MÉTODOS PARA AVALIAR A FUNÇÃO PLAQUETÁRIA

Abstract

The present application relates generally to methods for assessing platelet function, for example in a sample from a subject. These methods can be used to identify subjects based on their platelet reactivity or sensitivity to a platelet activating substance, such as collagen-related peptide (CRP), or a thrombin, ADP, thromboxane A2 or adrenaline receptor agonist. The application also provides methods that involve assessing the level of CD36 in platelets of a subject, the level of GPVI in platelets of the subject, and / or the age of the subject as indicators of the platelet function in that subject. The methods can be used to predict the responsiveness of a subject to anti-platelet therapy and so can form part of a therapeutic method.

Description

1 / 155 METHODS FOR EVALUATING PLATELET FUNCTION FIELD OF THE INVENTION

[001] The present invention relates generally to methods for evaluating platelet function, for example, in a sample from an individual. These methods can be used to identify individuals based on their platelet reactivity or sensitivity to a platelet-activating substance, such as collagen-related peptide (CRP), or a thrombin receptor agonist, ADP, thromboxane A2, or adrenaline. These methods can also be used to predict an individual's response to antiplatelet therapy and thus can form part of a therapeutic method. FUNDAMENTALS

[002] Platelets, or thrombocytes, are blood cells that help control bleeding. For example, platelets clump together at the site of a wound to form a blood clot (platelet aggregation), which can seal blood vessels to prevent or limit bleeding. Thus, platelets help protect against adverse bleeding, such as the effects of an injury.

[003] Platelets are involved in the pathology of several bleeding conditions and disorders, and abnormal platelet levels or functions may contribute to symptoms of abnormal bleeding. Petition 870250102203, dated 07 / 11 / 2025, page 10 / 175 2 / 155

[004] Platelets are also central to the pathology of cardiovascular disease (CVD), forming thrombi that occlude blood vessels and thus cause major adverse cardiovascular events such as heart attack (myocardial infarction, MI) and ischemic stroke. For example, thrombi form when platelets aggregate and when blood clots into a gelatinous form.

[005] More specifically, coronary artery disease (CHD) occurs when the coronary arteries are affected by atherosclerosis, resulting in narrowing due to the formation of fatty and inflamed plaques within the vessel. The narrowing of these arteries reduces the supply of oxygenated blood to the heart and can be further exacerbated by the rupture of the atherosclerotic plaque, which exposes subendothelial matrix proteins such as collagen. These proteins can trigger the formation of occlusive thrombi. Platelets play an important role in thrombosis under the high-shear conditions present in atherosclerotic coronary arteries, responding to collagen and other signs of vascular damage by aggregating to form a thrombus. Blood flow can be occluded when a thrombus forms within the coronary artery, resulting in MI. Thrombosis Petition 870250102203, dated 07 / 11 / 2025, page 11 / 175 3 / 155 can also occur in other parts of the body, including the cerebral arteries (the cause of ischemic strokes), as well as in veins and arteries.

[006] Platelet functions have also been increasingly associated with other biological processes and pathologies, including cancer (such as metastases), response to bacterial and viral infection (such as COVID-19) and inflammation (such as chronic inflammatory disease), among others.

[007] Current platelet function tests measure the propensity of platelets to perform functions that are central to hemostasis and thrombosis, such as aggregate formation, activation of integrin βIIbp3, or secretion of dense granules and α. These responses can be triggered by multiple stimuli, such as, but not limited to, collagen, adenosine diphosphate (ADP), and thrombin, to which platelets are exposed after vascular damage. There is a great degree of heterogeneity in the way platelets respond to these stimuli (Panzer et al., Ann Hematol. 2006;85(2):121-125; Jones et al., J Thromb Haemost. 2007;5(8):1756-1765; Jones CI et al., Blood. 2009; 114(7):1405-1416). Most current clinical tests for platelet function exhibit high variability and are only useful in specific clinical situations. They also require live, fresh cells that have been collected from the patient. Petition 870250102203, dated 07 / 11 / 2025, page 12 / 175 4 / 155 in the last few hours, therefore, have limited utility and make large-scale platelet function screening expensive and impractical. Therefore, a need remains in the art for a simpler, easier, and more reliable method to assess platelet function.

[008] Antiplatelet drugs, such as aspirin and clopidogrel, can prevent platelet clots and reduce the risk of stroke or myocardial infarction by inhibiting platelet aggregation and reducing the extent of thrombus growth after the rupture of an atherosclerotic plaque. However, antiplatelet drugs can also impair hemostasis and increase the risk of bleeding, including devastating cerebral hemorrhage. Therefore, the risk-benefit ratio of antiplatelet medication for patients at risk of cardiovascular events but without a prior history of CVD does not favor treatment, which is reserved for patients who have already suffered MI. However, patients already receiving antiplatelet therapy after a previous cardiovascular event may still suffer new events (e.g., due to failure of antiplatelet therapy).Thus, there remains a need for better identification of individuals most likely to benefit from antiplatelet therapy, so that the benefits and risks of this therapy can be balanced more effectively. Petition 870250102203, dated 07 / 11 / 2025, page 13 / 175 5 / 155 SUMMARY OF THE INVENTION

[009] The present invention relates generally to biomarkers that can be used to assess platelet function. In particular, the invention relates to methods involving assessing the level of CD36 in an individual's platelets, the level of GPVI in the individual's platelets and / or the individual's age as indicators of platelet function in that individual.

[0010] The invention provides a method for evaluating platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from an individual, the method comprising: (i) determine the CD36 level in the sample; (ii) determine the GPVI level in the sample; and / or (iii) determine the age of the individual from whom the platelets were obtained.

[0011] The method for evaluating platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from an individual may comprise (i) and (ii), (ii) and (iii), (i) and (iii), or (i), (ii) and (iii). A preferred method comprises: (i) determine a CD36 level in the sample; (ii) determine the GPVI level in the sample; and (iii) determine the individual's age.

[0012] The invention also provides methods that make Petition 870250102203, dated 07 / 11 / 2025, page 14 / 175 6 / 155 use of the method to assess platelet reactivity or sensitivity to a platelet-activating substance to predict an individual's response to therapeutic treatment with an antiplatelet therapy. Thus, the invention provides a method for predicting an individual's response to therapeutic treatment with an antiplatelet therapy, the method comprising: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[0013] This method may comprise any method for evaluating platelet reactivity or a method for evaluating sensitivity to a platelet-activating substance according to the present invention.

[0014] The methods of the invention may be particularly useful for identifying individuals who may have an increased or reduced risk of, for example, thrombosis, and / or who may be (more) positively or negatively affected by the use of antiplatelet therapy, for example, with an increased or reduced risk of bleeding, for example, bleeding in response to treatment with antiplatelet therapy. Methods for identifying platelet reactivity Petition 870250102203, dated 07 / 11 / 2025, p. 15 / 175 7 / 155 augmented

[0015] The invention provides methods that make use of the method for evaluating platelet reactivity or sensitivity to a platelet-activating substance of the invention to determine or identify the presence of increased or elevated platelet reactivity in a sample. For example, the method for evaluating platelet reactivity or sensitivity to a platelet-activating substance of the invention can be used to identify an individual who has hypersensitive platelets, to identify an individual who has elevated platelet reactivity or sensitivity to a platelet-activating substance, to identify an individual at increased risk of a disease, disorder or condition associated with increased platelet reactivity, to identify an individual suitable for treatment with antiplatelet therapy, or to select an appropriate antiplatelet therapy for the individual.

[0016] The invention provides a method for identifying an individual who has hypersensitive platelets, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention; wherein the presence of one, two or three of the following is indicative of the presence of hypersensitive platelets: Petition 870250102203, dated 07 / 11 / 2025, page 16 / 175 8 / 155 (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[0017] The invention also provides a method of identifying an individual exhibiting increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention; wherein the presence of one, two or three of the following is indicative of the presence of increased or elevated platelet reactivity or sensitivity to a platelet-activating substance: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[0018] The invention also provides a method for identifying an individual at increased risk of a disease, disorder or condition associated with increased platelet reactivity, such as thrombosis, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method of the invention; wherein the presence of one, two or three of the following is indicative of Petition 870250102203, dated 07 / 11 / 2025, p. 17 / 175 9 / 155 that the individual has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[0019] The invention also provides a method for identifying an individual suitable for treatment with antiplatelet therapy, comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention, wherein the presence of one, two or three of the following is indicative that the individual is suitable for treatment with antiplatelet therapy: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[0020] The invention also provides a method for identifying an individual with a reduced risk of bleeding, such as in response to treatment with antiplatelet therapy, wherein the presence of one, two or three of the following is indicative that the individual has a reduced risk of bleeding, wherein the presence of one, two or three of the following is indicative of a reduced risk of bleeding: Petition 870250102203, dated 07 / 11 / 2025, p. 18 / 175 10 / 155 (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[0021] Any of the methods described in this document that involves identifying an individual, such as the method for identifying an individual who has hypersensitive platelets, the method for identifying an individual who has high platelet reactivity or sensitivity to a platelet-activating substance, the method for identifying an individual at increased risk of a disease, disorder or condition associated with increased platelet reactivity, the method for identifying an individual suitable for treatment with antiplatelet therapy or the method for identifying an individual at reduced risk of bleeding, may further comprise a step of administering antiplatelet therapy to the individual.For example, such a method may involve administering antiplatelet therapy to an individual who has been identified as having hypersensitive platelets, to an individual who has been identified as having elevated platelet reactivity or sensitivity to a platelet-activating substance, to an individual who has been identified as having an increased risk of a disease, disorder, or condition associated with increased platelet reactivity, or to a... Petition 870250102203, dated 07 / 11 / 2025, page 19 / 175 11 / 155 an individual who has been identified as suitable for treatment with antiplatelet therapy or an individual who has been identified as having a reduced risk of bleeding, by a method as described herein. Antiplatelet therapy may be any suitable therapy, such as any antiplatelet therapy as described herein.

[0022] Similarly, the invention provides a method for treating a disease, disorder or condition associated with increased platelet reactivity, the method comprising: (i) evaluate platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention; and (ii) administer antiplatelet therapy to an individual who has any one, two, or three of the following: (a) a high level of CD36; (b) a high level of GPVI; and / or (c) the individual is at least 50 years old.

[0023] In any of the methods described in this document, such as the method for identifying an individual who has hypersensitive platelets, the method for identifying an individual who has reactivity or Petition 870250102203, dated 07 / 11 / 2025, p. 20 / 175 12 / 155 elevated platelet sensitivity to a platelet-activating substance, the method for identifying an individual at increased risk of a disease, disorder or condition associated with increased platelet reactivity, the method for identifying an individual suitable for treatment with antiplatelet therapy, the method for identifying an individual at reduced risk of bleeding or the method for treating a disease, disorder or condition associated with increased platelet reactivity, the method may determine the presence of one, two or all three of the following: (a) a high level of CD3 6; (b) a high level of GPVI; and / or (c) the individual is at least 50 years old.

[0024] For example, the method can determine the presence of (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c).

[0025] In one modality, the individual is at least 50 years old and the method determines the presence of: (a) a high level of CD36 in the sample; and (b) a high level of GPVI in the sample. [00 26] In another modality, the method determines the presence of all three among: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) the individual is at least 50 years old. Petition 870250102203, dated 07 / 11 / 2025, p. 21 / 175 13 / 155

[0027] Also described in this document are the corresponding therapies for use in the treatment of an individual exhibiting the desired characteristics. The treatment method may comprise performing the method for assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual according to the invention and then treating the individual who has been identified, according to the present invention, as exhibiting increased or elevated platelet reactivity or sensitivity to a platelet-activating substance.

[0028] For example, the invention provides an antiplatelet therapy for use in a method of treating an individual who needs it, the method comprising: (i) evaluate platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention; and (ii) administer antiplatelet therapy to an individual exhibiting any one, two, or three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[0029] The invention also provides a therapy Petition 870250102203, dated 07 / 11 / 2025, page 22 / 175 14 / 155 antiplatelet therapy for use in a method for treating an individual exhibiting the characteristic(s) of increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, as described herein. For example, the invention provides an antiplatelet therapy for use in a method of treating an individual in need thereof, wherein the individual exhibits: (a) a high level of CD36 in their platelets; (b) a high level of GPVI in their platelets; and / or (c) an age of at least 50 years.

[0030] In such use, or in the corresponding treatment method, which is also part of the present invention, the method of evaluating platelet reactivity or sensitivity to a platelet-activating substance of the present invention may or may not be performed as part of the use or treatment method.

[0031] The individual may present (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c). For example, in some modalities, the individual presents all three: (a) a high level of CD36; (b) a high level of GPVI; and (c) an age of at least 50 years.

[0032] When the invention relates to the treatment of an individual, the treatment may be the treatment of a Petition 870250102203, dated 07 / 11 / 2025, p. 23 / 175 15 / 155 disease, disorder or condition associated with increased platelet reactivity. The disease, disorder or condition associated with increased platelet reactivity may be selected from: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation. Cardiovascular disease may be selected from the group consisting of thrombosis, myocardial infarction, stroke, peripheral arterial disease, aortic disease and / or coronary artery disease. Methods for identifying reduced platelet reactivity

[0033] The invention also provides methods that make use of the method for evaluating platelet reactivity or sensitivity to a platelet-activating substance of the invention to determine or identify the presence of reduced or low platelet reactivity in a sample. For example, the method for evaluating platelet reactivity or sensitivity to a platelet-activating substance of the invention can be used to identify an individual who has hyposensitive platelets, to identify an individual who has low platelet reactivity or sensitivity to a platelet-activating substance, to identify an individual at risk. Petition 870250102203, dated 07 / 11 / 2025, page 24 / 175 16 / 155 reduced of a disease, disorder, or condition associated with increased platelet reactivity, to identify an individual unsuitable for treatment with antiplatelet therapy or to identify an individual at increased risk of bleeding.

[0034] For example, the invention provides a method for identifying an individual who has hyposensitive platelets, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention, wherein the presence of one, two or three of the following is indicative of the presence of hyposensitive platelets: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[0035] The invention also provides a method for identifying an individual at reduced risk of a disease, disorder or condition associated with increased platelet reactivity, such as thrombosis, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method of the invention; wherein the presence of one, two or three of the following is indicative that the individual has a reduced risk of a disease, Petition 870250102203, dated 07 / 11 / 2025, p. 25 / 175 17 / 155 disorder or condition associated with increased platelet reactivity: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[0036] The invention provides a method for identifying an individual who is not suitable for treatment with antiplatelet therapy, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention, wherein the presence of one, two or three of the following is indicative that the individual may not be suitable for treatment with antiplatelet therapy: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[0037] The invention provides a method for identifying an individual with a reduced risk of bleeding, such as in response to treatment with antiplatelet therapy, the method comprising assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of the invention, wherein the presence of one, two or three of the following is indicative that the individual has a reduced risk of Petition 870250102203, dated 07 / 11 / 2025, p. 26 / 175 18 / 155 bleeding: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[0038] In any of the methods described in this document, such as the method for identifying an individual with hyposensitive platelets, the method for identifying an individual with reduced platelet reactivity or sensitivity to a platelet-activating substance, the method for identifying an individual at reduced risk of a disease, disorder, or condition associated with increased platelet reactivity, the method for identifying an individual who is not suitable for treatment with antiplatelet therapy, the method for identifying an individual at increased risk of bleeding, or the method for treating a disease, disorder, or condition associated with low or reduced platelet reactivity, the method may determine the presence of one, two, or all three of the following: (a) a reduced level of CD36; (b) a reduced level of GPVI; and / or (c) the individual is under 50 years of age.

[0039] For example, the method can determine the presence of (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c). In some embodiments, the method determines the presence Petition 870250102203, dated 07 / 11 / 2025, p. 27 / 175 19 / 155 of all three among: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and (c) the individual is under 50 years of age.

[0040] In some modalities, the individual is under 50 years of age and the method determines the presence of: (a) a reduced level of CD36 in the sample; and (b) a reduced level of GPVI in the sample. Biomarkers

[0041] The invention relates to the use of one, two or three biomarkers to assess platelet reactivity.

[0042] One of the biomarkers that can be used according to the present invention is the age of the individual.

[0043] As described in this document, the presence of increased or elevated platelet reactivity may be associated with an older individual, such as an age of at least 50 or at least 55 years. Thus, a method of the invention that determines the presence of increased or elevated platelet reactivity can be performed on an individual, or on a sample of an individual, where the individual is at least 50 years old; or the individual is at least 55 years old.

[0044] As described in this document, the presence of reduced or low platelet reactivity may Petition 870250102203, dated 07 / 11 / 2025, page 28 / 175 20 / 155 may be associated with a younger individual, such as someone under 50 or under 45 years of age. Thus, a method of the invention that determines the presence of reduced or low platelet reactivity can be performed on an individual, or on a sample of an individual, where the individual is under 50 years of age; or the individual is under 45 years of age.

[0045] Another biomarker that can be used according to the present invention is the CD36 level in platelets or in a sample comprising platelets.

[0046] As described in this document, a high level of CD36 can be identified as: (i) a CD36 level that is in the upper 35th percentile compared to a reference population; (ii) a CD36 level that is at least 15% higher than the CD36 level in a control or reference sample comprising platelets; or (iii) a platelet or a platelet population that expresses at least 8,000 copies of CD36 per platelet.

[0047] As described in this document, a reduced level of CD36 can be identified as: (i) a CD36 level that is in the lower 65th percentile compared to a reference population; (ii) a CD36 level that is at least 15% lower than the CD36 level in a control or reference sample. Petition 870250102203, dated 07 / 11 / 2025, p. 29 / 175 21 / 155 comprising platelets; or (iii) a platelet or a platelet population expressing less than 8,000 copies of CD36 per platelet.

[0048] Another biomarker that can be used according to the present invention is the GPVI level in platelets or in a sample comprising platelets.

[0049] As described in this document, a high level of GPVI can be identified as: (i) a GPVI level that is in the upper 50th percentile compared to a reference population; (ii) a GPVI level that is at least 15% higher than the GPVI level in a control or reference sample comprising platelets; or (iii) a platelet or a platelet population that expresses at least 3,000 copies of GPVI per platelet.

[0050] As described in this document, a reduced level of GPVI can be identified as: (i) a GPVI level that is in the lower 50th percentile compared to a reference population; (ii) a GPVI level that is at least 15% lower than the GPVI level in a control or reference sample comprising platelets; or (iii) a platelet or a platelet population that expresses less than 3,000 copies of GPVI per platelet. Other aspects Petition 870250102203, dated 07 / 11 / 2025, page 30 / 175 22 / 155

[0051] The methods of the invention can be performed on a sample. The sample shall comprise platelets, such as a sample comprising platelets from an individual. In some embodiments, the sample: (i) consists of platelets from the individual; (ii) comprises or consists of a population of platelets from the individual; (iii) is an acellular sample; (iv) is whole blood; or (v) is plasma.

[0052] In some modalities, the sample comes from an individual who has not received antiplatelet therapy.

[0053] In some modalities, the individual has no prior history of the disease, disorder, or condition associated with increased platelet reactivity, optionally selected from: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation. For example, in some modalities, the individual has no prior history of cardiovascular disease.

[0054] In some modalities, the individual has, or is at risk of having, a disease, disorder, or condition selected from the following: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to an infection. Petition 870250102203, dated 07 / 11 / 2025, page 31 / 175 23 / 155 bacterial and / or viral and / or inflammation. In some cases, the individual is, or will be: a recipient of anticoagulant medication, undergoing surgery, and / or a blood donor.

[0055] When the invention relates to a disease, disorder or condition associated with increased platelet reactivity, then, in some embodiments, this disease, disorder or condition is selected from: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation. In some embodiments, the cardiovascular disease is selected from the group consisting of thrombosis, myocardial infarction, stroke, peripheral arterial disease, aortic disease and / or coronary artery disease.

