Method for treating traumatic brain injury

Abstract

A medicament and method for treating traumatic brain injury (TBI) by using annexin A5 or a variant thereof.

Description

The present application claims priority to the prior application with the patent application No. 17 / 653,579 entitled “METHODS OF TREATING TRAUMATIC BRAIN INJURY” filed with the United States Patent and Trademark Office on March 4, 2022, the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present disclosure relates to a method for treating a traumatic brain injury (TBI), and in particular, relates to a method for treating a traumatic brain injury by using annexin A5 or a variant thereof, and use of the annexin A5 or the variant thereof for the treatment of a traumatic brain injury, a pharmaceutical composition and a preparation thereof, and belongs to the field of biomedicines. BACKGROUND A traumatic brain injury (TBI) is a result of overpressure to the head from a blunt, jolt, or knock that disrupts brain functions. Mild TBI or mTBI subtype represents a part of TBI that is difficult to diagnose. In the present disclosure, mTBI is a subtype of TBI. The terms “mild TBI” (mTBI) and “concussion” are generally used interchangeably in the art and are associated with post-traumatic stress disorder (PTSD). Head injuries may range in severity from temporary changes in mental state or consciousness to persistent unconsciousness and amnesia. In the case of severe or multiple concussions, personality changes may produce devastating results. Every year, 1.5 to 2 million Americans suffer from traumatic brain injuries (Center for Disease Control and Prevention, National Center for Injury Prevention and Control, 2003, Vol. 2003). It is estimated that traumatic brain injuries cause 50,000 deaths and 100,000 hospitalizations each year in the United States. There are over 80,000 persons with disabilities each year, with about 17,000 persons requiring specialized life care (Kraus (1997) Head Injury, ed. Cooper (Williams & Wilkins Co., Baltimore) pp 1-19; Selectki et al. (1982) Australian & New Zealand Journal of Surgery 52(1): 93-102). In addition to the initial injury caused by sudden brain trauma, excessive biomechanical forces may trigger a series of secondary deleterious events that significantly increase lesion size, morbidity, and mortality within days to months following the initial injury (MchAosh et al. (1996) Lab Invest, 74(2):315-42; Stambrook et al. (1990) Can J Surg 33(2): 115-8). Despite such serious problems, no effective drug treatment for human traumatic brain injuries has been identified. Thus, there remains a need for new methods and therapeutic agents for treating traumatic brain injuries. Annexin A5 is a part of the phospholipid-binding protein family, with a molecular weight of about 35 kDa, and can bind to cationic phospholipids (e.g., phosphatidylserine) on the plasma membrane in a calcium-dependent manner. Annexin A5 was first discovered in human placenta in 1970. Its gene is located on chromosome 4q26-q28, with 13 exons and 12 introns. Because of its high molecular weight, it generally does not enter brain tissue. SUMMARY In order to solve the above technical problem, the present disclosure provides a method for treating a traumatic brain injury (TBI) in a patient in need thereof. The method comprises: (a) determining a patient having a traumatic brain injury or suspected of having a traumatic brain injury; and (b) administering to the patient a therapeutically effective amount of annexin A5 or a variant thereof. The present disclosure provides a method for treating a traumatic brain injury (TBI) in a patient in need thereof. The method comprises: (a) determining a patient having a traumatic brain injury or suspected of having a traumatic brain injury; and (b) administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of annexin A5 or a variant thereof. In some embodiments, the annexin A5 or the variant thereof comprises an amino acid sequence having at least 75% (e.g., 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence of SEQ ID NO: 1. In some embodiments, the traumatic brain injury is a mild, moderate, or severe traumatic brain injury. In some embodiments, the traumatic brain injury is caused by a head impact, a penetrating head injury, a non-penetrating head injury, a fall, a skull fracture, a sudden acceleration or deceleration, a concussion, or a contusion. In some embodiments, the patient is a mammal, e.g., a human. In some embodiments, the annexin A5, the variant thereof or the pharmaceutical composition reduces diffuse axonal injury, behavioral disorder, brain tissue injury, brain atrophy, neuronal cell death or apoptosis, microglial activation, or neuronal tissue loss in the patient having the traumatic brain injury. In some embodiments, the annexin A5, the variant thereof or the pharmaceutical composition increases a cerebral blood flow or a cerebral glucose uptake in the patient having the traumatic brain injury. In some embodiments, the annexin A5, the variant thereof or the pharmaceutical composition alleviates one or more symptoms associated with the traumatic brain injury in the patient. In some embodiments, the one or more symptoms associated with the traumatic brain injury include impaired level of consciousness, cognitive impairment, cognitive processing speed impairment, language impairment, motor activity impairment, memory impairment, motor skills impairment, sensory skills impairment, cerebral ischemia, edema, intracranial pressure, hearing loss, tinnitus, headache, seizures, dizziness, nausea, vomiting, blurred vision, decreased sense of smell or taste, decreased physical strength, or decreased coordination. In some embodiments, a first agent such as the annexin A5 or the variant thereof, or the pharmaceutical composition is administered over a period of time from the time of the traumatic brain injury to 4 weeks. In some embodiments, the first agent is administered within about 0 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the occurrence of the traumatic brain injury. In some embodiments, the therapeutically effective amount of the annexin A5 or the variant thereof is between about 0.01 mg / kg and about 10 mg / kg. In some embodiments, the therapeutically effective amount of the annexin A5 or the variant thereof is between about 0.01 mg / kg and about 0.5 mg / kg. In some embodiments, the therapeutically effective amount of the annexin A5 or the variant thereof is about 0.02 mg / kg, 0.06 mg / kg, or 0.2 mg / kg. In some embodiments, the method of the present disclosure further comprises administering to the patient a second agent or therapy. In some embodiments, the second agent or therapy is a cardioprotective medicament or therapy, wherein the cardioprotective medicament or therapy comprises one of beta blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering therapies, statins, nitrates, antiplatelet drugs, anticlotting agents, and anticoagulation agents or a combination thereof, and the above medicaments are used in therapies. In some embodiments, the step of determining a patient having a traumatic brain injury comprises performing a computed tomography (CT) scan or magnetic resonance imaging (MRI) on the patient. In some embodiments, the patient is identified as having the traumatic brain injury based on a modified neurological severity score (mNSS), rotarod test, Glasgow Coma Scale score, or Glasgow Outcome Scale score. In some embodiments, the mNSS or Glasgow Coma Scale score is between 3 and 8, 9 and 12, or 13 and 15. In some embodiments, if the mNSS or Glasgow Coma Scale score is below a reference level, the patient is identified as having the traumatic brain injury. In some embodiments, the reference level is obtained from a reference subject who has not suffered a head injury. In some embodiments, the step of identifying a patient having a traumatic brain injury comprises: determining a level of a biomarker in a sample from the patient; comparing the level of the biomarker with a reference level of the biomarker; and identifying the patient as having the traumatic brain injury if the determined level of the biomarker is increased as compared to the reference level of the biomarker. In some embodiments, the biomarker can be IL-1 P, TNF-a, IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, or phosphorylated Tau. In some embodiments, the sample is obtained after a patient's head is subjected to a physical shock, a blunt impact of an external mechanical force or other forces resulting in closed or open head trauma, one or more falls, explosions, blasts, solid explosions, gas explosions or other types of blunt trauma. In some embodiments, the sample is selected from a whole blood sample, a serum sample, a cerebrospinal fluid sample, and a plasma sample. In another aspect, the present disclosure further provides a method for reducing a level of a biomarker in a patient having a traumatic brain injury. The method comprises: (a) determining a patient having a traumatic brain injury; and (b) administering to the patient a therapeutically effective amount of annexin A5 or a variant thereof or a pharmaceutical composition comprising a therapeutically effective amount of the annexin A5 or the variant thereof; wherein the biomarker comprises a cytokine selected from: IL-1P, TNF-a and IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, and phosphorylated Tau. In some embodiments, the therapeutically effective amount of the annexin A5 or the variant thereof is an amount that causes the annexin A5 or the variant thereof to increase or decrease the level of the biomarker by at least 5%, 10%, 20%, 30%, 40%, or 50%. The present disclosure further provides use of annexin A5 or a variant thereof for the manufacturing of a medicament. The present disclosure further provides a pharmaceutical composition, wherein the pharmaceutical composition comprises annexin A5 or a variant thereof, preferably a therapeutically effective amount of the annexin A5 or the variant thereof. In some embodiments, the medicament is for use in one, two or more of the following uses selected from: treating and / or preventing a traumatic brain injury, for example a mild, moderate or severe traumatic brain injury; reducing diffuse axonal injury, behavioral disorder, brain tissue injury, brain atrophy, neuronal cell death or apoptosis, microglial activation in a patient having the traumatic brain injury, or neuronal tissue loss in a patient having the traumatic brain injury; increasing a cerebral blood flow or a cerebral glucose uptake in a patient having the traumatic brain