choice about whether or not to apply the means and methods described herein for the purposes of prevention and / or treatment (as well as the manner in which such e means and methods are applied for such a purpose) by the presence of both an elevated LDH level and an elevated vWF level (as defined herein) in the blood of the patient. Thus, in one specific aspect, the invention provides means and methods (including specific chemical entities, as further described herein) for use in the prevention or treating (again including, as mentioned herein, reducing and / or limiting the damage caused by) a hypoxic state (and / or tissue damage and / or the occurrence and / or formation of (micro-)thrombi) that is caused by, results from and / or is associated with one of the diseases, disorders or events that are listed in Table 1, where the subject to be treated has both an elevated LDH level (as defined herein) and an elevated vWF level (as defined herein). In particular, means and methods of the invention may be used for the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a traumatic event selected from the list consisting of acquired or hereditary thrombotic thrombocytopenic purpura (TTP), antiphospholipid antibody syndrome, non-occlusive thrombus, the formation of an occlusive thrombus, arterial thrombus formation, acute coronary occlusion, peripheral arterial occlusive disease, restenosis and disorders arising from coronary by-pass graft, coronary artery valve replacement and coronary interventions such angioplasty, atherectomy, hyperplasia after angioplasty, atherectomy or arterial stenting, occlusive syndrome in a vascular system or lack of patency of diseased arteries, transient cerebral ischemic attack, unstable or stable angina pectoris, cerebral infarction, HELLP syndrome, carotid endarterectomy, carotid artery stenosis, critical limb ischemia, cardioembolism, peripheral vascular disease, restenosis, sickle cell disease, myocardial infarct, unstable angina, stable angina, angina pectoris, embolus formation, deep vein thrombosis, hemolytic anemia, acute renal failure, thrombolytic complications, disseminated intravascular coagulopathy (DIG), thrombosis, coronary heart disease, thromboembolic complications, myocardial infarction, restenosis, atrial thrombosis formation atrial fibrillation, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, pre- eclampsia, embolism, restenosis and / or thrombosis, following angioplasty, anastomosis of vascular grafts, chronic exposure to cardiovascular devices, thromboembolism, reocculsion during and after thrombolytic therapy, angioplasty, coronary artery bypass. A traumatic event is broadly defined as an experience or situation that involves actual or threatened harm, injury and / or adverse effects on the human body. It may relate to a disease, a symptom of a disease, or a treatment of a disease. It may be a planned traumatic event, such as a surgery or an invasive treatment, or a follow-on event such as expected or unexpected complications of a treatment. In particular, the traumatic event and / or disease is one that is associated with vWF, for example a vWF thrombosis and / or an event where vWF is the driving force or is (one of) the major component in thrombus / thrombi. In particular, the traumatic event and / or disease may be one or more selected from the list consisting of heart failure, hemolysis (for example prosthetic valves or anastomosis of vascular grafts), thrombosis (for example arterial thrombosis (formation), atherectomy or arterial stenting, carotid artery stenosis, carotid endarterectomy, critical limb ischemia, deep vein thrombosis, embolism, embolus formation, non-occlusive thrombus formation, occlusive syndrome in a vascular system of lack of patency of diseased arteries; peripheral arterial occlusive disease, peripheral vascular disease, thromboembolic complications, thromboembolism, thrombosis), treatment related events (for example re-occlusion during or after thrombolytic therapy), restenosis (for example restenosis and disorders arising from coronary by-pass graft), stenting or atherectomy, central nervous system (CNS) diseases and disorders (for example cerebral venous thrombosis, cerebral infarction, transient cerebral ischemic attacks and strokes), drug-induced diseases and disorders (for example use, abuse or overdosing of recreational drugs), endocrine diseases and disorders (for example Cushing’s syndrome, diabetic muscle infarction), gastro-intestinal diseases and disorders (for example acute pancreatitis), hematological diseases and disorders (for example sickle cell disease, (inherited / congenital) TTP, acquired TTP, microangiopathic haemolytic anemia, (acquired) paroxysmal nocturnal hemoglobinuria (PNH), (acquired) immune hemolysis, complement- mediated thrombotic microangiopathy, haemolytic uremic syndrome), infectious diseases and disorders (for example COVID-19, tuberculosis, malaria, Legionnaires disease, disseminated intravascular coagulopathy (DIC)), malignancies (for example leukemias, lymphomas, solid tumors (such as testicular germ cell tumors)), neuromuscular diseases and disorders (for example myopathies (inherited, acquired and / or drug-induced)), diseases and disorders associated with pregnancy (for example pre-eclampsia, Hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome); pulmonary diseases and disorders (for example pulmonary embolism, infarction), kidney diseases and disorders (for example acute renal failure), rheumatological diseases and disorders (for example dermatomyositis, mixed connective tissue disease (MCTD), rheumatoid arthritis); and vasculitis(for example polyarteritis nodosa, granulomatosis with polyangiitis, Behçet's syndrome, sarcoidosis). Alternatively or in addition, the traumatic event and / or disease is one or more selected from the list consisting of coronary artery valve disease, angioplasty, atrial fibrillation, chronic exposure to cardiovascular devices, coronary artery bypass, transplantation, chemotherapy session, radiotherapy session, surgical intervention, plasma exchange session, by-pass graft, acute kidney injury, fluid imbalance, ischemic event, sclerosis, bacterial infection, (process) aging, stenosis, secondary TMAs such as viral / infection / COVID-19 induced thrombosis, TMA-associated lupus nephritis, systemic rheumatic, drug-induced TMA, TMA-associated severe hypertension, sepsis, oncology, auto-immune disorders and connective tissue diseases. In particular, the present invention is useful in any traumatic event and / or disease where lysis of blood clots, in particular lysis of vWF associated blood clots, may be beneficial (for, for example, mitigating adverse effects, improving prognosis, controlling the progresses of the disease, controlling side effects, prevention (or reducing the likelihood) of serious medical events, and / or improving patient’s overall health). Preferably, the traumatic event and / or disease is one or more selected from the group consisting of arterial thrombosis, arterial thrombosis formation, critical limb ischemia, deep vein thrombosis, embolism, embolus formation, re-occlusion during and after thrombolytic therapy, the formation of an occlusive thrombus, thromboembolic complications, thromboembolism, thrombosis, cerebral venous thrombosis, cerebral infarction, thrombolytic complications, diabetic muscle infarction, inherited / congenital TTP, acquired TTP (iTTP), microangiopathic hemolytic anemia, PNH, immune hemolysis, complement-mediated thrombotic microangiopathy, haemolytic uremic syndrome, disseminated intravascular coagulopathy (DIC), leukemias, lymphomas, solid tumors, HELLP syndrome, pulmonary embolism, infarction, acute renal failure, MCTD, traumatic events associated with atrial fibrillation, chronic exposure to cardiovascular devices, transplantation, chemotherapy session, acute kidney injury and ischemic events. More preferably, the traumatic event and / or disease is one or more selected from the group consisting of arterial thrombosis (formation), embolism, embolus formation, cerebral infarction, diabetic muscle infarction, complement-mediated thrombotic microangiopathy, pulmonary embolism, infarction, and ischemic events. Traumatic events and / or diseases that are particularly suitable for use in means and methods of the present invention include thrombotic thrombocytopenic purpura (TTP), acute ischemic stroke (AIS), pulmonary embolism (PE), Thrombotic microangiopathy (TMA) such as cancer associated TMA, transplant associated TMA and aHUS, myocardial infarction, acute coronary syndrome, atrial fibrillation, deep vein thrombolysis and venous thromboembolism. The means and methods of the present invention is capable of delivering plasminogen activator to the site of thrombi or tissue damage by binding to vWF, which is closely associated with the pathophysiology of these events / diseases, and therefore capable of arresting, reducing and / or reversing LDH elevation associated with tissue damages. Preferably, the means and methods of the present invention are used for the prevention or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of thrombotic thrombocytopenic purpura (TTP), acute ischemic stroke (AIS) or pulmonary embolism (PE). In one aspect of the invention, such means and methods may be applied in combination with a procedure, intervention or treatment that is directed towards the disease, disorder or event that has led to or is leading to, has caused or in causing, and / or is associated with the hypoxic event. Such procedures, interventions or treatments, and the manner in which the means and methods provided by the present invention may be suitably combined with such a procedure, intervention or treatment, will be clear to the skilled person based on the further disclosure herein. In one particular but non-limiting aspect of the invention, the hypoxic state and / or the disease, disorder or event should not be a disease, disorder or event that leads to and / or is associated with (excessive) bleeding or an excessive risk of bleeding (for example, cerebral hemorrhage).. However, in some other aspects of the invention, it is envisaged that the means and methods of the invention may for example be applied in the context of events that are associated with bleeding (such as trauma, surgery or medical interventions), as long as interventions and / or treatments are available and can be suitably applied that can stop or reduce bleeding. Table 1 also lists existing or known animal assays and / or models that may be further investigated for their suitabilities or usefulness in evaluating the efficacy of such hybrid protein for the particular disease. Based on the disclosure herein, it will also be clear to the skilled person damage to one tissue can, in particular if it is caused by and / or associated with, presence and / or the formation of thrombi and / or micro-thrombi (and irrespective of the particular cause or the particular composition of the (micro-)thrombi), lead to damage to surrounding and / or other tissues, in particular where (the formation of) the (micro-)thrombi spreads to or otherwise affects such other tissues (for example and without limitation, by interfering with the flow of oxygen and / or blood to such other and / or surrounding tissues). It should also be noted that, when it comes to the relationship between damage to a particular tissue and the present and / or formation of (micro-)thrombi in said tissue, that both these phenomena can (and in practice often will) occur in tandem, with one leading to the other and / or reinforcing the other, and sometimes without it being possible to determine (in particular in retrospect) which of these phenomena initially caused the other. Thus, generally, in the context of the present description and claims, when reference is made to tissue damage and the occurrence of micro-thrombi in a tissue, this should in its broadest sense not be interpreted as being limited to one causing the other or to a specific mechanism and / or explanation as to how either occurred or as to how one might have caused the other. Instead, in their broadest sense (and unless explicitly or otherwise mentioned herein), any references to these phenomena should be interpreted as any condition or state in which either occurs on its own (and then may result in the other) and / or in which both occur at essentially the same time or in association with each other. Such a condition or state of insufficient supply of oxygen to a tissue, in particular where the supply of oxygen is not at a sufficient level to maintain adequate homeostasis in (one or more of the cells of) the affected tissue(s), and more in particular where this results in the tissue damage and / or the presence and / or formation of (micro-) thrombi in (the microvasculature of or supplying blood to) the affected tissue(s) will also generally be referred to as (the affected tissue(s) being in) an “hypoxic state” or equivalent terminology. Exemplary diseases Acute ischemic stroke (AIS) Acute ischemic stroke (AIS) occurs when one or multiple thrombi obstruct blood flow supplying the brain, leading to ischemic tissue damage, tissue loss and / or neurological impairments. AIS is the second leading cause of mortality and the third leading cause of disability worldwide (Johnson et al., 2019, https: / / doi.org / 10.1016 / S1474-4422(19)30034-1). Treatment of AIS is focused on rapid thrombus dissolution and restoration of blood flow to reduce ischemic tissue damage. Two treatment strategies are available: 1) surgical intervention to remove the thrombus (e.g. mechanical thrombectomy), and 2) thrombolytic agents (ie intravenous (IV) thrombolytic agents). Surgical interventions are limited to occlusions in large blood vessels and also not widely available at all medical centers (Asif et al., 2023, https: / / doi.org / 10.1161 / CIRCULATIONAHA.122.063366). When distal microthrombi are present, thrombectomy, as this is only applicable to recanalize the large vessel, will lead to limited tissue reperfusion. Therefore, thrombolytic agents, such as recombinant human tissue plasminogen activator (rht-PA) variants like alteplase and tenecteplase, are the mainstay AIS treatments. However, the currently available fibrin-specific thrombolytics (e.g. alteplase and tenecteplase) have limited efficacy (Keselman et al., 2020, https: / / doi.org / 10.1161 / STROKEAHA.119.027071; Kunadian & Gibson, 2012, https: / / doi.org / 10.1111 / j.1755-5922.2010.00239.x). Consequently, less than half of the patients treated with rht-PA have successful recanalization after treatment (Lee et al., 2007, https: / / doi.org / 10.1161 / 01.STR.0000251788.03914.00; Saqqur et al., 2007, https: / / doi.org / 10.1161 / 01.STR.0000257304.21967.ba; Seners et al., 2016, https: / / doi.org / 10.1161 / STROKEAHA.116.014181). Reperfusion (the restoration of blood flow to the ischemic area of the brain) has also been a challenge to achieve in standard treatments. In thrombi both fibrin and multimeric von Willebrand factor (vWF) can form a meshwork that entraps platelets. Rht-PA thrombolytics need to bind to the fibrin within thrombi in order to convert endogenous fibrin-bound plasminogen into plasmin, the thrombolytic enzyme. Thrombolysis of AIS thrombi demonstrated a higher degree of resistance against degradation by rht-PA variants based upon their composition (Vandelanotte et al., 2024, https: / / doi.org / 10.1161 / STROKEAHA.123.04588). Previous researches show that the composition of occlusive thrombi is highly heterogeneous (Chernysh et al., 2020, https: / / doi.org / 10.1038 / s41598-020-59526-x; Staessens, Denorme, et al., 2020, https: / / doi.org / 10.3324 / haematol.2019.219881; Vandelanotte & De Meyer, 2024, https: / / doi.org / 10.1016 / j.neuroscience.2023.12.010), Histological analysis of thrombi extracted from large blood vessels of patients with AIS revealed a wide variation in composition, ranging from platelet-rich / RBC-poor to platelet-poor / RBC-rich thrombi. Platelet-rich / RBC-poor are characterized by high levels of platelets, along with fibrin, vWF, leukocytes and extracellular DNA and lower levels of RBCs, which limits the presence and / or accessibility of fibrin, thereby hampering the efficacy of fibrin-specific rht-PA agents (De Meyer et al., 2017, https: / / doi.org / 10.1177 / 1747493017709671; Jolugbo & Ariëns, 2021, https: / / doi.org / 10.1161 / STROKEAHA. 120.032810). This complicates treatment of AIS patients as thrombus composition cannot be determined before treatment in clinical settings. Consequently, targeting non-fibrin components such as vWF may offer a promising avenue for thrombolytic therapy development. Literature also shows elevated lactate dehydrogenase (LDH) level at admission is associated with poor prognosis of AIS (Xia-xia Jin et al., 2022, https: / / doi.org / 10.1371 / journal.pone.0275651). Thrombotic microangiopathy (TMA) Thrombotic microangiopathy (TMA) is a condition that involves the formation of small blood clots (thrombi) that obstruct the circulation such as arterioles, capillaries and venules. As a result TMAs are often associated with thrombocytopenia as result of platelet consumption by the microthrombi. The disease spectrum of TMA includes, amongst others, thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). Studies such as Damien et al., 2018 (PMID: 28748411) have suggested that VWF plays a role in various forms of thrombotic microangiopathy (TMA). Disease specific animal models that fully encompasses the TMA diseases are often lacking or largely untested. In ADAMTS13 - / - zebrafish, intravenous histone administration led to TMA with severe and persistent thrombocytopenia and a significantly increased mortality rate (Zheng et al., 2020, https: / / doi.org / 10.3324 / HAEMATOL.2019.237396). In rats and mice, intravenous histone administration lead to a decrease in platelet counts, indicating thrombocytopenia (Fuchs et al., 2011, https: / / doi.org / 10.1182 / BLOOD-2011-01-332676; Iba et al., 2015, https: / / doi.org / 10.1186 / S40635-015-0072-Z). Here, histones can directly activate platelets, that together with fibrinogen can lead to platelet aggregation (Carestia et al., 2013, https: / / doi.org / 10.1160 / TH13-02-0174). Histones may also provoke endothelial activation, leading to secretion of ultra-large vWF (Zheng et al., 2020, https: / / doi.org / 10.3324 / HAEMATOL.2019.237396). As such the histone-induced thrombotic thrombocytopenia observed in rats and mice differ from that in TTP, with vWF being a co- participant in the process instead of the lead-driver. As such, the histone model should represent a global model for the thrombosis observed in many forms of TMA. Besides thrombocytopenia, intravenous histone administration can have toxic effect in a dose- dependent manner. As such, histone doses should be titrated carefully in order to induce robust TMA, without causing high levels of toxicity upon which active pharmaceutical ingredient has no effect. As literature has mainly focused on mice, it was hypothesized that mice could be less sensitive to this toxic effect and be a more suitable animal model. Embolic pulmonary thrombosis (EPT) Acute pulmonary embolism (APE) is a life-threatening condition in which a thrombotic clot obstructs the pulmonary arteries in or around the lungs (Moser, 1990, https: / / doi.org / 10.1164 / AJRCCM / 141.1.235). Large embolic clots tend to obstruct the main pulmonary artery, causing deleterious cardiovascular effects, whereas small embolic clots tend to block the peripheral arteries, leading to pulmonary infarction by blocking the pulmonary vascular bed from performing the essential gas exchange, leading to a mismatch in ventilation- to-perfusion ratio. Due to the mechanical obstruction of the vascular bed, the pulmonary artery pressure increases if the occlusion is 30-50% of the total cross-sectional area of the pulmonary arterial bed (Morrone & Morone, 2018, https: / / doi.org / 10.4070 / KCJ.2017.0314). Overall, the lower lung lobes often show involvement of multiple embolic clots compared to the upper lobes. The majority of APE cases are related to deep vein thrombosis (DVT) of the lower extremities. In such cases, a (part of) the thrombi breaks and enters the pulmonary circulation. While APE is mostly originated by a thrombotic clot, under rare conditions it can also be caused by other materials such as air, fat or tumor cells (Coon & Willis, 1959, https: / / doi.org / 10.1016 / 0002- 9149(59)90145-6). These cases are not considered to be APE as a thrombotic clot is lacking. After coronary artery diseases and stroke, APE is the third most common type of cardiovascular disease with an incidence from 39 to 115 per 100,000 annually, with DVT being 53 to 162 per 100.000 annually (ISTH Steering Committee for World Thrombosis Day, 2014, https: / / doi.org / 10.1111 / jth.12698; Wendelboe & Raskob, 2016, https: / / doi.org / 10.1161 / CIRCRESAHA.115.306841). Treatment of APE varies depending on the background of the patient, however the use of anticoagulants, such as low-molecular-weight heparin and direct oral anticoagulants (DOAC), are considered to be the standard. Patients that show resistance against treatment with anticoagulants can be treated with thrombolytic against such as urokinase and tissue plasminogen activator (uPA and tPA respectively) (Dalla-Volta et al., 1992, https: / / doi.org / 10.1016 / 0735-1097(92)90002-5; Goldhaber et al., 1993, https: / / doi.org / 10.1016 / 0140- 6736(93)90274-K). Thrombolysis, the dissolution of thrombotic clots by using thrombolytic compounds such as uPA and tPA, is often only initiated when it can be started within 48 hours of symptom onset, but was also shown to be beneficial in patients that showed symptoms within 14 days (Daniels et al., 1997, https: / / doi.org / 10.1016 / S0002-9149(97)00315-9). Overall thrombolytics result in a significant reduction in mortality and recurrence of APE, but are accompanied with an increased risk in severe bleeding (Konstantinides et al., 2019, https: / / doi.org / 10.1183 / 13993003.01647-2019; Marti et al., 2015, https: / / doi.org / 10.1093 / EURHEARTJ / EHU218; Meyer et al., 2014, https: / / doi.org / 1 0.1056 / NEJMOA1302097). The overall composition of venous thrombi and pulmonary emboli are different compared to that of arterial thrombi (Chernysh et al., 2020, https: / / doi.org / 10.1038 / S41598-020-59526-X). Platelets are a minor component of most venous clots, including pulmonary emboli. While little is known about the von Willebrand factor (VWF) / ADAMTS13 axis in pulmonary embolism, it does play an important role in DVT and therefore venous thromboembolism (VTE). For DVT a reduced ADAMTS13 activity (< 86%) was associated with a moderate risk. Low ADAMTS13 activity and high VWF levels are considered strong risk factors that have a synergistic effect on DVT risk (Pagliari et al., 2021, https: / / doi.org / 10.1016 / j.thromres.2020.10.037). In the MEGA-study (case-control study), VWF and FVIII were associated with the highest risk of VTE in contrast to other coagulation factors (Rietveld et al., 2019a, https: / / doi.org / 10.1111 / jth.14343). Other case-control studies confirmed the relationship between the risk of VTE and VWF levels (Bruzelius et al., 2016, https: / / doi.org / 10.1182 / BLOOD-2016-05-711846; Karakaya et al., 2016, https: / / doi.org / 10.1080 / 10245332.2015.1125079; Rajpal et al., 2019, https: / / doi.org / 10.1007 / S12288-019-01092-Y; Rietveld et al., 2019b, https: / / doi.org / 10.1111 / jth.14343; Timp et al., 2015, https: / / doi.org / 10.1111 / jth.13113) . Case-control studies may have the drawback of bias and reverse causation and selection of controls. Yet, prospective studies have confirmed that indeed VWF levels are a risk factor for VTE (Edvardsen et al., 2021, https: / / doi.org / 10.1182 / BLOODADVANCES.2020003135; Tsai et al., 2002, https: / / doi.org / 10.1016 / S0002- 9343(02)01345-1). Since in most of these VTE studies APE-patients were also recruited, it can be concluded that VWF plays an important role as risk factor for VTE including DVT and APE (Bruzelius et al., 2016, https: / / doi.org / 10.1182 / BLOOD-2016-05-711846; Edvardsen et al., 2021, https: / / doi.org / 10.1182 / BLOODADVANCES.2020003135; Rajpal et al., 2019, https: / / doi.org / 10.1007 / S12288-019-01092-Y; Rietveld et al., 2019b, https: / / doi.org / 10.1111 / jth.14343; Timp et al., 2015, https: / / doi.org / 10.1111 / jth.131; Tsai et al., 2002, https: / / doi.org / 10.1016 / S0002-9343(02)01345-1). Studies by Magnus et al., 2021 (PMID: 33570640) also suggested that plasma level of vWF are associated with increased risk of venous thromboembolism. Additional animal models In addition to Table 1, and in addition to animal models used in the Examples described hereafter, animal models that may also be suitable for evaluating efficacy of the hybrid protein as described herein for five exemplary medical conditions are discussed in more detail in the paragraphs below. The use of hybrid proteins described herein in methods and / or means for the prevention or treatment of those medical conditions are within the scope of the present. 