[0056] When the invention relates to antiplatelet therapy, in some embodiments, the antiplatelet therapy is a platelet agglutination inhibitor or a platelet aggregation inhibitor. In some embodiments, the antiplatelet therapy is selected from the group consisting of: aspirin, dipyridamole, cyclooxygenase inhibitors (e.g., masoprolol, indomethacin, nabumetone, celecoxib, tolmetin, rofecoxib, piroxicam, fenoprofen, valdecoxib and / or diclofenac), ADP (P2Y) receptor antagonists (e.g., clopidogrel, prasugrel, ticagrelor). Petition 870250102203, dated 07 / 11 / 2025, p. 32 / 175 24 / 155 and / or cangrelor), GPVI inhibitors (e.g., glenzocimab, revacept, honokiol, losartan and / or tussilagone), a drug that targets another platelet receptor, such as a GPIIbIa inhibitor (e.g., tirofiban and / or eptifibatide), and / or a nonsteroidal anti-inflammatory drug (NSAID).

[0057] In some embodiments, the invention comprises determining the CD36 and / or GPVI level in a sample. In some embodiments, the CD36 and / or GPVI level is determined by: (i) an ELISA; (ii) a lateral flow test; (iii) flow cytometry; (iv) an immunoassay; (v) an antibody assay; (vi) a two-site antibody assay; or (vii) quantitative mass spectrometry. BRIEF DESCRIPTION OF THE FIGURES

[0058] Embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings: Figure 1. Thrombus formation on type I collagen is highly variable and correlates with sensitivity to stimulation by platelet-activating substances. A. Schematic illustration of thrombus formation measured in vitro.

[0059] Thrombus formation can be measured in vitro by perfusion of human whole blood over type I collagen and Petition 870250102203, dated 07 / 11 / 2025, page 33 / 175 25 / 155 by imaging the incorporation of labeled platelets into thrombi using confocal fluorescence microscopy. B. Variation in thrombus formation among individuals

[0060] Bi. Graph of thrombus growth (arbitrary fluorescence units (AFU)) measured in real time for 27 healthy donors.

[0061] Bii. Thrombus size after 520 s. C. Schematic illustration of receptors stimulated by ADP, TRAP-6, and CRP-XL in the PPAnalysis assay.

[0062] An analysis technique (Phenomic Analysis) Platelet Phenomic Analysis (PPAnalysis) was developed to help understand the differences in how platelets from different people form clots when stimulated by three different compounds: ADP, TRAP 6, and CRP-XL. It includes the functional outcome of α-granule release measured by the exposure of p-selectin on the platelet surface. D. Two different types of measurement are obtained by PPAnalysis: sensitivity and capability.

[0063] Representation of a concentration-response curve used to extract sensitivity and capability metrics from PPAnalysis assay data. E. Sensitivity results (Ei) and Petition 870250102203, dated 07 / 11 / 2025, page 34 / 175 26 / 155 capacity (Eii) measured using PPAnalysis in a cohort of 106 healthy donors.

[0064] When sensitivity and capacity measured in response to the three compounds (ADP, TRAP-6, CRP-XL) are compared to measurements of thrombus formation, high sensitivity to CRP-XL is associated with the formation of larger thrombi. F. Comparison of sensitivity and capability results

[0065] Scatter plots with linear regression comparing the sensitivity and capability results for ADP, TRAP-6, and CRP-XL in a subset of 23 blood samples for which thrombus formation was also measured. r2 and p values ​​were calculated using Pearson correlation. Figure 2. The sensitivity of GPVI responses can be predicted from age and the expression of GPVI and CD36 on the platelet surface. A. Scatter plots of Ai) sensitivity and Aii) capacity for a cohort of 461 healthy donors.

[0066] A second, larger cohort of blood donors was recruited to investigate the determinants of sensitivity to platelet-activating substances by performing PPAnalysis. B. Normalized levels of a panel of Petition 870250102203, dated 07 / 11 / 2025, page 35 / 175 27 / 155 platelet surface proteins measured by flow cytometry

[0067] Measurement of the quantity of several different proteins on the surface of platelets that may be a source of variability in sensitivity to platelet-activating substances. C. Recording of donor age, platelet count, mean platelet volume (MPV in femtoliters, fL), and BMI (body mass index).

[0068] F represents female donors, M represents male donors. D. The data were used to create a model in order to predict sensitivity to platelet-activating substances.

[0069] The cohort was divided into training and test cohorts—one to generate the model and the other to test it. The cohort was randomly assigned to the training and test cohorts in a 7:3 ratio. A forward regression with forward selection was performed using the training cohort data to identify predictors of sensitivity to platelet-activating substances. E. A model was created to identify parameters that could predict sensitivity to platelet-activating substances. Petition 870250102203, dated 07 / 11 / 2025, page 36 / 175 28 / 155

[0070] The model identified three variables — GPVI expression, CD36 expression, and age — as the combination with the highest r2e and the lowest Route Mean Square Error (RMSE) and Mean Absolute Error (MAE). These three parameters provided the best prediction of sensitivity to platelet-activating substances. F. Each of these parameters (GPVI expression, CD36 expression, and age) was tested in the test cohort.

[0071] Scatter plots of Fi) expression of GPVI, Fii) CD36 expression and Fiii) age plots related to CRP-XL sensitivity measured in the test cohort confirmed that these associations were also present in the test cohort. Fiv) Scatter plot comparing the predicted CRP-XL sensitivity for the test cohort using the identified multiple regression parameters with the training cohort data. r2 and p values ​​were calculated using Pearson's correlation. Each parameter was individually associated with CRP-XL sensitivity, and when the three parameters were used together, they could predict CRP-XL sensitivity with greater accuracy than when used in isolation. Figure 3. CD36 is a strong predictor of sensitivity to platelet-activating substances in individuals over 55 years of age. Petition 870250102203, dated 07 / 11 / 2025, p. 37 / 175 29 / 155 A. Scatter plots and linear regressions for CRP-XL sensitivity in relation to CD36 expression in healthy donors under 55 years of age (Ai) or 55 years of age or older (Aii).

[0072] The r2e p values ​​were calculated using Pearson correlations. CD36 performs better in predicting sensitivity to CRP-XL in older people (over 55 years). B. Scatter plots and linear regressions for CRP-XL sensitivity in relation to GPVI expression in healthy donors under 55 years of age (Bi) or 55 years of age or older (Bii)

[0073] The r2e p values ​​were calculated using Pearson correlations. GPVI is equally effective in predicting sensitivity to CRP-XL in people older or younger than 55 years. C. ROC plots for CD36 and GPVI expression as high-sensitivity predictors (greater than 33%) of CRP-XL in healthy donors under 55 years of age (Ci) or 55 years of age or older (Cii)

[0074] CD36 is as effective as GPVI in predicting sensitivity to CRP-XL in individuals over 55 years of age, but performs worse in individuals under 55 years of age. Figure 4. Stratification of sensitivity to substances Petition 870250102203, dated 07 / 11 / 2025, p. 38 / 175 30 / 155 platelet-activating hormones based on age and GPVI and CD36 expression A. Stratification algorithm to predict high, medium, or low sensitivity to platelet-activating substances based on age (55 years or older), CD36 expression (high = greater than 33%), and GPVI expression (high = greater than 50%).

[0075] An algorithm was created to predict whether a donor would likely have high, medium, or low sensitivity to platelet-activating substances based on age, CD36 levels, and GPVI levels. B. Graph of CRP-XL sensitivity for donors after stratification into low, medium, and high sensitivity subpopulations.

[0076] The algorithm was able to separate donors based on sensitivity to CRP-XL. Bars represent mean ± standard deviation, and p-values ​​were calculated using one-way ANOVA with Tukey's multiple comparisons test. Figure 5. Three-factor stratification predicts sensitivity to platelet-activating substances in patients with ischemic heart disease. A. Scatter plot of sensitivity to CRPXL compared to the expression of GPVI.

[0077] A cohort of 34 patients with disease Petition 870250102203, dated 07 / 11 / 2025, page 39 / 175 31 / 155 ischemic heart disease was recruited, and it was found that sensitivity to CRP-XL could be predicted by GPVI levels. r² and p values ​​were calculated using Pearson correlation. B. Scatter plot of sensitivity to CRPXL compared to CD36 expression.

[0078] In the same cohort, sensitivity to CRP-XL could be predicted by CD36 levels. r2e p values ​​were calculated using Pearson correlation. C. Scatter plot of sensitivity to CRPXL compared to age.

[0079] In the same cohort, sensitivity to CRP-XL could not be predicted by age—possibly because some patients were using antiplatelet medication (aspirin). r2e p values ​​were calculated using Pearson correlation. D. Graph comparing the age of patients who did not use aspirin and patients who did use aspirin (ASA)

[0080] The age of patients using aspirin was compared to that of those not using it, and it was found that patients using aspirin were, on average, older. P-values ​​were calculated using Student's t-tests. E. Graph comparing the sensitivity to CRP-XL in patients who did not use it and in patients who did use it. Petition 870250102203, dated 07 / 11 / 2025, page 40 / 175 32 / 155 aspirin (ASA)

[0081] Patients using aspirin also showed lower sensitivity to CRP-XL — suggesting that this is the reason why the relationship between age and sensitivity to CRP-XL was not present in this cohort of patients. P-values ​​were calculated using Student's t-tests. F. Graph of CRP-XL sensitivity for patients stratified into groups predicted to have low, medium, or high CRP-XL sensitivity.

[0082] When the algorithm (Figure 4) was used to predict high, medium, and low sensitivity to CRP-XL, it was found that few patients in this cohort were predicted to have low sensitivity (due to the patients' older age), but patients predicted to have high sensitivity were more sensitive to CRP-XL than those predicted to have medium sensitivity. P-values ​​were calculated using one-way ANOVA with Bonferroni multiple comparisons test. Figure 6. Three-factor stratification predicts thrombus formation in patients with ischemic heart disease. A. Scatter plot of in vitro thrombus volume compared to CRP-XL sensitivity.

[0083] Thrombus formation in vitro was also Petition 870250102203, dated 07 / 11 / 2025, page 41 / 175 33 / 155 measured in a cohort of 34 patients with ischemic heart disease. Thrombus formation was associated with sensitivity to CRP-XL (as observed in Figure 1F). r² and p values ​​were calculated using Pearson's correlation. Scatter plot of in vitro thrombus volume compared to GPVI expression.

[0084] In vitro thrombus formation was also measured in the cohort of 34 patients with ischemic heart disease. Thrombus formation was associated with GPVI levels. r2e p values ​​were calculated using Pearson correlation. B. Scatter plot of in vitro thrombus volume compared to CD36 expression.

[0085] In vitro thrombus formation was also measured in the cohort of 34 patients with ischemic heart disease. Thrombus formation was associated with CD36 levels. r2e p values ​​were calculated using Pearson correlation. C. Scatter plot of in vitro thrombus volume compared to age.

[0086] In vitro thrombus formation was also measured in the cohort of 34 patients with ischemic heart disease. Thrombus formation was associated with age (which was surprising, as it had previously been observed that sensitivity to CRP-XL was not associated with age due to Petition 870250102203, dated 07 / 11 / 2025, p. 42 / 175 34 / 155 to aspirin use by older patients). The r2e p values ​​were calculated using Pearson correlation. D. Graphs comparing in vitro thrombus volumes of patients who did not use aspirin and patients who did use aspirin (ASA).

[0087] The relationship between thrombus formation and age was present because thrombus formation was not reduced in patients using aspirin. P-values ​​were calculated using Student's t-tests. E. Graph of in vitro thrombus volumes for patients stratified into groups predicted to have low, medium, or high sensitivity to platelet-activating substances.

[0088] Patients stratified into groups predicted to have low, medium, and high sensitivity also showed different levels of thrombus formation, and patients with the largest thrombi were all in the group predicted to have high sensitivity to platelet-activating substances. P-values ​​were calculated using one-way ANOVA with Bonferroni multiple comparisons test. F. Representative images from in vitro thrombus formation experiments for patients predicted to have low, medium, or high sensitivity to platelet-activating substances. Petition 870250102203, dated 07 / 11 / 2025, page 43 / 175 35 / 155 Figure 7. CD36 flow cytometry versus CD36 mass spectrometry Figure 8. Other measures (whole blood assay (WBA), fluorescence-activated cell sorting (FACS), and plate-based aggregation (PBA)) of platelet functional responses regressed in relation to CD36 and GPVI expression. DETAILED DESCRIPTION

[0089] The inventors have surprisingly found a set of markers that can be used to assess platelet sensitivity or platelet reactivity. For example, CD36 and GPVI levels in a platelet population or sample, and the age of the individual from whom the sample was obtained, have been shown to be related to sensitivity to platelet-activating substances, such as collagen-related peptide (CRP, an activator of the GPVI receptor for platelet activation).

[0090] These markers were identified using platelets from healthy volunteers, and the present invention resulted from complex analyses of platelet function, including machine learning approaches to analyze complex combinations of multiple parameters. The identity of these markers was established through extensive analysis of platelets from healthy and diseased individuals, Petition 870250102203, dated 07 / 11 / 2025, page 44 / 175 36 / 155 using a high-throughput, "big data" approach to analyze platelet cell function in clinical or pharmaceutical studies. Artificial intelligence-based analysis technologies and complex statistical analyses were used to describe the unique combination of biomarkers that correlates with platelet functional reactivity. The validity of these markers as biomarkers of platelet function was reproduced across the entire cohort of 500 individuals and in a small cohort of patients with cardiovascular disease.

[0091] The markers allow predicting platelet function without the need to directly measure platelet function. This makes it feasible to investigate platelet reactivity in large cohorts and enables the incorporation of reactivity into treatment algorithms for myocardial infarction risk, among other applications of the invention. This allows evaluating platelet reactivity without the need to actually measure platelet function, which is specialized in nature, requires immediate analysis after blood sample collection, and requires specific equipment. The methods of the present invention can also be used to determine disease risk or appropriate therapies for non-thrombotic conditions, including cancer, response to bacterial and viral infection, and inflammation, among others.

[0092] Thus, the present invention relates to Petition 870250102203, dated 07 / 11 / 2025, page 45 / 175 37 / 155 markers that allow the identification of individuals with hypersensitive platelets who may benefit from personalized antiplatelet therapy to reduce the risk of cardiovascular events—which may include heart attacks and strokes—among other platelet-related conditions. Previous attempts to stratify which individuals would benefit from antiplatelet drugs based on patient characteristics (such as age, disease status, or body mass index (BMI)) or platelet function have generally been unsuccessful.

[0093] Markers can also be used to identify individuals more likely to experience treatment failure due to platelet hypersensitivity. Such individuals may benefit from modified therapy, such as therapy targeting their hypersensitive platelets. For example, modified therapy may include treatment with antiplatelet therapy, or treatment with a modified dose, for example, an increased dose, of antiplatelet therapy. For example, markers can be used to identify individuals at increased risk of thrombosis due to platelet hypersensitivity. This can be used to select these individuals for treatment with antithrombotic therapy, such as antiplatelet therapy or anticoagulant therapy. The Petition 870250102203, dated 07 / 11 / 2025, page 46 / 175 38 / 155 markers can also be used to identify individuals who may have a reduced risk of bleeding, for example, bleeding in response to antiplatelet therapy. Such individuals may benefit from modified therapy, such as a modified dose, for example, an increased dose, of antiplatelet therapy.

[0094] Markers can also be used to identify individuals with hyposensitive platelets. Such individuals may be less likely to respond to antiplatelet therapy. Such individuals may benefit from modified therapy, such as therapy targeted to their hyposensitive platelets. For example, this may include a modified, e.g., reduced dose of antiplatelet therapy, or treatment with a platelet agonist or clotting agent. Markers can be used to identify individuals at reduced risk of thrombosis due to platelet hyposensitivity. This can be used to select individuals who do not require treatment with antithrombotic therapy, such as antiplatelet therapy.The markers can also be used to identify individuals who may be at increased risk of bleeding, for example, bleeding in response to antiplatelet therapy, due to their platelets being hyposensitive. Such individuals may benefit from modified therapy, such as a dose adjustment. Petition 870250102203, dated 07 / 11 / 2025, p. 47 / 175 39 / 155 modified, for example, reduced, antiplatelet therapy to reduce or minimize bleeding, or the administration of a therapy intended to prevent or reduce bleeding, such as a platelet agonist or clotting agent.

[0095] Unlike platelet function tests, which are expensive and require specialized equipment not available in most hospitals, biomarker measurement according to the present invention can be standardized and performed using generic equipment.

[0096] Thus, the main benefits of the invention include: - preventing unnecessary treatments with antiplatelet drugs that can cause side effects, such as bleeding; - providing an alternative to platelet function analysis, which is normally specialized and time-sensitive; - the ability to use simple, routine, and low-cost tests to determine the levels of relevant protein biomarkers; - the ability to assess platelet function by testing stored samples; - the ability to conduct smaller clinical trials, Petition 870250102203, dated 07 / 11 / 2025, page 48 / 175 40 / 155 more targeted and / or cheaper for new treatments.

[0097] The invention will be useful for patients using anticoagulant drugs, who will undergo major surgery, who have abnormal blood conditions or abnormal platelet counts, for blood donors, or in other circumstances where bleeding or clotting may be a problem.

[0098] Unless defined otherwise in this document, all technical and scientific terms used in this document have the same meaning that is commonly understood by a person skilled in the art to which the present invention pertains. It should be understood that this invention is not limited to the specific methodology, protocols, and reagents, etc., described in this document, and may therefore vary. The terminology used in this document is intended to describe only particular cases and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0099] The terms a and an refer to one or more of one (i.e., at least one) of the grammatical objects of the article. For example, an element means one element or more than one element.

[00100] The term about, when referring to a measurable value, such as a quantity, a time duration Petition 870250102203, dated 07 / 11 / 2025, p. 49 / 175 41 / 155 and similar standards, covers variations of ±20% or, in some cases, ±10%, or, in some cases, ±5%, or, in some cases, ±1%, or, in some cases, ±0.1% of the specified value, as such variations are appropriate for the execution of the methods described.

[00101] The term individual is intended to include living organisms in which an immune response can be triggered. Preferably, the individual is a mammal. The methods described in this document may be useful for applications in humans or animals. More preferably, the individual is a human. In one embodiment, the individual is a patient, for example, an individual who needs treatment, or an individual who is receiving or is about to receive treatment. The individual may be an infant, a child, or an adult. Preferably, the individual is a human adult. The individual may be human and may be at least 20 years old, at least 30 years old, at least 40 years old, at least 50 years old, at least 60 years old, at least 70 years old, or at least 75 years old.

[00102] Throughout this description, various embodiments of the invention may be presented in strip format. It should be understood that the strip format description is merely for convenience and brevity, and should not be interpreted as an inflexible limitation to the scope of the Petition 870250102203, dated 07 / 11 / 2025, page 50 / 175 42 / 155 invention. Thus, the description of a range should be considered as having specifically described all possible sub-intervals, as well as individual numerical values ​​within that range. For example, the description of a range from 1 to 6 should be considered as having specifically described sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3 and 6. As another example, a range such as 95-99% identity includes something with 95%, 96%, 97%, 98% or 99% identity, and includes sub-ranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98% and 98-99% identity. This applies regardless of the width of the band.

[00103] Several embodiments of the compositions and methods in this document are described in more detail below. Additional definitions are provided throughout this descriptive report. Biomarkers

[00104] The methods described in this document involve the evaluation of one or more biomarkers, such as CD36 and / or GPVI, in a sample composed of platelets from an individual, and / or the determination of the age of the individual from whom the platelets were obtained.