injury; alleviating one or more symptoms associated with the traumatic brain injury in a patient, for example, impaired level of consciousness, cognitive impairment, cognitive processing speed impairment, language impairment, motor activity impairment, memory impairment, motor skills impairment, sensory skills impairment, cerebral ischemia, edema, intracranial pressure, hearing loss, tinnitus, headache, seizures, dizziness, nausea, vomiting, blurred vision, decreased sense of smell or taste, decreased physical strength, or decreased coordination; and reducing a level of a biomarker in a patient having the traumatic brain injury, for example, IL-lp, TNF-a and IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, and phosphorylated Tau; for example, wherein the medicament increases or decreases the level of the biomarker by at least 5%, 10%, 20%, 30%, 40%, or 50%. For example, the annexin A5 or the variant thereof comprises an amino acid sequence having at least 90% sequence identity to an amino acid sequence of SEQ ID NO: 1 or comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the traumatic brain injury is a mild, moderate or severe traumatic brain injury; for example, the traumatic brain injury is caused by a head impact, a penetrating head injury, a non-penetrating head injury, a fall, a skull fracture, a sudden acceleration or deceleration, a concussion, or a contusion; for example, the patient is a human; preferably, the medicament is in a unit dosage form; for example, the amount of the annexin A5 or the variant thereof in the medicament is between about 0.01 mg / kg and about 10 mg / kg of a patient's body weight, such as between about 0.01 mg / kg and about 0.5 mg / kg of the patient's body weight, e.g., about 0.02 mg / kg, 0.06 mg / kg, or 0.2 mg / kg of the patient's body weight; for example, the medicament is in a unit dosage form, and the amount of the annexin A5 or the variant thereof in the unit dosage form is 0.025 mg to 250 mg, such as 0.1 mg to 50 mg, 0.1 mg to 100 mg, 0.1 mg to 200 mg, or 0.1 mg to 250 mg, or 1 mg to 50 mg, 1 mg to 100 mg, 1 mg to 200 mg, or 1 mg to 250 mg. In some embodiments, the medicament is administered over a period of time from the time of the traumatic brain injury to 4 weeks, preferably within about 0 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the occurrence of the traumatic brain injury. More preferably, a first agent is administered to the patient within about 12 hours after the occurrence of the traumatic brain injury; for example, the medicament further comprises a cardioprotective medicament; for example, the cardioprotective medicament is selected from beta blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering therapies, statins, nitrates, antiplatelet drugs, anticlotting agents, and anticoagulation agents, or a combination thereof. The foregoing is not intended to limit every aspect of the present disclosure. Other aspects of the present disclosure are described elsewhere herein, for example, in the following detailed description. The present application is intended in its entirety as a unified and correlated disclosure. It should be understood that any combination of all features described herein should be considered as a technical solution described in the present disclosure even if it does not exist simultaneously in the same sentence, paragraph or section of the present application. Other features and advantages of the present disclosure will be described in more detail by the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments of the present disclosure, are intended for purposes of illustration only and that various changes and modifications made by those skilled in the art within the spirit and scope of the present disclosure shall fall within the protection scope of the claims of the present application. BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A and IB show the dose-dependent effect of the annexin A5 treatment on post-TBI neurological outcomes. FIG. 1A shows the results of mNSS, and FIG. IB shows the results of rotarod test (###P < 0.001, as compared to the sham group; *P < 0.05, as compared to the model group; **P< 0.01, as compared to the model group; ***P < 0.001, as compared to the model group; n = 10). In the figures, mNSS score represents the scores of mNSS, Fall latency represents the fall latency period, Sham represents the sham group, and Model represents the model group. FIG. 2 shows that the administration of annexin A5 significantly reduces TUNEL positive cells in the injured brain of post-TBI rats (###P < 0.001, as compared to the sham group; *P < 0.05, as compared to the model group; t-test, n = 5). In the figure, TUNEL positive cells represent the positive cell quantity, Sham represents the sham group, and Model represents the model group. FIG. 3 shows that the administration of 0.2 mg / kg annexin A5 significantly reduces GFAP positive cells in the injured brain of post-TBI rats (###P < 0.001, as compared to the sham group; *P < 0.05, as compared to the model group, t-test, n = 5). In the figure, Mean Fluorescence (arbitrary units) represents the mean fluorescence (arbitrary units), Sham represents the sham group, and Model represents the model group. FIG. 4 shows the effect of the annexin A5 treatment on post-TBI neurofunctional outcomes. In the figure, the top is the results of mNSS, and the bottom is the results of rotarod test. (###P < 0.001, as compared to the sham group; ***P < 0.001, as compared to the model group; n = 5). In the figures, mNSS score represents the scores of mNSS, Fall latency represents the fall latency period, Sham represents the sham group, Model represents the model group, A5 One Dose represents a dose of A5 given alone, and Time represents the time. FIG. 5 shows the effect of the annexin A5 treatment on post-TBI neurofunctional outcomes. In the figure, the top is the results of mNSS, and the bottom is the results of rotarod test. (###P < 0.001, as compared to the sham group; ***P < 0.001, as compared to the model group; n = 5). In the figures, mNSS score represents the scores of mNSS, Fall latency represents the fall latency period, Sham represents the sham group, Model represents the model group, A5 One Dose represents a dose of A5, and post-TBI represents after the TBI. FIG. 6 shows IL-ip, TNF-a and IFN-y levels in brain tissue (###P < 0.001, as compared to the sham group; **P < 0.01, as compared to the model group, n = 5). In the figure, protein represents the protein, Sham represents the sham group, and Model represents the model group. FIG. 7 is a graph showing the results of the effect of an annexin A5 solution on neurological deficit symptoms according to the embodiments of the present disclosure. FIG. 8 is a graph showing the results of the effect of the annexin A5 solution on the cerebral infarct size according to the embodiments of the present disclosure. FIG. 9 is a graph showing the results of the effect of annexin A5 on OGD injury of primary cortical neurons according to the embodiments of the present disclosure. FIG. 10 is a graph showing the results of the protective effect of annexin A5 on NMDA-induced excitatory injury in rat primary cortical neurons according to the embodiments of the present disclosure. FIG. 11 is a graph showing the results of detecting the content of EB in brain tissue by annexin A5 according to the embodiments of the present disclosure. DETAILED DESCRIPTION The embodiments described below with reference to the drawings are exemplary and are intended to explain the present disclosure rather than be construed as limiting the present disclosure. The inventors have surprisingly found that annexin A5 is capable of alleviating one or more symptoms caused by a traumatic brain injury (TBI). Thus, annexin A5 and a variant thereof represent an effective method for treating a traumatic brain injury in a patient. Method for treating a traumatic brain injury In one aspect, the present disclosure provides a method for treating a traumatic brain injury in a patient in need thereof. The method comprises: (a) determining a patient having a traumatic brain injury or suspected of having a traumatic brain injury; and (b) administering to the patient a therapeutically effective amount of annexin A5 or a variant thereof or a pharmaceutical composition comprising a therapeutically effective amount of the annexin A5 or the variant thereof. In some embodiments, the traumatic brain injury is a mild, moderate or severe traumatic brain injury. In some embodiments, the traumatic brain injury can be caused by a head impact, a penetrating head injury, a non-penetrating head injury, a fall, a skull fracture, an injury due to a sudden acceleration or deceleration, a concussion, or a contusion. In some embodiments, the patient is a mammal, e.g., a human. In some embodiments, the annexin A5 or the variant thereof reduces diffuse axonal injury, behavioral disorder, brain tissue injury, brain atrophy, neuronal cell death or apoptosis, microglial activation, or neuronal tissue loss in the patient having the traumatic brain injury. In some embodiments, the annexin A5 or the variant thereof reduces diffuse axonal injury or symptoms associated therewith. In some embodiments, the annexin A5 or the variant thereof increases a cerebral blood flow or a cerebral glucose uptake in the patient having the traumatic brain injury. In some embodiments, the annexin A5 or the variant thereof alleviates one or more symptoms associated with the traumatic brain injury in the patient. In some embodiments, the one or more symptoms associated with the traumatic brain injury include impaired level of consciousness, cognitive impairment, cognitive processing speed impairment, language impairment, motor activity impairment, memory impairment, motor skills impairment, sensory skills impairment, cerebral ischemia, edema, intracranial pressure, hearing loss, tinnitus, headache, seizures, dizziness, nausea, vomiting, blurred vision, decreased sense of smell or taste, decreased physical strength, or decreased coordination. Annexins belong to the phospholipid-binding protein family, are widely expressed and have many important functions. Annexin A5 is a calcium-dependent phospholipid-binding protein that binds to the surface of negatively charged phospholipids. Annexin A5 has a molecular weight of 35 kDa (see SEQ ID NO: 1), and is predominantly present in the cell membrane and endoplasmic reticulum. Radiolabeled annexin A5 can be distributed in the brain as an imaging agent. In addition, annexin A5 has the functions of anti-inflammation, anti-coagulation, and