1. Pulmonary Embolism Pulmonary embolism is a form of large vascular occlusion (LVO) and its studies are performed in a blinded manner (Shi et al., 2018). Rodents are anesthetized and receive intravenous injections for pain relief. Autologous or xenogenic thrombi (with or without the presence of labelled thrombus components) are formed ex vivo and administered to induce pulmonary embolism. Treatments or control are intravenously administered before or after thrombus formation. The blood flow is continuously recorded until cessation of the experiment. Measures of thrombolysis are recorded via differences vessel occlusion, recanalization, reperfusion, the presence of degradation products, or changes in tissue damage. 2. Disseminated intravascular coagulation (TMA) Disseminated intravascular coagulation (DIC) studies are performed in a blinded manner. Rodents will be anesthetized and receive intravenous injections for pain relief. Intravenous / Intraperitoneally infusion of endotoxin (i.e. lipopolysaccharides) or procoagulant triggers (i.e. tissue factor or thrombin) are used to trigger DIC. Treatments or control will be intravenously administered before or after thrombus formation. Measures of thrombolysis are recorded via differences in reperfusion, the presence of degradation products, platelet counts, changes in tissue damage, disease-related biomarkers or survival. 3. Arterial Thrombosis (LVO) Option A: Arterial thrombosis studies are performed in a blinded manner (Li et al., 2016). Rodents are anesthetized and receive intravenous injections for pain relief. FeCl3is applied topically to the exposed artery to induce thrombus formation. Treatments or control are intravenously administered before or after thrombus formation. The blood flow is continuously recorded until cessation of the experiment. Measures of thrombolysis are recorded via differences in time to occlusion, recanalization, reperfusion, the presence of degradation products, or changes in tissue damage. Option B: Arterial thrombosis studies are performed in a blinded manner (Matsuno et al., 1991). Rodents are anesthetized and receive intravenous injections for pain relief. Rodents receive an administration of rose Bengal whereafter the artery is transilluminated to induce thrombus formation. Treatments or control are intravenously administered prior to or after thrombus formation. The blood flow is continuously recorded until cessation of the experiment. Measures of thrombolysis are recorded via differences in vessel occlusion, recanalization, the presence of degradation products, or changes in tissue damage. 4. Histone driven thrombocytopenia (TMA) Histone-induced thrombocytopenia studies are performed in a blinded manner (Zheng et al., 2020). Rodents are anesthetized and receive intravenous injections for pain relief. Histones are administered to induce the formation of microthrombi and induce thrombocytopenia. Treatments or control are intravenously administered prior to or after histone infusion. Measures of thrombolysis are recorded via differences in platelet counts, tissue reperfusion, the presence of degradation products, or changes in tissue damage. 5. Deep venous Thrombosis (LVO) Option A: Deep venous thrombosis studies are performed in a blinded manner (Buyue et al., 2008; Li et al., 2016). Rodents are anesthetized and receive intravenous injections for pain relief. FeCl3 is applied topically to the exposed vein to induce thrombus formation. Treatments or control are intravenously administered prior to or after thrombus formation. The blood flow is continuously recorded until cessation of the experiment. Measures of thrombolysis are recorded via differences in vessel occlusion, recanalization, reperfusion, the presence of degradation products, or changes in tissue damage. Option B: Deep venous thrombosis studies are performed in a blinded manner (Cooley, 2011). Rodents are anesthetized and will receive intravenous injections for pain relief. The application of an electrical current induces thrombus formation. Treatments or control are intravenously administered prior to or after thrombus formation. The blood flow is continuously recorded until cessation of the experiment. Measures of thrombolysis are recorded via differences in vessel occlusion, recanalization, the presence of degradation products, or changes in tissue damage. Treatment In one specific but non-limiting aspect, the invention provides a hybrid protein for use in treating a subject having elevated serum lactate dehydrogenase (LDH) levels or at risk thereof following or during a traumatic event. In a further aspect, the invention relates to a hybrid protein comprising a (pro-)urokinase catalytic domain and a humanised VHH specifically binding to vWF for use in treating a patient having elevated serum lactate dehydrogenase (LDH) levels or at risk thereof following or during a traumatic event, wherein the treatment comprises administering the hybrid protein (i.e. according to a dosage regimen such) to reduce the serum LDH levels of the patient to below 300 U / L, preferably below 280 U / L, preferably less than 250 U / L, more preferably less than 230 U / L, or alternatively to a level below 120%, such as below 110%, for example below 105% and most preferably below the upper level of the ULN level (as described herein). According to the invention the damage is directly or indirectly related to thrombotic events, which in turn are associated with hypoxia of the tissue affected. LDH levels more than 10% higher than normal range are considered elevated. Stated in an alternative way LDH levels that are greater than 1.1 times, 1.5 times, 2.0 times the Upper Limit Normal (ULN) level are considered elevated. The measurement of LDH levels tends to vary per test and / or lab testing. However, all labs and / or hospitals have ranges that they consider normal. According to the invention 10% and certainly 25% above their upper limit of a normal range must be considered as elevated. Tissue damage is typically caused by some form of damage (trauma) to the body of a subject. One of the leading causes of long lasting negative effects is hypoxia to tissue because of the trauma. If the trauma is the result of a thrombus, the effect of the hybrid proteins described herein is directly on the cause of the trauma. However many forms of trauma (unplanned as well as planned) will lead to local hypoxia, which in itself will lead to thrombotic reactions and thus cause indirect tissue damage according to the invention. Any event that leads to (local) hypoxia will lead to tissue damage that can be prevented or treated according to the invention. Particularly in the case of planned trauma (such as surgery) it is an object of the present invention to maintain LDH levels low, for instance for the duration of the trauma. In such instances one may administer the hybrid protein of the invention before the trauma starts, during the procedure and probably for some time after. Thus the invention also provides a hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use according to the invention wherein when the traumatic event is a planned event such as a transplantation, a chemotherapy session, a radiotherapy session, a surgical intervention, a thrombectomy, or a plasma exchange session, the hybrid protein is provided for at least 2 days, preferably two consecutive days, starting prior to or during the traumatic event. When the trauma is unplanned, typically the LDH levels need to be lowered first after which it may still be helpful to limit the damage by maintaining the LDH levels low for a longer period of time. This may require continuous dosing, or redosing the hybrid protein described herein and / or maintaining the level of the hybrid protein in the circulation at or above a level sufficient to keep LDH levels in check. This level is about 0.5×104ng / mL. There are also diseases where keeping a level of the molecules of the invention is not required, but redosing may be required. In diseases such as TTP, there are often flare ups after a certain time. The lack of immunogenicity of the molecules of the invention allows for such redosing. Another important part of the unwanted clotting according to the invention is the platelet count. According to the invention it is possible with the molecules of the invention to keep the count within acceptable limits. Thus the invention provides a hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use according to the invention, wherein the patient is treated until the serum platelet count in the patient is at least 150×109 / L, at least 200×109 / L, preferably at least 250×109 / L. It is furthermore an object of the invention to keep the levels of fibrinogen substantially unchanged. In particular, in the invention, the fusion protein / hybrid protein will be administered prior to (e.g. when there is a risk of), during, and / or following the hypoxic event (as defined herein) or the associated tissue damage occurring. In particular the fusion protein / hybrid protein will be administered prior to, during, and / or following the event that may lead to (e.g. carry the risk of). leads to or has led to, respectively the event (i.e. the traumatic event, disease or disorder) that may or has given rise to (the risk of) the hypoxic or ischemic event, the tissue damage and / or the increased LDH level. In one particular aspect of the invention, when the subject to be treated has an elevated LDH level (as defined herein), the fusion protein is administered in a manner such, and in one or more amounts such, and according to a dosage regimen such, and for a period of time such, that level of LDH in the blood of the patient is reduced by at least 10%, such as at least 20%, for example at least 30%, 40%, 50%, 60% or 70% or more (i.e. compared to the LDH level at the time when treatment is initiated) and / or is reduced by at least 10 U / L, such as at least 30 U / L, for example at least 50 U / L or 100 U / L or more (also depending on the LDH level at the start of treatment): and / or, and preferably, until such time that the LDH level return to normal (as defined herein). Again, this can be determined by the treating physician, based on the disclosure herein and by determining LDH levels (in the manner described herein) in samples of blood taken from the patient. Again, as mentioned herein, in determining the amount(s) to be administered, the treatment regimen and the duration and / or course of treatment, the treating physician may also be guided by the specific factors and (clinical) signs referred to herein in addition to the LDH levels, including the condition of the patient and (the severity of) the underlying disease and disorder and / or the chosen treatment for the underlying disorder or injury. As mentioned herein, vWF levels may also be monitored, in particular where the same are predictive for the progression of the disease and / or the effectiveness or therapy (which may not be the case if the underlying disease or cause has not been treated yet or if the treatment for the same has not taken effect or been completed yet). Molecules The means and methods applied according to the invention to the prevention and / or treatment (including, as mentioned herein, reducing and / or limiting the damage caused by) of a hypoxic state (as further described herein) involves the use of a chemical entity / a molecule (or a pharmaceutical composition comprising the same), for example a hybrid protein. Such a hybrid protein (for example a fusion protein) comprises a plasminogen activator and in particular an urokinase catalytic domain, and a targeting agent for targeting the plasminogen activator to a site of a thrombus. The important aspect of the invention is that the hybrid protein used in means and methods of the invention comprise at least two different elements, in which one binds to vWF and the other is capable of lysing clots. Embodiments such as string beads wherein both binding parts and lysing parts are lined in any way are also within the inventive concept, but a simpler one polypeptide string comprising one lysing domain and one antibody-like domain is preferred. The antibody component can be a single heavy chain or a part thereof, such as a VH, preferably a VHH. It may also be a scFv. Peptide linkers to fuse the binding part are well known in the art. Glu-Ser linkers are preferred. The lysing part can be any polypeptide sequence that is capable of lysing (or enabling lysing) clots, but the relevant urokinase domain as disclosed herein is preferred. Lactase dehydrogenate levels are associated with tissue damage. According to the invention the damage is directly or indirectly related to thrombotic events. This often involves or is the result of inflammatory reactions, in particular of the innate immune system. The targeting agent comprises a VHH specifically binding to vWF, enabling the linked urokinase catalytic domain to drive the conversion of plasminogen to plasmin, which then degrades fibrin and / or VWF into smaller fragments. Preferably, the VHH is a humanized VHH specifically binds to vWF. Means and methods of the invention may also be useful in the prevention and / or treatment of a traumatic event, wherein the traumatic event involves complement activation. Elements from that pathway are often found in the clots to be treated according to the invention. The vWF that is involved in the actual formation of thrombi is so-called unrolled vWF (also referred to as the “unfolded” vWF). The hybrid proteins according to the invention preferably bind to this unrolled vWF. Thus the invention provides a hybrid protein, preferably a fusion protein, comprising a urokinase catalytic domain and a VHH, preferably a humanized VHH, specifically binding to vWF for use according to the invention wherein the VHH specifically binds to unfolded vWF and, preferably, comprises a complementarity determining region 3 (CDR3) comprising at least one of the amino acid sequences SEQ ID NO: 5 – 27. The complementarity determining region 1 (CDR1) preferably comprises any of the amino acid sequences listed in SEQ ID NO: 28 – 50, and the complementarity determining region 2 (CDR2) preferably comprises any of the amino acid sequences listed in SEQ ID NO: 51 – 73. The affinity of the molecules of the invention for unfolded / unrolled vWF is preferably highr than the affinity for inactive vWF in circulation. The Koff of the molecules of the invention for “normal” vWF is preferably such that the hybrid protein according to the invention is regularly released from vWF in order to be able to find unrolled vWF and bring the catalytic activity to the site of the unwanted thrombus. The invention therefore provides a hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use according to the invention, wherein preferably the affinity is in at least in the micromolar range, for example at least better than 10µM, preferably in the nanomolar range, for example at least better than or equal to 10 nM. In preferred embodiment of the present invention, the VHH of the hybrid protein has an affinity to VWF of at least equal to or better than 500 nM, at least better than or equal to 200 nM, at least better than or equal to 100 nM, at least better than or equal to 50 nM, at least better than or equal to 10nM, at least better than or equal to 1nM, at least better than or equal to 500 pM, at least better than or equal to 300 pM, at least better than or equal to 150 pM. In one preferred embodiment of the present invention, the VHH of the hybrid protein has an affinity to VWF of better than 100pM. It has also been found that the plasminogen activator, more specifically the urokinase catalytic domain of the plasminogen activator, has at least two elements that may negatively impact the stability and thereby the therapeutic performance. First of all, there is a possible cleavage site of thrombin, resulting in inactivation of the urokinase catalytic domain. This cleavage site has been found to be located at the arginine at position 153 of the urokinase catalytic domain. The cleavage site can be removed by changing the arginine at position 153. For this, an amino acid should be chosen that is not susceptible for cleavage by thrombin. Preferably, the amino acid is structurally and / or chemically similar to arginine. The most similar amino acid is histidine, but histidine has a benzene ring, making it a less suitable candidate because of its impact on the structure. Because of this, other amino acids were considered, glutamine is the most suitable candidate according to the invention. A second effect that was observed to possibly negatively impact the stability of the urokinase catalytic domain is incorrect or incomplete glycosylation, which can seriously impact the half-life time of the protein and may result in immunogenicity problems. The urokinase catalytic domain has been found to comprise an endogenous N- glycosylation site located at the asparagine at position 299. The possibly unwanted endogenous N-glycosylation site may be removed by changing the asparagine at position 299. Thus the hybrid protein of the present invention comprises a urokinase catalytic domain, wherein preferably the arginine residue at position 153 is substituted with a different amino acid residue, preferably a glutamine residue. In a further embodiment hybrid protein of the present invention comprises a substitution of the asparagine residue at position 299. Most preferably the asparagine residue at position 299 is substituted with a glutamine residue. These mutants retain their structure and activity at least to a useful extent. Furthermore, the immunogenicity of these mutants is acceptable for therapeutic use according to our tests (in silico and others). In another embodiment the hybrid protein of the present invention comprises a substitution of the lysine residue at position 297. Preferably the lysine residue at position 297 is substituted with histidine. The lack of immunogenicity of the molecules of the invention and their suitable half life are important features that enables such applications. An example of in-silico immunogenicity risk assessments is EpiMatrix system (commercially available at EpiVax), which uses algorithms to analyse protein sequences and predict which segments are likely to be identified by the host’s immune system, a crucial step in the immune response. The skilled person is familiar with various assessments methodologies and setups that can be used to perform an in-silico immunogenicity risk assessment using, for example, the EpiMatrix system. The EpiMatrix score for a given protein sequence represents the likelihood that it will be recognized by the immune system and potentially provoke an immune response. High EpiMatrix scores suggest that a protein sequence is likely to be immunogenic, meaning it could stimulate an immune response. The invention therefore provides a hybrid protein comprising a urokinase catalytic domain and a VHH, preferably a humanized VHH, specifically binding to vWF for use according to the invention, wherein the hybrid protein has an in silicon prediction score as measured by EpiMatrix of no more than -15. The half-life of the molecules of the invention may affect, amongst other things, route, dosage and / or frequency of administration. For example, short half-life may require adaptations of dosing schedule to maintain therapeutic levels, for example extension of infusion duration, short bolus intravenous administration, intra-arterial injections versus intravenous injections, combination of bolus intravenous injection and intra-arterial injections, and / or for example when dosing during endovascular thrombectomy (EVT). Furthermore, the combination of half- life and clearance characteristics of the molecule may impact the efficacy and / or side effects of the molecule when administered in subjects. A suitable half-life of the molecule of the invention may be in the range of 0,1 to 10 hours. One preferred molecule of the invention has a half life in the range of 1.8 to 8.1 hours. Preferred hybrid proteins are fusion proteins as described in WO2019 / 185723. Specifically, fusion protein may comprise more than one targeting agent. Also, as described in more detail in WO2019 / 185723, such a fusion protein preferably is a fusion protein in which the targeting agent comprises at least one of: a) an antibody variable domain that specifically binds to at least one of VWF, platelets, and activated vascular endothelium; and, b) a binding domain from a protein that naturally binds VWF, platelets and activated or injured vascular endothelium, which binding domain specifically binds to at least one of VWF, platelets, and activated or injured vascular endothelium. Thus, as described in more detail in WO2019 / 185723, in such a fusion protein, the antibody variable domain preferably is a VHH, more preferably a humanized VHH. Alternatively, as also described in WO2019 / 185723, in such a fusion protein, binding domain from a protein that naturally binds VWF, platelets and activated or injured vascular endothelium preferably comprises a binding domain selected from the group consisting of: i) the platelet GP1B receptor-binding A1 domain from VWF; ii) a VWF-binding domain from one of ADAMTS13, Factor XII, Factor H (complement regulator), plasminogen and Factor VIII; and, iii) a membrane binding domain selected from the vitamin K-dependent carboxylation / gamma- carboxyglutamic (GLA) domain, the C-domain from factor V and the C-domain from factor VIII. As also described in more detail in WO2019 / 185723, in a fusion protein according to WO2019 / 185723, the plasminogen activator preferably comprises the