[00105] The term biomarker refers to a biological marker that indicates a state, process, response, disease, Petition 870250102203, dated 07 / 11 / 2025, p. 51 / 175 43 / 155 specific physiological or pathological disorder or condition. A marker can be a physical marker, such as a natural molecule (e.g., a DNA molecule, a gene, an allele, an RNA molecule, or a protein), or it can be a characteristic (e.g., age) that can be measured. The terms biomarker and marker are used interchangeably in this document. In the context of the present invention, the marker can be CD36. In the context of the present invention, the marker can be GPVI. In the context of the present invention, the individual's age can be a marker.

[00106] The term CD36 refers to the glycoprotein receptor of cluster of differentiation 36 (CD36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV). The CD36 antigen is an integral membrane protein and is present on the surface of platelets.

[00107] The term GPVI refers to glycoprotein VI, a glycoprotein receptor for collagen present on the surface of platelets. GPVI is also known as GP6, BDPLT11, GPIV, and platelet glycoprotein VI.

[00108] The methods of the invention may comprise a step of determining the age of the individual. Such determination Petition 870250102203, dated 07 / 11 / 2025, page 52 / 175 44 / 155 may involve obtaining data from a patient's medical record or from the individual themselves. In the methods of the invention, the step of determining the individual's age may be omitted. For example, in some embodiments, the individual's age is known or already recorded, so it may not be necessary to determine that individual's age. For example, in some embodiments, the methods may be performed on a sample of an individual of known age. The individual's age is preferably expressed in whole years, so that, for example, an individual over 50 years of age but under 51 years of age is classified as being 50 years old.

[00109] The term level, in relation to a biomarker such as CD36 or GPVI, may refer to the quantity of the biomarker protein or of a nucleic acid molecule that encodes the biomarker protein. In some methods of the invention, a level of a biomarker protein is evaluated. In some methods, a level of a nucleic acid molecule that encodes a biomarker protein is evaluated. In some methods, an mRNA molecule that encodes a biomarker protein is evaluated. In some methods, a DNA molecule that encodes a biomarker protein is evaluated. In some methods of the invention, an expression level of a biomarker is evaluated. In some methods of the invention, a quantity, such as a quantified quantity or Petition 870250102203, dated 07 / 11 / 2025, p. 53 / 175 45 / 155 relative, or a copy number or relative copy number of a biomarker. The quantity can be assessed by directly measuring the amount of the relevant molecule or can be assessed indirectly by evaluating the binding of the molecule to a known ligand or by evaluating the function of the relevant molecule. For example, the level of a marker can be assessed using the binding of the marker to a specific binding partner, such as an antibody or other specific binding molecule for that marker. In the methods of the present invention, the biomarker can be CD36 and / or GPVI. In the methods of the invention, the level of CD36 and / or GPVI can be determined. In the methods of the invention, the expression level of CD36 and / or GPVI can be evaluated. In the methods of the invention, the amount of CD36 protein and / or GPVI protein can be evaluated.In some modalities, the level or quantity of CD36 and / or the level of GPVI is determined by: an ELISA, a lateral flow test, flow cytometry, an immunoassay, an antibody assay, a two-site antibody assay, or quantitative mass spectrometry.

[00110] The term expression refers to the transcription and / or translation of a specific nucleotide sequence. In some embodiments, expression comprises the translation of an mRNA introduced into a cell. Unless otherwise indicated, classify a cell, a population of cells, a Petition 870250102203, dated 07 / 11 / 2025, page 54 / 175 46 / 155 platelet, a platelet population, or a sample or composition comprising cells and / or platelets as “not expressing,” or as showing an absence of, or being “negative for,” a specific marker may not necessarily mean an absolute absence of the marker. A person skilled in the art may easily compare the cell, platelet, population, sample, or composition with a positive and / or negative control and / or define a predetermined threshold and classify the cell, platelet, population, sample, or composition as not expressing or being negative for the marker when the cell, platelet, population, sample, or composition shows an expression level below the predetermined threshold or an overall expression level below the predetermined threshold using conventional detection methods, for example, by flow cytometry.

[00111] The term “encoding” refers to the inherent property of specific nucleotide sequences in a polynucleotide, such as a gene, cDNA, or mRNA, to serve as templates for the synthesis of other polymers and macromolecules in biological processes that possess a defined nucleotide sequence (e.g., rRNA, tRNA, and mRNA) or a defined amino acid sequence and the resulting biological properties. Thus, a gene, cDNA, or RNA encodes a protein if the transcription and translation of the mRNA corresponding to that gene produce the protein in a Petition 870250102203, dated 07 / 11 / 2025, p. 55 / 175 47 / 155 cell or other biological system. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is normally provided in sequence listings, and the non-coding strand, used as a template for the transcription of a gene or cDNA, can be referred to as coding for the protein or other product of that gene or cDNA.

[00112] Unless otherwise specified, a nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The expression "nucleotide sequence encoding a protein or RNA" may also include introns, insofar as the protein-encoding nucleotide sequence may, in some versions, contain one or more introns.

[00113] The term "homologous" or "identity" refers to the identity of the subunit sequence between two polymeric molecules, for example, between two nucleic acid molecules, such as two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both molecules is occupied by the same monomeric subunit—for example, if a position in each of two DNA molecules is occupied by adenine—they are homologous or identical at that position. The homology between two sequences is a direct function of the number of Petition 870250102203, dated 07 / 11 / 2025, p. 56 / 175 48 / 155 coincident or homologous positions; for example, if half (e.g., five positions in a polymer with ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 out of 10) coincide or are homologous, the two sequences are 90% homologous.

[00114] The term isolated means altered or removed from its natural state. For example, a nucleic acid or peptide naturally present in a living animal is not isolated, but the same nucleic acid or peptide, partially or totally separated from the coexisting materials of its natural state, is considered isolated. An isolated nucleic acid or protein may exist in a substantially purified form, or may exist in a non-native environment, such as, for example, a host cell.

[00115] The term nucleic acid, nucleic acid molecule, polynucleotide, or polynucleotide molecule refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and their polymers, in single- or double-stranded form. Unless specifically limited, the term includes nucleic acids containing known analogues of natural nucleotides that have binding properties similar to those of the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. In Petition 870250102203, dated 07 / 11 / 2025, page 57 / 175 49 / 155 In some embodiments, a “nucleic acid”, “nucleic acid molecule”, “polynucleotide” or “polynucleotide molecule” comprises a nucleotide / nucleoside derivative or analog. Unless otherwise indicated, a specific nucleic acid sequence also implicitly includes its conservatively modified variants (e.g., degenerate codon substitutions, i.e., conservative substitutions), alleles, orthologs, SNPs and complementary sequences, as well as the explicitly indicated sequence. Specifically, degenerate codon substitutions, i.e., conservative substitutions, can be obtained by generating sequences in which the third position of one or more selected codons (or all) is replaced by mixed bases and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8: 91-98 (1994)).

[00116] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to a compound consisting of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that can make up the sequence of a protein or peptide. Polypeptides include any peptide or protein comprising two or more amino acids. Petition 870250102203, dated 07 / 11 / 2025, page 58 / 175 50 / 155 more amino acids linked together by peptide bonds. As used in this document, the term refers both to short chains, which are also commonly referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which are generally referred to in the art as proteins, of which there are many types.

[00117] Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination of the two.

[00118] The invention may use antibodies. The antibody may bind specifically to its intended target, such as CD36 or GPVI, for example, and may bind to that target and not to other related molecules. For example, the antibody may bind to CD36 or GPVI, but not to other naturally occurring glycoprotein receptors. The antibody may bind to CD36 or GPVI, but not to other molecules naturally occurring on the surface of platelets. The antibody may bind to human CD36 or human GPVI, but not to CD36 or GPVI of a different species. The antibody may be a monoclonal or polyclonal antibody. The antibody Petition 870250102203, dated 07 / 11 / 2025, p. 59 / 175 51 / 155 may be a humanized antibody. The antibody may be a human antibody. The term antibody also includes fragments of a complete antibody that retain the ability to bind to the relevant target antigen. Suitable antigen-binding fragments may include Fab, Fc, Fv, scFv, dAb, Fd, Fab', F(ab')2, or an isolated complementarity-determining region (CDR) that has sufficient structure to bind to the target. The antibody may not have an Fc region. A Fab fragment may be a monovalent fragment composed of the VL, VH, CL, and CHI domains. An F(ab')2 fragment may be a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region. An Fc fragment may consist of the CH2 and CH3 domains. An Fv fragment may consist of the VL and VH domains of a single arm of an antibody. A dAb fragment (Ward et al. (1989) Nature 341:544-546; incorporated herein by reference) may consist of a VH domain. An isolated complementarity-determining region (CDR) possessing sufficient structure to bind may be an antigen-binding portion of a variable region. Methods for assessing platelet reactivity

[00119] The invention provides methods for evaluating platelet reactivity, such as platelet reactivity Petition 870250102203, dated 07 / 11 / 2025, page 60 / 175 52 / 155 in a sample comprising platelets from an individual. The invention provides methods for evaluating platelet sensitivity, such as platelet sensitivity in a sample comprising platelets from an individual.

[00120] The term “platelet function” or “platelet reactivity,” as used in this document, refers to the propensity of platelets to perform functions that are central to hemostasis and thrombosis, such as aggregate formation, activation of integrin IIbp3, or secretion of dense granules and α. These responses can be triggered by multiple stimuli, such as collagen, adenosine 5'-diphosphate (ADP), and thrombin. In one embodiment, platelet reactivity is indicated by platelet sensitivity and platelet capacity as independent metrics. The term “platelet sensitivity” refers to the sensitivity of a platelet or a population of platelets to an agonist. The term “capacity” refers to the ability or magnitude of a platelet or a population of platelets to generate a functional response.

[00121] The methods of the invention allow platelet reactivity or platelet sensitivity to be assessed without the need to actually measure platelet function. Instead, the methods utilize biomarkers that can be readily determined or Petition 870250102203, dated 07 / 11 / 2025, page 61 / 175 53 / 155 measured in a sample from an individual, in order to provide a measure of platelet reactivity or platelet sensitivity. In one aspect, the invention provides a method for evaluating platelet reactivity in a sample comprising platelets from an individual, the method comprising: (i) determine the CD36 level in the sample; (ii) determine the GPVI level in the sample; and / or (iii) determine the age of the individual from whom the platelets were obtained.

[00122] In one aspect, the invention provides a method for evaluating platelet sensitivity in a sample comprising platelets from an individual, the method comprising: (i) determine the CD36 level in the sample; (ii) determine the GPVI level in the sample; and / or (iii) determine the age of the individual from whom the platelets were obtained.

[00123] The invention also provides a method for evaluating or predicting sensitivity to a platelet-activating substance, such as CRP (collagen-related peptide), including evaluating or predicting sensitivity to a platelet-activating substance, such as CRP, in a sample containing platelets from an individual, wherein the method comprises: (i) determine the CD36 level in the sample; (ii) determine the GPVI level in the sample; and / or Petition 870250102203, dated 07 / 11 / 2025, page 62 / 175 54 / 155 (iii) determine the age of the individual from whom the platelets were obtained.

[00124] The term "platelet-activating substance" refers to any substance capable of activating platelets. In some embodiments, the platelet-activating substance is selected from CRP, CRP-XL, tissue factor, collagen, vWF, PAF, ristocetin, arachidonic acid, adenosine 5'-diphosphate (ADP), thrombin, TRAP-6, epinephrine, and U46619. In some embodiments, the platelet-activating substance is a platelet agonist as described in this descriptive report. In some embodiments, the platelet-activating substance is CRP. In some embodiments, the platelet-activating substance is CRP-XL. In some embodiments, the platelet-activating substance is ADP. In some embodiments, the platelet-activating substance is epinephrine. In some embodiments, the platelet-activating substance is thrombin receptor activator peptide (TRAP-6). peptide 6). In some forms, the platelet-activating substance is the enzyme thrombin.In some embodiments, the platelet-activating substance is U46619 ((5Z)-7-{(1R,4S,5S,6R)-6-[(1E,3S)3-Hydroxyoct-1-en-1-yl]-2-oxabicyclo[2.2.1]heptan-5yl}hept-5-enoic acid). When a platelet-activating substance is mentioned in this document, it is intended to encompass more than one platelet-activating substance. Petition 870250102203, dated 07 / 11 / 2025, p. 63 / 175 55 / 155 platelets. For example, an individual who exhibits sensitivity, such as increased, reduced, high, low, or medium, to a platelet-activating substance may exhibit this sensitivity to one or more platelet-activating substances, such as any one or more of the platelet-activating substances described in this document. The platelet-activating substance may refer to CRP and one or more other platelet-activating substances. The platelet-activating substance may refer to CRP-XL and one or more other platelet-activating substances. The platelet-activating substance may refer to CRP, ADP, TRAP-6, and / or epinephrine.

[00125] The term “sensitivity to a platelet-activating substance” refers to the ability of a platelet or a population of platelets to respond to a platelet-activating substance, for example, by fibrinogen binding (a marker of IIbp3 activation) and / or P-selectin exposure on the platelet surface (a marker of α-granule secretion). Sensitivity to a platelet-activating substance can be used as an indicator of platelet reactivity.

[00126] When the methods described in this document refer to a platelet-activating substance, they also cover more than one platelet-activating substance. For example, a method for evaluating or predicting the Petition 870250102203, dated 07 / 11 / 2025, p. 64 / 175 56 / 155 sensitivity to a platelet-activating substance can assess or predict sensitivity to one or more platelet-activating substances. Any method described in this document for assessing or predicting sensitivity to a platelet-activating substance can assess or predict sensitivity to any one or more of the platelet-activating substances described in this document. For example, the method can assess or predict sensitivity to CRP and one or more other platelet-activating substances. The method can assess or predict sensitivity to CRP-XL and one or more other platelet-activating substances. The method can assess or predict sensitivity to CRP, ADP, TRAP-6, and / or epinephrine.

[00127] The term CRP refers to a collagen-related peptide, which is a type of synthetic peptide that mimics the triple helix structure of collagen and can bind to and activate glycoprotein receptor VI (GPVI) for platelet activation. CRPs have a glycine residue every three residues in the peptide, allowing folding into a triple helix. An example of a CRP contains a repetition of the amino acid sequence (Gly-Pro-Hyp) or (GPO), for example ((Gly-Pro-Hyp)10 or (GPO)10). A CRP may have cysteine ​​residues at the N-terminal and C-terminal ends that allow cross-linking (Slatter et al., 2012, Peptides, 36(1):86-89). For example, CRPcys has Gly triplets. Petition 870250102203, dated 07 / 11 / 2025, page 65 / 175 57 / 155 Pro-Cys added to both the N-terminal and C-terminal ends.

[00128] The term CRP-XL refers to a synthetic collagen-related peptide with cross-links. Cross-linking increases the ability of a CRP to form quaternary structure. A cross-linked CRP (CRP-XL) is a more potent platelet agonist than a non-cross-linked CRP (Smethurst et al., 2012, J Bio Chem, 282(2):1296-1304). CRP-XL can be cross-linked via cysteine ​​residues at its N-terminal and C-terminal ends. For example, CRP-XL has the sequence (GPC-(GPO)10GPCG-amide)3. An example of a CRP-XL variant is a synthetic triple helical collagen peptide (STH-CP), which has the same primary sequence as CRP-XL ((GPC-(GPO)10-GPCG-amide)3), and at both the N-terminal and C-terminal ends it is fixed to a support with a binding site for each of the three peptide chains (Sang et al., 2019, Thromb Haemost, 119(12): 2005-2013).

[00129] The terms “CRP sensitivity”, “CRP-XL sensitivity”, “CRP sensitivity” or “CRP-XL sensitivity” are used interchangeably and refer to the ability of a platelet or a population of platelets to respond to CRP or CRP-XL, respectively, for example, by binding fibrinogen (a marker of Petition 870250102203, dated 07 / 11 / 2025, p. 66 / 175 58 / 155 activation of αIIbp3) and / or exposure of P-selectin on the platelet surface (a marker of α-granule secretion). Sensitivity to CRP and CRP-XL can be used as an indicator of platelet reactivity.

[00130] The term “high sensitivity”, in relation to a platelet-activating substance, such as CRP or CRPXL, refers to an increased ability of a platelet or a platelet population to respond to that substance, for example, by fibrinogen binding (a marker of «IIbp3» activation) and / or P-selectin exposure on the platelet surface (a marker of α-granule secretion), compared to a control or reference platelet or platelet population.

[00131] The term “low sensitivity”, in relation to a platelet-activating substance, such as CRP or CRPXL, refers to a reduced ability of a platelet or a platelet population to respond to that substance, for example, by fibrinogen binding (a marker of «IIbp3» activation) and / or P-selectin exposure on the platelet surface (a marker of α-granule secretion), compared to a control or reference platelet or platelet population.

[00132] The term “average sensitivity”, in relation to a platelet-activating substance, such as CRP or CRPXL, refers to a platelet or a population of platelets. Petition 870250102203, dated 07 / 11 / 2025, p. 67 / 175 59 / 155 who do not exhibit high or low sensitivity to this substance.

[00133] The inventors discovered that a set of biomarkers correlates with sensitivity to a platelet-activating substance, such as CRP. Thus, in one aspect, the invention provides a method for evaluating sensitivity to a platelet-activating substance, such as CRP, in a sample comprising platelets from an individual, the method being composed of: (i) determine the CD36 level in the sample; (ii) determine the GPVI level in the sample; and / or (iii) determine the age of the individual from whom the platelets were obtained.

[00134] The methods of the invention relate to three biomarkers (also referred to in this document as markers), namely, CD36 level, GPVI level, and the individual's age. In the methods of the invention, including methods comprising the assessment of platelet reactivity and / or the assessment or prediction of sensitivity to a platelet-activating substance, any one, two, or three of these markers may be assessed. Thus, the methods may comprise assessing: - the CD36 level; - the GPVI level; - the individual's age; Petition 870250102203, dated 07 / 11 / 2025, p. 68 / 175 60 / 155 - the CD36 level and the GPVI level; - the CD36 level and the individual's age; - the GPVI level and the individual's age; or - the CD36 level, the GPVI level, and the individual's age.

[00135] In the methods of the invention, a step to determine the age of the individual may be included. This determination may involve obtaining data from a patient's medical record. In the methods of the invention, the step to determine the age of the individual may be omitted, for example, if the age of the individual is known. For example, in some embodiments, the methods may be performed on a sample of an individual of known age.

[00136] In some methods of the invention, the CD3 6 level and / or the GPVI level is determined in a sample. The sample may be a sample obtained from the individual of interest, such as the individual to be evaluated or the individual to be treated in the relevant method.

[00137] The term "sample obtained from" refers to a biological sample originating from an individual. When the sample is used for the evaluation of one or more biomarkers in platelets, the sample will normally comprise platelets. Thus, in the methods of the invention, the CD36 level and / or the GPVI level can be determined in a sample comprising platelets from the individual. In a Petition 870250102203, dated 07 / 11 / 2025, page 69 / 175 In one embodiment, the sample may be a whole blood sample. In another embodiment, the sample may be plasma. In another embodiment, the sample comprises or consists of platelets from the individual. In another embodiment, the sample comprises or consists of a population of platelets from the individual.

[00138] The sample may be provided in vitro. The sample may be a sample obtained from an individual, wherein the sample is provided in vitro for use in the present methods. The sample may be provided directly or immediately from the individual for use in the methods of the invention, or it may be stored under suitable conditions known in the art before being used in the methods of the invention.

[00139] When the methods involve determining the level of CD36 and / or GPVI in a sample and determining the age of the individual, CD36 and / or GPVI are determined in a sample from the individual whose age is being determined. When the methods of the invention relate to the determination or evaluation of information about an individual, such as platelet sensitivity, platelet reactivity, sensitivity to a platelet-activating substance, risk of a disease, disorder or condition associated with increased platelet reactivity, or suitability for treatment with antiplatelet therapy, the sample used to evaluate CD36 and / or GPVI in the methods is a sample from that individual. When the methods of the invention relate to Petition 870250102203, dated 07 / 11 / 2025, page 70 / 175 62 / 155 treatment of an individual, such as the treatment of an individual with antiplatelet therapy, the sample used to evaluate CD36 and / or GPVI is a sample from that individual.