improvement of endothelial injury and organ dysfunction. Annexin A5 entering the brain can be used for treating brain diseases such as traumatic brain injuries. Annexin A5 useful in the disclosed methods includes, but is not limited to, a full-length native human annexin A5 polypeptide or a variant / fragment thereof. The A5 polypeptide may be provided from any source or method, such as natural isolate or recombinant or synthetic sources or suitable combinations of the above. The polypeptide sequence of annexin A5 may be based on complete or partial native amino acid sequences or variants of these complete or partial native amino acid sequences. The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acids of any chain length. The polymer may be linear or branched, may comprise modified amino acids, and may be interrupted by the insertion of non-amino acids. These terms further include amino acid polymers modified, for example, by disulfide bonding, glycosylation, lipidation, acetylation, phosphorylation, pegylation, or any other manipulation (e.g., conjugation to a labeling component). As used herein, the term “amino acid” includes natural and / or unnatural or synthetic amino acids, including glycine and D or L optical isomers, as well as amino acid analogs and peptidomimetics. As used herein, a peptide or polypeptide “fragment” refers to a peptide, polypeptide, or protein with a length less than its full length. For example, a peptide or polypeptide fragment may have a length of at least about 3, at least about 4, at least about 5, at least about 10, at least about 20, at least about 30, or at least about 40 amino acids, or a unit length thereof. For example, a fragment may be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or more amino acids in length. There is no upper limit for the size of the peptide fragment. However, in some embodiments, the peptide fragment may be less than about 500 amino acids in length, less than about 400 amino acids in length, less than about 300 amino acids in length, or less than about 250 amino acids in length. As used herein, the term “variant” refers to a first component (e.g., a first molecule) in relation to a second component (e.g., a second molecule, also referred to as a “parent” molecule). Variant molecules may be derived from, isolated from, based on, or homologous to the parent molecule. The term variant may be used to describe a polynucleotide or polypeptide. When applied to polynucleotides, variant molecules may have complete nucleotide sequence identity to the original parent molecule, or may have less than 100% nucleotide sequence identity to the parent molecule. For example, a variant of a nucleotide sequence of a gene may be a second nucleotide sequence that is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or more identical in the nucleotide sequence as compared to the original nucleotide sequence. Polynucleotide variants also include polynucleotides comprising the entire parent polynucleotide, and further comprise other fused nucleotide sequences. Polynucleotide variants also include polynucleotides that are a part or subsequence of a parent polynucleotide; for example, the present disclosure further includes unique subsequences of the polynucleotides disclosed herein (e.g., as determined by standard sequence comparison and alignment techniques). When applied to proteins, variant polypeptides may have complete amino acid sequence identity to the original parent polypeptide, or may have less than 100% amino acid identity to the parent protein. For example, a variant of an amino acid sequence may be a second amino acid sequence that is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or more identical in the amino acid sequence as compared to the original amino acid sequence. Polypeptide variants include polypeptides comprising the entire parent polypeptide, and further comprise other fused amino acid sequences. Polypeptide variants also include polypeptides that are a part or subsequence of a parent polypeptide; for example, unique subsequences of the polypeptides disclosed herein (e.g., as determined by standard sequence comparison and alignment techniques) are also included in the present disclosure. As used herein, a “functional variant” of a protein refers to a variant of a protein that at least partially retains the activity of the protein. Functional variants may include mutants (which may be insertion, deletion or substitution mutants), including polymorphs, etc. Also included in functional variants are fusion products of such a protein with another, usually unrelated, nucleic acid, protein, polypeptide or peptide. Functional variants may be naturally occurring or may be artificial. Variants of annexin A5 may be (i) variants in which one or more amino acid residues are substituted with a conservative amino acid residue or a non-conservative amino acid residue, e.g., a conservative amino acid residue, and such substituted amino acid residue may or may not be encoded by a genetic code; (ii) variants in which one or more modified amino acid residues are present, e.g., variants in which one or more residues are modified by linking a substituent; (iii) those the polypeptides of which are mutated splice variants of the polypeptides of the present disclosure; (iv) fragments of a polypeptide; and / or (v) variants in which the polypeptide is fused with other polypeptides which are, for example, a leader or secretory sequence or a sequence for purification (e.g., His-tag) or for detection (e.g., Sv5 epitope tag). These fragments include polypeptides produced by proteolytic cleavage (including multi-site proteolysis) of the original sequence. Variants may be post-translational or chemically modified. It should be understood that acquiring and applying such variations falls within the ability of those skilled in the art based on the teachings herein. The percent identity between two amino acid sequences may be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 residue weight table, with a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the algorithm of Needleman and Wunsch (J. Mol. Biol. 48:444453 (1970)), which has been incorporated into the GAP program in the GCG software package (available at www.GCG.com), using either the Blossum62 matrix or the PAM250 matrix, with a gap weight of 16, 14, 12, 10, 8, 6 or 4 and a length weight of 1, 2, 3, 4, 5 or 6. Or, the protein sequences of the present disclosure may be further used as “query sequences” to search public databases, for example, to identify related sequences. Such a search may be performed using theXBLAST program (version 2.0) of Altschul et al. (1990) J. Mol. Biol. 215:40310. BLAST protein searches may be performed using the XBLAST program (score = 50, word length = 3) to obtain amino acid sequences homologous to the antibody molecule of the present disclosure. To acquire gapped alignments for comparison purposes, gapped BLAST may be as described in Altschul et al. (1997) Nucleic Acids Res. 25(17):3389-3402. When BLAST and gapped BLAST programs are used, default parameters for the respective programs (e.g., XBLAST and NBLAST) may be used (see www.ncbi.nlm.nih.gov). For the determination of protein sequence identity, the included values are those defined by NCBI as “identities” and do not take into account residues which are not conserved but have similar properties. In some embodiments, the detectable tags may be conjugated or linked to the N- and / or C-terminus of annexin A5. The detectable tags and affinity tags may also be separated by one or more amino acids. In some embodiments, a detectable tag may be conjugated or linked to a variant by a cleavable element. In the context of the present disclosure, the term “cleavable unit” relates to a peptide sequence that is susceptible to cleavage by a chemical reagent or enzymatic means (e.g., a protease). The protease may be sequence-specific (e.g., thrombin) or may have limited sequence specificity (e.g., trypsin). Cleavable units I and II may also be included in the amino acid sequence of the detection tag or polypeptide, particularly where the last amino acid of the detection tag or polypeptide is K or R. As used herein, the term “conjugate” or variation thereof, or “link” or variation thereof refers to two or more entities linked to form one entity. Conjugates include peptide-small molecule conjugates and peptide-protein / peptide conjugates. The term “fusion polypeptide” or “fusion protein” refers to a protein produced by linking two or more polypeptide sequences together. Fusion polypeptides encompassed in the present disclosure include a translation product of a chimeric gene construct that links a nucleic acid sequence encoding a first polypeptide to a nucleic acid sequence encoding a second polypeptide to form a single open reading frame. In other words, a “fusion polypeptide” or “fusion protein” is a recombinant protein of two or more proteins linked via peptide bonds or several peptides. The fusion protein may further comprise a peptide linker between two domains. In some embodiments, annexin A5 comprises an amino acid sequence having at least 75% (e.g., 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 1. In some embodiments, annexin A5 comprises the amino acid sequence of SEQ ID NO: 1. (SEQ ID NO: 1) AQVLRGTVTDFPGFDERADAETLRKAMKGLGTDEESILTLLTSRSNAQRQEISAAFKTLF GRDLLDDLKSELTGKFEKLIVALMKPSRLYDAYELKHALKGAGTNEKVLTEIIASRTPEEL RAIKQVYEEEYGSSLEDDWGDTSGYYQRMLWLLQANRDPDAGIDEAQVEQDAQALFQ AGELKWGTDEEKFITIFGTRSVSHLRKVFDKYMTISGFQIEETIDRETSGNLEQLLLAWK SIRSIPAYLAETLYYAMKGAGTDDHTLIRVMVSRSEIDLFNIRKEFRKNFATSLYSMIKGDT SGDYKKALLLLCGEDD Annexin A5 capable of repairing or alleviating injuries such as traumatic brain injuries and the like may be a full-length or partial amino acid sequence of a natural human annexin A5 polypeptide, or may be a variant of a full-length or partial amino acid sequence of a natural human annexin A5 polypeptide. The manufacturing or acquisition of these natural annexins or variants may be based on any source or method, e.g., direct isolation from naturally occurring substances, direct artificial synthesis or any combination of these methods. For example, useful annexin A5 has at least 97% or at least 98%, such as at least 98.5%, at least 98.8% or at least 99%, e.g., at least 99.3% or at least 99.5%, or at least 99.6% sequence identity to the native full-length human annexin A5. These amino acid sequences, which show identities to the native full-length human annexin A5, may show differences of one amino acid, two amino acids, three amino acids, four amino acids, or even five, six or seven