protease domain of tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), plasminogen, streptokinase or staphylokinase; it being preferred that, in such a fusion protein, the plasminogen activator further comprises at least the cysteine-containing part of the connecting peptide that naturally occurs in the plasminogen activator immediately upstream of its protease domain. In particular, the plasminogen activator preferably (at least) comprises or essentially consists of a urokinase catalytic domain (i.e. as present in and / or derived from a plasminogen activator). Optionally, also described in more detail in WO2019 / 185723, a fusion protein as described in WO2019 / 185723 may comprise a linker amino acid sequence linking the targeting agent and the plasminogen activator. As also described in more detail in WO2019 / 185723, a fusion protein according to WO2019 / 185723 preferably comprises in a N- to C- terminal order: a) one or more targeting agents as defined above, whereby, optionally the targeting agents are linked by linker amino acid sequences; b) optionally a linker amino acid sequence; and, c) a plasminogen activator or plasminogen-derived protease domain as defined above. A further example of the fusion protein of the present invention is the fusion protein as described in De Maat et al., Blood, 2022 Jan 27; 139(4): 597-607. The fusion protein consisting of a high-affinity VHH targeting the CT / CK domain of vWF and the protease domain of uPA, which is capable of for localized plasminogen activation on microthrombi. This fusion protein, which is also called Microlyse, can be used as a thrombolytic agent targeting vWF for clearance of (micro)vascular thrombosis. The non-prepublished European application EP 23218291.5, filed on 19 December 2023 and entitled “Targeting and lysing microthrombi associated with aberrant blood clotting” also describes the fusion protein of De Maat at al. (referred to in EP 23218291.5 as “Microlyse variant 1.0” or “ML1.0”) as well as an number of improved variants thereof (see SEQ ID NOs 1 to 3 in EP 23218291.5), one of which (see SEQ ID NO: 1 in EP 23218291.5) is referred to in EP 23218291.5 as “Microlyse variant 1.1” or “ML1.1”). The amino acids sequences of ML1.0 and of some of the specific variant of ML1.0 described in EP 23218291.5 (including ML1.1) are given below as SEQ ID NO:1 to SEQ ID NO: 4, respectively. SEQ ID NO:1 (ML1.0) EVQLVESGGGLVQAGGSLRLSCAASGRTFSSNAMGWFRQAPGKEREFVAAISWSGGS TYYLDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGSAGLGYVGDPDAMD YWGKGTQVTVSSSAAGGGGSGGGGSAAALKFQCGQKTLRPRFKIIGGEFTTIENQP WFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLGRSRLNSNTQ GEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDP QFGTSCEITGFGKENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAAD PQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR SHTKEENGLAL SEQ ID NO:2 (ML1.1, SEQ ID NO: 1 in EP 23218291.5) EVQLVESGGGLVQPGGSLRLSCAASGRTFSSNAMGWFRQAPGKGREFVAAISWSGGS TYYLDSVKGRFTISRDNAKNTVYLQMNSLRAEDTAVYYCAGSAGLGYVGDPDAMD YWGKGTQVTVSSSAAGGGGSGGGGSAAALKFQCGQKTLRPQFKIIGGEFTTIENQP WFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLGRSRLNSNTQ GEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDP QFGTSCEITGFGKEQSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAAD PQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR SHTKEENGLAL SEQ ID NO:3 (further variant of ML1.0 according to EP 23218291.5, SEQ ID NO: 2 in EP 23218291.5) DVQLVESGGGLVQPGGSLRLSCAASGRTFSSNAMGWFRQAPGKGREFVAAISWSGG STYYLDSVKGRFTISRDNAKNTVYLQMNSLRAEDTAVYYCAGSAGLGYVGDPDAM DYWGKGTQVTVSSSAAGGGGSGGGGSAAALKFQCGQKTLRPQFKIIGGEFTTIENQP WFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLGRSRLNSNTQ GEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDP QFGTSCEITGFGKEQSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAAD PQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR SHTKEENGLAL SEQ ID NO:4 (further variant of ML1.0 according to EP 23218291.5, SEQ ID NO: 3 in EP 23218291.5) DVQLVESGGGLVQPGGSLRLSCAASGRTFSSNAMGWFRQAPGKGREFVAAISWSGG STYYLDSVKGRFTISRDNAKNTVYLQMNSLRAEDTAVYYCAGSAGLGYVGDPDAM DYWGKGTQVTVSSSAAGGGGSGGGGSAAALKFQCGQKTLRPQFKIIGGEFTTIENQP WFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLGRSRLNSNTQ GEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDP QFGTSCEITGFGHEQSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAAD PQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR SHTKEENGLAL As described herein, the hybrid protein of the present invention fusion protein is preferably as further described in WO2019 / 185723 (and in particular as described in De Maat et al., more preferably as described in the non-prepublished European application EP 23218291.5) and may in particular have the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and / or SEQ ID NO:4 (in particular the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, and / or SEQ ID NO:4); and most preferably has the amino acid sequence of SEQ ID NO:2 (ML1.1). Furthermore, as further described herein, the methods applied in each of the aspects A-1 to A-22 comprises administering such a fusion protein to a subject as described in such aspect. Amino acid sequences as described herein also cover variants of the sequences with a similarity of at least 85%. In the present text, the term "similarity" or "sequence similarity" indicates that, at any particular position in an aligned sequence, amino acid residues are of a similar type between sequences. For example, leucine may be substituted with an isoleucine or valine residue. As noted elsewhere herein, this may be referred to as a conservative substitution. In one embodiment, the amino acid sequence is modified by conservative substitution of any amino acid residues contained therein such that the modification does not affect the binding specificity or functional activity of the modified polypeptide as compared to the unmodified (native) Hp polypeptide. Reference to “at least 85%” means, for example, after best alignment or best fit analysis, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94 %, 95%, 96%, 97%, 98%, 99% or 100% sequence identity or similarity. Formulation and administration Formulation of the molecules according to the invention will typically be within the skill in the art. The amount can be determined through rising dose animal and clinical studies as is known in the art. Therefore, the invention provides a hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use according to any one of the afore going claims wherein the hybrid protein is administered at a daily dosage of 0.01 to 2.5, preferably 0.02 to 2, more preferably 0.02 to 1.5, most preferably 0.04 to 1.5, milligram per kilogram of body weight. Alternatively or preferably, the hybrid protein is administered at a fixed daily dosage of 1-32mg, preferably 2 to 32 mg, more preferably 4 to 16 mg, most preferably 4 to 8 mg, for example 4 mg or 8 mg. When used in the methods of the invention, the (pharmaceutical composition comprising) the fusion protein may be administered in a suitable manner known per se (also depending on the specific formulation used). As described in WO2019 / 185723, such administration may for example comprise parenteral administration (including intravenous, intra-arterial, intralymphatic, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration) or systemic administration (including oral, intravenous, intraperitoneal and intramuscular administration), with (a form of) parenteral administration generally being preferred and intra- arterial and / or intravenous administration (e.g. by infusion or injection, such as a bolus injection) being particularly preferred. In one specific aspect of the invention, the administration is performed at, directly into or close to the tissue that is undergoing the hypoxic event, for example into the bloodstream at a location slightly upstream in the circulation of the affected tissue (e.g. into an artery that will carry the fusion protein to the affected tissue). Generally, when used in the methods of the invention, the (pharmaceutical composition comprising) the fusion protein will be administered according to a “suitable treatment regimen”, by which is generally meant administration in one or more amounts and according to an administration / dose regimen (and preferably over a period of time) that will is suitable / sufficient to achieve the desired therapeutic effect (i.e. to prevent and / or treat - which as mentioned herein includes reducing and / or limiting the damage caused by – the hypoxic state in the affected tissue(es). The treating physician will, based on the disclosure herein, be capable to determine suitable amounts and a suitable administration regimen, depending on factors such as the specific disease or disorder, the condition of the subject to the treated, the specific fusion protein used and the route of administration. In doing so, the treating physician may also be guided by the (clinical and / or diagnostic) signs of the hypoxic state (and / or of the associated tissue damage) and / or by the (clinical and / or diagnostic) signs of the (underlying) disease, disorder or event / trauma that may has led to the hypoxic state (or to the risk of the hypoxic state occurring). In particular, the selected dose regimen / treatment will usually be continued until such signs abate or improve, until the risk of a hypoxic state and / or the associated tissue damage occurring is (sufficiently) reduced, until any treatment applied to the underlying disease or trauma has sufficiently taken effect, or any combination thereof (and generally, in the judgement of the treating physician); generally, in the methods of the invention, a sufficient level, concentration and / or amount of the fusion protein will be maintained in the blood(stream) of the patient until such time that this is the case (again, generally, in the judgement of the treating physician) and / or that the treating physician judges that the treatment can be stopped or reduced. Generally, given that only a small amount of vWF (usually less than 0.5 percent, and often less than 0.1 percent) of the total amount of vWF that is present in the body of the subject to be treated will be involved in and / or form part of the (micro-)thrombi that are causing or associated with the hypoxic state (with the remainder, i.e. more than 99%, of the vWF being / remaining in circulation), the amount(s) administered and the dosage regimen used should be such that a sufficient amount of the fusion protein reaches, is present at and is maintained (i.e. for a sufficient period of time) at the site of the (micro- )thrombi to be treated (or where the formation of such (micro-)thrombi should be prevented or reduced). Again, this can be determined by the skilled person, based on the disclosure herein and the specific factors and signs referred to herein. In one particular aspect of the invention, when the subject to be treated has an elevated LDH level (as defined herein), the fusion protein is administered in a manner such, and in one or more amounts such, and according to a dosage regimen such, and for a period of time such, that level of LDH in the blood of the patient is reduced by at least 10%, such as at least 20%, for example at least 30%, 40%, 50%, 60% or 70% or more (i.e. compared to the LDH level at the time when treatment is initiated) and / or is reduced by at least 10 U / L, such as at least 30 U / L, for example at least 50 U / L or 100 U / L or more (also depending on the LDH level at the start of treatment): and / or, and preferably, until such time that the LDH level return to normal (as defined herein). Again, this can be determined by the treating physician, based on the disclosure herein and by determining LDH levels (in the manner described herein) in samples of blood taken from the patient. Again, as mentioned herein, in determining the amount(s) to be administered, the treatment regimen and the duration and / or course of treatment, the treating physician may also be guided by the specific factors and (clinical) signs referred to herein in addition to the LDH levels, including the condition of the patient and (the severity of) the underlying disease and disorder and / or the chosen treatment for the underlying disorder or injury. Administration may be through infusion or as a bolus injection. Since the hybrid proteins of the invention are useful to treat tissue damage as a result of hypoxia in general, the hybrid proteins of the invention may also be given together with other treatments of diseases leading to such tissue damage. The term “infusion injection” (or “infusion”) used herein generally refers to injections performed over a period of at least 10 minutes, at least 20 minutes, at least 40 minutes, preferably 60 minutes. The term “bolus injection” (or “bolus”) used herein generally refers to injections performed over a period of no more than 10 minutes, preferably no more than 5 minutes, more preferably no more than 1 minute. As further described herein, it is also possible to administer the fusion protein / hybrid protein of the invention (i.e. according to a suitable treatment regimen, as described herein) in combination with one or more other active principles or compounds (i.e. according to suitable combined treatment regimen) and / or in conjunction with further treatment or medical intervention. For example and without limitation, such other active principles or compounds or treatment may be intended or used for preventing or treating the (underlying) disease, disorder or condition that is causing, carries the risk of and / or is associated with the hypoxic state or tissue damage, and / or to prevent and / or treat diseases or complications that may arise out of the hypoxic state. Such active principles or compounds or treatment will be clear to the skilled person based on the disclosure herein and factors such as the condition of the patient, the nature of the underlying disease / disorder and the nature of the tissue(s) affected by the hypoxic state and the associated tissue damage or ischemic event. In such a combined treatment, the hybrid protein and the other active principles or compounds may be administered simultaneously (including, but without limitation, as part of a combination product) or sequentially. The invention also provides a hybrid protein, such as a hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use according to the invention wherein the hybrid protein is administered in combination with one or more second pharmaceutical composition selected from the group consisting of: a further thrombolytic agent, a further anticoagulant, a complement inhibitor, preferably c5 inhibitor such as such as eculizumab, an immune suppressant, an autophagy inhibitor, a chemotherapy agent, a platelet activation inhibitor, an inflammation inhibitor, and an anti-cancer drug. The hybrid protein and the second pharmaceutical composition are administered simultaneously or sequentially. The hybrid protein is preferably administered in a dosage from 0.01, from 0.02, from 0.03, from 0.04, from 0.05, from 0.06, from 0.07, from 0.08, from 0.09, up to 2.0, up to 1.9, up to 1.8, up to 1.7, up to 1.6, up to 1.5, up to 1.4, up to 1.3, up to 1.2, up to 1.1, up to 1.0, up to 0.9, up to 0.8, milligram (mg) per kilogram (kg) of body weight. Of course, the skilled person would understand that the dosage of the hybrid protein may be partly dictated by the administration route. Preferably, the hybrid protein is administered via intravenous infusion or intravenous bolus in a dosage from 0.02 to 0.8, for example from 0.02 to 0.7 mg per kg of body weight. Alternatively, the hybrid protein is administered via intravenous infusion or intravenous bolus in a dosage from 0.02 to 0.6mg per kg of body weight or at a fixed dosage from 0.2 to 32 mg, preferably from 1 to 32 mg, more preferably from 2 to 16 mg, for example from 2 to 8 mg, with a dose adjustment, for example of approximately 20%, if subjects weigh less than 65kg. Generally, in the invention and depending on factors such as the risk and / or severity of the hypoxic state (and / or the associated tissue damage), the condition of the subject to be treated (including the clinical signs shown by the patient), the nature and severity of the underlying disease or trauma, the fusion protein used and the route of administration used, a suitable treatment regimen may for example comprise: in case of parenteral (for example bolus injection) administration, administration (continuously or as one or more discrete doses) of a total daily amount of between 0.2 to 32 mg for a subject to be treated (and optionally between 0,03 and 0.25 mg / kg body weight of the subject to be treated), for a period of between 1 to 14 days, or as chronic administration until recovery of thrombotic signs & symptoms. A typical daily dosage of the hybrid protein of the present invention for a subject to be treated via parenteral administration may range between 1mg and 32mg, preferably between 2mg and 16mg. In a further aspect of the invention, the fusion protein / hybrid protein of the invention is administered (i.e. according to a suitable treatment regimen, as described herein) prior to, during, and / or following a traumatic event, in which the traumatic event may in particular (but without limitation be a planned event (e.g. a planned treatment or medical intervention) such as a transplantation, a chemotherapy session, a radiotherapy session, a surgical intervention, a thrombectomy, or a plasma exchange session. In one specific aspect of the invention, the fusion protein / hybrid protein of the invention is administered. In one specific aspect, the hybrid protein is provided for at least 2 days, preferably two consecutive days, starting prior to or during the traumatic event. According to the preceding aspect of the invention, the fusion protein / hybrid protein may in particular be used as a prophylactic / preventative means, and in particular as a prophylactic / preventative means in combination with monitoring the LDH level in the patient, wherein the prophylactic treatment is applied to keep said LDH levels from going above a certain level (e.g. above 200% of ULN or 150% of ULN, or above 300 U / L) or in a certain range (e.g. within normal levels or levels from normal up to 120%, such as 110% of ULN or from normal up to 325 U / L such as up to 300 U / L), depending on the event involved (and taken into account that certain events may cause a temporary spike in LDH levels). Preferably, in the present invention the peak plasma level of the hybrid protein is at least 1 ng / mL, at least 5 ng / mL, at least 10 ng / mL, at least 20 ng / mL, preferably at least 100 ng / mL, most preferably at least 200 ng / mL. The peak plasma level of the hybrid protein may be for example no more than 3000 ng / mL, preferably no more than 2000 ng / mL, more preferably no more than 1500 ng / mL, for example no more than 1000 ng / mL. For example the peak plasma level of the hybrid protein is from 100ng / mL to 2000 ng / mL, preferably from 150 ng / mL to 1500 ng / mL, more preferably from 200 ng / mL to 1000 ng / mL, typically from 300 ng / mL to 800 ng / mL, during the treatment. Maintaining the peak plasma level of the hybrid protein within a preferred range helps to achieve desired therapeutic effects whilst keeping undesirable side effects under control. As discussed above, the amount of the hybrid protein present in the blood is such that a substantial amount of, for example at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of, the VWF being / remaining in circulation is bound to the hybrid protein. The peak plasma level of the hybrid protein therefore is sufficient to deliver an effective amount of the hybrid protein to the site of microthrombi to be treated. The effective plasma level of the hybrid protein and / or the average plasma level of the hybrid protein may be determined by a combination of factors such as the dosage, the administration route and the half life of the hybrid protein. In a further aspect of the invention, the fusion protein / hybrid protein of the invention is administered (i.e. according to a suitable treatment regimen, as described herein) prior to, during, and / or following a traumatic event, in which the traumatic event involves or leads to complement activation. In one specific aspect of the invention, the fusion protein / hybrid protein of the invention is administered. In one specific aspect, the hybrid protein is provided for at least 2 days, preferably two consecutive days, starting prior to or during the traumatic event. Figures Figure 1 shows susceptibility of Microlyse variants to cleavage by thrombin. Figure 2 shows the EpiMatrix Protein Immunogenicity Scale of ML 1.0 and ML 1.1 Figure 3(1) to 3(3) show that ML 1.1 attenuates the symptoms of acute TTP in ADAMTS13 knockout mice. In particular, a) platelet count, b) mean platelet volume, c) LDH activity, d) hemoglobin level, e) hematocrit percentage, and f) rhVWF percentage (compared to a human plasma reference) of ADAMTS13 knockout mice (ADAMTS13- / -), treated with either vehicle (saline) or ML 1.1 (0.25 mg / kg, 1 mg / kg, or 2 mg / kg dose), at baseline and 24 hours post-TTP attack. **P<0.01; ***P<0.001; ****P<0.0001, compared to either baseline (7 days prior to TTP attack) or saline by a one-way ANOVA with post-hoc Dunnett’s multiple comparison test. Figures 4(1) to 4(3) show that ML 1.1 causes rapid improvement of platelet counts and LDH levels in a murine model of cTTP. In particular, a) platelet count, b) mean platelet volume, c) hemoglobin level, d) hematocrit percentage, e) LDH level, and f) rhVWF percentage of ADAMTS13 KO mice, treated with ML 1.1 (0.25mg / kg, 1 mg / k g, or 2 mg / kg), at baseline and at 0.25, 1, 4 and 24 hours post-TTP trigger. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, compared to vehicle by a one-way ANOVA with post-hoc Dunnett’s multiple comparison test. Colors correspond to the ML 1.1 dose groups. Figures 5(1) to 5(3) shows that ML 1.1 attenuates the symptoms of acute TTP at 24 hours post- TTP attack in mice with an acquired ADAMTS13 deficiency following exposure to anti- ADAMTS13 antibodies. In particular, it shows A) platelet count, B) mean platelet volume, C) LDH activity, D) rhVWF percentage (compared to a human plasma reference), E) hemoglobin level, and F) hematocrit percentage of mice, treated with either vehicle (saline) or ML 1.1 (0.25 mg / kg, 1 mg / kg, or 2 mg / kg dose), at baseline and 24 hours post-TTP attack. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, or not significant (ns) compared to either baseline (7 days before TTP attack) or vehicle by a one-way ANOVA with Dunnet’s post-hoc comparison test. Figure 6 shows that ML 1.1 improves reperfusion, measured as the percentage of cerebral blood flow (CBR), after distal thrombotic AIS with platelet-rich thrombi. In particular, it shows measurements made at 10 to 20 minutes post-stroke onset (before treatment), 20 to 30 minutes at post-stroke onset (after treatment started), and at 60 to 70 minutes post-stroke onset (0 to 10 minutes after treatment ended). *P<0.05 compared to vehicle-treated mice by the Wilcoxon Test. Figure 7 shows that ML 1.1 reduces lesion volume at 24 hours post-stroke following distal thrombotic AIS with platelet-rich thrombi in mice. In particular, it shows the A) lesion volumes and B) recanalization score distribution for vehicle and ML 1.1 treated mice at 24 hours in a model of distal thrombotic stroke *P<0.05 and **P<0.01 versus vehicle-treated group by Each pair student’s T-test. Figure 8 shows that ML 1.1 improves the reperfusion of hyperglycemic mice after thrombotic stroke. In particular, it shows the reperfusion, measured as the percentage of cerebral blood flow (CBF), of hyperglycemic mice after thrombotic stroke. Measurements made A) 10 to 20 minutes post-stroke onset (before treatment), B) 20 to 30 minutes post-stroke onset (0 to 10 minutes after treatment started), and C) 60 to 70 minutes post-stroke onset (40 to 50 after treatment started, 0 to 10 minutes after treatment ended). *P<0.05 compared to vehicle-treated mice using the Steel-Dwars with control test. Figure 9 shows that ML 1.1 reduces lesion volume at 24 hours in hyperglycemic mice following thrombin-induced AIS. (NS is not significant, *P<0.05 compared to vehicle-treated mice by the Wilcoxon each pair test.) Figure 10 shows that ML 1.1 improves Neuroscores following thromboembolic stroke in rats. In particular, it shows Neuroscore results of rats treated at A) two and B) four hours post-stroke. *P<0.05 compared to vehicle-treated rats by the Steel test. Figure 11 shows that ML 1.1 reduces tissue loss following thromboembolic stroke in rats. In particular, it shows the A) lesion volume on day 3 and B) the tissue loss at day 28 of rats treated with vehicle, alteplase, or ML 1.1 either 2 or 4 hours following thromboembolic stroke.*P<0.05 compared to vehicle-treated rats by the Steel test. Figures 12(1) and 12(2) show Effect of Histone dose on ADAMTS13 wild type (WT) and knockout (KO) animals. In particular, it shows a) platelet count, b) mean platelet volume, c) hemoglobin level and d) lymphocytes of ADAMTS13 KO or wild type mice, at predose or 0.5, 1, 6 and 24 hours post-histone trigger. Figures 13(1) to 13(4) show ML1.1 partially restored thrombocytopenia in a histone induced TMA model within 45 minutes. In particular, it shows a) platelet count, b) mean platelet volume, c) hemoglobin level, d) hematocrit percentage, e) lymphocytes, f) neutrophils and g) LDH levels of wild type mice, treated with vehicle or ML1.1 (2.4 mg / kg), at predose or 1, hour post-histone trigger. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, compared to vehicle by a Brown-Forsythe and Welch ANOVA with post-hoc Dunnett’s T3 multiple comparison test. Colors correspond to the treatment groups. Figure 14 shows embolic pulmonary thrombosis (EPT) in a rat model induces significant, time dependent, differences in right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP). Note: *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, by unpaired t-tests. Figure 15 shows experimental setup to demonstrate ML1.1 efficacy in embolic pulmonary thrombosis in rats. Figure 16 shows ML1.1 efficacy in embolic pulmonary thrombosis rat model. Note: *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, compared to vehicle by a One-way ANOVA with post- hoc Dunnett’s multiple comparison test. Colors correspond to the treatment groups. Figure 17 shows that ML1.1 degrades ex vivo thrombi extracted from patients with acute ischemic stroke in vitro. Note. Thrombolysis was measured as the residual thrombus weight expressed as a percentage of the initial weight over time. Thrombus 1 – 10 were incubated with 3 µg / ml of ML1.1. Thrombus 2 was excluded due to missing histology data. Negative controls (NC 1 - 5) were incubated with formulation buffer Figure 18 shows incubation with ML1.1 leads to greater thrombolysis of ex vivo human thrombi compared to negative controls. Note. Thrombolysis was measured as the residual thrombus weight expressed as a percentage of the initial weight over time. Ten thrombi were incubated with 3 µg / ml of ML1.1. Five thrombi were incubated with formulation buffer (negative control). Data are the mean ± the standard deviation. **P<0.01 or ***P<0.001 ML1.1-incubated thrombi compared to negative controls using multiple T-tests. Figures 19(1) to 19(3) shows the correlations between thrombus composition components and thrombolysis at 180 minutes for thrombi incubated with ML1.1. The correlation between the percentage of the thrombus dissolved after 180 minutes and the A) Red blood cell (RBC), B) Fibrin, C) von Willebrand factor (VWF), D) platelet, E) Leukocyte, and total DNA content. Histology sections were stained with Martius Scarlet Blue to identify RBCs and fibrin. Immunohistochemical staining was used to identify platelets (CD42b) and VWF. A Feulgen’s reaction was used to visualize intracellular and extracellular DNA (collectively “total DNA”). Pearson or Spearman’s correlation was used to assess the strength and direction of the relationship between the extent of thrombolysis and histological compositions. Example 1 – Susceptibility of Microlyse variants ML 1.0 and ML 1.1 to cleavage by thrombin The cDNA sequence for both human and mouse urokinase (PLAU) was obtained from the NCBI database (NM_002658.4 and NM_008873.3 respectively). The sequence for the signal peptide, EGF-like and Kringle domain were removed as well as the first part of the connecting peptide. To the remaining connecting peptide and S1 peptidase domain (Catalytic domain) a N-terminal sequence coding for a Tobacco Etch Virus cleavage site followed by an GGGGS linker was added. In the GGGGS linked a PstI and BamHI digestion site were incorporated without disturbing the amino acid sequence. At the 5’ side an EcoRI digestion site was added and at the 3’ side and NotI digestion was added after the STOP codon of PLAU. In the case of the Microlyse variant 1.1 (ML 1.1) arginine residue at position 153 is substituted with a glutamine residue and asparagine residue at position 299 is substituted with a glutamine residue (to remove the N-glycosylation site) in the Urokinase sequence prior to ordering both sequences (ML 1.0 and ML 1.1) as custom gene construct from IDT (Integrated DNA Technologies, Leuven, Belgium). Coding sequences for nanobodies (also known as VHH) kept as the original llama sequence of humanized via 4 distinct amino substitutions within the nanobody framework (A14P, E44G, K87R, P88A). Hereafter, the sequences were codon optimized via IDT for expression in a human host cells. At the N-terminal side of the VHH coding sequence, a sequence coding for a Tobacco Etch Virus cleavage site was placed and at the C-terminal side a GGGGS linker (encoding a PstI and BamHI digestion site). These DNA segments were obtained from IDT as Double stranded DNA fragments (gBLocks). The custom gene constructs were propagated in E.coli TOP10 and selected by ampicillin resistance. Obtained plasmid DNAs were digested by EcoRI and NotI. The resulting inserts (886) were separated on and isolated from agarose gel and ligated into a modified pcDNA6 expression vector (pSM2) (De Maat et al, 2016 J Allergy Clin Immunol Nov;30;138(5):1414- 23)). pSM2 encodes a N-terminal murine IgK secretion signal and a double STREP isolation tag whereafter the modified UPA constructs were ligated. The gBlocks were ligated into the pJET1.2 cloning vector according to manufacturer instructions (CloneJET PCR Cloning Kit; Thermo Fisher). The constructs were propagated in E.coli TOP10 and selected by ampicillin resistance. Obtained plasmid DNAs were digested by EcoRI and BamHI. The resulting insert was separated on and isolated from agarose gel and ligated into the pSM2 vector containing the miniUPA construct. The nanobody / mUPA-pSM2 constructs were transfected into HEK293 FreeStyleTM cells using 239Fectin as instructed by the manufacturer (ThermoFisher) in 6-well plates. After 7 days of production samples were harvested and centrifugated at 2000xg for 10 minutes. Supernatant contain the Microlyse variant was separated from the biomass and centrifugated again to remove the final cellular debri. Microlyse titers were determined via the VWF binding ELISA as previously published (De Maat et al, 2022 Blood Jan;27;139(4):597-607)). Titers of Microlyse variants were equalized via the dilution with supernatant of mock-transfected HEK293 FreeStyleTM cells. The Microlyse variants used in this Example contain the purification tags as they were produced in HEK cells. 20 µL of Microlyse variant supernatant was incubated with 5 µL of vehicle or Thrombin (prediluted in 0.2% w / v BSA-HBS) and incubated at 37 °C for 30 minutes. Hereafter the reaction was stopped via the addition of reducing sample buffer (25 Mm DTT). Samples were heated to 95 °C for 10 minutes and subsequently separated on a 4-12% gradient Bis-Tris gel in MES buffer. The gel is transferred onto a Immobilon-FL membrane in blotting buffer for 1 hour at 125 Volt. The membrane is blocked with 0.5x Odyssey blocking buffer where after the constructs are detected with a rabbit polyclonal anti human UPA antibody in combination with an IR800 labeled Goat-anti-Rabbit antibody. Results were analyzed via the near-infrared odyssey scanner (Licor) according to manufacturer instructions. In Figure 1 results are shown indicating susceptibility of Microlyse variants ML 1.0 and ML 1.1 to cleavage by thrombin. ML 1.1 contains a glutamine at position 153, while ML 1.0 contains an arginine at position 153. For both ML 1.0 and ML 1.1 a distinct band at around 35 Kd is observed, indicating cleavage of Microlyse by thrombin. Example 2 – PreDeFT immunogenicity analysis ML1.0 and ML 1.1 used in this Example were produced in Pichia pastoris and therefore do not contain the purification tags. In silicon evaluation was performed for sequences of ML 1.0 and ML 1.1 (SEQ ID NO:1 and SEQ ID NO:2, respectively) for their immunogenic potential in humans. Methods The amino acid sequences of ML 1.1 and ML 1.0 were screened for the presence of Class II (HLA-DR) restricted HLA ligands or putative T cell epitopes using the EpiMatrix system. The sequence subunits were evaluated for global and regional immunogenic potentials. To determine whether any of the putative T cell epitopes identified by EpiMatrix are homologous to predicted epitopes found within the human proteome, and thereby less likely to drive anti- therapeutic immune response, all the putative epitopes identified by EpiMatrix were screened against the human proteome using the JanusMatrix algorithm. Further, to identify any predicted T cell epitopes which may have been previously studied and evaluated, all putative T cell epitopes identified by EpiMatrix were screened against a version of the Immune Epitope Database (IEDB). The information was collated to provide an EpiMatrix score as a measure of immunogenic potential. Results Regional analysis revealed 12 putative T cell epitope clusters; five of these are derived from the VhH domain and seven are derived from the UPA domain. Of the 12 putative T cell epitope clusters identified, six clusters (9-31, 33-48, 57-79, 76-94 of the VhH domain; 192-207 and 249-267 of the UPA domain) are expected to be tolerated by the human immune system and, under normal circumstances, may be actively tolerogenic in at least some human subjects. The remaining six T cell epitope clusters score high on the EpiMatrix scale and low on the JanusMatrix scale and one cluster (44-58) overlaps an antibody complementarity determining region (CDR). Under normal circumstances, it is possible that these peptides could be seen as foreign by the human immune system and may help to induce anti-therapeutic immune response. At a global level, the Tregitope-adjusted EpiMatrix Score of the ML 1.1 (-20.54) falls in the low range on the EpiMatrix Protein Immunogenicity Scale (Figure 1), suggesting a minimal potential for driving anti-therapeutic immune response. As expected, the humanization of the VHH domain had reduced the immunological potential of ML 1.1 compared to ML-CTCK- hUPA (-14.83; Figure 1). Investigation of ML 1.1 domains revealed that the VHH domain (- 25.16) and linker (-25.58) fell in the low range, while the catalytic domain of UPA fell in the low-neutral range (-13.97). Conclusion ML 1.1 falls in the low range on the EpiMatrix Protein Immunogenicity Scale, suggesting a minimal potential for driving anti-therapeutic immune response in humans. Overall, the score is higher than that of Caplacizumab, but this is mainly due to the catalytic domain, which is considered to be well tolerated based on clinical data from Urokinase variants. Example 3 – preliminary toxicity and pharmacokinetics study ML 1.1 was tested to determine its pharmacokinetics profile and the potential toxicity (in Wistar Han IGS rats). Methods ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 12 mg / mL. ML 1.1 was administered 4 times to Wistar Han IGS rats (3 animals / sex / group) at 1, 4, or 12 mg / kg on Days 1, 3, 5, and 8 by intravenous bolus injection. Terminal sacrifice was performed on Day 9, one day after the last dose. Blood was collected at specific timepoints via venous puncture using sodium citrate of K2 EDTA as an anticoagulant. Where necessary, blood plasma was created via centrifugation. The assessment of toxicity was based on mortality, clinical observations, changes in body weight, clinical pathology parameters (hematology, coagulation, clinical chemistry), organ weights, and macroscopic and microscopic examinations. A separate satellite group of Wistar Han IGS rats were used for toxicokinetic (TK) evaluation and dosed with 1 mg / kg. Blood samples for TK were collected for up to 24 hours after dosing. Results Individual plasma concentration-time profiles, C0, and AUC0-24h values were similar between males and females (F:M AUC0-24hratio was 0.836) indicating that systemic exposure to ML 1.1 was independent of sex. ML 1.1 was quantifiable for 8 hours after administration with a half- life of 2 hours. Pharmacokinetic properties are summarized in Table 2. Table 2. The pharmacokinetic properties of male and female Wistar Han IGS rats treated with a single intravenous bolus injection of 1 mg / kg ML 1.1 1 mg / kg PK parameter Male Female Combined C0(ng / mL) 14000 14600 14200 Tlast 8 8 8 t1 / 2(h) 1.83 2.33 2.04 AUC(tlast) (ng / mL*h) 5440 4470 4950 AUC(0-24h) (ng / mL*h) 5900 4940 5420 F:MaNA 0.836 N / A AUC(inf) (ng / mL*h) 5590 4660 5120 Vz (mL / kg) 574 720 471 CL (mL / h / kg) 179 215 195 Note: C0: Extrapolated initial concentration; Tlast: time to last quantifiable concentration; t1 / 2: half-time; AUC(tlast): Area under the concentration time curve from 0 to the time of last quantifiable concentration; AUC(0-24h): Area under the concentration time curve from the start of dose administration to 24 hours postdose;aAUC(0-24h)Female: AUC(0-24h) Male; AUC(inf): Area under the concentration time curve extrapolated to infinity; Vz: Volume of distribution; CL: Clearance. Overall, ML 1.1 administration was well tolerated locally and systemically at 1 mg / kg and above. Repeated intravenous injections of ML 1.1 at 1, 4 and 12 mg / kg doses were not associated with any treatment-related premature sacrifice during the study. No clinical signs, body weight changes or clinical pathology changes were observed. A markedly lower white blood cell count and lymphocyte count was observed in one female at 12 mg / kg. As the decreases were only observed in 1 / 6 animals in this dose group and as there were no other related findings for this female, a test item-related effect was considered unlikely. There were no test item-related gross or organ weight changes. In the liver, test item-related microscopic changes consisted of an increased number of hepatocellular mitoses, minimal to mild with a discrete dose-relationship in males (at 1 mg / kg and above) and females (at 4 mg / kg and above). These findings were considered not adverse. At the injection site, minimal to mild (at 1 mg / kg and above, in males and females), subacute to chronic perivascular and / or vascular inflammation was associated with minimal to mild, not dose-related, perivascular hemorrhage and mononuclear cell infiltrate in the subcutaneous tissue. These changes were considered related to the administration procedure and are consistent with a good local tolerance. Conclusion Over a period of 9 days, four IV intravenous (bolus) administrations of ML 1.1 to Wistar Han IGS rats at 1, 4, or 12 mg / kg doses were well tolerated locally and systemically. Histopathological test item-related findings were considered not adverse. Example 4 – Efficacy in a murine model of congenital TTP (cTTP) ML 1.1’s efficacy, in particular the temporal resolution of thrombocytopenia and tissue damage at various time points following treatment with ML 1.1 was investigated in a murine model of cTTP. Methods Female and male ADAMTS13 knockout mice (ADAMTS13- / -; CASA / Rk-C57BL / 6J- 129X1 / SvJ background) were used to model human patients with cTTP, as was previously described by de Maat et al. (2022). A pre-study optimization experiment was performed to assess the safety of different rhVWF doses in mice. Based on the result of the pre-study optimisation (discussed in more detail below), an intravenous injection of 1000 U / kg recombinant human VWF (rhVWF; Veyvondi, Takeda) was used to trigger a TTP attack in the ADAMTS13 knockout mice. ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 12 mg / mL. Fifteen minutes after the rhVWF administration, mice were given an intravenous bolus injection of either vehicle (saline) or ML 1.1. Mice were divided between one vehicle and three ML 1.1 treatment groups (0.25 mg / kg, 1 mg / kg, and 2 mg / kg). Platelet count, mean platelet volume, lactate dehydrogenase (LDH) activity, hemoglobin levels, hematocrit percentage, and percentage of rhVWF (compared to a human plasma reference) were measured at baseline (7 days prior to TTP trigger) and at several time points (0.25, 1, 4, and 24 hours) within 24 hours post-TTP trigger. For baseline vs 24-hour study, twelve mice were treated with ML 1.1. For the 0.25-hour, 1-hour and 4-hour study, twenty-six mice were treated with ML 1.1. Each mouse had blood drawn at baseline and at one other time point following the cTTP trigger, such that there were four to five data points per timepoint per treatment group. A one-way analysis of variance (ANOVA) with post-hoc Dunnett’s multiple comparison test was used to investigate statistically significant differences between vehicle and treatment groups at 24 hours post-TTP attack. A two-way ANOVA with Dunnet’s multiple comparison test was used to investigate statistically significant differences in outcome measures between ML 1.1 dose groups and the vehicle control at each time point. Results In the preparations for the study, it was found that a lower dose of rhVWF (1000 U / kg) was required to trigger TTP symptomology while preventing unwanted lethality compared to the previously published study that was conducted with Microlyse (2250 U / kg; see De Maat et al., 2022). A different rhVWF preparation (Veyvondi, Takeda) was used in the present study and was found to be more prothrombotic, which led to a dose of 1000 U / kg being sufficient to induce TTP symptoms and doses above 1500 U / kg being fatal to the mice (see table 3 below). In addition, a lower rhVWF dose was considered beneficial to the interpretation of the cTTP model as less exogenous VWF was involved and of influence to the effective ML 1.1 dosing. Table 3: The outcomes of the pre-study optimization experiment Dose of rhVWF (U / kg) Number of mice exposed Survival rate (n) 1000 1 100% (1 / 1) 1500 3 33% (1 / 3) 2000 2 0% (0 / 2) 2250 1 0% (0 / 1) Mice treated with vehicle displayed continued platelet count depreciation and LDH elevation at one and four hours post-TTP onset (Figure 4a and Figure 14e, respectively). In contrast, the 1 and 2 mg / kg ML 1.1 treatment groups started to show normalization of platelet counts (Figure 4a) and LDH levels (Figure 4e) at one hour post-TTP trigger (45 minutes post-treatment), but this was not yet statistically different to the vehicle group. By the four-hour time point, the 1 and 2 mg / kg ML 1.1 treatment groups had statistically significantly higher platelet levels than the vehicle group (P<0.0001; Figure 4a), while all three ML 1.1 doses achieved lower LDH (P<0.001; Figure 4e) levels compared to the vehicle group. Furthermore, the LDH levels in the 1 and 2 mg / kg ML 1.1 dose groups had almost completely normalized to baseline levels at the four-hour timepoint. These findings indicate that ML 1.1 had significantly reduced thrombocytopenia and tissue damage within four hours in this murine model of cTTP. The levels of rhVWF peaked at 15 minutes post-TTP onset and decline with time in all treatment groups (Figure 4f). However, the ML 1.1-treated mice show faster rhVWF clearance. Specifically, the 1 and 2 mg / kg ML 1.1 dose groups had lower rhVWF levels compared to the vehicle group at the one and four hour time points (P<0.05; Figure 4f), indicating improved clearance of prothrombotic rhVWF. This finding could have beneficial implications of increased clearance of pro-thrombotic, disease-driving, VWF strands in human patients. Mice treated with vehicle displayed the expected presentation of cTTP-associated characteristics at 24 hours post-TTP attack. Specifically, compared to baseline, the vehicle- treated mice had: 1. Lower platelet counts (P<0.0001; Figure 3a), as platelets were consumed in VWF- platelet-rich blood clots 2. Increased platelet volumes (P<0.0001; Figure 3b), possibly due to the formation of new larger platelets in response to the thrombocytopenia (Leader et al., 2012), or alternatively the increase in volume could be explained by two platelets binding to each other 3. Increased LDH activity (P<0.0001; Figure 3c), indicative of elevated tissue damage in response to thrombocytopenia (Drent et al., 1996) 4. Lower hemoglobin (P<0.01; Figure 3d) and hematocrit levels (P<0.001; Figure 3e), as a result of the thrombi causing hemolytic anemia 5. A higher percentage of circulating rhVWF (P<0.0001; Figure 3f) Treatment with ML 1.1 attenuated the cTTP-associated effects at 24 hours post-TTP attack in a dose-dependent manner. Specifically, in comparison to vehicle-treated mice, ML 1.1 treated mice had: 1. Higher circulating platelet counts (P<0.001; Figure 3a) 2. Normalized mean platelet volumes (P<0.0001; Figure 3b) 3. Normalized LDH activity (P<0.0001; Figure 3c) 4. Normalized hemoglobin (Figure 3d) and hematocrit levels (Figure 3e) 5. Decreased rhVWF percentage (P<0.001; Figure 3f) Mean platelet volume, hematocrit, and hemoglobin levels only differed between baseline and treatment groups at 24 hours post-TTP, indicating a delayed onset of changes compared to platelet count and LDH. Compared to baseline, at 15 minutes post-TTP onset (0.25 hour time point; before treatment), all treatment groups had: 1. Lower platelet counts (P<0.0001; Figure 4a), as platelets were consumed in VWF- platelet-rich thrombi; 2. Elevated LDH activity (P<0.05; Figure 4e), indicative of immediate elevated tissue damage in response to thrombocytopenia (Drent et al., 1996); 3. High levels of rhVWF (P<0.0001; Figure 4f) after administration to invoke TTP symptomology. Therefore, treatment with ML 1.1 was able to limit thrombocytopenia, reduce tissue damage to near baseline levels, limit hemolytic anemia, and clear the prothrombotic rhVWF from circulation at 24 hours post-TTP attack. The 1 and 2 mg / kg ML 1.1 doses appeared to achieve the maximum therapeutic effect, while the 0.25 mg / kg dose improved the cTTP-associated deficits to a lesser extent in this model (Figure 3). Conclusion ML 1.1 was well-tolerated and attenuated thrombocytopenia. It showed improvement in thrombocytopenia and tissue damage within one hour of administration. In addition, by four hours post-treatment, ML 1.1 was able to reduce tissue damage (LDH) to baseline levels, while platelets were steadily rising and significantly higher than vehicle-treated mice. At 24-hour post-TTP attack in this murine model of cTTP, it is shown to have reduced tissue damage, improved markers of hemolytic anemia, and cleared prothrombotic rhVWF compared to vehicle-treated mice. The 1 and 2 mg / kg ML 1.1 doses achieved the maximum beneficial effect at 24 hours post-TTP attack, while the 0.25 mg / kg dose was marginally less effective. As already discussed in the background section, it takes several days for platelet normalization in the current TTP treatment, during which the patients are still exposed to ischemia and organ damage despite treatment. This study indicates that ML 1.1 could diminish thrombosis and initiate reperfusion within one hour, and significantly reduce symptoms by four hours of administration. If this holds true for human patients with TTP, it would result in considerably faster symptom resolution than available treatments. This could have significant implications for limiting tissue damage, improving patient outcomes, and lessening the high healthcare burdens associated with TTP. These findings indicate a potential clinical benefit to patients with cTTP given the model’s translational relevance. The findings of this study were also in agreement with the published results of Microlyse in the same cTTP model (de Maat et al., 2022), which indicated that the changes made to create ML 1.1 had not limited its efficacy in the murine cTTP model. Example 5 – Efficacy in a murine model of immune-mediated TTP (iTTP) In this study, ML 1.1’s efficacy, in particular measures of thrombocytopenia and tissue damage at baseline and 24 hours post-TTP attack, was investigated in a marine model of antibody- mediated TTP (iTTP). Methods Baseline blood samples were taken from mice seven days before TTP was induced. Two inhibitory monoclonal murine anti-ADAMTS13 antibodies (13B4 and 14H7, 1.25 mg / kg each) were used to block endogenous ADAMTS13 activity in either male or female wild-type mice (n=16; ADAMTS13+ / +, C57Bl / 6 background), as described by Deforche et al. 2016. As a control, the ADAMTS13 activity level was assessed using the FRETS-VWF73 assay (fluorescent resonance energy transfer assay; as described in De Cock et al., 2015) in three mice at baseline and 48 hours after antibody injection to confirm suppression of ADAMTS13 activity. ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 5.18 mg / mL. TTP symptoms were triggered by the IV injection of recombinant human VWF (rhVWF; 500 U / Kg) 24 hours after anti-ADAMTS13 antibody administration. Fifteen minutes after TTP onset, mice were given an IV injection with vehicle (saline) or ML 1.1. Four mice were included in each treatment group. Mice were evaluated for TTP symptoms seven days before (baseline) and 24 hours after the TTP trigger. Outcomes were compared to baseline or vehicle-treated mice by a one-way analysis of variance (ANOVA) with Dunnet’s multiple comparisons test. Results Administration of anti-ADAMTS13 antibodies resulted in complete suppression of ADAMTS13 activity levels (<10%; Table 4) for the time span of the iTTP model. Table 4. The ADAMTS13 activity levels of three mice at baseline and 48 hours after administration of anti- ADAMTS13 antibodies. Mouse Baseline ADAMTS13 activity (%) ADAMTS13 activity 48 hours post-antibody administration (%) 1 116.9 9.5 2 144.2 7.5 3 116.4 6.3 Note. ADAMTS13 activity levels are expressed as a percentage relative to normal murine pooled plasma (100%). The ADAMTS13 activity assay has a background signal of approximately 10% and therefore activities of less than 10% represent negligible ADAMTS13 activity. Treatment with ML 1.1 was well-tolerated. There were no treatment-related fatalities and no apparent adverse clinical observations during the study period at the ML 1.1 doses tested (0.25 – 2 mg / kg). Mice treated with vehicle displayed the expected presentation of TTP-associated characteristics at 24 hours post-TTP attack. Specifically, compared to baseline, the vehicle-treated mice had: 1. Lower platelet counts (P<0.0001; Figure 5A), as platelets were consumed in VWF- platelet-rich blood clots; 2. Increased platelet volumes (P<0.0001; Figure 5B), possibly due to the formation of new larger platelets in response to the thrombocytopenia (Leader et al., 2012), or the increase in volume could be explained by two platelets binding to each other; 3. Increased lactate dehydrogenase (LDH) activity (P<0.0001; Figure 5C), indicative of elevated tissue damage caused by the thrombi (Drent et al., 1996); 4. Lower hemoglobin (P<0.01; Figure 5e) and hematocrit levels (P<0.05; Figure 5F), as a result of the thrombi causing hemolytic anemia. In contrast, treatment with ML 1.1 attenuated the TTP-associated thrombocytopenia at 24 hours post-TTP attack. Specifically, in comparison to vehicle-treated mice, ML 1.1-treated mice had: 1. Higher circulating platelet counts (P<0.0001, Figure 5A), and normalized mean platelet volumes (P<0.0001, Figure 5B), as the thrombi in the microvasculature were degraded and platelets were liberated indicating a resolution of the thrombocytopenia; 2. A complete normalization of plasma LDH activity (P<0.0001, Figure 5C), because the (micro)vascular thrombi had been removed, blood flow could resume, and the ischemic tissue injury had thus been terminated; 3. A decrease in rhVWF percentage (P<0.0001, Figure 5D), due to faster clearance of prothrombotic rhVWF; 4. Normalized hemoglobin and hematocrit levels as the hemolytic anemia was limited due to the removal of thrombi in the vasculature (P<0.05, except for the hematocrit level of the 1 mg / kg ML 1.1 dose, which was not significantly different to the vehicle-treated mice; Figure 1E and F, respectively). In terms of ML 1.1 doses, all three tested doses were equally effective at resolving thrombocytopenia and tissue damage when measured 24 hours post-TTP attack. In contrast to the findings of this study, the 0.25 mg / kg ML 1.1 dose was less effective than higher doses in the ADAMTS13 knockout mouse model (Example 4). The increased efficacy observed with the 0.25 mg / kg dose in this iTTP study could be due to the lower levels of rhVWF used in this model to induce the TTP attack (500 vs 1000 U / kg), which would result in less plasma VWF for ML 1.1 to bind to. Conclusion ML 1.1 was well-tolerated and attenuated thrombocytopenia, reduced tissue damage, and improved markers of hemolytic anemia at 24 hours post-TTP onset in an antibody-mediated model of TTP. This Example complements the findings in Example 4 and indicates that ML 1.1 can improve symptoms of TTP irrespective of the cause of ADAMTS13 deficiency. These findings imply a potential clinical benefit to patients with cTTP and iTTP given both models’ translational relevance. Similar to the findings in Example 4, in this Example all doses of ML 1.1 also achieved complete TTP symptom resolution within 24 hours in the presence of continually low ADAMTS13 activity. If this holds true for human patients with TTP, it would result in considerably faster symptom resolution than available treatments. This could have significant implications for limiting tissue damage, improving patient outcomes, and lessening the high healthcare burdens associated with TTP. Example 6 – Efficacy in a mouse model of distal thrombotic stroke with platelet-rich thrombi ML 1.1 was assessed in a model of arterial ischemic stroke (AIS) characterized by the formation of distal, platelet-and VWF-rich thrombi. Methods Thrombotic stroke was induced in male Swiss mice by the topical application of FeCl3 on the MCA. Vascular occlusion was measured for 20 minutes and was required to be stable. ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 1.93 mg / mL. Mice received vehicle or ML 1.1 (0.27, 0.8, or 2.4 mg / kg) via intravenous (IV) injection (10% bolus followed by 90% infusion over 40 minutes) 20 minutes after stroke induction. Laser speckle flowmetry was completed at 10 to 20 minutes (before treatment), 20 to 30 minutes (directly after treatment initiation), and 60 to 70 minutes (after completion of treatment infusion) post-stroke onset to assess cerebral blood flow (CBF) evolution and provide an index of cortical perfusion. MRI was conducted at 24 hours to measure lesion volume, recanalization, and haemorrhagic transformation. Mice were thereafter euthanised and blood plasma and brain samples were taken. The primary efficacy outcome was lesion volume at 24 hours, while the primary safety outcomes were mortality and hemorrhagic transformation. Results ML 1.1 was well-tolerated and did not increase mortality. There were no differences in body weights across the time points or treatment groups (Two-way ANOVA: P= 0.9885). None of the animals had a visible intracerebral haemorrhage on MRI at 24 hours post-stroke initiation. In terms of CBF, there were no differences in groups before treatment (Figure 6A). Directly after treatment initiation, the ML 1.12.4 mg / kg group had increased CBF in the ischemic core compared to vehicle-treated mice (Wilcoxon test: P=0.0126; Figure 6B), suggesting rapid thrombolysis. After completion of the infusion treatment, both the ML 1.12.4 mg / kg (Wilcoxon test: P=0.0153) and 0.27 mg / kg (Wilcoxon test, central area P=0.0083) dose groups had improved CBF in the ischemic core compared to the vehicle group (Figure 6C), indicating further restoration of blood flow. In terms of lesion volume at 24 hours post-stroke, the ML 1.12.4 mg / kg (Each pair student’s T-test: P=0.0012), ML 1.10.8 mg / kg (P=0.0212) and ML 1.10.27 mg / kg (P=0.0148) treated mice all had reduced lesion volumes compared to vehicle-treated mice (Figure 7A). In addition, there was a trend for the ML 1.12.4 mg / kg treated mice to have higher proportions of partial or full recanalization at 24 hours post-stroke compared to vehicle-treated mice (Fisher’s exact test P= 0.0972; Figure 7B). Importantly, none of the animals suffered from hemorrhage after treatment. Conclusion ML 1.1 improved reperfusion, reduced the volume of affected tissue, and showed indications of improving recanalization following AIS with platelet-rich thrombi. These data indicate that ML 1.1 was safe and effective in a platelet-rich thrombotic stroke model. Rh-tPA at 10.0 mg / kg was proven ineffective in a similar study set-up (van Moorsel et al., 2022). Example 7 – Efficacy in a thrombin-induced model of thrombotic stroke in hyperglycemic mice Example 7 was performed to evaluate whether ML 1.1 could improve outcomes following AIS with thrombin-induced fibrin-rich thrombi without increasing hemorrhage risk in hyperglycemic mice, which have an elevated bleeding risk. Methods Twenty-one days before thrombotic stroke induction, male Swiss OF1 mice were made hyperglycemic by repeated streptozotocin administration. Hyperglycemia was confirmed 4 and 2 days before stroke induction. Thrombotic stroke was induced by thrombin injection into the MCA. ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 1.93 mg / mL. Twenty minutes after stroke onset, mice received ML 1.1 (0.27 or 2.4 mg / kg), rh-tPA (alteplase; 10 mg / kg), or vehicle. All treatments were administered as an intravenous bolus (10% of treatment volume) followed by a 40-minute intravenous infusion (90% of treatment volume). Laser speckle flowmetry was completed at 10 to 20 minutes (before treatment), 20 to 30 minutes (directly after treatment initiation), and 60 to 70 minutes (after completion of treatment infusion) post-stroke onset to assess cerebral blood flow (CBF) evolution and provide an index of cortical perfusion. Lesion volumes and potential hemorrhagic transformation were assessed at 24 hours and 7 days after stroke by MRI. The primary efficacy outcome was lesion volume at 24 hours, while the primary safety outcomes were mortality and hemorrhagic transformation. Results ML 1.1 was well-tolerated and did not increase mortality. In terms of CBF, there were no differences in groups before treatment. However, mice treated with 2.4 mg / kg ML 1.1 had increased reperfusion in the central stroke area after the end of the treatment infusion compared to vehicle-treated mice (Steel-Dwass with control test: P = 0.0416; Figure 8C), indicating thrombus lysis and restoration of blood flow. The increased perfusion in the ML 1.12.4 mg / kg treated mice resulted in smaller lesion volumes at 24 hours post-stroke compared to vehicle- treated mice (Wilcoxon each pair test: P= 0.0261; Figure 9), indicating a prevention of tissue damage. In contrast, rh-tPA treatment did not improve reperfusion or reduce lesion volume compared to vehicle-treated mice (Figure 8C). Rh-tPA has been shown to be less effective in hyperglycemic mice (Fan et al., 2012). Importantly, none of the treatments increased parenchymal hemorrhagic transformation on D1 or D7 when compared to vehicle. In terms of haemorrhagic transformation, there were no differences in haemorrhagic maximal score between treatment groups on day 1 (Kruskal-Wallis test: P=0.5449) or day 7 (Kruskal- Wallis test: P= 0.3146). Similarly, there were no differences in haemorrhagic total score between treatment groups on D1 (Kruskal-Wallis test: P=0.5569) or D7 (Kruskal-Wallis test: P= 0.3571). Therefore, ML 1.1 treatment did not elevate haemorrhagic risk following stroke in hyperglycaemic mice that have an elevated bleeding risk. Conclusion ML 1.1 was well-tolerated and improved reperfusion and reduced lesion volumes without increasing intracerebral hemorrhage in hyperglycemic mice, which have a higher propensity for bleeding complications and are more resistant to thrombolytic treatment. Example 8 – Efficacy in a thromboembolic stroke model in rats The effect of ML 1.1 was assessed at two and four hours post-stroke on tissue loss and its correlation to early and late-stage neurological function in rats using a thromboembolic- induced stroke. Methods Autologous thrombi were prepared in vitro from adult male Wistar rats. Specifically, blood samples were taken from the tail vein 120 minutes before stroke induction and allowed to coagulate for 110 minutes. The resultant thrombi were fragmented by aspiration and ejection through a sterile needle. Five standardized-sized thrombi were selected and applied to the MCA to cause a thromboembolic stroke. ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 3.61, or 2.08 mg / mL. Rats received Vehicle, rh-tPA (2.5 mg / kg; starting at 2 or 4 hours post-stroke induction), or ML 1.1 (0.27 mg / kg started at 2 hours after stroke induction; 2.4 mg / kg starting at 2 or 4 hours post-stroke induction) via IV injection (10% bolus followed by 90% infusion over 40 minutes). Compared to previous studies this delayed treatment administration more accurately resembles the reality of thrombolytic treatment in human patients. Neurological functions were measured on days 2, 7, 14, 21, and 28 post-treatment. Rats were euthanized on day 28 for brain sampling to assess tissue loss and hemorrhagic transformation. Satellite groups of animals were sampled on day 3 to evaluate blood-brain barrier opening and hemorrhagic transformation. The primary efficacy outcomes were neurological scoring and tissue loss, while the primary safety outcomes were mortality, hemorrhagic transformation and BBB opening. Results ML 1.1 was well-tolerated and did not increase mortality. In terms of safety measures, ML 1.1 did not increase BBB opening on day 3 or hemorrhagic scores on days 3 and 28 compared to vehicle-treated mice, indicating that ML 1.1 did not increase BBB disruption or hemorrhagic risk when administered at 2 or 4 hours post-stroke. Rats treated at 2 hours post-stroke with 2.4 mg / kg ML 1.1 and rh-tPA showed consistently lower Neuroscores throughout the observation period compared to vehicle-treated mice (Figure 10A), indicating continual early to long-term neurological benefits. Specifically, treatment with the 2.4 mg / kg ML 1.1 dose administered 2 hours after stroke onset improved Neuroscores on days 2 (Steel test: P<0.05) and 28 (Steel test: P<0.05) compared to vehicle-treated mice. Similarly, rh-tPA administered at 2 hours improved Neuroscores on days 2 (Steel test: P<0.05) and 28 (Steel test: P<0.05) compared to vehicle-treated mice. ML 1.1 2.4 mg / kg reduced neurological deficits by 40% on day 2, compared to vehicle. Regarding lesion volume on day 3 post-stroke, the 2.4 mg / kg ML 1.1 (2-hour administration) treatment group showed a trend toward decreased lesion volume (median: 133 mm3[IQR: 58 – 241]) compared to vehicle-treated rats (median: 224 mm3[IQR 85 – 250]; Figure 11A), but low sample size limited statistical power in this analysis. The cerebral tissue loss on day 28 differed between treatment groups (Kruskal Wallis: P=0.008; Figure 11B). Treatment with 2.4 mg / kg of ML 1.1 at 2 hours post-stroke decreased the tissue loss at 28 days (median: 28 mm3[IQR: 9 – 77]) compared to vehicle-treated rats (median: 118 mm3[IQR: 62 – 160]; Steel test: P<0.05), while treatment with rh-tPA at 2 hours (median: 38 mm3[IQR: 18 – 100]) only showed a trend toward decreased tissue loss compared to vehicle (Steel test: P=0.07; Figure 11B). The ML 1.10.27 mg / kg dose administered at 2 hours (Figure 10A), the ML 1.12.4 mg / kg dose administered at 4 hours (Figure 10B), and rh-tPA administered at 4 hours (Figure 10B), did not significantly improve Neuroscores or reduce tissue loss at 28 days (Figure 11B), indicating that earlier administration is important to maximize the therapeutic benefit, similar to rh-tPA. Importantly, none of the treatments, whether administered at 2 hours or 4 hours post stroke induction, increased hemorrhagic scores on D3 or D28. Conclusion ML 1.1 was well-tolerated and did not increase mortality, BBB opening, or intracerebral hemorrhage occurrence in the rats following thromboembolic AIS. Administration of 2.4 mg / kg of ML 1.1 at two hours improved early and late-stage neurological deficits and reduced tissue loss. Administration of the same ML 1.1 dose at four hours did not have the same beneficial effects, indicating that earlier administration is important to maximize the therapeutic benefit, similar to rh-tPA. This observation is considered to be related to other processes driving tissue damage upon delayed treatment administration. We have no indication whether recanalization was achieved at this time point of administration. Importantly, the four hour administration did not increase hemorrhagic transformation either. The 0.27 mg / kg ML 1.1 dose administered at 2 hours did not significantly improve stroke outcomes, suggesting that higher dose is required for efficacy in this model. Example 9 – Efficacy in a histone induced thrombotic microangiopathy model in mice As the first part of this Example, histone was titrated in to determine optimal concentration to induce thrombotic microangiopathy while limiting toxic effect. Then, in the second part of the Example, the effect of ML1.1 on histone induced thrombotic microangiopathy in mice was assessed. Methods ML 1.1 was produced in Pichia pastoris. It was purified and formulated at 5.18 mg / mL. Baseline whole blood counts were performed at ± day -14. For this, mice were anesthetized^^^^^ ^^^^^^^^^^^ ^^^ ^ ^^^^^ ^^ ^^^^^ ^^^^ ^^^^^^^^^ ^^^ ^^^^^^^^^^^^^ ^^^^^^^^ ^^ ^ ^^ ^^^^^^^^^ ^^ ^^^^^ ^^ ^^^^^ ^^^^ ^^^^^ ^^ ^^ ^^ ^^ ^^^^ ^^^^^^ ^^^^^^^^ ^^^^^^ ^^^ ^^^^^^^^^upon centrifugation at 800xg for 6 minutes using a table-top Eppendorf centrifuge. Plasma was stored at -80°C. EDTA Whole blood count was measured using the Vetscan HM5 hematology analyzer. A working solution of 10 mg / mL lysine-rich histones (Sigma-Aldrich, Cat.No. H5505) dissolved in saline was prepared and aliquots were stored at -80°C. At day 0, lysine-rich histones were injected via a retro-orbital intravenous injection at the indicated dose under anesthesia. In case of treatment, 15 minutes post histone administration, vehicle (ML1.1 formulation buffer) or 2.4 mg / kg ML1.1 was administrated intravenously as bolus. Blood was collected in the pilot study before administration of histones and ML1.1 and at 0.5, 1.6 and 24 hours after, in the main study before administration of histone and ML1.1 and at 1 hour after. For this, mice were anesthetized using isoflurane, and 2 drops of blood were^^^^^^^^^ ^^^ ^^^^^^^^^^^^^ ^^^^^^^^ ^^ ^ ^^ ^^^ ^ ^^^^^ ^^^^^ ^^^^^ ^^^^^ ^^^ ^^^^^^^^using the Vetscan HM5 hematology analyzer. A terminal blood withdrawal was performed at the final time via heart puncture.16 drops of^^^^^ ^^^^^ ^^^^ ^^^^^ ^^ ^^ ^^ ^^ ^^^^ ^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^ ^^^^^^^^^ ^^^centrifugation and stored at -80 °C. Plasma was collected upon centrifugation at 800xg for 6 minutes using a table-top Eppendorf centrifuge. Plasma was stored at -80°C. Results Effect of Histone doses - The effect of intravenous histone administration in either ADAMTS13 WT or ADAMTS13 knockout (KO) mice was tested at 50 and 70 mg / kg (Figure 12). At either dose, thrombocytopenia was almost immediate as characterized by a sharp drop in platelet count within 30 minutes. Platelet counts slowly increased back to baseline within 24 hours. No difference in mean platelet volume and hemoglobin were observed, but lymphocytes demonstrated a ~50% drop from baseline that recovered with 24 hours. This shows that the model is transient. Small differences were observed between the 50 and 70 mg dose in a dose dependent manner. No real difference was observed between wildtype and knock out animals, demonstrating that endogenous ADAMTS13 has no effect on this model. Effect of ML1.1 on histone induced thrombotic microangiopathy - Based upon the data collected from the histone titration, wild type animals were used in this model to collectively represent all TMA. Wild type mice were treated with 50 mg / kg of histone as this induces significant thrombocytopenia without too many toxic side-effects. After 15 minutes, animals received vehicle or 2.4 mg / kg of ML1.1 as an intravenous bolus administration. 