[00140] In some embodiments, the individual has not received antiplatelet therapy. Thus, the sample may be from an individual who has not received antiplatelet therapy. For example, the sample may be obtained from the individual before he or she receives any antiplatelet therapy. The individual may never have received antiplatelet therapy. The individual may not have received antiplatelet therapy for a period of at least 1 month, 3 months, 6 months, or 1 year prior to the method of the invention or prior to providing the sample used in the present invention. Antiplatelet therapy may refer to any antiplatelet therapy as discussed herein, such as a platelet agglutination inhibitor or a platelet aggregation inhibitor.Antiplatelet therapy can be selected from the group consisting of aspirin, dipyridamole, cyclooxygenase inhibitors (e.g., masoprolol, indomethacin, nabumetone, celecoxib, tolmetin, rofecoxib, piroxicam, fenoprofen, valdecoxib and / or diclofenac), ADP (P2Y) receptor antagonists (e.g., clopidogrel, prasugrel, ticagrelor and / or cangrelor), GPVI inhibitors (e.g., glenzocimab, etc.). Petition 870250102203, dated 07 / 11 / 2025, p. 71 / 175 63 / 155 revacept, honokiol, losartan and / or tussilagone), a drug that targets another platelet receptor, such as a GPIIb1IIa inhibitor (e.g., tirofiban and / or eptifibatide), and / or a nonsteroidal anti-inflammatory drug (NSAID).

[00141] In some embodiments, the individual has no prior history of a disease, disorder, or condition associated with increased platelet reactivity. For example, the individual's medical history or record may not show a prior occurrence or diagnosis of such a disease, disorder, or condition. In some embodiments, the individual does not have a disease, disorder, or condition associated with increased platelet reactivity at the time the method of the invention is performed, for example, at the time the sample used in a method of the invention was obtained from the individual. The individual may receive or have received tests to confirm that such a disease, disorder, or condition is not present at the time of the method of the invention, for example, at the time a sample comprising platelets is obtained for use in the present invention.In some modalities, the individual has not been diagnosed with a disease, disorder, or condition that can be treated with antiplatelet therapy and / or has not been previously treated with antiplatelet therapy. In one modality, the individual has not been diagnosed with a disease, disorder, or condition associated with reactivity. Petition 870250102203, dated 07 / 11 / 2025, page 72 / 175 64 / 155 increased platelet count. In some modalities, the disease, disorder, or condition associated with increased platelet reactivity may be any of the diseases, disorders, or conditions described herein, such as cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, cancer, a response to a bacterial and / or viral infection, and / or inflammation. For example, in some modalities, the individual has no prior history of cardiovascular disease. Cardiovascular disease may include thrombosis, myocardial infarction, stroke, peripheral arterial disease, aortic disease, and / or coronary artery disease.

[00142] In some modalities, the individual is at risk of a disease, disorder, or condition associated with increased platelet reactivity. For example, the individual may be, or have been, identified through examinations, previous medical history, or family history as having a risk, or increased risk, of a disease, disorder, or condition associated with increased platelet reactivity. The disease, disorder, or condition associated with increased platelet reactivity may be any of the diseases, disorders, or conditions described in this document, such as a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, a Petition 870250102203, dated 07 / 11 / 2025, p. 73 / 175 65 / 155 abnormal platelet count, cancer, a response to a bacterial and / or viral infection and / or inflammation. For example, in some modalities, the individual has no risk or increased risk of cardiovascular disease. Cardiovascular disease may include thrombosis, myocardial infarction, stroke, peripheral arterial disease, aortic disease and / or coronary artery disease. In some modalities, the individual is, or will be: a user of anticoagulant medication, undergone surgery and / or a blood donor.

[00143] The sample used in the methods of the invention preferably comprises platelets. For example, a sample from an individual comprises platelets from that individual. The sample may be obtained directly from the individual, such as a whole blood sample. The sample may be processed before being used in a method of the invention, for example, by removing components. The components may be removed selectively or based on specific properties, such as size. The sample may be a plasma sample. The sample may be treated or processed to increase the platelet concentration, for example, by removing other components from the sample obtained from the individual. The sample may comprise or consist of platelets from the individual, or it may comprise or consist of a population of platelets from the individual. Petition 870250102203, dated 07 / 11 / 2025, page 74 / 175 66 / 155 Methods of identifying individuals

[00144] The methods of the invention, such as any methods for assessing platelet reactivity and / or assessing or predicting platelet sensitivity, such as sensitivity to a platelet-activating substance, as described above, can be used to identify, predict, or diagnose an individual with specific characteristics.

[00145] In some modalities, a method is provided for identifying an individual who exhibits high platelet reactivity or sensitivity to a platelet-activating substance. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[00146] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be Petition 870250102203, dated 07 / 11 / 2025, pp. 75 / 175 67 / 155 any sample as described in this document. The individual may be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative of the presence of elevated platelet reactivity or sensitivity to a platelet-activating substance: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[00147] Thus, the presence of high platelet reactivity or sensitivity to a platelet-activating substance may be indicated by the presence of one, two, or three of the options (a), (b), and (c), such as (a)+(b), (b)+(c), (a)+(c), or (a)+(b)+(c). High platelet reactivity or sensitivity to a platelet-activating substance may refer to platelet reactivity or sensitivity to a platelet-activating substance when compared to a control, such as platelet reactivity or sensitivity to a platelet-activating substance in a normal individual or group of individuals, for example, an individual or group of individuals who have a normal level of platelet reactivity, such as individuals who do not have platelet hypersensitivity or hyposensitivity.

[00148] In some modalities, a method is provided. Petition 870250102203, dated 07 / 11 / 2025, page 76 / 175 68 / 155 identification of an individual presenting with hypersensitive platelets. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) determine the individual's age;

[00149] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described herein. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described herein. The individual may be any individual as described herein. In these methods, the presence of one, two, or three of the following is indicative of the presence of hypersensitive platelets: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[00150] Thus, an individual with hypersensitive platelets may be indicated by the presence of one, two Petition 870250102203, dated 07 / 11 / 2025, page 77 / 175 69 / 155 or three of the options (a), (b) and (c), such as (a)+(b), (b)+(c), (a) + (c) or (a) + (b) + (c).

[00151] The term hypersensitive platelets refers to a platelet or platelet population with a greater responsiveness to a platelet agonist (e.g., increased sensitivity) and / or capable of generating a functional response of greater magnitude (e.g., greater capacity) compared to a control or reference platelet or platelet population. Platelet agonists can induce a signaling cascade that results in an activation-dependent conformational change in the major platelet membrane receptor allpb3. Examples of platelet agonists include adenosine diphosphate (ADP), thromboxane A2 (TxA2), collagen, thrombin, platelet-activating factor, epinephrine, and serotonin.

[00152] In some modalities, a method is provided for predicting an individual's response to therapeutic treatment with antiplatelet therapy. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample comprising the individual; and / or (iii) determine the individual's age.

[00153] For example, the method may include Petition 870250102203, dated 07 / 11 / 2025, page 78 / 175 70 / 155 assessment of platelet reactivity and / or assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described herein. Consequently, the method may comprise any one, two or three of the options (i), (ii) and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii) or (i)+(ii)+(iii). Antiplatelet therapy may be any antiplatelet therapy as described herein. The sample may be any sample as described herein. The individual may be any individual as described herein.

[00154] The term responsiveness, as used in this document, refers to the ability to respond or react to a therapeutic treatment, for example, the ability of an individual, a cell (e.g., a platelet) or a population of cells (e.g., a population of platelets) to respond or react to a therapeutic treatment. Responsiveness may include the time required for an individual, cell or population of cells to respond or react to a therapeutic treatment, the level or magnitude of the response to the therapeutic treatment, or the effectiveness with which an individual, cell or population of cells responds or reacts to a therapeutic treatment.

[00155] In some modalities, a method is provided Petition 870250102203, dated 07 / 11 / 2025, page 79 / 175 71 / 155 to identify an individual suitable for treatment with antiplatelet therapy. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[00156] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described herein. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described herein. The individual may be any individual as described herein. In these methods, the presence of one, two, or three of the following is indicative that the individual may be suitable for treatment with antiplatelet therapy: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[00157] Thus, an individual suitable for treatment with antiplatelet therapy may be indicated by Petition 870250102203, dated 07 / 11 / 2025, p. 80 / 175 72 / 155 presence of one, two or three of the options (a), (b) and (c), such as (a) + (b), (b) + (c), (a) + (c) or (a) + (b) + (c).

[00158] Such methods can also be used to select an appropriate antiplatelet therapy for the individual, or to select another therapeutic method appropriate for that individual. For example, if an individual is identified as having increased platelet sensitivity or hypersensitive platelets, subsequent treatment of that patient may be selected to avoid, or reduce the dose of, a platelet agonist, since any platelet agonist can elicit a functional response of increased magnitude in that individual. If an individual is identified as having increased platelet reactivity, subsequent treatment of that patient may be selected to include, or increase the dose of, a platelet antagonist or other antiplatelet therapy, in order to reduce any undesirable effects or consequences arising from this increased platelet reactivity.

[00159] In some modalities, a method is provided for identifying an individual with a reduced risk of bleeding. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample that Petition 870250102203, dated 07 / 11 / 2025, page 81 / 175 73 / 155 comprises the individual's platelets; and / or (iii) determine the individual's age.

[00160] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described in this document. The individual may be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative of a reduced risk of bleeding in the individual: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old.

[00161] Thus, a reduced risk of bleeding may be indicated by the presence of one, two or three of options (a), (b) and (c), such as (a) + (b), (b) + (c), (a) + (c) or (a) + (b) + (c).

[00162] A reduced risk of bleeding, as described in this document, may be a reduced risk of bleeding in response to treatment with a therapy. Petition 870250102203, dated 07 / 11 / 2025, p. 82 / 175 74 / 155 antiplatelet therapy. For example, some antiplatelet therapies may result in an unwanted bleeding side effect in certain individuals, which may be difficult to predict but potentially dangerous. Such a reaction or side effect may be less likely to occur in an individual with increased platelet sensitivity, such as an individual identified by a method described herein. A reduced risk of bleeding, as described herein, may be a reduced risk of bleeding in any circumstances where bleeding may occur, such as bleeding resulting from an injury, surgery, or underlying medical condition, for example, in an individual receiving anticoagulant medication, undergoing surgery, or who is a blood donor. A reduced risk of bleeding may be a reduced risk of unwanted bleeding or excessive bleeding.A reduced risk of bleeding may correspond to a decrease in the likelihood of bleeding occurring, such as unwanted bleeding; it may correspond to a decrease in the amount of bleeding or a decrease in the duration of time that bleeding occurs. A reduced risk of bleeding may be related to the risk of bleeding when compared to a control, such as the risk of bleeding in a normal individual or group of individuals, for example, individuals who present with a reduced risk of bleeding. Petition 870250102203, dated 07 / 11 / 2025, page 83 / 175 75 / 155 a normal level of platelet reactivity, such as individuals who do not exhibit platelet hypersensitivity or hyposensitivity. The methods of the present invention allow the identification of individuals in whom this bleeding, particularly unwanted or excessive bleeding, is less likely to occur due to the increased sensitivity or reactivity of that individual's platelets. Thus, an individual identified by a method described herein as having hypersensitive platelets is more likely to exhibit a coagulation reaction in response to a hemorrhagic stimulus. This information can be used to select appropriate therapy for use in that individual. For example, an individual identified by a method described herein as having a reduced risk of bleeding may be treated with antiplatelet therapy or with an increased dose of antiplatelet therapy.An individual identified by a method described in this document as having a reduced risk of bleeding may be less likely to require anti-hemorrhagic therapy or prophylaxis.

[00163] In some modalities, a method is provided for identifying an individual at increased risk of a disease, disorder, or condition associated with increased platelet reactivity. The disease, disorder, or condition may Petition 870250102203, dated 07 / 11 / 2025, page 84 / 175 76 / 155 being any disease, disorder, or condition associated with increased platelet reactivity, as described in this document. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[00164] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described in this document. The individual may be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative that the individual has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) the individual is at least 50 years old. Petition 870250102203, dated 07 / 11 / 2025, p. 85 / 175 77 / 155

[00165] Thus, an individual with an increased risk of disease, disorder, or condition associated with increased platelet reactivity may be indicated by the presence of one, two, or three of the options (a), (b), and (c), such as (a) + (b), (b) + (c), (a) + (c), or (a) + (b) + (c). An increased risk of a disease, disorder, or condition associated with increased platelet reactivity may refer to the risk of a disease, disorder, or condition associated with increased platelet reactivity when compared to a control, such as the risk in a normal individual or group of individuals, such as an individual or group of individuals who have a normal level of platelet reactivity, such as individuals who do not have platelet hypersensitivity or hyposensitivity.

[00166] In some modalities, the disease, disorder, or condition associated with increased platelet reactivity is thrombosis, or a disease, disorder, or condition involving thrombosis. Thus, the methods described in this document can be used to identify an individual at increased risk of thrombosis. An increased risk of thrombosis may refer to the risk of thrombosis when compared to a control, such as the risk of thrombosis in a normal individual or group of individuals, for example, individuals who have a normal level of platelet reactivity, such as individuals who do not have hypersensitivity or Petition 870250102203, dated 07 / 11 / 2025, p. 86 / 175 78 / 155 Platelet hyposensitivity. The methods of the present invention allow the identification of individuals in whom thrombosis is more likely to occur due to increased sensitivity or reactivity of that individual's platelets. Thus, an individual identified by a method described herein as having hypersensitive platelets is more likely to experience an excessive coagulation reaction, such as thrombosis. This information can be used to select appropriate therapy for use in that individual. For example, an individual identified by a method described herein as having an increased risk of thrombosis may be selected for treatment with a therapy designed to reduce platelet reactivity, such as antiplatelet therapy, or with an increased dose of antiplatelet therapy.An individual identified by a method described in this document as having an increased risk of thrombosis may be selected for treatment with antithrombotic therapy, such as antiplatelet therapy or an anticoagulant. For example, an individual identified by a method described in this document as having an increased risk of thrombosis may be treated prophylactically or therapeutically, in order to prevent or reduce thrombosis, with antiplatelet therapy or anticoagulant therapy. Petition 870250102203, dated 07 / 11 / 2025, page 87 / 175 79 / 155 identified by a method described in this document as having an increased risk of thrombosis and who presents signs or symptoms of thrombosis may be treated with antiplatelet therapy or anticoagulant therapy.

[00167] In some modalities, a method is provided for identifying an individual exhibiting low platelet reactivity or sensitivity to a platelet-activating substance. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[00168] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described in this document. The individual may be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative of the presence of reactivity. Petition 870250102203, dated 07 / 11 / 2025, p. 88 / 175 80 / 155 or reduced platelet sensitivity to a platelet-activating substance: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[00169] Thus, the presence of low platelet reactivity or sensitivity to a platelet-activating substance may be indicated by the presence of one, two, or three of the options (a), (b), and (c), such as (a) + (b), (b) + (c), (a) + (c), or (a) + (b) + (c). Low platelet reactivity may be related to platelet reactivity when compared to a control, such as platelet reactivity in a normal individual or group of individuals, or an individual or group of individuals who do not exhibit platelet hypersensitivity or hyposensitivity.

[00170] In some modalities, a method is provided for identifying an individual with hyposensitive platelets. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) determine the individual's age;

[00171] For example, the method may include the assessment of platelet reactivity and / or the assessment or Petition 870250102203, dated 07 / 11 / 2025, page 89 / 175 81 / 155 prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described herein. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described herein. The individual may be any individual as described herein. In these methods, the presence of one, two, or three of the following is indicative of the presence of hyposensitive platelets: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[00172] Thus, an individual with hyposensitive platelets may be indicated by the presence of one, two, or three of options (a), (b), and (c), such as (a)+(b), (b)+(c), (a)+(c), or (a)+(b)+(c).

[00173] The term hyposensitive platelets refers to a platelet or platelet population with a reduced responsiveness to a platelet agonist (e.g., reduced sensitivity) and / or capable of generating a functional response of lesser magnitude (e.g., reduced capacity) compared to a control or reference platelet or platelet population. An individual with platelets Petition 870250102203, dated 07 / 11 / 2025, page 90 / 175 82 / 155 hyposensitive may be related to platelet sensitivity compared to a control group, such as reduced platelet sensitivity compared to a normal individual or group of individuals, or an individual or group of individuals with a normal level of platelet reactivity, such as individuals who do not exhibit platelet hypersensitivity or hyposensitivity.

[00174] In some modalities, a method is provided for identifying an individual who is not suitable for treatment with antiplatelet therapy. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[00175] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described in this document. The Petition 870250102203, dated 07 / 11 / 2025, p. 91 / 175 83 / 155 The individual can be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative that the individual may not be suitable for treatment with antiplatelet therapy: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[00176] Thus, an individual who is not suitable for treatment with antiplatelet therapy may be indicated by the presence of one, two or three of options (a), (b) and (c), such as (a) + (b), (b) + (c), (a) + (c) or (a) + (b) + (c).

[00177] Such methods can also be used to select an appropriate antiplatelet therapy for the individual, or to select another therapeutic method appropriate for that individual. For example, if an individual is identified as having reduced platelet sensitivity or hyposensitive platelets, subsequent treatment of that patient may be selected to include, or increase the dose of, a platelet agonist, since any platelet agonist may elicit a reduced functional response in that individual.

[00178] In some modalities, a method is provided for identifying an individual with a reduced risk of a disease, disorder, or condition associated with increased risk. Petition 870250102203, dated 07 / 11 / 2025, page 92 / 175 84 / 155 platelet reactivity or sensitivity. The disease, disorder, or condition may be any disease, disorder, or condition associated with increased platelet reactivity, as described herein. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) to determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) to determine the individual's age.

[00179] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described in this document. The individual may be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative that the individual has a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or Petition 870250102203, dated 07 / 11 / 2025, p. 93 / 175 85 / 155 (c) the individual is under 50 years of age.

[00180] Thus, an individual with a reduced risk of disease, disorder, or condition associated with increased platelet reactivity may be indicated by the presence of one, two, or three of the options (a), (b), and (c), such as (a) + (b), (b) + (c), (a) + (c), or (a) + (b) + (c). A reduced risk of a disease, disorder, or condition associated with increased platelet reactivity may refer to the risk of a disease, disorder, or condition associated with increased platelet reactivity when compared to a control, such as the risk in a normal individual or group of individuals, such as an individual or group of individuals who have a normal level of platelet reactivity, such as individuals who do not have platelet hypersensitivity or hyposensitivity.

[00181] In some modalities, the disease, disorder, or condition associated with increased platelet reactivity is thrombosis, or a disease, disorder, or condition involving thrombosis. Thus, the methods described in this document can be used to identify an individual at reduced risk of thrombosis. A lower or reduced risk of thrombosis may refer to the risk of thrombosis when compared to a control, such as the risk of thrombosis in a normal individual or group of individuals, for example, individuals exhibiting a normal level of platelet reactivity, such as Petition 870250102203, dated 07 / 11 / 2025, p. 94 / 175 86 / 155 as individuals who do not exhibit platelet hypersensitivity or hyposensitivity. The methods of the present invention allow the identification of individuals in whom thrombosis is less likely to occur due to the reduced sensitivity or reactivity of that individual's platelets. Thus, an individual identified by a method described herein as having hyposensitive platelets is less likely to experience a coagulation reaction, such as thrombosis. This information can be used to select appropriate therapy for use in that individual. For example, an individual identified by a method described herein as having a reduced risk of thrombosis may be selected for treatment with a therapy that has an increased risk of thrombosis as a side effect.An individual identified by a method such as that described in this document as having an increased risk of thrombosis may be less likely to require treatment with antithrombotic therapy, such as antiplatelet therapy or an anticoagulant.