amino acids. These amino acid differences may be conservative amino acid substitutions with amino acids in the native full length human annexin A5 sequence. “Conservative amino acid substitution” may refer to the substitution of an amino acid residue with another amino acid residue having biological, chemical, or structural similarity. Structural similarity means that the amino acids have side chains of similar length, such as alanine, glycine or serine, or side chains of similar size. Chemical similarity means that the amino acids have the same charge or are both hydrophilic or hydrophobic. For example, the hydrophobic residues isoleucine, valine, leucine or methionine are substituted with one another. Or, polar amino acids, such as arginine, glutamic acid, glutamine and serine are substituted with lysine, aspartic acid, asparagine, and threonine, respectively. The above-mentioned amino acid sequences showing identities or sequences showing conservative amino acid substitutions may be acquired by artificial design synthesis, or may be present directly in other species in nature. It has been found that annexin A5 is conserved and shows high identity in different species. The amino acid sequence set forth in SEQ ID NO: 1 is identical to the amino acid sequence of native human annexin A5 except that the amino acid of the N-terminus of the sequence set forth in SEQ ID NO: 1 is alanine (A), while the amino acid of the N-terminus of native human annexin A5 is acetylated alanine. Therefore, the variation sites and variant amino acids present in different species shown in Table 1 below are compared with the amino acid sequence of SEQ ID NO: 1, reflecting the differences between the annexin A5 sequence and the native human annexin A5 in different species in nature. Compared with the sequence of SEQ ID NO: 1, a mutation is present in Gorilla with the amino acid at position 3 being mutated from valine to isoleucine. For another example, it has been reported in the document J. Mol. Biol. 223 (3), 683704 (1992) and the document J. Mol. Biol. 223 (3), 683-704 (1992) that there is also a mutation in the native human annexin in humans, i.e., the amino acid at position 76 is mutated from glutamic acid to glutamine or from glutamic acid to glycine as compared to native human annexin A5. The variation sites and corresponding variant amino acids present in some species as compared to the sequence of SEQ ID NO: 1 are listed in Table 1 below. These sequences are available from NCBI according to NCBI Access Number or directly from corresponding reference documents. Table 1. Variation sites and variant amino acids present in different species as compared to SEQ ID NO: 1 Species Corresponding sites in SEQ ID NO: 1 Mutation NCBI Access Number or reference documents Gorilla 3 V^I XP 004040389.1 Human 76 E—>Q J. Mol. Biol. 223 (3), 683-704 (1992) Human 76 E^G J. Mol. Biol. 223 (3), 683-704 (1992) Human 134 S^L CAG38759.1 Lipotes vexillifer 53-54 SA^AV XP 007464903.1 207 K^R Orcinus orca 53-54 SA^AV XP 004265141.1 207 K^R 318 D^E Tursiops truncatus 53-54 SA^AV XP_004321032.1 207 K^R 272 M^V Lagenorhynchus obliquidens 53-54 SA^AV XP 026959424.1 207 K^R 272 M^V 88 R^Q Nomascus leucogenys 141 G^E XP 003271381.1 209 F^L 317-318 ED^GE Delphinapterus leucas 1-3 AQV^SQA XP_022451968.1 53-54 SA^AV 207 K^R Macaca fascicularis 105 N^D NP 001270160.1 317-318 ED^GE Saimiri boliviensis 54 A^E XP_010345019.1 51 E^K 315 C—>CG According to some embodiments of the present disclosure, the annexin A5 is native human annexin A5. According to some embodiments of the present disclosure, the annexin A5 or a functional equivalent thereof is recombinant human annexin A5 expressed in a prokaryotic expression system. 5 Therefore, the recombinant human annexin A5 may be quickly and efficiently acquired by a prokaryotic expression system and is inexpensive. In addition, it has been proved that recombinant human annexin A5 has no immunotoxicity and has very low immunogenicity. The tolerated dose of A5 protein is higher than 4500 pg / kg in rats and cynomolgus monkeys, and even higher than 9000 pg / kg in rats. In some embodiments of the present disclosure, the amino acid sequence of io annexin A5 expressed by a prokaryotic expression system is set forth in SEQ ID NO: 1. The amino acid sequence set forth in SEQ ID NO: 1 is identical to the amino acid sequence of native human annexin A5. Annexin A5 is efficiently and quickly available and has proven to be very safe, causing no risk of drug use even at high doses. It has important value in the treatment of traumatic brain injuries. In addition, it has been found that the sequence of annexin A5 is conserved and has high identity in different species and plays a similar or identical role. The highly homologous or conserved annexin A5 sequences may be used for treating traumatic brain injuries or manufacturing medicaments for traumatic brain injury. For example, in some embodiments of the present disclosure, the sequence identity of annexin A5 is more than 96% as compared to native human annexin A5, or more than 96.5%, 97%, 97.5%, 98%, 98.3%, 98.5%, 98.8%, 99%, 99.3% or 99.5% as compared to the sequence set forth in SEQ ID NO: 1, for example. In some embodiments, annexin A5 comprises one conservative amino acid substitution, two conservative amino acid substitutions, three conservative amino acid substitutions, four conservative amino acid substitutions, or five conservative amino acid substitutions as compared to SEQ ID NO: 1. These highly homologous or conservative amino acid substitutions of annexin A5 may be synthesized by artificial design or codon optimization, or isolated or synthesized from native annexin A5. According to some embodiments of the present disclosure, the annexin A5 or the functional equivalent thereof is in an injectable form. Annexin A5 may be used in single or multiple applications. Annexin A5 may be administered by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intrathecal injection, nasal spray, or oral spray. Annexin A5 may also be administered for short-term, rapid administration, including but not limited to, rapid intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intrathecal injection, nasal spray, oral spray, etc. Annexin A5 may be administered in a sustained exposure manner, including but not limited to, sustained slow intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intrathecal injection, etc. Considering that annexin A5 belongs to protein drugs, lyophilized powder or other injection drugs with specific specifications are preferably used for manufacturing injection liquid to achieve rapid treatment in vivo and high bioavailability. According to the embodiments of the present disclosure, the annexin A5 or the functional equivalent thereof is administered. In some embodiments, the dose of the annexin A5 or the variant thereof is 0.01 mg / day to 500 mg / day, preferably 2 mg / day to 200 mg / day. For example, the dose may be 0.01 mg / day to 500 mg / day or 0.01 mg / day to 450 mg / day, such as 0.01 mg / day to 400 mg / day, 0.01 mg / day to 350 mg / day, 0.01 mg / day to 300 mg / day, 0.01 mg / day to 250 mg / day, 0.01 mg / day to 200 mg / day, etc. In addition, the dose of A5 protein or a variant thereof may be less, such as, 0.01 mg / day to 100 mg / day, or 0.01 mg / day to 10 mg / day, in some patients having a mild traumatic brain injury. In one example, if the daily dose of annexin A5 is about 0.05 mg to 500 mg, the content of annexin A5 or a variant thereof in a unit dosage form may be adapted to be 0.025 mg to 250 mg, such as 0.1 mg to 50 mg, 0.1 mg to 100 mg, 0.1 mg to 200 mg or 0.1 mg to 250 mg, or 1 mg to 50 mg, 1 mg to 100 mg, 1 mg to 200 mg or 1 mg to 250 mg, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or 200 mg. By manufacturing a proper annexin A5 injection, the treatment of traumatic brain injuries is achieved, and the injection is safe, non-toxic and free of side effects. A drug in unit dosage form refers to a unit dosage form designed to manufacture a drug into different dosage forms. For example, if the tablet is sized to 400 mg, 400 mg is the unit dosage form of the drug. For example, the drug is designed as injections, each of the injections is individually packaged as a unit dosage form. Typically, the unit dosage form of the drug is used as a daily dose for one day or a daily dose for half a day. The content of annexin A5 in these unit dosage forms may vary between 0.025 mg and 250 mg, and the annexin A5 is formulated together with other pharmaceutically acceptable carriers into unit dosage forms. In some embodiments, the therapeutically effective amount of annexin A5 is between about 0.01 mg / kg and about 10 mg / kg. In some embodiments, the therapeutically effective amount of annexin A5 is between about 0.01 mg / kg and about 0.5 mg / kg. In some embodiments, the therapeutically effective amount of annexin A5 is about 0.02 mg / kg, 0.06 mg / kg, or 0.2 mg / kg. In some embodiments, a first agent, such as the annexin A5 or the variant thereof, or the pharmaceutical composition is administered over a period of time from the time of the traumatic brain injury to 4 weeks. In some embodiments, a first agent is administered within about 0 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the occurrence of the traumatic brain injury. In some embodiments, a first agent is administered to the patient within about 12 hours after the occurrence of the traumatic brain injury. In some embodiments, a first agent is administered to the patient about 12 hours (e.g., 12 hours) after the occurrence of the traumatic brain injury. In some embodiments, the annexin A5 is administered to a patient as a single-dose treatment, three-dose QD (once daily) treatment, QD treatment (e.g., for 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or 20 days), or BID (twice daily) treatment (e.g., for 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or 20 days). In some embodiments, the pharmaceutical composition comprises a second agent or therapy, such as an anti-inflammatory agent. The anti-inflammatory agent may be selected from aceclofenac, acemetacin, acetylsalicylic acid, 5-aminoacetylsalicylic acid, aldofenac, amfenac, bendazac, benoxaprofen, bermoprofen, bromfenac, 5-bromoacetate salicylic acid, butyrchloric acid, butibufen, caffeic acid, carprofen, cromoglycate, cinmethacin, clinnamic acid, clopirac, diclofenac sodium, diflunisal, 3,4-dihydroxybenzoic acid, enfenamic acid, etodolac, felbinac, fenbufen, fenclonic acid, fendosal, fenoprofen, fentizole, flufenac, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, 