1 hour after histone administration (45 minutes after ML1.1 administration), animals were terminated and terminal blood withdrawal was performed. Data show a partial, but significant, restoration of platelet counts when ML1.1 was administrated compared to Vehicle (Figure 13). As in the previous experiment (as described in the paragraph above), mean platelet volume, hemoglobin, neutrophils showed no difference between the three groups. Hematocrit, showed a non-significant elevation for vehicle vs predose, yet the increase in hematocrit was significant for predose vs ML1.1. No significant difference was observed between vehicle and ML1.1. This suggest that the elevation was most like due to the histone itself rather than the treatment. Difference in spread between the data seems to drive the difference in significance. In this model we opted to measure lactate dehydrogenase (LDH) as a marker for tissue damage. At 1 hour post histone injection LDH levels are significantly elevated for both the vehicle and ML1.1 groups compared to predose. No difference was observed between vehicle and ML1.1. This was to be expected as 1 hour post histones is most likely too fast for LDH levels to drop significantly. Conclusion ML1.1 was well-tolerated and showed improvement in histone-induce thrombocytopenia with 45 minutes after treatment. This study confirmed that histones can exert toxic when the dose effects at higher doses. Both the 50 and 70 mg / kg histone administration demonstrated a similar thrombocytopenic reaction (Figure 12) where the model displayed increased transient behaviour than the previous performed TTP models (Examples 4 and 5 above). This complicated the timing of blood collection for analysis. As such, within the limited scope of this example, a dose of 50 mg / kg was chosen with a 1-hour post-histone administration end- point. This limited the potential of toxic effects from the histones on influencing the model. The data collected, despite being limited by the 1-hour timepoint, already demonstrated a clear and significant increase in platelet counts. It can be concluded that the intravenous bolus administration of ML1.1 was pharmaceutically beneficial in a histone-induced microangiopathy model in mice. Example 10 – Efficacy on embolic pulmonary thrombosis (EPT) in rats The effect of ML 1.1 after intravenous administration (bolus and infusion) on embolic pulmonary thrombosis in rats was assessed. Methods ML 1.1 used in this Example was produced in Pichia pastoris. It was purified and formulated at 2.1 mg / mL. A) – Induction of embolic pulmonary thrombosis (EPT) Sprague-Dawley rats of 5-weeks old on the day of arrival were collectively housed for 1 week prior to the experiment in cages, with free access to food (RM1, SDS Dietex) and drinking water ad libitum. One day prior to induction of embolic pulmonary thrombosis (EPT), 1 mL of whole blood was collected from the animals via the caudal tail vein and transferred to a silicon tube. Twenty- thirty minutes prior to the induction of PE, the formed thrombus was pushed out of the silicon tube and into a sterile Petri dish containing 0.9% w / v isotonic saline. The thrombus was cut into 50 thrombi of around 1mm x 3 mm. Prior to induction of EPT, animals are anesthetized and the thrombi were administrated via exposed and isolated jugular vein on the left side of the neck at a flow rate of 0.5 mL / min to induce EPT. After administration the exposed vein and skins were sutured. B) – Echocardiographic assessments At baseline or 10 minutes after induction of EPT, vascular occlusion was confirmed by Doppler-echocardiography, using the Vevo F2 LT Imaging system (Fujifilm Visual sonics) combined with a 22 MHz phased-array-transducer. Image acquisition, measurements and calculations were done in accordance with the American Society of Echocardiography (Schiller et al., 1989) and the previous validated method for rats (Litwin et al., 1994). Briefly, a single trained operator acquired the images according to the parasternal short and long axis plan of the right ventricular outflow tract level. These data will be used to assess pulmonary arterial acceleration time (PAAT) and right ventricular (RV) ejection time (ET). C) – Treatment of embolic pulmonary thrombosis with ML1.1 ML1.1 was prediluted in 0.9% w / v isotonic saline and administrated intravenously (IV) via the tail vein at a concentration of 2.4mg / kg. Treatment was initiated 20 minutes after induction of pulmonary embolism (PE) and given as a 50% bolus and 50% infusion over a 20-minute period. As a vehicle control, formulation buffer of ML1.1 (but without ML1.1) was diluted and administrated in similar fashion as ML1.1. Moreover a sham group treated with vehicle was included. See Table 5 for group and treatment overview. Table 5. Experimental setup to test ML1.1 efficacy in embolic pulmonary thrombosis Group N Disease Treatment Administration Final Assessment at 2 hours 1 15 Sham Vehicle 1mL IV Hemodynamic ^ RVSP, mPAP 2 15 Embolic Vehicle 50% bolus + 50% Terminal blood sample ^ Plasma Pulmonary infusion in 20 Left lung ^ NBF 10% / Eth 70% 3 15 ML1.1 Thrombosis minutes Right lung ^ NBF 10% / Eth 70% Note: Eth, ethanol; IV, intravenous; mPAP, mean pulmonary arterial pressure; NBF, neutral-buffered formalin; RVSP, right ventricular systolic pressure D) – Terminal measurements at 2 hours after induction of pulmonary embolic thrombosis Two hours after induction of EPT, ML1.1 efficacy was determined via the measurement of right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). After completion of the hemodynamic measurements, 2 mL of whole blood was collected via direct intracardiac puncture.1 mL of whole blood was transferred to a K3EDTA or citrate tube, mixed and centrifugated at 2,000-5,000×g for 10-15 minutes. Approximately 300 µL of plasma was transferred into a new tube, snap frozen on liquid nitrogen and stored at -80 °C. The lungs of all animals were also collected and prepared for histological analysis. E) – Statistical analysis If samples are drawn from normally distributed populations with equal variances, differences in hemodynamic measurements will be assessed with an analysis of variance (one way ANOVA) followed by appropriate correction test. If samples are drawn from non-normal populations, a Kruskal-Wallis ANOVA on ranks will be performed followed by appropriate correction test. A level of probability less than 0.05 will be accepted as significant. Results Development of the embolic pulmonary thrombosis model in rats - To test the embolic pulmonary thrombosis (EPT) model in rats, rats were induced as previously described (Shi et al., 2018), after which the right ventricular systolic pressure (RVSP) and the mean pulmonary artery pressure (mPAP) were measured at specific timepoints (Figure 14). Ten minutes after clot injection, both RVSP and mPAP show a significant elevation over sham operated animals. For RVSP, this elevation quickly reverts to baseline, leading to a loss of significant effect after 10 minutes. For mPAP the elevation remains significant up to 2 hours, with the 3 hour timepoint being slightly above significance (P> 0.07). These data indicate that, while the model shows almost direct results upon clot injection, these symptoms revert to normal within a time period of ~6 hours. Based upon the time-dependent effects determined in the pilot study, ML1.1 administration started10 minutes after EPT induction (Figure 15). As RVSP and mPAP cannot be measured real-time, an end point of 2 hours for RVSP and mPAP determination was chosen. While RVSP was not expected to demonstrate a significant effect at this timepoint, the mPAP should still be able to demonstrate a significant pharmacological effect. As it was unknown which administration method (bolus or infusion) should be effective, an intermediate approach was chosen. ML1.1 was administrated at 2.4 mg / kg with 50% as bolus and 50% as a 20 minute infusion. In this manner, it was expected that the exposure of ML1.1 would be sufficient while still allowing for sufficient time between end of administration and the 2 hour end point to show significant pharmacological effect on mPAP. As expected, RVSP did not demonstrate any difference between sham and EPT induced animals at 2 hours after EPT onset (Figure 16). As such, ML1.1 also did not demonstrate any difference. With mPAP, the EPT significantly induced an increase in pressure. Treatment with 2.4 mg / kg ML1.1 reduced mPAP back to sham levels, demonstrating complete reversal of EPT. Mortality was observed within this model upon introduction of EPT but not sham. All death were observed prior to administration of ML1.1, leading to the conclusion that ML1.1 did not induce any toxic or lethal effects. Conclusion Acute pulmonary embolism is a deadly disease in which thrombolytic compounds can have significant impact on the patients outcome compared to standard of care treatment with anticoagulants. With ML1.1previously demonstrating efficacy in animal models of thrombosis such as acute ischemic stroke and thrombotic thrombocytopenic purpura, its efficacy in a rat model of embolic pulmonary thrombosis (which is mimicking human acute pulmonary embolism in animals) was investigated in this Example. Development of such a model in rats demonstrated the transient nature of the model which suggest the presence of endogenous plasmin activity that attack the administrated clot. Literature shows, that this EPT model is often performed in the presence of tranexamic acid (TXA) which is a lysine-analogue and neutralizes the activation of plasminogen and / or the activity of plasmin (Karpov et al., 2022). This indicates that the endogenous plasmin forming capacity in the rat lung is sufficient to revert this model back to baseline within the 6-hour time frame. Application of TXA to further extent the model timeline is most likely impossible as it was previously found that it would neutralize the therapeutic effect of ML1.1. In the future an inhibitory anti-tPA, anti-UPA receptor or anti-uPA (that is not cross-reactive with ML1.1) might be tested to see if the model can be stabilized beyond 2 hours. For this Example a timepoint of 2 hours after EPT onset was chosen as the final timepoint to measure the pharmacodynamic action of ML1.1. While this would not give significant difference of RVSP, it would still result in a difference in mPAP, which is considered to be the most reliable marker for this model. Under the conditions chosen, a significant elevation in mPAP, but not RVSP, was detected compared to sham operated animals (Figure 16). For ML1.1 a rapid bolus & infusion strategy was chosen to ensure sufficient exposure. As a one-hour infusion strategy might not allow for sufficient time for ML1.1to demonstrate efficacy due to the 2 hour end point, a 50% bolus and 50% infusion strategy of 21 minutes was chosen. In the future different dose levels as well as administration methods might be investigated. In conclusion, ML1.1 demonstrated statistically significant effect in a rat model of EPT. Example 11 – In vitro thrombolysis of ex vivo thrombi from patients with acute ischemic stroke using ML1.1 This Example aims to investigate the in vitro thrombolytic activity of ML1.1 using ex vivo thrombi obtained from endovascular thrombectomy (EVT) procedures conducted in patients with acute ischemic stroke (AIS). Methods A) Thrombus collection Ten thrombi were retrieved from patients with AIS during EVTs conducted at the AZ Groenige Hospital (Kortrijk, Belgium). Each thrombus was divided into two parts, with one half used for the thrombolysis experiment and the other for histological analysis to assess thrombus composition. The thrombi were used within 48 hours after retrieval. Previous studies have indicated that thrombus composition is consistent within a single thrombus (Staessens, Fitzgerald, et al., 2020), allowing a section to be representative of the whole thrombus. Only thrombi large enough to allow sufficient material for both the thrombolysis and histological analysis were included. B) Preparation of pooled normal human plasma Whole blood was collected in sodium citrate tubes from healthy volunteers (9:1 blood:sodium citrate, 3.2% vol / vol). Whole blood was pooled and centrifuged for 15 minutes at 2200 g to generate normal human plasma (NHP). NHP samples were stored at -80ºC until use. C) Thrombolysis experiment ML 1.1 was produced in Pichia pastoris, purified, formulated, aliquoted and frozen. Prior to the experiment, it was thawed and diluted into NHP to 3 µg / ml. Each thrombus was placed into the diluted ML1.1 or with formulation buffer (negative control; NC). Thrombus weight was measured on a precision balance at baseline and after 10, 30, 60, 120, and 180 minutes. The degree of thrombolysis was determined as the residual thrombus weight expressed as a percentage of the initial weight at each time point. D) Histological analysis The thrombus sections used for histological analysis were incubated in 4% paraformaldehyde at 4°C for 24 hours and thereafter embedded in paraffin blocks. A 5 µm-thick section, exposing a large cross-sectional area of the thrombus, was selected for staining. Thrombus sections were stained with a Martius Scarlet Blue (Crystal Ponceau 6R: sc-214779, Santa Cruz, Dallas, USA; Naphtol Yellow S: sc-215544, Santa Cruz, Dallas, USA; Methyl blue: M6900-50G, Sigma, St. Louis, MO, USA) to identify red blood cells (yellow), fibrin (dark pink / red), a haematoxylin. Eosin staining (H&E, HT110216, Sigma-Aldrich, St. Louis, MO, USA) and a Feulgen’s reaction staining (1079070001, Merck Chemicals, MA, USA) were used to identify DNA (pink). Immunohistochemical (IHC) stainings were performed to examine the presence of^^^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^ ^^^ ^^^^^ ^^^ ^^^ ^^^^^^^^^^^Agilent Technologies, Santa Clara, CA, USA). In the IHC stainings, nuclei were stained green using a Methyl Green solution (H-3402, Vector Laboratories, Peterborough, UK). E) Statistic analysis Statistical analysis was performed using GraphPad Prism (v10.4.1; GraphPad Software, San Diego, CA). Multiple unpaired t-tests were used to assess the difference in thrombolysis, expressed as a percentage of the initial thrombus weight, between samples incubated with ML1.1 or formulation buffer (negative control) at each time point. Simple linear regression was used to investigate the correlation between histological parameters (e.g. VWF, RBC, or platelet levels etc.) and the degree of thrombolysis at 180 minutes. Thrombus 2, which was incubated with ML1.1, had a failed histology analysis and was excluded from the analysis. Therefore, nine thrombi incubated with ML1.1, and five thrombi incubated with formulation buffer were included in the final analysis Results Thrombolysis experiment - Incubation with ML1.1 (3 µg / ml) reduced the thrombus weight in all ten thrombi included in the thrombolysis experiment (Figure 17), indicating that ML1.1was able to induce thrombolysis of human AIS thrombi. By the end of the experiment, thrombus weights had reduced (from 100%) to between 8% and 66% of their initial weights (Figure 17). In contrast, and as expected, the thrombi incubated with formulation buffer (negative controls) showed minimal reduction in thrombus weights over the 3-hour experiment (Figure 17). The degree of thrombolysis observed in samples incubated with ML1.1 was significantly higher at the 60 (P=0.007), 120 (P=0.002), and 180-minute (P<0.001) timepoints compared to the negative control samples (Figure 18). Histological analysis - Histological analysis was conducted on the ten thrombi that were incubated with ML1.1 to determine the thrombus composition regarding RBC, fibrin, platelet, VWF, and DNA content. The histological analysis of one of the thrombi (Thrombus 2) failed for experimental reasons and therefore only nine thrombi were included in the analysis. The compositions of the 10 thrombi were heterogenous, with RBC content ranging from 14% to 64%, fibrin from 14% to 58%, platelets from 0.2% to 37%, and VWF from 16% to 68% (Table 6). The 10 thrombi therefore included both platelet-rich and RBC-rich compositions. Table 6: The histological compositions of each of the ten thrombi used in the thrombolysis experiment with ML1.1. Thrombus RBC (%) Fibrin (%) Platelets (%) VWF (%) Leukocytes (%) Total DNA (%) 1 58.8 25.7 2.6 15.5 - 0.7 2 Histology analysis failed, data excluded from study 3 27.9 27.8 31.2 46.0 18.1 7.1 4 29.6 45.0 36.9 30.6 28.1 19.4 5 61.0 32.1 21.9 29.9 3.6 6.0 6 64.4 14.4 21.7 33.7 2.4 1.5 7 60.6 15.2 16.4 37.0 13.3 3.2 8 29.5 29.0 2.2 31.5 14.9 10.5 9 26.4 22.4 4.8 46.1 7.3 10.4 10 14.1 58.4 27.7 67.5 1.8 2.0 Note. RBC: Red blood cells; VWF: von Willebrand factor. Correlation between histology and ML1.1 thrombolysis - The relationship between thrombus composition and the extent of ML1.1-induced thrombolysis at 180 minutes was evaluated. A significant correlation was observed between the extent of thrombolysis and RBC and VWF content (Figure 19). Specifically, higher VWF levels were linked with enhanced thrombolysis, while higher RBC levels were associated with reduced thrombolysis. No significant association was found between thrombolysis and the other thrombus components. Conclusion This Example demonstrates that ML1.1 can effectively lyse human thrombi ex vivo. These findings support the previous in vivo preclinical studies showing that ML1.1 degrades thrombi and improves outcomes in AIS models. The analyzed thrombi had varying levels of VWF, fibrin, RBC, and platelets, indicating that ML1.1 is effective across a range of thrombus compositions. Consistent with ML1.1’s mechanism of action, thrombi with higher levels of VWF were degraded more rapidly. It is also observed in this Example that the current standard of care rht-PA demonstrated reduced thrombolytic efficacy against RBC-poor thrombi (Vandelanotte & De Meyer, 2024). These findings suggest that ML1.1 may be more effective in lysing thrombi that are resistant to rht-PA, potentially offering a therapeutic advantage in such cases. Example 12 – First in human administration of ML1.1 A Phase I randomized, double-blind, placebo-controlled study (TG1-CL-101) to assess the safety and pharmacokinetics of single-ascending doses of ML1.1 in healthy volunteers has been conducted. 34 healthy male participants have been administered a single dose of ML1.1 or placebo in four cohorts (Table 7). The first cohort was divided into two sub-cohorts (1a and 1b). In Cohort 1a, the 1 mg starting dose ML1.1 or placebo was administered as a 1-hour IV administration to five participants. This administration was deemed well tolerated in a safety review meeting, and the administration time in cohort 1b (1 mg ML1.1) and subsequent cohorts was reduced to a 1 minute controlled rapid IV administration. Within the cohorts, participants were randomized to ML1.1 or placebo, respectively, in a 3:2 (Cohort 1a and 1b) or 3:1 (Cohort 2 - 4) ratio. In total, 24 participants received ML1.1 and 10 received a placebo. Participants in Cohorts 1 to 3 have completed the study, while the 8 participants in Cohort 4 have been evaluated up to the 48-hour safety evaluation. ML 1.1 used in this study was produced in Pichia pastoris. It was purified and formulated at 2.0 mg / mL. Table 7: Available data for study TG1-CL-101, A Phase 1 randomized, double-blind, placebo-controlled study to assess the safety and pharmacokinetics of single-ascending doses of ML1.1 in healthy volunteers Planned participants Completed Cohort Dose Route of Administration (n) participants (n) 1a 5 5 1 mg 1-hour IV infusion 1b 5 5 1 mg 1-minute IV infusion Planned participants Completed Cohort Dose Route of Administration (n) participants (n) 2 8 8 2 mg 1-minute IV infusion 3 8 8 1.7 mg 1-minute IV infusion 48-hour safety 4 8 1.4 mg 1-minute IV infusion evaluation After the dosing of the eight participants in Cohort 2 (2 mg dose level), clinical effects and pharmacology markers, indicative of ML1.1 on-target effects, were observed in more than 50% of the participants. Intermediate dose levels of 1.7 mg and 1.4 mg ML1.1 were defined to further characterize the slope of the pharmacological effect, the PK and the associated safety profile in the healthy participants A) Pharmacokinetics in humans A validated ECLIA is used to determine the total (both free and VWF-bound; zymogen and activated forms) concentration of ML1.1 in human EDTA plasma. Preliminary individual plasma concentration profiles are shown in Figure 20. Preliminary results of the plasma PK samples are summarized in a short description and Table 8 with AUC, Cmax and t1 / 2. Table 8: Preliminary mean or median pharmacokinetic parameters of ML1.1 in study TG1-CL-101 ML1.1 Dose Cmax Tmax AUC0-12 CL Vz (mg) t ½Cohort(infusion (hour) (ng / mL) (h) (h*ng / mL) (mL / h) (mL) time) 1a 1 271 1.25 1290 5.41 611 4760 (N=3) (60 min) (218 - 345) (1 - 1.25) (842 - 1,740) (3.8 - 8.1) (366 - 1,000) (3,420 - 7,400) 1b 1 296 0.25 1460 5.71 534 4400 (N=3) (1 min) (242 - 394) (0.05 - 1.5) (1,280 - 1,590) (3.7 - 6.4) (470 - 572) (3,050 - 5,310) 2 2 712 0.05 1930 3.03 1150 5020 (N=6) (1 min) (492 - 920) (0.05 - 0.25) (1,600 - 2,610) (1.8 - 6.7) (588 - 2,020) (4,070 - 5,780) 3 1.7 669 0.05 2490 4.10 695 4110 (N=6) (1 min) (488 - 840) (0.05 - 0.25) (2,120 - 2,700) (2.0 - 7.3) (463 - 1,650) (3,340 - 4,870) Note. All pharmacokinetic (PK) parameters are presented as geometric means, except for Tmax, which is presented as the median. The minimum and maximum values for the pharmacokinetic parameters per cohort are shown in parentheses. Cmax: maximum concentration;Tmax: time to maximum concentration; AUC(0-12): area under the concentration-time curve from 0 to 12 hours; t1 / 2: half-life; CL: clearance;Vz: volume of distribution. Plasma concentration profiles were used to evaluate PK parameters. Tmaxwas generally reached within or at 15 minutes after the end of infusion. Individual Cmaxvalues ranged from 218 to 265 ng / mL in Cohort 1a, 242 to 394 ng / mL in Cohort 1b, 492 to 920 ng / mL in Cohort 2 and 488 to 840 ng / mL in Cohort 3. The mean dose-normalized Cmaxvalues were comparable between dose cohorts with values of 296, 356 and 394 ng / mL / mg for Cohort 1b, Cohort 2 and Cohort 3, respectively. The calculated volume of distribution ranged from 3050 to 7400 mL and was comparable between dose cohorts. The CL and T½presented with a high variability between individuals. Individual calculated t1 / 2 values ranged from 1.8 to 8.1 hours and the clearance values ranged from 366 to 2020 mL / h. The geometric mean CL was higher in Cohort 2 (1,150 mL / h, CV 45.7%) compared to the other cohorts: 1a (611 mL / h, CV 53.7%), 1b (534 mL / h, CV 11.2%) and 3 (695 mL / h, CV 48.0%). The geometric mean t1 / 2was lower in Cohort 2 (3.03 h; CV 50%) compared to the other cohorts: 1a (5.41 h; CV 39.3%), 1b (5.71 h; CV 39.8%) and 3 (4.1h; CV 48.9%) but with high variability. Individual AUC0-12values were similar in Cohort 1a and 1b with a mean (range) of 1,290 (842 - 1,740) and 1,460 (1,280 - 1,590) h*ng / mL, respectively. A dose-proportional increase in AUC0-12was observed between 1 and 1.7 mg with a mean (range) AUC0-12 of 2,490 (2,120 - 2,700) h*ng / mL in Cohort 3. The mean (range) AUC0-12of Cohort 2 (2 mg) at 1,930 (1,600 - 2,610) was lower than the AUC0-12 in Cohort 3 (1.7 mg), but exposure ranges are overlapping. B) Pharmacodynamics Plasma levels of plasminogen, fibrinogen, VWF, VWF binding activity, alpha2-antiplasmin^^^^^^^^ ^^^^^^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^ ^^^ ^^^^^^^ ^^^ ^^^^^ ^^^^^^^^ ^^pharmacodynamic (PD) markers in study TG1-CL-101. In addition, rotational thermoelectrometry (ROTEM) analysis and skin bleeding tests are being performed. Preliminary review of limited PD markers of participants in Cohorts 1a, 1b, 2 and 3, revealed no effects in the skin bleeding test, whereas a trend in dose-dependent response induced by ML1.1 for most of the remaining markers was observed. C) Safety and tolerability Neither infusion-related reactions nor local or systemic symptoms were observed during the administration of the IMP or directly thereafter. In preliminary assessment on blinded study safety reports, 12 AEs have been reported, of which eight were preliminary considered related to the IMP or other medical procedures. Regarding severity, seven AEs were mild (grade 1), and five were moderate (grade 2) as per CTCAE v5.0. None required action to be taken with the IMP. Two non-related AE required the use of concomitant medication. The vascular system was the most commonly affected organ class. There have been no serious adverse events reported in the Phase 1 study TG1-CL-101.