[00182] In some modalities, a method is provided to identify an individual with an increased risk of bleeding. The method comprises: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample that Petition 870250102203, dated 07 / 11 / 2025, page 95 / 175 87 / 155 comprises the individual's platelets; and / or (iii) determine the individual's age.

[00183] For example, the method may comprise the assessment of platelet reactivity and / or the assessment or prediction of platelet sensitivity, such as sensitivity to a platelet-activating substance, according to any method described in this document. Consequently, the method may comprise any one, two, or three of the options (i), (ii), and (iii), such as (i)+(ii), (ii)+(iii), (i)+(iii), or (i)+(ii)+(iii). The sample may be any sample as described in this document. The individual may be any individual as described in this document. In these methods, the presence of one, two, or three of the following is indicative of an increased risk of bleeding: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

[00184] Thus, the presence of a high risk of bleeding may be indicated by the presence of one, two, or three of the options (a), (b), and (c), such as (a)+(b), (b)+(c), (a)+(c), or (a)+(b)+(c).

[00185] An elevated risk of bleeding, as described in this document, may be an elevated risk of bleeding in response to treatment with a therapy. Petition 870250102203, dated 07 / 11 / 2025, p. 96 / 175 88 / 155 antiplatelet therapy. For example, some antiplatelet therapies may result in an unwanted bleeding side effect in certain individuals, which may be difficult to predict but potentially dangerous. An elevated bleeding risk, as described herein, may be an elevated risk of bleeding in any circumstances where bleeding may occur, such as bleeding resulting from an injury, surgery, or underlying medical condition. An elevated bleeding risk may be an elevated risk of unwanted bleeding or excessive bleeding. An elevated bleeding risk may correspond to an increased likelihood of bleeding occurring, as unwanted bleeding may correspond to an increase in the amount of bleeding or the duration of time that bleeding occurs.An elevated risk of bleeding may be related to the risk of bleeding when compared to a control, such as the risk of bleeding in a normal individual or group of individuals, for example, individuals with a normal level of platelet reactivity, such as individuals without platelet hypersensitivity or hyposensitivity. The methods of the present invention allow the identification of individuals in whom such bleeding, particularly unwanted or excessive bleeding, is more likely to occur due to sensitivity or... Petition 870250102203, dated 07 / 11 / 2025, page 97 / 175 89 / 155 reduced platelet reactivity in this individual. Thus, an individual identified by a method described in this document as having hyposensitive platelets is less likely to exhibit a coagulation reaction in response to a hemorrhagic stimulus. This information can be used to select appropriate therapy for use in this individual. For example, an individual identified by a method such as that described in this document as having an increased risk of bleeding may be treated with a lower dose of antiplatelet therapy. An individual identified by a method described in this document as having a high risk of bleeding may be more likely to require anti-hemorrhagic therapy or prophylaxis.An individual identified by a method such as that described in this document as having an increased risk of bleeding may be subsequently treated with anti-hemorrhagic therapy or prophylaxis, such as an agent that promotes blood clotting. Biomarker levels

[00186] The methods of the invention involve evaluating one or more biomarkers, such as CD3 6 and / or GPVI, in a sample composed of platelets from an individual, and / or the age of the individual from whom the platelets were obtained.

[00187] In some methods of the invention described in Petition 870250102203, dated 07 / 11 / 2025, page 98 / 175 90 / 155 of this document, for example, in a method for identifying an individual exhibiting hypersensitive platelets, in a method for identifying an individual exhibiting increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, in a method for identifying an individual at increased risk of a disease, disorder or condition associated with increased platelet reactivity, in a method for identifying an individual suitable for treatment with antiplatelet therapy, or in a method for identifying an individual at reduced risk of bleeding, the method may determine the presence of: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years.

[00188] In some modalities, the method can determine the presence of: - a high level of CD36 in the sample; - a high level of GPVI in the sample; - an age of at least 50 years old; - a high level of CD36 in the sample and a high level of GPVI in the sample; - a high level of CD36 in the sample and age equal to or greater than 50 years; - a high level of GPVI in the sample and age equal to or Petition 870250102203, dated 07 / 11 / 2025, p. 99 / 175 91 / 155 older than 50 years; or - a high level of CD36 in the sample and a high level of GPVI in the sample and age equal to or greater than 50 years.

[00189] In some modalities, the method can determine the presence of all three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) an age of at least 50 years.

[00190] In some modalities, the method can determine the presence of: (a) a high level of CD36 in the sample; and (b) a high level of GPVI in the sample; in which the individual is at least 50 years old.

[00191] The term elevated level may refer to a high, superior, or increased amount of a biomarker protein or nucleic acid molecule compared to a control or reference amount of the biomarker protein or nucleic acid molecule.

[00192] In one embodiment, an elevated CD36 level is defined as a platelet or a population of platelets that expresses a CD36 level that is at least in the upper 35th percentile compared to a reference population, for example, in the 35th, 34th, 33rd, 32nd, 31st, 30th, 25th, 20th, 15th or 10th percentiles.

[00193] In one mode, a high level of CD36 Petition 870250102203, dated 07 / 11 / 2025, pp. 100 / 175 92 / 155 is defined as being at least 15% higher than the CD36 level in a control or reference sample comprising platelets, for example, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 45%, or at least 50% higher.

[00194] In one embodiment, a high CD36 level is defined as a platelet or a population of platelets expressing at least 8000 copies of CD36 per platelet, for example, at least 8100, at least 8200, at least 8300, at least 8400, at least 8500, at least 8600, at least 8700, at least 8800, at least 8900, at least 9000 or at least 10000 copies of CD36 per platelet.

[00195] In one embodiment, an elevated GPVI level is defined as a platelet or platelet population that expresses a GPVI level that is at least in the top 50th percentile compared to a reference population, for example, in the 50th, 49th, 48th, 47th, 46th, 45th, 40th, 35th, 30th, 25th, 20th, 15th or 10th percentiles.

[00196] In one embodiment, a high GPVI level is defined as being at least 15% higher than the CD36 level in a control or reference sample comprising platelets, for example, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 45% or Petition 870250102203, dated 07 / 11 / 2025, page 101 / 175 93 / 155 at least 50% higher.

[00197] In one embodiment, a high level of GPVI is defined as a platelet or a population of platelets that expresses at least 3000 copies of GPVI per platelet, for example, at least 3100, at least 3200, at least 3300, at least 3400, at least 3500, at least 3600, at least 3700, at least 3800, at least 3900, at least 4000 or at least 5000 copies of GPVI per platelet.

[00198] An individual who is at least 50 years old may be at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, or at least 90 years old. For example, the individual may be at least 50 years old or at least 55 years old. The individual may be 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 years old. The individual may be 50 to 60, 50 to 70, 50 to 80, 50 to 90, 50 to 100, 55 to 60, 55 to 70, 55 to 80, 55 to 90, 55 to 100, 60 to 70, 60 to 80, 60 to 90, 60 to 100, 70 to 80, 80 to 90, or 90 to 100 years old.

[00199] In one embodiment, an elevated CD36 level, an elevated GPVI level and / or the fact that the individual is at least 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased platelet reactivity or sensitivity. Petition 870250102203, dated 07 / 11 / 2025, p. 102 / 175 94 / 155 or elevated to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00200] In one embodiment, an elevated CD36 level is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00201] In one embodiment, an elevated GPVI level is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with platelet reactivity. Petition 870250102203, dated 07 / 11 / 2025, p. 103 / 175 95 / 155 increased; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00202] In one embodiment, the fact that the individual is at least 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who requires antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00203] In one embodiment, an elevated CD36 level and an elevated GPVI level is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) a Petition 870250102203, dated 07 / 11 / 2025, pp. 104 / 175 96 / 155 individual who has a reduced risk of bleeding.

[00204] In one embodiment, an elevated CD36 level and the fact that the individual is at least 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who requires antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00205] In one embodiment, an elevated GPVI level and the fact that the individual is at least 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding. Petition 870250102203, dated 07 / 11 / 2025, pp. 105 / 175 97 / 155

[00206] In one embodiment, an elevated CD36 level, an elevated GPVI level, and the fact that the individual is at least 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00207] In one embodiment, a reduced CD36 level, an elevated GPVI level, and the fact that the individual is at least 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00208] In one mode, a high level of CD36, Petition 870250102203, dated 07 / 11 / 2025, pp. 106 / 175 98 / 155 an elevated GPVI level and the fact that the individual is under 50 years of age is indicative of (a) an individual who has hypersensitive platelets; (b) an individual who has increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has an increased risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is suitable for treatment with antiplatelet therapy; (e) an individual who needs antiplatelet therapy; and / or (f) an individual who has a reduced risk of bleeding.

[00209] In some methods of the invention described herein, for example, in a method for identifying an individual exhibiting hyposensitive platelets, in a method for identifying an individual exhibiting reduced or low platelet reactivity or sensitivity to a platelet-activating substance, in a method for identifying an individual with a reduced risk of a disease, disorder or condition associated with increased platelet reactivity, in a method for identifying an individual unsuitable for treatment with antiplatelet therapy, or in a method for identifying an individual with an increased risk of bleeding, the method may determine the presence of: (a) a reduced level of CD36 in the sample; Petition 870250102203, dated 07 / 11 / 2025, page 107 / 175 99 / 155 (b) a reduced level of GPVI in the sample; (c) an age less than 50 years.

[00210] In some modalities, the method can determine the presence of: - a reduced level of CD36 in the sample; - a reduced level of GPVI in the sample; - an age younger than 50 years old; - a reduced level of CD36 in the sample and a reduced level of GPVI in the sample; - a reduced level of CD36 in the sample and age less than 50 years; - a reduced level of GPVI in the sample and age less than 50 years; or - a reduced level of CD36 in the sample and a low level of GPVI in the sample and age less than 50 years.

[00211] In some modalities, the method can determine the presence of all three of the following: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and (c) an age less than 50 years old;

[00212] The method can determine the presence of: (a) a reduced level of CD36 in the sample; and (b) a reduced level of GPVI in the sample; in which the individual is under 50 years of age. Petition 870250102203, dated 07 / 11 / 2025, pp. 108 / 175 100 / 155

[00213] The term “reduced level” refers to a reduced, lower, or lesser number or quantity of a biomarker protein or nucleic acid molecule compared to a control or reference number or quantity of the biomarker protein or nucleic acid molecule.

[00214] In one embodiment, a reduced CD36 level is defined as a platelet or a population of platelets that expresses a CD36 level that is at least in the 65th percentile lower compared to a reference population, for example, in the 65th, 66th, 67th, 68th, 69th, 70th, 75th, or 80th percentiles.

[00215] In one embodiment, a reduced CD36 level is defined as being at least 15% lower than the CD36 level in a control or reference sample comprising platelets, for example, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 45% or at least 50% lower.

[00216] In one embodiment, a reduced CD36 level is defined as a platelet or a population of platelets expressing fewer than 8000 copies of CD36 per platelet, for example, fewer than 7900, fewer than 7800, fewer than 7700, fewer than 7600, fewer than 7600, fewer than 6400, fewer than 7300, fewer than 7200, fewer than 7100, fewer than 7000, fewer than 6000 or fewer Petition 870250102203, dated 07 / 11 / 2025, pp. 109 / 175 101 / 155 of 5000 CD36 copies per plate.

[00217] In one embodiment, a reduced GPVI level is defined as a platelet or a population of platelets that expresses a GPVI level that is at least in the 50th percentile lower compared to a reference population, for example, in the 50th, 51st, 52nd, 53rd, 54th, 55th, 60th, 65th or 70th percentiles.

[00218] In one embodiment, a reduced GPVI level is defined as being at least 15% lower than the CD36 level in a control or reference sample comprising platelets, for example, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 45% or at least 50% lower.

[00219] In one embodiment, a reduced GPVI level is defined as a platelet or a population of platelets expressing less than 3000 copies of GPVI per platelet, for example, less than 2900, less than 2800, less than 2700, less than 2600, less than 2500, less than 2400, less than 2300, less than 2200, less than 2100, less than 2000 or less than 1000 copies of GPVI per platelet.

[00220] An individual under 50 years of age may be under 50, under 49, under 48, under 47, under 46, under 45, under 44, under 43, under 42, under 41, under 40, under 35, under 35 or Petition 870250102203, dated 07 / 11 / 2025, pages 110 / 175 102 / 155 under 30 years of age. In one category, the individual is under 50 years of age. The individual may be 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40 years of age. The individual can be 0 to 49, 5 to 49, 10 to 49, 15 to 49, 20 to 49, 25 to 49, 30 to 49, 35 to 49, 40 to 49, 45 to 49, 0 to 45, 5 to 45, 10 to 45, 15 to 45, 20 to 45, 25 to 45, 30 to 45, 35 to 45, 0 to 40, 5 to 40, 10 to 40, 15 to 40, 20 to 40, 25 to 40, 30 to 40, 35 to 40 years old.

[00221] In one embodiment, a reduced CD36 level, a reduced GPVI level, and the fact that the individual is under 50 years of age is indicative of (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00222] In one embodiment, a reduced CD36 level is indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a Petition 870250102203, dated 07 / 11 / 2025, p. 111 / 175 103 / 155 platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00223] In one embodiment, a reduced GPVI level is indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00224] In one embodiment, the fact that the individual is under 50 years of age is indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as Petition 870250102203, dated 07 / 11 / 2025, p. 112 / 175 104 / 155 CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00225] In one embodiment, a reduced CD36 level and a reduced GPVI level are indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00226] In one embodiment, a reduced CD36 level and the fact that the individual is under 50 years of age are indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; Petition 870250102203, dated 07 / 11 / 2025, p. 113 / 175 105 / 155 (c) an individual who has a reduced risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00227] In one embodiment, a reduced GPVI level and the fact that the individual is under 50 years of age are indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00228] In one embodiment, a reduced CD36 level, a reduced GPVI level, and the fact that the individual is under 50 years of age are indicative of: (a) an individual with hyposensitive platelets; (b) an individual with reduced platelet reactivity or sensitivity. Petition 870250102203, dated 07 / 11 / 2025, pp. 114 / 175 106 / 155 or low to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00229] In one embodiment, a reduced CD36 level and an elevated GPVI level are indicative of: (a) an individual who has hyposensitive platelets; (b) an individual who has reduced or low platelet reactivity or sensitivity to a platelet-activating substance, such as CRP or CRP-XL; (c) an individual who has a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity; (d) an individual who is not suitable for treatment with antiplatelet therapy; (e) an individual who needs an alternative to antiplatelet therapy; and / or (f) an individual who has an increased risk of bleeding.

[00230] In one embodiment, a reduced CD36 level, a reduced GPVI level, and an individual at least 50 years of age are indicative of an individual with average platelet reactivity or sensitivity to a platelet-activating substance such as CRP or CRP-XL. In one embodiment, Petition 870250102203, dated 07 / 11 / 2025, pp. 115 / 175 107 / 155 A reduced CD36 level, a reduced GPVI level, and an individual under 50 years of age are indicative of an individual with moderate platelet reactivity or sensitivity to a platelet-activating substance such as CRP or CRP-XL. In one embodiment, a high CD36 level, a low GPVI level, and an individual under 50 years of age are indicative of an individual with moderate platelet reactivity or sensitivity to a platelet-activating substance such as CRP or CRP-XL.

[00231] A “reference population,” “control,” or “reference sample” refers to a control or reference sample or population in which platelet sensitivity or reactivity is normal or in which platelet sensitivity or reactivity is expected to be normal. A determination that the level of a marker of interest is increased relative to this control therefore indicates that the marker level is “elevated” or “increased.” In one embodiment, the reference sample or population is or comprises a platelet, a population of platelets, or a sample containing platelets obtained from a donor. In one embodiment, the reference sample or population comprises platelets, populations of platelets, or a sample containing platelets obtained from a donor population. In one embodiment, the reference sample or population comprises platelets, populations of platelets, or samples containing platelets. Petition 870250102203, dated 07 / 11 / 2025, pages 116 / 175 108 / 155 platelets obtained from multiple donors. When the reference population, control, or reference sample is based on values ​​obtained from multiple donors, the comparison can be made with a combined value, such as that of a combined sample. When the reference population, control, or reference sample is based on values ​​obtained from multiple donors, the comparison can be made with an average value, such as the arithmetic mean or the median value of the donors. The sample or samples used as a reference are preferably of the same type of sample used to determine the individual's platelet reactivity or sensitivity in the methods of the invention, such as, for example, a sample containing platelets, a whole blood sample, or a plasma sample.The reference population or sample may be derived from one or more donors known to have a normal level of platelet sensitivity or reactivity, that is, without a significant increase or decrease in platelet reactivity or sensitivity. The reference population or sample may be based on a population of donors with unknown or unevaluated platelet sensitivity or reactivity, for example, when it is expected that, within this population, the average level of platelet sensitivity and / or reactivity will be within the normal range.

[00232] The donor or donors may or may not have been previously assessed for reactivity or Petition 870250102203, dated 07 / 11 / 2025, pages 117 / 175 109 / 155 platelet sensitivity by a method of the invention or by any other suitable method. In one embodiment, the donor or donor population has no prior history of a disease, disorder, or condition associated with increased platelet reactivity as described herein, such as selected from the following: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, cancer, a response to a bacterial and / or viral infection and / or inflammation. In one embodiment, the donor or donor population has no prior history of cardiovascular disease. In one embodiment, the donor or donor population has not previously received antiplatelet therapy. In one embodiment, the donor or donor population is not currently undergoing treatment with antiplatelet therapy.In one embodiment, the donor or donor population was not exhibiting symptoms of a disease, disorder, or condition associated with increased platelet reactivity selected from the following: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation, when the sample comprising platelets was obtained from the donor.

[00233] When a donor population is used for Petition 870250102203, dated 07 / 11 / 2025, pages 118 / 175 110 / 155 To provide a reference population, a control, or a reference sample, this can provide a range of values ​​or a set of percentile values ​​for the reference population, control, or sample. For example, when the reference population, control, or sample is based on values ​​obtained from a donor population, such as the donor population described above, the range and spread of values ​​from these donors can be used to assess the relative level of the marker(s) in the sample from the individual. For example, this can be useful to determine if the level of the marker(s) is elevated in the individual's sample compared to the average level (e.g., arithmetic mean) of the reference donor population. This can also be useful to determine if the level of the marker(s) is elevated in the individual's sample compared to the median level in the reference donor population.For example, the level in the individual's sample can be compared to the levels in the reference population of donors in order to identify the relative position or ranking of the individual's sample within the range of values ​​of the reference population. In some modalities, the level in the individual's sample can be assigned a percentile based on the relative level of the marker in the sample, compared to the levels of the reference population. A percentile can be calculated by providing the levels of each. Petition 870250102203, dated 07 / 11 / 2025, pp. 119 / 175 111 / 155 donors in the reference population, ordering or classifying them according to the marker level in each individual and then dividing the classified values ​​so that one percent of the population donors are in each percentile. The top 1% of donors, who are those with the highest marker level based on the classification ordered by marker level, form the 1st percentile. The top 5% of donors, based on the classification ordered by marker level, form the 1st, 2nd, 3rd, 4th, and 5th percentiles, which may be described in this document as the top 5 percentiles. For example, a classification indicating that the sample is in the The upper 5th percentile means that up to 5% of the samples from the reference population have a higher level of the marker.