1-hydroxynaphthoic acid, ibufenac, ibuprofen, indomethacin, indoprofen, isofezolac, isoxacic acid, ketoprofen, ketorolac, loxoprofen, meclofenamic acid, mefenamic acid, mesalamine, 3,4-methylenedioxycinnamic acid, metiazinic acid, mofezolac, montelukast, mycophenolic acid, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, pyrazolac, pirprofen, pranoprofen, protizinic acid, sulindac, suprofen, suxibutazone, tiaprofenic acid, tinoridine acid, tolfenamic acid, tolmetin, tropesin, xenbucin, ximoprofen, zaltoprofen, and zomepirac. In some embodiments, the method of the present disclosure further comprises administering to the patient a second agent or therapy. In some embodiments, the administration of a second agent or therapy is carried out before, after, or together with the administration of the annexin A5. In some embodiments, the second agent or therapy is a cardioprotective medicament or therapy, wherein the cardioprotective medicament or therapy comprises one of beta blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering therapies, statins, nitrates, antiplatelet drugs, anticlotting agents, and anticoagulation agents or a combination thereof, and the above medicaments are used in therapies. In some embodiments, the step of determining a patient having a traumatic brain injury comprises performing a computed tomography (CT) scan or magnetic resonance imaging (MRI) on the patient. In some embodiments, the patient is identified as having the traumatic brain injury based on a modified neurological severity score (mNSS), rotarod test, Glasgow Coma Scale score, or Glasgow Outcome Scale score. In some embodiments, the mNSS or Glasgow Coma Scale score is between 3 and 8, 9 and 12, or 13 and 15. In some embodiments, the step of identifying the patient as having the traumatic brain injury comprises: determining a level of a biomarker in a sample from the patient; comparing the level of the biomarker to a reference level of the biomarker; and identifying the patient as having the traumatic brain injury if the determined level of the biomarker is increased as compared to the reference level of the biomarker. In some embodiments, the biomarker may be IL-1 P, TNF-a, IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, or phosphorylated Tau. In some embodiments, the annexin A5, the variant thereof or the pharmaceutical composition (e.g., the annexin A5 and / or the variant thereof used in combination with a second agent or therapy) increases or decreases the level of the biomarker by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, or 300%. In some embodiments, the sample is obtained after a patient's head is subjected to a physical shock, a blunt impact (resulting in closed or open head trauma) of an external mechanical force or other forces, one or more falls, explosions, or blasts, or other types of blunt trauma. In some embodiments, the sample is selected from a whole blood sample, a serum sample, a cerebrospinal fluid sample, and a plasma sample. In another aspect, the present disclosure further provides a method for reducing a level of a biomarker in a patient having a traumatic brain injury. The method comprises: (a) identifying a patient having a traumatic brain injury; and (b) administering to the patient a therapeutically effective amount of annexin A5 or a variant thereof or a pharmaceutical composition comprising a therapeutically effective amount of the annexin A5 or the variant thereof, wherein the biomarker comprises a cytokine selected from IL-1 P, TNF-a and IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, and phosphorylated Tau. In some embodiments, the pharmaceutical composition comprises a second agent or therapeutic agent, such as an anti-inflammatory agent. In some embodiments, the method of the present disclosure further comprises administering to the patient a second agent or therapy. In some embodiments, the administration of a second agent or therapy is carried out before, after, or together with the administration of the annexin A5. In some embodiments, the annexin A5, the variant thereof or the pharmaceutical composition (e.g., the annexin A5 and / or the variant thereof used in combination with a second agent or therapeutic agent) increases or decreases the level of the biomarker by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, or 300%. In some embodiments, the therapeutically effective amount of the annexin A5 or the variant thereof is an amount that causes the annexin A5 or the variant thereof to increase or decrease the level of the biomarker by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, or 300%. Composition In the treatment of traumatic brain injuries, a pharmaceutical composition comprising annexin A5 and a variant thereof may be provided. The pharmaceutical composition for use according to the present method may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. Thus, annexin A5 may be formulated for administration by, for example, injection, inhalation or insufflation (through mouth or nose) or oral, buccal, parenteral or rectal administration. In one embodiment, the agent is administered topically, e.g., at a site where target cells are present, e.g., by use of a patch. The pharmaceutical composition may be formulated for various amounts of administration, including systemic or local administration. Such techniques and preparations are commonly found in Remmington’s Pharmaceutical Sciences, Meade Publishing Co., Easton, PA. For systemic administration, injections are preferred, including intramuscular, intravenous, intraperitoneal or subcutaneous injections. For injections, the agents may be formulated in liquid solutions, preferably in physiologically compatible buffers, such as Hank’s solution or Ringer’s solution. In addition, these agents may be formulated in a solid form and redissolved or suspended immediately prior to use. The pharmaceutical composition of the present disclosure further comprises lyophilized forms. For oral administration, the pharmaceutical composition may take the form of, for example, tablets, lozenges or capsules. The tablets, lozenges or capsules can be prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fdlers (e.g., lactose, microcrystalline cellulose or dicalcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium dodecyl sulfate). Tablets can be coated by methods well known in the art. Liquid preparations used for oral administration can take the form of, for example, solutions, syrups or suspensions, or can be presented as a dry product together with water or other suitable vehicle prior to use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous carriers (e.g., cationic oils, oily esters, ethanol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl paraben or sorbic acid). The preparations may also contain buffer salts, flavouring agents, colorants, and sweeteners as appropriate. Preparations for oral administration may be suitably formulated to control the release of the active compound. Pharmaceutical compositions that may be oxidized and lose biological activity, particularly those in liquid or semi-solid form, may be prepared under nitrogen atmosphere or sealed in an oxygen-free capsule and / or foil package (e.g., Capsugel™). For inhalation administration, the agent may be conveniently delivered in the form of an aerosol spray from a pressurized package or atomizer, with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., gelatin capsules and cartridges) for use in an inhaler or insufflator may be formulated in the form of a powder mixture containing agents and a suitable powder matrix (such as lactose or starch). The pharmaceutical composition may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Preparations for injection may be presented in unit dosage form, e.g., ampoules or multi-dose containers, with the addition of a preservative. These reagents may be present in the form of suspensions, solutions or emulsions in oily or aqueous carriers, and may contain preparation adjuvants, such as suspending agent, stabilizer and / or dispersants. Or, the active ingredients may be in a powder form for mixing with a suitable carrier (e.g., a sterile pyrogen-free water) before use. These reagents may also be formulated into rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the preparations described above, the pharmaceutical composition may also be formulated into long-acting preparations. Such long-acting preparations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the reagents may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins or as slightly soluble derivatives (e.g., as a slightly soluble salt). Controlled release preparations further include patches, such as transdermal patches. The patch can be used with a sonic applicator that deploys ultrasound in a unique waveform combination to introduce drug molecules that are not normally effectively delivered transdermally into the skin. In some embodiments, the pharmaceutical composition (including a cosmetic preparation) can comprise about 0.00001% to 100%, e.g., 0.001% to 10% or 0.1% to 5%, by weight of one or more reagents described in the present disclosure. The pharmaceutical composition described herein may also be incorporated into a topical preparation containing topical preparation adjuvants typically suitable for topical administration and containing any such materials known in the art. The topical carrier may be selected to provide the composition in a desired form, such as an ointment, emulsion, cream, microemulsion, gel, oil, solution, or the like, and may be composed of materials of natural or synthetic origin. Preferably, the carrier is selected so as not to adversely affect the active agent or other components of the topical preparation. Examples of suitable topical carriers for use herein include water, alcohols and other non-toxic organic solvents, glycerin, mineral oil, silicone, petrolatum, lanolin, fatty acids, vegetable oils, parabens, waxes, etc. In some embodiments, the preparation may be a colorless and odorless ointment, emulsion, cream, microemulsion, and gel. The pharmaceutical composition may be incorporated into an ointment, which is typically a semi-solid preparation, typically based on petrolatum or other petroleum derivatives. As will be appreciated by those skilled in the art, the particular ointment base used will provide optimal drug delivery, and preferably, will also provide other desirable characteristics, such as moisturizing and the like. Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and insensitive. As explained by Remington, ointment bases may be divided into four classes: oily bases, emulsified bases, emulsion bases, and water-soluble bases. For example, oleaginous ointment bases include vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsified ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearic acid sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Exemplary water-soluble ointment bases are prepared from polyethylene glycols (PEGs) of different molecular weights. Please refer to the Remington’s book described above for more information. In some embodiments, the pharmaceutical composition may be incorporated into an emulsion which is typically a preparation that is applied to the skin surface without friction, and is typically a liquid or semi-liquid preparation in which solid particles, including the active agent, are present in water or alcohol bases. Emulsions are typically solid suspensions and may comprise liquid oilin-water emulsions. Emulsions are the preferred preparation for treating large areas of the body because it is easier to apply more liquid ingredients. It is generally necessary to finely divide the insoluble matters in the lotion. Emulsions generally contain suspending agents to produce better dispersions, and compounds for locating and maintaining the active agent in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose and the like. An exemplary emulsion preparation for use in conjunction with the present method comprises propylene glycol mixed with hydrophilic petrolatum, for example, commercially available from Beiersdorf, Inc. (Norwalk, Conn.) under the trademark Aquaphor™. In some embodiments, the pharmaceutical composition can be incorporated into a cream which is typically a viscous liquid or semisolid emulsion in a form of oil-in-water or water-in-oil. The cream base is water-washable and comprises an oily phase, an emulsifier and an aqueous phase. The oily phase is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase typically (although not necessarily) exceeds the oily phase in volume and typically contains a humectant. As described in the Remington’s book above, the emulsifier in the cream preparation is typically a nonionic, anionic, cationic or amphoteric surfactant. In some embodiments, the pharmaceutical composition can be incorporated into a microemulsion which is generally a thermodynamically stable, isotropic, transparent dispersion of two immiscible liquids (e.g., oil and water), stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9). For the manufacturing of microemulsions, surfactants (emulsifiers), cosurfactants (coemulsifiers), an oily phase and an aqueous phase are necessary. Suitable surfactants include any surfactant that can be used to manufacture an emulsion, such as the emulsifiers typically used to manufacture creams. Cosurfactants (or “coemulsifiers”) are generally selected from polyglycerol derivatives, glycerol derivatives and fatty alcohols. Preferred combinations of emulsifier / coemulsifier are generally, although not necessarily, selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; caprylic and capric triglycerides and oleoyl macrogolglycerides. The aqueous phase comprises not only water but typically also buffers, glucose, propylene glycol, and polyethylene glycol, preferably a low molecular weight of polyethylene glycol (e.g., PEG 300 and PEG 400) and / or glycerol and the like, while the oily phase typically comprises, for example, fatty acid esters, modified vegetable oils, silicone oils, a mixture of mono-, di- and tri-glycerides, mono- and di-esters of PEG (e.g., oleoyl macrogolglycerides), etc. In some embodiments, the pharmaceutical composition may be incorporated into a gel preparation which is typically a suspension consisting of small inorganic particles (a two-phase system) or a semi-solid system consisting of large organic molecules substantially uniformly distributed throughout a carrier liquid (a single-phase gel). For example, the active agent, the carrier liquid and a suitable gelling agent such as tragacanth (2-5%), sodium alginate (2-10%), gelatin (2-15%), methylcellulose (3-5%), sodium carboxymethylcellulose (2-5%), carbomer (0.3-5%) or polyvinyl alcohol (10-20%) can be mixed together until a characteristic semi-solid product is produced. Other suitable gelling agents include methylhydroxycellulose, polyoxyethylene-polyoxyethylene, hydroxyethylcellulose and gelatin. While an aqueous carrier liquid is typically used in gels, alcohols and oils may also be used as carrier liquids. Various additives known to those skilled in the art may be included in the preparation, such as topical preparations. Examples of additives include, but are not limited to, solubilizers, skin penetration enhancers, clouding agents, preservatives (e.g., antioxidants), gelling agents, buffering agents, surfactants (particularly nonionic and amphoteric surfactants), emulsifiers, emollients, thickeners, stabilizers, humectants, colorants, fragrances, and the like. It is particularly preferred to include solubilizers and / or skin penetration enhancers as well as emulsifiers, emollients, and preservatives. The optimal topical preparation comprises about: 2% to 60% by weight, preferably 2% to 50% by weight of a solubilizer and / or a skin penetration enhancer; 2% to 50% by weight, preferably 2% to 20% by weight of an emulsifier; 2% to 20% by weight of an emollient; and 0.01% to 0.2% by weight of a preservative, wherein the active agent and the carrier (e.g., water) constitute the remainder of the preparation. Skin penetration enhancers are used to enhance a therapeutic level of the active agent to penetrate through a reasonably sized area of unbroken skin. Suitable enhancers are well known in the art and include, for example: lower alkanols such as methanol, ethanol and 2-propanol; alkyl methyl sulfoxides such as dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (Cio MSO), and tetradecyl methyl sulfoxide; pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone and N-(hydroxyethyl)pyrrolidone; urea; N,N-diethyl-m-toluamide; C2-6 alkanediol; other solvents, such as dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tetrahydro furfuryl alcohol; and 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecyl -azacycloheptan-2-one (laurocapram; commercially available from Whitby Research Incorporated of Richmond, Virginia under the trademark AzoneRTM). Examples of solubilizers include, but are not limited to, the following substances: hydrophilic ethers, such as diethylene glycol monoethyl ether (ethoxydiglycol, commercially available as Transcutol™) and diethylene glycol monoethyl ether oleate (commercially available as softcutol™); polyethylene castor oil derivatives, such as polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil and the like; polyethylene glycols, particularly a low molecular weight of polyethylene glycol, such as PEG 300 and PEG 400, and polyethylene glycol derivatives, such as PEG-8 caprylic / capric glycerides (commercially available as Labrasol™); alkyl methyl sulfoxides such as DMSO; pyrrolidones, such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers may also act as absorption enhancers. A single solubilizer may be incorporated into the preparation or a mixture of solubilizers may be incorporated therein. Suitable emulsifiers and coemulsifiers include, but are not limited to, those described with respect to microemulsion preparations. Emollients include, for example, propylene glycol, glycerin, isopropyl myristate, propylene glycol-2 (PPG-2) myristyl ether propionate, etc. In some embodiments, other active agents such as anti-inflammatory agents, analgesics, antibacterial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunscreens commonly found in sunscreen preparations may also be included in the preparations, including, but not limited to, anthranilates, benzophenones (particularly benzophenone-3), camphor derivatives, cinnamates (e.g., octyl methoxycinnamate), dibenzoylmethanes (e.g., butyl methoxydibenzoylmethane), p-aminobenzoic acid (PABA) and derivatives thereof, and salicylates (e.g., octyl salicylate). In certain topical preparations, the active agent is present in an amount of about 0.25% to 75% by weight of the preparation, preferably about 0.25% to 30% by weight of the preparation, more preferably about 0.5% to 15% by weight of the preparation, and most preferablyabout 1.0% to 10% by weight of the preparation. The topical skin treatment composition may be packaged in a suitable container to suit its viscosity and intended use by consumers. For example, the lotion or cream may be packaged in a bottle or roll-ball applicator, or in a propellant-driven aerosol device or a container equipped with a pump suitable for finger operation. When the composition is cream, it may simply be stored in a non-deformable bottle or a squeeze container, such as a tube or lidded jar. The composition may also be contained in capsules such as those described in U.S. Patent 5,063,507. Thus, a closed container containing a cosmetically acceptable composition is also provided. In some embodiments, a pharmaceutical preparation for oral or parenteral administration is provided, in which case the preparation may comprise the microemulsion as described above containing the active compound, and may comprise alternative pharmaceutically acceptable carriers, vehicles, additives and the like which are particularly suitable for oral or parenteral administration. Or, the microemulsion containing the active compound may be administered orally or parenterally, substantially as described above, without modification. Definitions To facilitate an understanding of the composition and the method according to the present disclosure, some explicit definitions are provided herein in order to explicitly disclose various aspects of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. As used herein, “patient” refers to both human and non-human animals. Examples of non-human animals include all vertebrates, e.g., mammals, such as non-human mammals, non-human primates (particularly higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats, and rabbits, as well as non-mammals, such as birds, amphibians, reptiles, and the like. In one embodiment, the patient is a human. In another embodiment, the patient is a laboratory animal or an animal suitable as a disease model. As used herein, “treatment”, “treat” or variation thereof refers to the administration of a compound or agent to a patient having a disease with the purpose of curing, alleviating, relieving, remedying and delaying the onset of the disease, preventing or ameliorating the disease, the