[0002] SEQ ID NO. # CDR3 5 GEILTTSARDYDY 6 SRRQTLYTRTQEYRD 7 SRRQTLYTRSQEYND 8 RVPSYYFGSYGRSSDY 9 DLTIKKTHTIAVVTTRDDY 10 KRGLGPWQYEY 11 AEKYSSRSERYNY 12 AESYSSRSDRYKY 13 AESYSSRSERYNY 14 AESYSSRSERYNY 15 AESYSTRSERYNY 16 ADSYSCRSETYNY 17 SYGLVATMEMEMSDFSS 18 QGGIATVADPDAYDY 19 QGGMATVADPDAYDY 20 QGGMATVSDTEAYDD 21 QGGIATMADMDAYDY 22 SAGLGYVGDPDAMDY 23 AYTWNTRTPDGLVDF 24 AYTIAVVTAMREYDF 25 DPRDSGFYDY 26 RHDSRGTYYSSRGYDY 27 RSSAFSSGIYYREGSYAY SEQ ID NO. # CDR1 28 GRTASSY 29 GRTSDNY 30 GRTSDNY 31 GGVFTPN 32 GSIFSIN 33 GYRFGIN 34 GRSISNY 35 GRSFSSY 36 GRSFSRH 37 GRSFSRY 38 GRRGSSY 39 GLTFSRH 40 GRTFDSY 41 GRTFSSV 42 GRTFSSV 43 GRTFSNY 44 GRTFSSV 45 GRTFSSN 46 GLTFSNY 47 GQTLSNY 48 GRTFSNY 49 GRTFSTY 50 GRTFSSL SEQ ID NO. # CDR2 51 GTAGS 52 SWSGTS 53 SWSGTS 54 TSDGT 55 TSGGR 56 TSGGS 57 TSSGLS 58 TRSGLD 59 TWSGLD 60 TWSGLD 61 TWSGLD 62 TCNGLN 63 SWSGGS 64 NWSGGS 65 SWSGGS 66 SWSGGN 67 NWSGGS 68 SWSGGS 69 SKSGGN 70 SRVGGS 71 MWSAAS 72 YWRDGS 73 GSDSS