[00234] Comparison with a “reference population”, “control” or “reference sample” in the methods of the invention may involve a direct comparison with a suitable reference population, control or sample, in which the relevant marker(s) are determined in the reference population, control or sample at the same time or as part of the same method as the sample from the individual. Thus, the method of the invention may further comprise: (i) determining the CD36 level in the reference population, control or sample; and / or (ii) determining the GPVI level in the reference population, control or sample. Petition 870250102203, dated 07 / 11 / 2025, pages 120 / 175 112 / 155

[00235] Comparison with a “reference population”, “control” or “reference sample” in the methods of the invention may involve a direct comparison with a suitable reference population, control or sample, in which the relevant marker(s) are determined in the reference population, control or sample using the same method or assay employed to determine the marker(s) in the sample from the individual. Thus, the method of the invention may further comprise: (i) determining the CD36 level in the reference population, control or reference sample by the same assay used to determine the CD36 level in the sample from the individual; and / or (ii) determining the GPVI level in the reference population, control or reference sample by the same assay used to determine the GPVI level in the sample from the individual.

[00236] Comparison with a “reference population”, “control” or “reference sample” in the methods of the invention may involve a comparison with known values ​​for the marker(s) in a suitable reference population, control or sample, such as in cases where the marker(s) have already been determined in the reference population, control or sample, such as in cases where the relevant marker(s) have already been determined in the reference population, control or Petition 870250102203, dated 07 / 11 / 2025, pp. 121 / 175 113 / 155 in the reference sample, using the same method or assay used to evaluate the marker(s) in the individual's sample. For example, when the population, control, or reference sample is based on a donor population as described above, a set of standard control values ​​can be obtained for use as a reference population, control, or reference sample in the methods of the invention. The set of standard control values ​​can be used as a reference population, control, or reference sample in the methods of the invention, for example, to allow comparison with the marker level in the sample from the individual, in order to determine whether the marker level is increased or decreased, elevated or low.The set of standard control values ​​can be used as a reference population, control, or reference sample in the methods of the invention, for example, to allow classification of the level in the sample from the individual, so that the sample can be assigned to a percentile in comparison with a reference population, control, or sample.

[00237] The CD36 and / or GPVI level can be determined by any suitable method. These methods can be used to determine the absolute or relative level of CD36 and / or GPVI in platelets, the amount of CD36 or GPVI displayed on the platelet membrane, or the levels of soluble CD36 or GPVI in plasma. As used in Petition 870250102203, dated 07 / 11 / 2025, pp. 122 / 175 114 / 155 in this document, the term relative means that the absolute level is not determined, but rather evaluated in comparison with a control or reference sample.

[00238] In any of the methods described in this document for determining the CD36 and / or GPVI level, the method can determine the CD36 and / or GPVI level in a sample as described in this document, for example, a platelet sample, a whole blood sample, or a plasma sample. In addition, in any of the methods described in this document for determining the CD36 and / or GPVI level, the method can determine the CD36 and / or GPVI level in a control sample, for example, a platelet sample, a whole blood sample, or a plasma sample, such as a whole blood or plasma sample from a reference donor or donor population with no prior history of disease, disorder, or condition associated with increased platelet reactivity.

[00239] In some embodiments, the level of the protein product CD36 and / or GPVI is determined by means of ELISA, lateral flow assay, flow cytometry, immunoassay, antibody assay (or fragment or derivative thereof), two-site antibody assay or quantitative mass spectrometry. For example, an assay Petition 870250102203, dated 07 / 11 / 2025, pp. 123 / 175 A two-site immunoassay in an ELISA environment can be used. The term two-site means that the assay uses two types of antibodies, each of which binds to a different antigen present in the target molecule, for example, CD36 or GPVI. Typically, one type of antibody is labeled and the other is bound to a solid-phase support, allowing for precise and reproducible evaluation of a target molecule.

[00240] An example of an ELISA assay for CD36 is described in Allred, CC, Krennmayr, T., Koutsari, C., Zhou, L., Ali, AH and Jensen, MD, 2011. A novel ELISA to measure CD36 protein in human adipose tissue. Journal of Lipid Research, 52(2), pp.408-415.

[00241] An example of an ELISA assay for GPVI is described in Al-Tamimi, M., Mu, FT, Moroi, M., Gardiner, EE, Berndt, MC and Andrews, RK, 2009. Measuring platelet-soluble VL glycoprotein in human plasma by ELLSA. Platelets, 20(3), pp.143-149.

[00242] An example of an antibody assay for GPVI is described in Samaha, FF, Hibbard, C., Sacks, J., Chen, H., Varello, MA, George, T. and Kahn, ML, 2004. Measurement of platelet collagen receptor density in human subjects. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(11), pp. el81-el82.

[00243] For example, the level of the protein product CD36 and / or GPVI can be determined by measuring light absorbance. Petition 870250102203, dated 07 / 11 / 2025, pp. 124 / 175 116 / 155 UV at a wavelength of 280 nm or 205 nm through a sample. Such methods are known in the art, for example, as described in Grimsley, GR and Pace, CN, 2003. Spectrophotometric determination of protein concentration. Current protocols in protein science, 33(1), pp.3-1.

[00244] For example, the level of the protein product CD36 and / or GPVI can be determined by a colorimetric protein quantification assay, such as the Bradford assay, the bicinchoninic acid (BCA) assay, or the Lowry assay, as described in Sapan, CV, Lundblad, RL, and Price, NC, 1999. Colorimetric protein assay techniques. Biotechnology and applied Biochemistry, 29(2), pp. 99-108.

[00245] For example, the level of the protein product CD36 and / or GPVI can be determined by a NanoOrange fluorescent protein quantification assay, as described in Jones, LJ, Haugland, RP and Singer, VL, 2003. Development and characterization of the NanoOrange® protein quantification assay: a fluorescence-based assay of proteins in solution. Biotechniques, 34(4), pp.850-861.

[00246] The presence of the protein product CD36 and / or GPVI can be detected based on its molecular weight, for example, using comparative electrophoretic mobility or mass spectrometry, or using isoelectric focusing. Petition 870250102203, dated 07 / 11 / 2025, pages 125 / 175 117 / 155

[00247] For example, the level of CD36 and / or GPVI can be determined by measuring the expression of CD36 or GPVI in the individual's platelets. Expression can be measured, for example, by quantitative Western blotting using antibodies specific for the CD36 or GPVI protein. Expression can also be measured, for example, by Northern blotting or quantitative reverse transcription polymerase chain reaction (RT-qPCR, quantitative quantitative polymerase chain reaction) using probes specific for the CD36 or GPVI mRNA molecule, or by DNA microarrays, for example, as described by Ding, Y., Xu, L., Jovanovic, BD, Helenowski, IB, Kelly, DL, Catalona, ​​WJ, Yang, XJ, Pins, M. and Bergan, RC, 2007. The methodology used to measure differential gene expression affects the result. Journal of Biomolecular Techniques: JBT, 18(5), p. 321.

[00248] For example, the level of the protein product CD36 and / or GPVI can be determined using quantitative mass spectrometry, as described, for example, in Burkhart, JM, Vaudel, M., Gambaryan, S., Radau, S., Walter, U., Martens, L., Geiger, J., Sickmann, A., and Zahedi, RP, 2012. The first comprehensive and quantitative analysis of human plaque protein composition allows comparative analysis of structural and functional pathways. Blood: 120(15), pp. e73-e82. Petition 870250102203, dated 07 / 11 / 2025, pp. 126 / 175 118 / 155

[00249] The expression of CD36 and / or GPVI can also be determined, for example, using RNA sequencing (RNA-seq), such as bulk RNA-seq or single-cell RNA-seq (scRNA-seq) to detect the mRNA transcript of CD36 or GPVI. For example, as described in Kukurba, KR and Montgomery, SB, 2015. RNA sequencing and analysis. Cold Spring Harbor Protocols, 2015(11), pp.pdb-top084970.

[00250] The expression of CD36 and / or GPVI can also be determined, for example, by means of digital PCR (dPCR), to quantify the absolute number of copies of a target DNA or complementary DNA (cDNA) in a sample, as described in Pohl, G. and Shih, IM, 2004. Principle and applications of digital PCR. Specialist Review in Molecular Diagnostics, 4(1), pp. 41-47.

[00251] The expression of CD36 and / or GPVI can also be determined, for example, using fluorescence in situ hybridization (FISH) to detect CD36 and / or GPVI DNA or mRNA molecules in a sample, as described in Young, AP, Jackson, DJ, and Wyeth, RC, 2020. A technical review and guide to RNA fluorescence in situ hybridization. PeerJ, 8, p.e8806 and associated supplementary information.

[00252] CD36 and / or GPVI levels can also be determined using an immunochromatographic test of Petition 870250102203, dated 07 / 11 / 2025, pp. 127 / 175 119 / 155 lateral flow, for example, comprising antibodies specific for the CD36 or GPVI protein, as described in Zhou, G., Mao, X. and Juncker, D., 2012. Immunochromatographic assay on thread. Analytical chemistry, 84(18), pp.7736-7743 and associated supplementary information.

[00253] CD36 and / or GPVI levels can be determined by flow cytometry, for example, using fluorescently labeled antibodies specific for the CD36 or GPVI protein, as described in Ray, FA, Friedrich, TD, Laffin, J. and Lehman, JM, 1996. Protein Quantitation using flow cytometry. In The Protein Protocols Handbook (pp. 33-38). Humana Press. An example of flow cytometry to measure CD36 is described in Cserti-Gazdewich, CM, Dzik, WH, Dorn, ME, Quagliaroli, RO, Xu, S., Ssewanyana, I., Nayyar, R. and Preffer, FI, 2009. Quantitation of CD36 (platelet glycoprotein IV) expression on platelets and monocytes by flow cytometry: application to the study of Plasmodium falciparum malaria. Cytometry Part B: Clinical Cytometry: The Journal of the International Society for Analytical Cytology, 78(2), pp.127-134.

[00254] The CD36 level and / or the GPVI level can be determined indirectly. For example, CD36 activity and / or GPVI activity can be determined, which can indicate the CD36 level and / or the GPVI level. Petition 870250102203, dated 07 / 11 / 2025, pages 128 / 175 120 / 155 respectively. For example, CD36 activity and / or GPVI activity can be assessed using a flow cytometry-based assay that measures platelet activation in response to a platelet-activating substance and / or using a flow cytometry-based assay that measures platelet activation in response to an oxidized lipid agonist of CD36. For example, CD36 activity and / or GPVI activity can be assessed using a flow cytometry-based assay that measures platelet activation in response to a platelet-activating substance and platelet activation in response to an oxidized lipid agonist of CD36.

[00255] The methods of the invention are not limited to any specific method for determining the CD36 and / or GPVI level, and other suitable methods known to those skilled in the art may also be used to determine the CD36 and / or GPVI level.

[00256] Methods for determining the CD36 level and / or the GPVI level may be used in the context of any method of the invention. Treatments

[00257] The invention further relates to the treatment of individuals as described herein, such as the treatment of individuals whose platelet reactivity or sensitivity to a substance Petition 870250102203, dated 07 / 11 / 2025, pp. 129 / 175 The invention relates to the treatment of individuals whose responsiveness to therapeutic treatment with an antiplatelet therapy has been determined by a method of the present invention. The invention relates to the treatment of an individual identified as having hypersensitive platelets by a method of the invention. The invention relates to the treatment of an individual identified as having increased or elevated platelet reactivity or sensitivity to a platelet-activating substance by a method of the invention. The invention relates to the treatment of an individual identified as having an increased risk of a disease, disorder, or condition associated with increased platelet reactivity by a method of the invention. The invention relates to the treatment of an individual identified as suitable for treatment with an antiplatelet therapy by a method of the invention.The invention relates to the treatment of an individual identified as having a reduced risk of bleeding by a method of the invention. The invention relates to the treatment of an individual identified as having hyposensitive platelets by a method of the invention. The invention relates to the treatment of an individual identified as having reduced or low platelet reactivity or sensitivity to a platelet-activating substance by a method of the invention. The invention. Petition 870250102203, dated 07 / 11 / 2025, pages 130 / 175 122 / 155 refers to the treatment of an individual identified as having a reduced risk of a disease, disorder, or condition associated with increased platelet reactivity by a method of the invention. The invention relates to the treatment of an individual identified as unsuitable for treatment with antiplatelet therapy by a method of the invention. The invention relates to the treatment of an individual identified as having an increased risk of bleeding by a method of the invention.

[00258] Thus, a method of the invention, such as a method for determining the responsiveness to therapeutic treatment with an antiplatelet therapy, a method for identifying an individual exhibiting hypersensitive platelets, a method for identifying an individual exhibiting increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, a method for identifying an individual exhibiting an increased risk of a disease, disorder or condition associated with increased platelet reactivity, a method for identifying an individual suitable for treatment with an antiplatelet therapy or a method for identifying an individual exhibiting a reduced risk of bleeding, may comprise an additional step of administering an antiplatelet therapy to the individual.

[00259] A method of the invention, such as a method Petition 870250102203, dated 07 / 11 / 2025, pages 131 / 175 123 / 155 for determining the responsiveness to therapeutic treatment with an antiplatelet therapy, a method for identifying an individual exhibiting hypersensitive platelets, a method for identifying an individual exhibiting increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, a method for identifying an individual exhibiting an increased risk of a disease, disorder or condition associated with increased platelet reactivity, a method for identifying an individual suitable for treatment with an antiplatelet therapy or a method for identifying an individual exhibiting a reduced risk of bleeding, may comprise an additional step of administering an antithrombotic therapy, such as an antiplatelet therapy or an anticoagulant, to the individual.

[00260] In one embodiment, the invention provides a method for treating a disease, disorder or condition associated with increased platelet reactivity, the method comprising: (i) evaluate platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using a method of the invention; and (ii) administer antiplatelet therapy to an individual who has one, two, or three of the following: Petition 870250102203, dated 07 / 11 / 2025, pp. 132 / 175 124 / 155 (a) a high level of CD3 6; (b) a high level of GPVI; and / or (c) the individual is at least 50 years old.

[00261] In some forms, administration is given to an individual who possesses (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c).

[00262] A method is also provided for treating an individual who needs antiplatelet therapy, where the individual presents with: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years.

[00263] In some modalities, the individual presents (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c). The individual may present all three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) an age of at least 50 years.

[00264] In cases where treatment methods are described, the invention also encompasses equivalent medical uses, such as antiplatelet therapies for use in these treatment methods. Thus, a method is also provided for treating a disease, disorder, or condition associated with increased platelet reactivity, the method comprising: Petition 870250102203, dated 07 / 11 / 2025, pp. 133 / 175 125 / 155 (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) determine the individual's age; administer antiplatelet therapy to an individual who has one, two, or three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years.

[00265] In some forms, administration is given to an individual who possesses (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c).

[00266] Antiplatelet therapy is also provided for use in a treatment method for an individual who needs it, the method comprising: (i) evaluate platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using a method of the invention; and (ii) administer antiplatelet therapy to an individual who has one, two, or three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years. Petition 870250102203, dated 07 / 11 / 2025, pp. 134 / 175 126 / 155

[00267] In some forms, administration is given to an individual who possesses (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c).

[00268] Antiplatelet therapy is also provided for use in a method of treating an individual who needs it, the method comprising: (i) determine the CD3 level in a sample comprising the individual's platelets; (ii) determine the GPVI level in a sample comprising the individual's platelets; and / or (iii) determine the individual's age; administer antiplatelet therapy to an individual who has one, two, or three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years.

[00269] In some forms, the administration is given to an individual who possesses (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c).

[00270] Antiplatelet therapy is also provided for use in a treatment method for an individual who needs it, where the individual presents with: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years. Petition 870250102203, dated 07 / 11 / 2025, pp. 135 / 175 127 / 155

[00271] In some modalities, the individual presents (a) and (b), (b) and (c), (a) and (c), or (a), (b) and (c). The individual may present all three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) an age of at least 50 years.

[00272] In any of these treatment methods and medical uses, the method may be a method of treating or preventing a disease, disorder, or condition associated with increased platelet reactivity. In any of these treatment methods and medical uses, antiplatelet therapy may be administered to treat or prevent a disease, disorder, or condition associated with increased platelet reactivity. The disease, disorder, or condition associated with increased platelet reactivity may be any disease, disorder, or condition described herein. For example, in some modalities, antiplatelet therapy may be administered to treat or prevent thrombosis. The sample may be any sample as described herein. The individual may be any individual as described herein. The antiplatelet therapy may be as described herein.

[00273] In any of these medical methods and uses, the method may involve the administration of therapy Petition 870250102203, dated 07 / 11 / 2025, pp. 136 / 175 128 / 155 antiplatelet therapy for an individual who presents one, two, or three of the options (a), (b), and (c), such as (a) and (b), (a) and (c), (b) and (c), or (a), (b), and (c). The method may comprise a step of determining one, two, or three of the options (a), (b), and (c), such as (a) and (b), (a) and (c), (b) and (c), or (a), (b), and (c). The method may determine the presence of one, two, or three of the options (a), (b), and (c), such as (a) and (b), (a) and (c), (b) and (c), or (a), (b), and (c).

[00274] In some modalities, the individual is at least 50 years old.

[00275] In some modalities, the method determines the presence of: (a) a high level of CD36 in the sample; and (b) a high level of GPVI in the sample; where the individual is at least 50 years old.

[00276] In some modalities, the method determines the presence of all three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) the individual is at least 50 years old.

[00277] In addition, the use of an antiplatelet agent in the manufacture of a medicament for the treatment of a disease, disorder or condition associated with increased platelet reactivity is described in this document, wherein the treatment comprises: Petition 870250102203, dated 07 / 11 / 2025, pages 137 / 175 129 / 155 (i) determine the CD3 level in a sample comprising platelets from the individual to be treated; (ii) determine the GPVI level in a sample comprising platelets from the individual to be treated; and / or (iii) determine the age of the individual to be treated. administer the medication to an individual who presents with one, two, or three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) an age of at least 50 years.

[00278] Also described in this document is the use of an antiplatelet agent in the manufacture of a medicament for the treatment of a disease, disorder or condition associated with increased platelet reactivity, and the treatment comprises: (i) evaluate platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual using the method of any of claims 1 to 3; and (ii) administer the drug to an individual who has one, two, or three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) an age of at least 50 years.

[00279] The use of an agent is also foreseen. Petition 870250102203, dated 07 / 11 / 2025, pp. 138 / 175 130 / 155 antiplatelet agent in the manufacture of a medicine for the treatment of a disease, disorder or condition associated with increased platelet reactivity, in which the individual presents: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and / or (c) an age of at least 50 years.

[00280] The individual may exhibit all three of the following: (a) a high level of CD36 in the sample; (b) a high level of GPVI in the sample; and (c) an age of at least 50 years.

[00281] The medical methods and uses described in this document may also be used to select an appropriate antiplatelet therapy for the individual, or to select another appropriate therapeutic method for that individual. For example, if an individual is identified as having increased platelet sensitivity or hypersensitive platelets, subsequent treatment of that patient may be selected to avoid, or reduce the dose of, a platelet agonist, since any platelet agonist may elicit a functional response of increased magnitude in that individual. If an individual is identified as having increased platelet reactivity, subsequent treatment of that patient may be Petition 870250102203, dated 07 / 11 / 2025, pages 139 / 175 131 / 155 selected to include, or increase the dose of, an antiplatelet agent or other antiplatelet therapy in order to reduce any undesirable effects or consequences arising from this increased platelet reactivity. When the methods described herein refer to the administration of antiplatelet therapy, the antiplatelet therapy may be any appropriate antiplatelet therapy as described herein. When the methods described herein refer to the administration of antiplatelet therapy, the antiplatelet therapy may be replaced by, or combined with, any other antithrombotic therapy. For example, if an individual is identified as having increased platelet sensitivity or hypersensitive platelets, the treatment of that patient may be selected to include, or increase the dose of, an antithrombotic agent, such as antiplatelet therapy or an anticoagulant.The treatment of this patient may be selected to include, or increase the use or dose of, an antiplatelet agent, another antiplatelet therapy, or another antithrombotic agent. If an individual is identified as having increased platelet sensitivity or hypersensitive platelets, the treatment of this patient may be selected to avoid, or reduce the use or dose of, an agent that may promote or increase this. Petition 870250102203, dated 07 / 11 / 2025, pages 140 / 175 132 / 155 the risk of thrombosis.

[00282] The use of an alternative to antiplatelet therapy is also provided in a method for treating an individual who needs it, where the individual presents: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) an age less than 50 years old;

[00283] The individual may exhibit all three of the following: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and (c) an age less than 50 years old;

[00284] The method may comprise administering alternative antiplatelet therapy to an individual who presents one, two, or three of the options (a), (b), and (c), such as (a) and (b), (a) and (c), (b) and (c), or (a), (b), and (c). The method may comprise a step of determining one, two, or three of the options (a), (b), and (c), such as (a) and (b), (a) and (c), (b) and (c), or (a), (b), and (c). The method may determine the presence of one, two, or three of the options (a), (b), and (c), such as (a) and (b), (a) and (c), (b) and (c), or (a), (b), and (c).

[00285] These methods can be used to select an appropriate antiplatelet treatment for the individual, or to select another therapeutic method. Petition 870250102203, dated 07 / 11 / 2025, pp. 141 / 175 133 / 155 appropriate for that individual. For example, if an individual is identified as having reduced platelet sensitivity or hyposensitive platelets, subsequent treatment for that patient may be selected to include, or increase the dose of, a platelet agonist, since any platelet agonist may elicit a reduced functional response in that individual. Subsequent treatment for that patient may be selected to exclude, or reduce the dependence on, or dose of, an antiplatelet agent or other antiplatelet therapy, since antiplatelet therapy is less likely to be beneficial in an individual with reduced platelet sensitivity or reactivity.If an individual is identified as having reduced platelet sensitivity or hyposensitive platelets, treatment for that patient may be selected to avoid, or reduce the use or dose of, an antithrombotic agent, such as antiplatelet therapy or an anticoagulant. If an individual is identified as having increased platelet sensitivity or hypersensitive platelets, they may be more susceptible to bleeding, such as unwanted or excessive bleeding. Thus, if an individual is identified as having increased platelet sensitivity or hypersensitive platelets, treatment for that patient may be selected to avoid or reduce this. Petition 870250102203, dated 07 / 11 / 2025, pages 142 / 175 134 / 155 the use or dose of an agent that may promote or increase the risk of bleeding. If an individual is identified as having increased platelet sensitivity or hypersensitive platelets, treatment for that patient may be selected to include, or increase the use or dose of, an agent or other therapy capable of treating or preventing bleeding.

[00286] The terms effective amount or therapeutically effective amount are used interchangeably in this document and refer to an amount of a compound, formulation, material or composition, as described in this document, that is effective in achieving a specific biological result.

[00287] As used in this document, the terms treat, treatment, and treating refer to the reduction or improvement of the progression, severity, and / or duration of a disease, disorder, or condition, or the improvement of one or more symptoms (preferably one or more discernible symptoms) of a disease, disorder, or condition. In specific embodiments, the terms treat, treatment, and treating refer to the improvement of at least one measurable physical parameter of a disease, disorder, or condition associated with increased platelet reactivity, for example, selected from: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, a Petition 870250102203, dated 07 / 11 / 2025, pp. 143 / 175 135 / 155 abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation, such as the growth of a thrombus, not necessarily perceptible to the patient. In other modalities, the terms treat, treatment, and treating refer to inhibiting the progression of a disease, disorder, or condition associated with increased platelet reactivity, either physically, for example, by stabilizing a perceptible symptom, or physiologically, for example, by stabilizing a physical parameter, or both. In other modalities, the terms treat, treatment, and treating refer to reducing or stabilizing the size of a thrombus.In some modalities, the terms treat, treatment, and being treated encompass prophylactic treatment to prevent the onset, progression, worsening, or recurrence of a disease, disorder, or condition associated with increased platelet reactivity, or of symptoms of a disease, disorder, or condition associated with increased platelet reactivity.

[00288] A treatment as described in this document may be therapeutic or prophylactic. The term therapeutic, as used in this document, means a treatment. A therapeutic effect is obtained by the reduction, suppression, remission, or eradication of a pathological state. The term prophylaxis or prophylactic, as used in this document, means the prevention or Petition 870250102203, dated 07 / 11 / 2025, pages 144 / 175 136 / 155 protective treatment of a disease or pathological condition.

[00289] The term antiplatelet therapy refers to therapy designed to decrease platelet aggregation and / or inhibit thrombus formation. In one modality, antiplatelet therapy may be a platelet agglutination inhibitor or a platelet aggregation inhibitor. In one embodiment, antiplatelet therapy may be selected from the group consisting of aspirin, dipyridamole, cyclooxygenase inhibitors (e.g., masoprolol, indomethacin, nabumetone, celecoxib, tolmetin, rofecoxib, piroxicam, fenoprofen, valdecoxib, and / or diclofenac), ADP (P2Y) receptor antagonists (e.g., clopidogrel, prasugrel, ticagrelor, and / or cangrelor), GPVI inhibitors (e.g., glenzocimab, revacept, honokiol, losartan, and / or tussilagone), a drug targeting another platelet receptor, such as a GPIIbIa inhibitor (e.g., tirofiban and / or eptifibatide), and / or a nonsteroidal anti-inflammatory drug (NSAID).Other antiplatelet therapies may be known to those skilled in the art. In one embodiment of the methods described herein, the administration of the antiplatelet therapy does not occur before the method of the invention. In another embodiment of the methods described herein, the administration of the antiplatelet therapy occurs after the method of the invention. The timing of administration is not fixed and... Petition 870250102203, dated 07 / 11 / 2025, pages 145 / 175 137 / 155 in other embodiments, may occur before or during the method of the invention.

[00290] The term individual in need of antiplatelet therapy refers to an individual (e.g., a patient) who has, or is at risk of having, a disease, disorder, or condition that can be treated with antiplatelet therapy, or an individual who is, or will be, on anticoagulant medication, will undergo surgery, and / or is a blood donor, and who may benefit from antiplatelet therapy. Specific, but not limited, examples of surgeries to which an individual may be undergoing or may undergo include: major surgical procedures known to carry a high risk of significant blood loss, cardiothoracic surgery, orthopedic surgery, organ transplantation (e.g., liver, heart, lung, and / or kidney), trauma surgery, brain surgery (e.g., including invasive imaging), and / or vascular surgery.An individual requiring antiplatelet therapy may exhibit elevated levels of platelet reactivity, which can result in adverse effects. Treating the individual with antiplatelet therapy may reduce platelet reactivity in that individual. Treating the individual with antiplatelet therapy may reduce the occurrence or development of adverse effects. Petition 870250102203, dated 07 / 11 / 2025, pages 146 / 175 138 / 155 caused by increased platelet reactivity in this individual. Treatment of the individual with antiplatelet therapy may reduce the response of the individual's hypersensitive platelets to a stimulus, such as a stimulus that would cause blood clotting, for example, surgery.

[00291] As used in this document, the term disease, disorder, or condition refers to a disease, disorder, or pathological condition, for example, associated with increased platelet reactivity. In one embodiment, the disease, disorder, or condition associated with increased platelet reactivity is a cardiovascular disease (CVD), a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection, and / or inflammation. In one embodiment, the cardiovascular disease is a thrombosis, a disease, disorder, or condition comprising or associated with thrombosis, a myocardial infarction, a stroke, a peripheral arterial disease, an aortic disease, and / or a coronary artery disease (CHD). In one embodiment, the individual is, or will be: a recipient of anticoagulant medication, undergoing surgery, and / or a blood donor.

[00292] The term abnormal platelet count, as used in this document, refers to a Petition 870250102203, dated 07 / 11 / 2025, pages 147 / 175 139 / 155 low platelet count (e.g., < 50 x 109 / L). In some modalities, an abnormal or low platelet count may be caused by reduced platelet production by the bone marrow (e.g., in cancer patients due to bone marrow infiltration or iatrogenic causes), increased platelet destruction (e.g., in patients with antibody-mediated thrombocytopenias), increased consumption (e.g., in patients with disseminated intravascular coagulation), or hypersplenism.

[00293] The term abnormal blood condition, as used in this document, refers to a condition in which the blood exhibits abnormal characteristics or function. In some modalities, the abnormal blood condition may be an acquired or congenital defect of platelet function and / or a hereditary bleeding disorder, including, but not limited to: disseminated intravascular coagulation (DIG), prothrombin deficiency, deficiency of factors V, VII or X, factor XI deficiency (hemophilia C), hemophilia A, hemophilia B, idiopathic thrombocytopenic purpura (ITP), Von Willebrand disease (types I, II and III), Glanzmann thrombasthenia and / or an acquired coagulopathy, such as liver disease and / or viral hepatitis.

[00294] The term cancer refers to a disease whose Petition 870250102203, dated 07 / 11 / 2025, pages 148 / 175 140 / 155 Characterization is given by the rapid and uncontrolled growth of abnormal cells. Cancerous cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of different types of cancer are described in this document and include, but are not limited to: breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, and similar cancers. In some modalities, the cancers treated by the methods described in this document include multiple myeloma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. The terms tumor and cancer are used interchangeably in this document and encompass both solid and liquid tumors, for example, diffuse or circulating tumors.As used in this document, the term cancer or tumor includes pre-malignant as well as malignant tumors.

[00295] The appropriate term for treatment with antiplatelet therapy refers to an individual identified as likely to respond to treatment with antiplatelet therapy. In one modality, the individual may be identified as sensitive to a platelet-activating substance such as CRP or CRP-XL. In another modality, the individual may be identified as highly sensitive to Petition 870250102203, dated 07 / 11 / 2025, pages 149 / 175 141 / 155 a platelet-activating substance, such as CRP or CRP-XL. In one embodiment, the individual may be identified as having a high level of CD36 expression in the individual's platelet population. In one embodiment, the individual may be identified as having a high level of GPVI expression in the individual's platelet population. In one embodiment, the individual may be identified as being at least 50 years old. In one embodiment, the individual may be identified as being at least 55 years old.

[00296] The term “not suitable for treatment with antiplatelet therapy” refers to an individual identified as unlikely to respond to treatment with antiplatelet therapy. In one embodiment, the individual may be identified as not sensitive to a platelet-activating substance, such as CRP-XL. In one embodiment, the individual may be identified as not highly sensitive to a platelet-activating substance, such as CRP-XL. In one embodiment, the individual may be identified as having a low level of CD36 expression in the individual's platelet population. In one embodiment, the individual may be identified as having a low level of GPVI expression in the individual's platelet population. In one embodiment, the individual may be identified as being younger than 55 years of age. Petition 870250102203, dated 07 / 11 / 2025, pages 150 / 175 142 / 155 In one embodiment, the individual may be identified as being younger than 50 years of age. In another embodiment, the individual unsuitable for treatment with antiplatelet therapy receives an alternative therapy to antiplatelet therapy. In another embodiment, the individual unsuitable for treatment with antiplatelet therapy receives a modified dose of antiplatelet therapy as described herein, for example, an increased or decreased dose of antiplatelet therapy as described herein. Kits

[00297] Also provided in this document is a kit comprising means for determining the level of CD36 and / or GPVI in a platelet or in a population of platelets from an individual.

[00298] Also provided in this document is a kit for determining whether an individual has, or is at risk of having, a disease, disorder or condition associated with increased platelet reactivity, which comprises means for determining the level of CD36 and / or GPVI in a platelet or in a population of platelets from an individual.

[00299] The means of determination may include an antibody, or fragment or derivative thereof, specific for the protein expression product of CD36 or GPVI. The Petition 870250102203, dated 07 / 11 / 2025, pages 151 / 175 143 / 155 means of determination may include an antibody, or fragment or derivative thereof, specific for CD36 and an antibody, or fragment or derivative thereof, specific for GPVI.

[00300] The kits may be supplied with all the reagents necessary for the detection of the CD36 and / or GPVI molecule. For example, the kits may include markers for the detection of bound antibodies, or probes, reagents for isolation or obtaining mRNA or cDNA from a biological sample obtained from the individual.

[00301] The kits may be provided with instructions for use as a test to determine whether an individual has, or is at risk of having, a disease, disorder or condition associated with increased platelet reactivity. EXAMPLES

[00302] The invention is described in detail with reference to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be interpreted as limited to the following examples, but rather as encompassing any and all variations that become apparent as a result of the teachings provided herein. EXAMPLE 1: IDENTIFICATION AND VALIDATION OF CD36, GPVI AND Petition 870250102203, dated 07 / 11 / 2025, pp. 152 / 175 144 / 155 Age as a biomarker of platelet function. Methods Blood donation and cohorts

[00303] The study was conducted in accordance with Declaration of Helsinki. The selection of healthy, fasting, non-smoking donors aged 30 to 65 years and free from medications known to influence platelet function (cohort 1) was approved by the Research Ethics Committee of the University of Reading. The selection of non-fasting donors aged 18 to 75 years (cohort 2) was approved by the Research Ethics Committee of Cambridge East.

[00304] Biomarkers were determined using platelet samples from healthy volunteers. The analysis was also validated in patients with cardiovascular disease, with and without diabetes. All samples were collected with written informed consent, using processes approved by the university and NHS ethics committees (where applicable), and, in the case of patients, also with approval from the Health Research Authority.

[00305] Patient samples used for biomarker validation were obtained from an ongoing clinical study in collaboration with the University Department of Cardiology at Royal Berkshire NHS. Petition 870250102203, dated 07 / 11 / 2025, pages 153 / 175 145 / 155 Foundation Trust. Platelet function assay

[00306] The flow cytometry assay measured the binding of fluorescein isothiocyanate-conjugated antifibrinogen antibodies and PE-Cy5-conjugated anti-P-selectin antibodies after stimulation with ADP (0.03-30 mM), collagen-related peptide (CRP; 0.003-3 g / mL), epinephrine (0.1-30 mM), thrombin receptor activator peptide 6 (TRAP-6; 0.05-15 mM), and U46619 (0.3-100 mM), using an Accuri C6 (BD, Winnersh, UK) for cohort 1 and a Beckman-Coulter EPICS Profile XL for cohort 2, as described in Supplementary Section 2 of Dunster 2021 (Dunster et al., Multiparameter phenotyping of platelet reactivity for stratification of human cohorts, Blood Adv (2021) 5(20) : 4017-4030) . Platelet phenonomic analysis (PPAnalysis) of sensitivity and capacity

[00307] The Platelet Phenomenal Analysis (PPAnalysis) assay was performed as described in Dunster 2021. PPAnalysis consists of a flow cytometry-based assay and custom software developed to make data analysis simple, fast, and reproducible. The assay simultaneously measures two aspects of platelet activation: fibrinogen binding (a marker of IIbp3 activation) and P-selectin exposure on the platelet surface (a Petition 870250102203, dated 07 / 11 / 2025, pages 154 / 175 146 / 155 marker of alpha granule secretion). The supplementary information accompanying Dunster 2021 provides step-by-step instructions for setting up and running the PPAnalysis assay, as well as for data analysis. In vitro thrombus formation assay

[00308] Thrombus formation on immobilized type I collagen was performed using the VenaFlux platform and Vena8Fluor+ biochips (Cellix). Channels were coated with collagen overnight at 4°C, blocked with 1% BSA / PBS for 1 hour, then washed with PBS. Blood was collected in sodium citrate (4% w / v). Platelets in whole blood were incubated with 10 mM DiOC6 (Thermo Fisher Scientific) for 10 min. Perfusion was performed at 37°C with an arterial shear rate of 1000 s-1 for at least 520 seconds. Thrombus formation was visualized with a 20x magnification lens on a Nikon A1-R confocal microscope. Images were corrected for brightness and converted into a binary mask using automatic thresholds defined by the software. Particles from the binary mask were then analyzed to determine thrombus count and size. Identification of biomarkers through statistical analysis.

[00309] A stepwise two-way linear regression was used to identify possible Petition 870250102203, dated 07 / 11 / 2025, pp. 155 / 175 147 / 155 predictors of sensitivity to a platelet-activating substance, such as CRP-XL, were identified from a set of candidate variables. At each step, variables were included based on p-values, and the AIC was used to define the maximum number of variables included in the final model. Age, CD36 expression, and GPVI expression were identified as predictors of sensitivity to a platelet-activating substance, such as CRP-XL. Biomarker measurement

[00310] To measure levels, for example, the number of copies, of CD36 and GPVI expressed by platelets, a two-site immunoassay in ELISA format is used. Surface levels of CD36 and GPVI can also be measured by flow cytometry. Results GPVI sensitivity to platelet stimulation predicts thrombus formation on collagen.

[00311] The variation in platelet thrombus growth in vitro on type I collagen was measured in a cohort of 27 healthy donors, perfusing citrated whole blood through flow chambers at an arterial shear rate of 1000 s-1 (Figure 1A). Thrombus growth occurred at different rates (Figure 1Bi) and a large variation (7.4 times between the largest and smallest thrombus) was observed after 520 seconds (Figure 1Bii). A Petition 870250102203, dated 07 / 11 / 2025, pp. 156 / 175 Platelet reactivity was also investigated in the same cohort of healthy donors by measuring Pselectin exposure in response to TRAP-6, ADP, and CRP-XL (Figure 1C) using PPAnalysis, which provides two reactivity parameters for each agonist: sensitivity and capacity (Figure 1D). Sensitivity to TRAP-6 showed the least variation, while sensitivity to CRP-XL was highly variable, and ADP exhibited intermediate variability (Figure 1Ei). The variation in capacity was similar for all three agonists (Figure 1Eii). Comparison between each reactivity measure and thrombus size, using Pearson's correlation (Figure 1F), showed a significant correlation only for sensitivity to CRP-XL (Figure 1F). 1Fvi). Age and surface expression of GPVI and CD36 in platelets predict sensitivity to platelet-activating substances.

[00312] Measuring thrombus formation in vitro is impractical in a clinical setting, and even incorporating a platelet reactivity measure, such as PPAnalysis, into clinical trials or routine clinical practice presents a significant financial and logistical challenge. Identifying biomarkers associated with these functional measures facilitates their clinical application. Biomarkers potentially associated with Petition 870250102203, dated 07 / 11 / 2025, pages 157 / 175 149 / 155 sensitivity to platelet-activating substances in a large cohort of 461 healthy donors. Measurement of P-selectin exposure in response to TRAP-6, ADP, and CRP-XL by PPAnalysis identified the same trends of variation in sensitivity and capacity (Figure 2A) previously observed in the smaller cohort (Figure 1E). Surface expression of a series of platelet membrane proteins with potential to influence platelet reactivity was also measured by flow cytometry, and data on age, sex, body mass index (BMI), platelet count, and mean platelet volume (MPV, in femtoliters, fL) were collected (Figures 2B-C).In a randomly selected training cohort (Figure 2D), investigating 18 traits as potential biomarkers of sensitivity to platelet-activating substances, a two-way linear regression model with stepwise selection identified three traits—age, CD36 expression, and GPVI expression—as predictors (Figure 2E). The associations between GPVI expression, CD36 expression, and age versus sensitivity to CRP-XL were investigated by Pearson correlation in the test cohort and were found to be significant (Figure 2Fi-iii). The multiple regression model identified in the training cohort was then used to predict sensitivity to CRP-XL in the test cohort, based on biomarker parameters and values. Petition 870250102203, dated 07 / 11 / 2025, pages 158 / 175 150 / 155 predicted values ​​were plotted against experimentally measured CRPXL sensitivity (Figure 2Fiv). The correlation between CD36 expression and sensitivity to platelet-activating substances increases with age.