Claims

1. Claims 1. A hybrid protein comprising a urokinase catalytic domain and a VHH specifically binding to vWF for use in treating a patient having elevated serum lactate dehydrogenase (LDH) levels or at risk thereof following or during a traumatic event, wherein the treatment comprises administering the hybrid protein to reduce the serum LDH levels of the patient to a target range of less than 280 U / L, preferably less than 250 U / L, more preferably less than 230 U / L.

2. A hybrid protein for use according to claim 1, further comprising maintaining serum lactate dehydrogenase (LDH) levels in a patient within the target range, wherein the hybrid protein is administered prior to, during, and / or following a traumatic event.

3. A hybrid protein for use in maintaining serum lactate dehydrogenase (LDH) levels in a patient within the target range for at least 48 hours, preferably at least 72 hours, more preferably for at least 96 hours, wherein the hybrid protein is administered prior to, during, and / or following a traumatic event.

4. A hybrid protein for use according to any one of claims 1 to 3, wherein the elevated serum LDH level is greater than 1.5 times, preferably greater than 2.0 times, the Upper Limit Normal (ULN) level.

5. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein is administered at least twice during one treatment.

6. A hybrid protein for use according to any one of the afore going claims, wherein the peak plasma level of the hybrid protein is at least 100 ng / mL, preferably at least 200 ng / mL, and preferably from 200 ng / mL to 500 mg / mL during the treatment.

7. A hybrid protein for use according to any one of the afore going claims, wherein the subject is treated until the serum platelet count in the subject is at most 250×109 / L, at most 200×109 / L, preferably at most 150×109 / L .

8. A hybrid protein for use according to any one of the afore going claims, wherein the VHH comprises a complementarity determining region 3 (CDR3) comprising at least one of the amino acid sequences SEQ ID NO: 5 – 27, and preferably wherein the VHH is humanized.

9. A hybrid protein for use according to any one of the afore going claims, wherein the arginine residue at position 153 of the urokinase catalytic domain is substituted with a glutamine residue.

10. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein has an in silicon prediction score as measured by EpiMatrix of no more than -15.

11. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein is a fusion protein.

12. A hybrid protein for use according to any one of the afore going claims, wherein the urokinase catalytic domain and the humanised VHH are connected through a peptide linker.

13. A hybrid protein for use according to any one of the afore going claims, wherein the VHH has an affinity to human VWF at least better than or equal to 10 nM, preferably at least better than or equal to 1 nM, more preferably at least better than or equal to 500 pM, most preferably at least better than or equal to 150 pM.

14. A hybrid protein for use according to any one of the afore going claims, wherein the traumatic event is one or more selected from the list consisting of: acquired or hereditary thrombotic thrombocytopenic purpura (TTP), antiphospholipid antibody syndrome, non-occlusive thrombus, the formation of an occlusive thrombus, arterial thrombus formation, acute coronary occlusion, peripheral arterial occlusive disease, restenosis and disorders arising from coronary by-pass graft, coronary artery valve replacement and coronary interventions such angioplasty, atherectomy, hyperplasia after angioplasty, atherectomy or arterial stenting, occlusive syndrome in a vascularsystem or lack of patency of diseased arteries, transient cerebral ischemic attack, unstable or stable angina pectoris, cerebral infarction, HELLP syndrome, carotid endarterectomy, carotid artery stenosis, critical limb ischemia, cardioembolism, peripheral vascular disease, restenosis, sickle cell disease, myocardial infarct, unstable angina, stable angina, angina pectoris, embolus formation, deep vein thrombosis, hemolytic anemia, acute renal failure, thrombolytic complications, disseminated intravascular coagulopathy (DIG), thrombosis, coronary heart disease, thromboembolic complications, myocardial infarction, restenosis, atrial thrombosis formation atrial fibrillation, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, pre-eclampsia, embolism, restenosis and / or thrombosis, following angioplasty, anastomosis of vascular grafts, chronic exposure to cardiovascular devices. Thromboembolism, reocculsion during and after thrombolytic therapy, angioplasty, coronary artery bypass.

15. A hybrid protein for use according to any one of the afore going claims, wherein the traumatic event involves complement activation.

16. A hybrid protein for use according to any one of the afore going claims, wherein when the traumatic event is a planned event such as a transplantation, a chemotherapy session, a radiotherapy session, a surgical intervention, a thrombectomy, or a plasma exchange session, the hybrid protein is provided for at least 2 days, preferably two consecutive days, starting prior to or during the traumatic event.

17. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein is administered at a daily dosage of 0.01 to 2.5, preferably 0.02 to 2, more preferably 0.02 to 1.5, most preferably 0.04 to 1.5, milligram per kilogram of body weight.

18. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein is administered by infusion.

19. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein is administered in combination with one or more second pharmaceuticalcomposition selected from the group consisting of: a further thrombolytic agent, a further anticoagulant, a complement inhibitor, preferably c5 inhibitor such as such as eculizumab, an immune suppressant, an autophagy inhibitor, a chemotherapy agent, a platelet activation inhibitor, an inflammation inhibitor, and an anti-cancer drug.

20. A hybrid protein for use according to any one of the afore going claims, wherein the hybrid protein and the second pharmaceutical composition are administered simultaneously or sequentially.

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