[00313] Further investigation of the association between CD36 expression and CRP-XL sensitivity showed that this association is weaker in individuals under 55 years of age (r2= 0.19) than in those 55 years of age or older (r2= 0.36, Figure 3A). The association between GPVI receptor expression and CRP-XL sensitivity was similar between age groups under 55 years (r2= 0.34) and 55 years of age or older (r2= 0.38). This finding suggests that CD36 and GPVI expression have similar predictive value for CRP-XL sensitivity, which is surprising considering that CRP-XL is a GPVI-specific ligand. The ability of GPVI and CD36 expression to predict high sensitivity to platelet-activating substances, such as CRP-XL (upper 33% percentile), was investigated in both age groups using ROC analysis (Figure 3C).The area under the curve (AUC) for CD36 (55.0%) was lower than that of GPVI (66.0%) in the group under 55 years of age, but in the group 55 years of age or older, the AUC of CD36 (72.2%) was higher than that of GPVI (65.8%). Thus, CD36 expression may have high predictive value in patients with ischemic heart disease, a condition that becomes more prevalent with age. Petition 870250102203, dated 07 / 11 / 2025, pp. 159 / 175 151 / 155 of age. Stratification of sensitivity to platelet-activating substances based on age and surface expression of CD36 and GPVI.

[00314] The inventors developed a stratification algorithm using age and CD36 and GPVI expression levels to predict low, medium, or high sensitivity to platelet-activating substances (Figure 4A). The first step stratifies the data based on an age cutoff of 55 years, and all those over 55 years of age are ultimately predicted to have medium or high sensitivity. If age is > 55 years and CD36 expression is high (upper 33rd percentile), sensitivity should be high; if CD36 expression is low but GPVI expression is high (higher 50th percentile), sensitivity is also predicted to be high; but if GPVI expression is also low, sensitivity is predicted to be medium. In individuals under 55 years of age, both CD36 and GPVI expression must be high for sensitivity to platelet-activating substances to be predicted to be high.If CD36 or GPVI expression is high, the predicted sensitivity is medium. The predicted sensitivity will only be low if the age is less than 55 years and both CD36 and GPVI expression are low. When the stratification algorithm was applied to the cohort, they were... Petition 870250102203, dated 07 / 11 / 2025, pp. 160 / 175 152 / 155 identified three groups with significantly different sensitivities to platelet-activating substances (CRP-XL), according to the model predictions (Figure 4B). Stratification of sensitivity to platelet-activating substances and thrombus formation in vitro in a cohort of patients with ischemic heart disease.

[00315] The inventors proceeded to test the stratification algorithm in a cohort of 38 patients with ischemic heart disease, measuring CD36 and GPVI expression and performing the PPAnalysis assay. Sensitivity to platelet-activating substances (CRP-XL) correlated significantly with CD36 and GPVI expression (Figures 5A and 5B). However, the association between sensitivity to platelet-activating substances and age was not significant in this patient cohort (Figure 5C). It was hypothesized that aspirin use might be more prevalent among older patients and that this could counteract the expected positive association between age and sensitivity to platelet-activating substances.In fact, the mean age of patients using ASA (65 ± 8 years) was significantly higher than that of patients not using ASA (58 ± 13 years, Figure 5D), and the sensitivity to CRP-XL of patients receiving ASA (7.2 ± 0.37 log g / mL) was significantly lower than that of patients not using ASA. Petition 870250102203, dated 07 / 11 / 2025, pages 161 / 175 153 / 155 (7.4 ± 0.49 log g / mL, Figure 5E), suggesting that aspirin use in older patients neutralized the expected association between CRP-XL sensitivity and age. The stratification algorithm predicted only 4 patients with low CRP-XL sensitivity, due to the generally high age of the cohort (only 8 patients were under 55 years old, Figure 5F). The differences in mean CRP-XL sensitivity between patients predicted to have high or medium sensitivity were significant; however, comparisons with the low-sensitivity group did not reach statistical significance, possibly due to the small number of patients in that group.

[00316] The volumes of thrombi formed after perfusion of whole blood over type I collagen for 6 minutes at an arterial shear rate of 1000s-1 were measured to investigate the potential of the stratification algorithm in identifying patients prone to large thrombus formation. First, the sensitivity to CRP-XL was compared to thrombus volume, confirming that the previously observed relationship (Figure 1Fiii) was also present in this cohort of patients, with a significant association (Figure 6A). Next, the inventors investigated whether the individual components of the stratification algorithm correlated with thrombus volume. There were significant associations between GPVI expression. Petition 870250102203, dated 07 / 11 / 2025, pages 162 / 175 154 / 155 and CD36 and thrombus volume (Figures 6B and 6C). In contrast to the absence of a significant correlation between CRP-XL sensitivity and age in this cohort, a significant correlation was observed between thrombus volume and age (Figure 6F). The hypothesis that the increased platelet reactivity associated with age would be neutralized by the more frequent use of aspirin in older patients did not apply to thrombus volume measurements, which did not differ significantly between patients with and without aspirin use (Figure 6G). Since the individual components of the stratification algorithm were associated with thrombus volume, the algorithm was applied to these data, revealing that patients predicted to have high CRP-XL sensitivity had significantly larger thrombi than patients predicted to have medium or low sensitivity (Figures 6G and 6I). References Bigalke B, Haap M, Stellos K, Geisler T, Seizer P, Kremmer E, Overkamp D, Gawaz M. Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain. Thromb Res. 2010;125(5):el84189. Dunster JL, Bye AP, Kriek N, Sage T, Mitchell JL, Kempster C, Batista J, McKinney H, Thomas P, Jones CI, Downes K, Unsworth AJ, Gibbins JM. Multiparameter phenotyping of Petição 870250102203, de 07 / 11 / 2025, pág. 163 / 175 155 / 155 platelet reactivity for stratification of human cohorts. Blood Adv. 2021 Oct 26;5 (20) :4017-4030. Knowles JW, Wang H, Itakura H, Southwick A, Myers RM, Iribarren C, Fortmann SP, Go AS, Quertermous T, Hlatky MA. Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction. Am Heart J. 2007; 154(6) :1052-1058 . Sherva R, Miller MB, Pankow JS, Hunt SC, Boerwinkle E, Mosley TH, Weder AB, Curb JD, Luke A, Morrison AC, Fornage M, Arnett DK. A whole genotype scan for stroke or myocardial infarction in families from family blood pressure programs. Stroke. 2008,-39(4):1115-1120. EQUIVALENTS

[00317] The descriptions of each and every patent, patent application, and publication cited in this descriptive report are incorporated herein by reference in their entirety. Although this invention has been described with reference to specific aspects, it is evident that other aspects and variations of this invention may be conceived by other persons skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be interpreted to include all such equivalent aspects and variations. Petition 870250102203, dated 07 / 11 / 2025, pp. 164 / 175

Claims

1 / 16 CLAIMS 1. A method for evaluating platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from an individual, the method characterized in that it comprises: (i) determining the CD36 level in the sample; (ii) determining the GPVI level in the sample; and / or (iii) determining the age of the individual from whom the platelets were obtained.

2. Method according to claim 1, characterized in that the method comprises: (I) (i) determining the CD36 level in the sample; and (ii) determining the GPVI level in the sample; or (II) (i) determining the CD36 level in the sample; and (ii) determining the age of the individual from whom the platelets were obtained; or (III) (i) determining the GPVI level in the sample; and (ii) determining the age of the individual from whom the platelets were obtained.

3. Method according to claim 1, characterized in that the method comprises: (i) determining a CD36 level in the sample; (ii) determining the GPVI level in the sample; and (iii) determining the age of the individual.

4. Method for predicting an individual's response to a therapeutic treatment with an antiplatelet therapy, the method characterized in that it comprises: (i) determining the CD3 level in a sample comprising platelets from the individual; (ii) determining the GPVI level in a sample comprising platelets from the individual; and / or (iii) determining the age of the individual. Optionally, the method comprises assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3.

5. Method for identifying an individual who has hypersensitive platelets, the method characterized in that it comprises evaluating platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative of the presence of hypersensitive platelets: (a) an elevated CD36 level in the sample; (b) an elevated GPVI level in the sample; and / or (c) the individual is at least 50 years of age.

6. Method for identifying an individual exhibiting increased or elevated platelet reactivity or sensitivity to a platelet-activating substance, the method characterized in that it comprises assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative of the presence of increased or elevated platelet reactivity or sensitivity to a platelet-activating substance: (a) an elevated CD36 level in the sample; (b) an elevated GPVI level in the sample; and / or (c) the individual is at least 50 years of age.

7. Method for identifying an individual at increased risk of a disease, disorder or condition associated with increased platelet reactivity, the method characterized in that it comprises assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative that the individual has an increased risk of a disease, disorder or condition associated with increased platelet reactivity or sensitivity to a platelet-activating substance: (a) an elevated CD36 level in the sample; (b) an elevated GPVI level in the sample; and / or (c) the individual is at least 50 years of age.

8. Method for identifying an individual suitable for treatment with antiplatelet therapy, characterized in that it comprises assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative that the individual may be suitable for treatment with antiplatelet therapy: (a) an elevated CD36 level in the sample; (b) an elevated GPVI level in the sample; and / or (c) the individual is at least 50 years of age.

9. Method for identifying an individual with a reduced risk of bleeding, for example, in response to treatment with antiplatelet therapy, the method characterized in that it comprises assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; Petition 870250102198, dated 11 / 07 / 2025, p. 13 / 26 5 / 16 wherein the presence of one, two or three of the following is indicative that the individual has a reduced risk of bleeding: (a) an elevated CD36 level in the sample; (b) an elevated GPVI level in the sample; and / or (c) the individual is at least 50 years of age.

10. A method according to any one of claims 5 to 9, characterized in that it further comprises a step of administering antiplatelet therapy to the individual.

11. A method for treating a disease, disorder, or condition associated with increased platelet reactivity, characterized in that it comprises: (i) assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; and (ii) administering antiplatelet therapy to an individual who has one, two, or three of the following: (a) an elevated CD36 level; (b) an elevated GPVI level; and / or (c) the individual is at least 50 years of age.

12. Method according to any one of claims 5 to 11, characterized in that the method determines the presence of: Petition 870250102198, dated 07 / 11 / 2025, p. 14 / 26 6 / 16 (a) an elevated level of CD36 in the sample; and (b) a high level of GPVI in the sample; wherein the individual is at least 50 years of age.

13. Method according to any one of claims 5 to 11, characterized in that the method determines the presence of all three of the following: (a) an elevated level of CD36 in the sample; (b) an elevated level of GPVI in the sample; and (c) the individual is at least 50 years of age.

14. Antiplatelet therapy for use in a method of treating an individual in need thereof, the method characterized in that it comprises: (iii) assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; and (ii) administering the antiplatelet therapy to an individual who has one, two or three of the following: (a) an elevated CD36 level in the sample; (b) an elevated GPVI level in the sample; and / or (c) the individual is at least 50 years of age.

15. Antiplatelet therapy for use in a method of treating an individual in need thereof, the method characterized by the fact that the individual has: (a) an elevated level of CD36 in their platelets; Petition 870250102198, dated 07 / 11 / 2025, page 15 / 26 7 / 16 (b) an elevated level of GPVI in their platelets; and / or (c) an age of at least 50 years.

16. Antiplatelet therapy for use according to claim 14 or 15, characterized in that the method is a method of treating a disease, disorder or condition associated with increased platelet reactivity.

17. Antiplatelet therapy for use in accordance with any of claims 14 to 16, characterized in that the individual has all three of the following: (a) an elevated CD36 level; (b) an elevated GPVI level; and (c) an age of at least 50 years.

18. Method for identifying an individual with hyposensitive platelets, the method characterized in that it comprises evaluating platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative of the presence of hyposensitive platelets: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and / or (c) the individual is under 50 years of age.

19. Method for identifying an individual unsuitable for treatment with antiplatelet therapy, the method Petition 870250102198, dated 11 / 07 / 2025, page 16 / 26 8 / 16 characterized in that it comprises evaluating platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative that the individual may be unsuitable for treatment with antiplatelet therapy: (a) a reduced CD36 level in the sample; (b) a reduced GPVI level in the sample; and / or (c) the individual is under 50 years of age.

20. Method for identifying an individual at increased risk of bleeding, for example, in response to treatment with antiplatelet therapy, the method characterized in that it comprises assessing platelet reactivity or sensitivity to a platelet-activating substance in a sample comprising platelets from the individual by the method as defined in any one of claims 1 to 3; wherein the presence of one, two or three of the following is indicative that the individual has an increased risk of bleeding: (a) a reduced CD36 level in the sample; (b) a reduced GPVI level in the sample; and / or (c) the individual is under 50 years of age. Petition 870250102198, dated 07 / 11 / 2025, p. 17 / 26 9 / 16 21. A method according to any one of claims 18 to 20, characterized in that the method determines the presence of all three of the following: (a) a reduced level of CD36 in the sample; (b) a reduced level of GPVI in the sample; and (c) the individual is under 50 years of age.

22. Method according to any one of claims 18 to 20, characterized in that the method determines the presence of: (a) a reduced level of CD36 in the sample; and (b) a reduced level of GPVI in the sample; and where the individual is under 50 years of age.

23. A method according to any one of claims 1 to 13, or antiplatelet therapy for use according to any one of claims 14 to 17, characterized in that: (i) the individual is at least 50 years of age; or (ii) the individual is at least 55 years of age.

24. Method according to any one of claims 1 to 4 or 18 to 22, characterized in that: (i) the individual is under 50 years of age; or (ii) the individual is under 45 years of age.

25. Method according to any one of claims 5 to 13 or 23, or antiplatelet therapy for use according to any one of claims 14 to 17 or 23, Petition 870250102198, dated 11 / 07 / 2025, pp. 18 / 26 10 / 16 characterized in that an elevated CD36 level is identified as: (i) a CD36 level that is in the upper 35th percentile compared to a reference population; (ii) a CD36 level that is at least 15% higher than the CD36 level in a control or reference sample comprising platelets; or (iii) a platelet or a platelet population that expresses at least 8,000 copies of CD36 per platelet.

26. Method according to any one of claims 18 to 22 or 24, characterized in that a reduced CD36 level is identified as: (i) a CD36 level that is in the lower 65th percentile compared to a reference population; (ii) a CD36 level that is at least 15% lower than the CD36 level in a control or reference sample comprising platelets; or (iii) a platelet or a platelet population that expresses less than 8,000 copies of CD36 per platelet.

27. A method according to any one of claims 5 to 13, 23 or 25, or antiplatelet therapy for use according to any one of claims 14 to 17, 23 or 25, characterized in that an elevated GPVI level is defined as: (i) a GPVI level that is in the upper percentile of 50 compared to a reference population; (ii) a GPVI level that is at least 15% higher than the GPVI level in a control or reference sample comprising platelets; or (iii) a platelet or a population of platelets that expresses at least 3,000 copies of GPVI per platelet.

28. Method according to any one of claims 18 to 22, 24 or 25, characterized in that a reduced GPVI level is defined as: (i) a GPVI level that is in the lower 50th percentile compared to a reference population; (ii) a GPVI level that is at least 15% lower than the GPVI level in a control or reference sample comprising platelets; or (iii) a platelet or a platelet population that expresses less than 3,000 copies of GPVI per platelet.

29. Method according to any one of claims 1 to 13 or 18 to 28, or antiplatelet therapy for use according to any one of claims 14, 23, 25 or 27, characterized in that the platelet-activating substance is: (i) CRP; (ii) CRP-XL; (iii) ADP; (iv) TRAP-6; Petition 870250102198, dated 07 / 11 / 2025, page 20 / 26 12 / 16 (v) epinephrine; (vi) selected from the group consisting of CRP, CRP-XL, tissue factor, collagen, vWF, PAF, ristocetin, arachidonic acid, ADP, TRAP-6, epinephrine, U46619 and thrombin; or (vii) any two or more different platelet-activating substances, as defined in (i) to (vi).

30. A method according to any one of claims 1 to 13 or 18 to 29, or antiplatelet therapy for use according to any one of claims 14 to 17, 23, 25, 27 or 29, characterized in that the sample: (i) consists of platelets from the individual; (ii) comprises or consists of a population of platelets from the individual; (iii) is an acellular sample; (iv) is whole blood; or (v) is plasma.

31. A method according to any one of claims 1 to 13 or 18 to 30, or antiplatelet therapy for use according to any one of claims 14 to 17, 23, 25, 27 or 29 to 30, characterized in that the sample is obtained from an individual who has not received antiplatelet therapy.

32. Method according to any one of claims 1 to 13 or 18 to 31, or antiplatelet therapy for use in Petition 870250102198, dated 07 / 11 / 2025, p. 21 / 26 13 / 16 according to any one of claims 14 to 17, 23, 25, 27 or 29 to 31, characterized in that the individual has no prior history of a disease, disorder or condition associated with increased platelet reactivity, optionally selected from: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation.

33. A method according to claim 32, or antiplatelet therapy for use according to claim 32, characterized in that the individual has no prior history of cardiovascular disease.

34. A method according to any one of claims 1 to 13 or 18 to 33, or antiplatelet therapy for use according to any one of claims 14 to 17, 23, 25, 27 or 29 to 33, characterized in that the individual has, or is at risk of having, a disease, disorder or condition selected from the following: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation.

35. Method according to any one of claims 1 to 13 or 18 to 34, or antiplatelet therapy for use in Petition 870250102198, dated 07 / 11 / 2025, page 22 / 26 14 / 16 according to any one of claims 14 to 17, 23, 25, 27 or 29 to 34, characterized in that the individual is, or will be: a recipient of anticoagulant medication, undergoing surgery and / or a blood donor.

36. A method according to claim 7 or 11, or antiplatelet therapy for use according to claim 16, characterized in that the disease, disorder or condition associated with increased platelet reactivity is selected from: a cardiovascular disease, a metabolic or endocrine disease, an abnormal blood condition, an abnormal platelet count, a cancer, a response to a bacterial and / or viral infection and / or inflammation.

37. A method according to any one of claims 32 to 34 or 36, or antiplatelet therapy for use according to any one of claims 32 to 34 or 36, characterized in that the cardiovascular disease is selected from the group consisting of thrombosis, myocardial infarction, stroke, peripheral arterial disease, aortic disease and / or coronary artery disease.

38. Method according to any of claims 4, 8 to 11, 19, 31 or any claim dependent thereon, or antiplatelet therapy for use according to any of claims 14 to 17, 31 or any Petition 870250102198, dated 07 / 11 / 2025, p.23 / 26 15 / 16 claim dependent on the same, characterized in that the antiplatelet therapy is: (a) a platelet agglutination inhibitor; (b) a platelet aggregation inhibitor; and / or (c) selected from the group consisting of: aspirin, dipyridamole, cyclooxygenase inhibitors (e.g., masoprolol, indomethacin, nabumetone, celecoxib, tolmetin, rofecoxib, piroxicam, fenoprofen, valdecoxib and / or diclofenac), ADP (P2Y) receptor antagonists (e.g., clopidogrel, prasugrel, ticagrelor and / or cangrelor), GPVI inhibitors (e.g., glenzocimab, revacept, honokiol, losartan and / or tussilagone) and / or a drug that targets another platelet receptor, such as a GPIIbIa inhibitor (e.g., tirofiban and / or eptifibatide), and / or a nonsteroidal anti-inflammatory drug (NSAID).

39. A method according to any one of claims 1 to 13 or 18 to 38, or antiplatelet therapy for use according to any one of claims 14 to 17, 23, 25, 27 or 29 to 38, characterized in that the CD36 level and / or the GPVI level is determined by: (i) an ELISA; (ii) a lateral flow test; (iii) flow cytometry; (iv) an immunoassay; (v) an antibody assay; or (vi) a two-site antibody assay; (vii) quantitative mass spectrometry.

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