symptoms of the disease, a disease state secondary to the disease, or susceptibility to the disease. An “effective amount” or “therapeutically effective amount” refers to an amount of a compound or medicament that is capable of producing a medically desirable result in a treated subject. The treatment method may be performed in vivo or ex vivo, alone or in combination with other drugs or therapies. A therapeutically effective amount may be administered in one or more administrations, applications or doses and is not limited to a specific preparation or route of administration. As used herein, the term “in vitro” refers to events occurring in an artificial environment, such as in a test tube or reaction vessel, in cell culture, etc., rather than in a multicellular organism. As used herein, the term “in vivo” refers to an event that occurs in a multicellular organism, such as a non-human animal. The term “disease” as used herein is generally synonymous to and is used interchangeably with the terms “disorder” and “condition” (as in medical conditions), as all reflect abnormal conditions of the human or animal body or a part thereof that impair normal function, often manifested as obvious signs and symptoms, and result in a reduction in the longevity or the quality of life of the human or animal. The terms “reduce”, “decrease”, “alleviate”, and “inhibit” and variation thereof are used herein to generally refer to a statistically significant amount of decrease. However, for the avoidance of doubt, “reduce”, “decrease”, “alleviate” or “inhibit” or variation thereof refers to a decrease of at least 10% as compared to a reference level, such as a decrease of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absence as compared to a reference sample), or any decrease between 10% and 100% as compared to a reference level. As used herein, the term “modulate” or its variant refers to any change, i.e., increase, decrease, etc., in a biological state. The terms “increase”, “improve”, “enhance”, and “activate” and variations thereof as used herein generally mean an increase in a statically significant amount. For the avoidance of any doubt, the terms “increase”, “improve”, “enhance” and “activate” and variation thereof refer to an increase of at least 10% as compared to a reference level, such as an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10% and 100% as compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold or at least about 10-fold increase, or any increase of 2-fold to 10-fold or more as compared to a reference level. The term “effective amount” or “effective dose” is defined as an amount sufficient to achieve, or at least partially achieve, the desired effect. A “therapeutically effective amount” or “therapeutically effective dose” of a medicament or therapeutic agent refers to any amount of the medicament that, when used alone or in combination with another therapeutic agent, promotes disease regression, as manifested by a decrease in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic phases, or the prevention of damage or disability due to the affliction of the disease. A “prophylactically effective amount” or “prophylactically effective dose” of a medicament refers to an amount of the medicament that, when administered alone or in combination with another therapeutic agent to a patient at risk of disease progression or recurrence, inhibits disease progression or recurrence. The ability of a therapeutic or prophylactic agent to promote disease regression or inhibit disease progression or recurrence may be assessed using various methods known in the art, for example in human patients during clinical trials, in animal model systems that predict human efficacy, or by measuring the activity of an agent in an in-vitro assay. The dosage is usually associated with body weight. Thus, a dose expressed as [g, mg or other unit ] / kg (or g, mg, etc.) generally refers to [g, mg or other unit ] “per kg (or g, mg, etc.) of body weight”, even if the phrase “body weight” is not explicitly mentioned. The terms “reagent” and “agent” are used herein to represent a compound, a mixture of compounds, a biological macromolecule (e.g., a nucleic acid, an antibody, a protein or a portion thereof, such as a peptide) or an extract made from biological materials, such as bacteria, plants, fungus or animals (in particular mammalians) cells or tissues. The activity of these medicaments may make them suitable as “therapeutic agents”, a biologically, physiologically or pharmacologically active substance (or substances) that act(s) locally or systemically in a patient. The terms “therapeutic agent”, “medicament capable of treating”, and “treating agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effects when administered to a patient. Beneficial effects include enabling diagnostic assays; amelioration of a disease, symptom, disorder, or pathological condition; reduction or prevention of the onset of a disease, symptom, disorder, or condition; usually counteracting a disease, symptom, disorder, or pathological condition. As used herein, unless clearly indicated in the context otherwise, the “combination” therapy is meant to include administration of two or more therapeutic agents in a coordinated manner, and includes, but is not limited to, simultaneous administration. In particular, the combination therapy includes co-administration (e.g., administration of a compound preparation or simultaneous administration of separate therapeutic compositions) and continuous or sequential administration, provided that administration of one therapeutic agent is dependent in some way on administration of another therapeutic agent. For example, a therapeutic agent can only be administered after a different therapeutic agent has been administered and allowed to act over a defined period of time. See, for example, Kohrt et al. (2011) Blood 117:2423. “Sample”, “test sample”, and “patient sample” are used interchangeably herein. The sample may be a sample of serum, urine plasma, amniotic fluid, cerebrospinal fluid, cells (e.g., antibodyproducing cells), or tissues. Such samples may be obtained directly from the patient or may be pretreated by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to alter the properties of the sample, as described herein or otherwise known in the art. The terms “sample” and “biological sample” as used herein generally refer to a biological material that is being tested for and / or suspected of containing an analyte of interest (e.g., an antibody). The sample may be any tissue sample from a patient. The sample may comprise proteins from a patient. The terms “inhibit” and “antagonize” as used herein refer to a decrease in the expression, stability, function or activity of a molecule, reaction, interaction, gene, mRNA and / or protein or the complete prevention thereof in a measurable amount. Inhibitors are compounds, e.g., antagonists, that bind to, partially or completely block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down-regulate the stability, expression, function, and activity of proteins, genes, and mRNAs. “Parenteral” administration of the composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection or infusion techniques. As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound used in the present disclosure with other chemical ingredients (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). The pharmaceutical composition facilitates the administration of the compound to an organism. There are a variety of techniques in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. As used herein, the term “pharmaceutically acceptable” refers to materials, such as carriers or diluents, that do not eliminate the biological activity or properties of the composition and are relatively non-toxic. These materials may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components contained in the composition. The term “pharmaceutically acceptable carrier” includes a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid fdler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the disclosed compound in or to a patient such that it can perform its intended function. Typically, these compounds are carried or transported from one organ or part of the body to another organ or another part of the body. Each salt or carrier has to be “acceptable” in the sense of being compatible with the other ingredients of the preparation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and derivatives thereof, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; Scutellariae radix powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, soybean oil, and the like; glycol, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethanol; phosphate buffer solution; diluents; granulating agents; lubricants; binders; disintegrants; wetting agents; emulsifiers; colorants; mold release agents; coating agents; sweeteners; flavoring agents; fragrances; preservatives; antioxidants; plasticizers; gelling agents; thickeners; hardening agents; coagulants; suspending agents; surfactants; humectants; carriers; stabilizers; and other non-toxic compatible materials used in pharmaceutical preparations, or any combination thereof. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial agents and antifungal agents, and absorption delaying agents, and the like, that are compatible with the activity of the compound and are physiologically acceptable to a patient. Supplementary active compounds may also be incorporated into the composition. As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound for administration that is prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. It is noted herein that, as used in this specification and the appended claims, the singular forms include plural referents unless clearly dictated in the context otherwise. Unless otherwise indicated, the terms “comprise”, “include”, “contain”, “have” and variations thereof are intended to cover the items listed thereafter and equivalents thereof as well as other subject matter. The phrases “in one embodiment”, “in various embodiments”, “in some embodiments”, and the like are used repeatedly. These phrases should not be construed to refer to the same embodiment, but they may refer to the same embodiment unless dictated in the context otherwise. The term “and / or” or refers to any item, any combination of items, or all items associated with the term. The term “substantially” does not exclude “completely”, e.g., a composition that is “substantially free” of Y may be completely free of Y. The term “substantially” may be omitted from the definitions of the present disclosure as necessary. As used herein, the term “about” or “approximately” as applied to one or more numerical values refers to values similar to the referenced values. In some embodiments, the term “about” or “approximately” refers to a range of values that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the stated reference value, unless otherwise stated or dictated in the context otherwise (unless the number exceeds 100% of the possible values). Unless otherwise indicated herein, the term “about” or “approximately” is intended to include values, e.g., weight percentages, close to the stated range that are equivalent in function of an individual ingredient, composition, or example. It should be understood that in the context of the values and ranges provided herein, all values and ranges encompassed within these values and ranges are intended to be encompassed within the present disclosure. Moreover, all values falling within these ranges, as well as upper or lower limits of the range of values, are also contemplated by the present application. As used herein, the term “each”, when used to refer to a collection of items, is intended to identify a single item in the collection, but does not necessarily refer to every item in the collection. Exceptions may occur if the explicit disclosure or context clearly dictates otherwise. The use of any and all examples, or exemplary expressions (e.g., “such as” or “as”) provided herein, is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure unless otherwise claimed. Any description in the specification should not be construed as an admission that any of the non-claimed features are essential to the practice of the present disclosure. The word “exemplary” when used in this document is intended to mean “by way of example”, rather than indicating that a particular exemplary item is preferred or required. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. With respect to any of the methods provided, the steps of the method may occur simultaneously or sequentially. When steps of a method occur in sequence, the steps may occur in any order, unless otherwise specified. Where a method includes a combination of steps, each combination or sub-combination of steps is included within the scope of the present disclosure unless otherwise indicated herein. Each of the publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety, but are not inconsistent with the present disclosure. The publications disclosed herein are provided solely for their disclosure prior to the filing date of the present disclosure. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior invention. In addition, the issued date provided may be different from the actual issued date, and may require independent confirmation. It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of the present application and the scope of the appended claims. Examples Example 1 This example describes the experimental design and materials and methods used in the following examples. The experiment was performed as follows: 1.1. Experiment 1 To investigate whether annexin A5 (A5) has a therapeutic effect on the traumatic brain injury, A5 was administered at doses of 0.02 mg / kg, 0.06 mg / kg and 0.2 mg / kg immediately after a traumatic brain injury (TBI) model was established. The same dose of A5 was then administered at 6 hours, 24 hours, 30 hours and 48 hours post-TBI. The sham and model groups were treated in parallel with the same volume of vehicle. Nervous system outcome was assessed using a modified neurological severity score (mNSS) and a rotarod test at 24 hours, 48 hours, and 72 hours post-TBI. Apoptosis and glial activation levels were assessed using TUNEL method and immunofluorescence observation, respectively. 1.2. Experiment 2 To further assess the time course of neurological protection of A5 on TBI animals, A5 was administered as a single-dose treatment, three-dose QD (once daily) treatment, QD treatment for 7 days, and BID (twice daily) treatment for 7 days. All A5 treatments were first performed immediately after the TBI model was established. The mNSS assessment and the rotarod test were performed at 24 hours, 48 hours, 72 hours and 168 hours post-TBI. 1.3. Experiment 3 The therapeutic time window (i.e., the time interval between the onset of TBI and the start of treatment) is a key element of drugs for TBI treatment. Most drugs tested in the animal TBI model would lose efficacy with increasing time interval between injury and first treatment. For example, the N-type Ca2+ channel blocker ziconotide improved mitochondrial function when first administered at 15 minutes post-moderate TBI in rats, but rapidly lost efficacy when first administered at 1-10 hours post-TBI. Rats to be treated for TBI were divided into four A5 treatment groups to determine the possible therapeutic time window for A5, where 0.2 mg / kg of A5 was given immediately at (0 hours), 3 hours, 6 hours and 12 hours post-TBI. The same dose was given at 6 hours, 24 hours, 30 hours and 48 hours post-TBI. The mNSS test and the rotarod test were performed at 24 hours, 48 hours, and 72 hours post-TBI. At the end of the experiment, cytokine levels in the ipsilateral hemisphere were assessed by ELISA method. 1. Materials and methods 1.1. Animals All animal care and experimental procedures were in compliance with the guidelines of the Animal Management Regulations of the Ministry of Health of the People’s Republic of China (Document No. 55, 2001) and were approved by the Experimental Animal Ethics Committee of the Chinese Academy of Medical Sciences. Adult male Sprague-Dawley rats (200-220 g) were obtained from Vital River Laboratories Technology Co., Ltd. (Beijing, China). Animals were kept in a temperature-controlled (21-26 °C) room at 45-70% humidity on a 12-hour light / dark cycle with ad libitum access to standard rodent feed and water. 1.2. Surgical procedures and drug management The rats anesthetized with isoflurane were intubated and placed in a stereotaxic frame (Model 6801, RWD Life Science Co., LTD, Shenzhen, China). A craniectomy with a diameter of 5 mm was performed 1 mm posterior to the bregma and 2 mm lateral to the sagittal suture in the right hemisphere, and the bone flap was removed using a portable drill. TBI was induced using a modified Feeney’s weight-drop injury (WDI) model by pushing a 5-mm impact bar into the exposed parietal cortex and then dropping 40 g of body weight from a height of 25 cm. Rats in the sham group received surgery without the effects of vehicle treatment. Test compounds or vehicles (0.7% saline) were administered intravenously as described in the Experimental Design section. After the surgery, animals were fed under the same conditions as described above. 1.3. Assessment of neurological function Nervous system outcome was assessed using a modified neurological severity score (mNSS), a multi-functional assessment scale consisting of sensory, balance, motor, and reflex tests (Table 2). 5   This measurement was performed by an observer blinded to individual treatment. The neurological score was 0-18 (normal score was 0; maximum defect score was 18). The higher the score was, the more severe the nerve damage was. Table 2. Modified neurological severity score (mNSS) Test Point Motion test Lifting rat with tail Flexion of forelimbs 1 Flexion of hindlimbs 1 Head movement over 10° (vertical axis) 1 Placing rat on the ground Incapable of walking straight 1 Rotation to paralytic side 1 Fall down to paralytic side 1 Sensory test Visual and tactile placement 1 Proprioception test (deep sensation) 1 Beam balance test Grasping the lateral sides of the beam 1 Embracing the beam, with one leg falling off from the beam 2 Embracing the beam, with both legs falling from or rotating on the beam (> 60 s) 3 Trying to keep balance on the beam, but falling (> 40 s) 4 Trying to keep balance on the beam, but falling (> 20 s) 5 Falling off: no attempt was made to balance or grab the beam (< 20 s) 6 Absence of reflexes (blunt or sharp stimuli): Auricle reflex (head shaking when touching the auditory canal) 1 Comeal reflex (blinking when gently touching the cornea with cotton) 1 Startle reflex (motion response to short loud paper noise) 1 Seizure, myoclonus, muscular dystrophy 1 Maximum number of points 18 *One point for inability to perform tasks or lack of test reflexes. 1.4. Rotarod test A rotarod test was performed to assess whole body motor function, in particular coordination and balance. The rats were placed on a rotating rod cylinder and the rotational speed slowly increased from 5 rpm to 25 rpm over 180 seconds. The time when each rat left on the rotating rod was recorded as the fall latency. Fall latencies exceeding 180 seconds were recorded as 180 seconds. Each experiment was repeated 3 times and the average of three tests was used. 1.5. Brain tissue preparation and TUNEL staining Rats anesthetized with isoflurane were perfused intracardially with 0.1 M PBS, followed by perfusion with 4% paraformaldehyde (PFA) in 0.1 M PBS. The whole brain was removed, further fixed in 4% PFA for 48 hours, and embedded in paraffin. Coronal sections (4 pm thick) were mounted on glass slides for subsequent TUNEL staining. Briefly, brain tissue sections were deparaffinized, and washed and rehydrated with gradient ethanol. Antigen retrieval was performed by incubating the sections in 20 pg / mL proteinase K without DNase at 37 °C for 25 minutes. After three washes in PBS on a shaker every 5 minutes, TUNEL staining solution was added in a volume of 80 pL / section and incubated in the dark at 37 °C for 75 minutes. Hoechst33342 was added to stain the nuclei for 15 minutes at room temperature. After three washes with PBS every 5 minutes, the sections were fixed. Images were captured using an ECLIPSE 80i (Nikon Corporation Healthcare Business Unit) fluorescence microscope. Three separate images were taken from each part of the area near the injured site. A total of 3 images were analyzed for TUNEL positive cell counts. 1.6. Frozen sections and immunofluorescence staining Rats anesthetized with isoflurane were perfused intracardially with 0.1 M PBS, followed by perfusion with 4% paraformaldehyde (PFA) in 0.1 M PBS. The whole brain was removed, further fixed in 4% PFA for 48 hours, and then dehydrated in 10%, 20% and 30% sucrose solutions until the brain sequentially sunk into the bottom of the tube. The brain was removed from 30% sucrose solution and frozen in isopentane for 15 seconds. Frozen coronal sections (25 pm thick) were stored in a freezer at -80 °C until staining. The frozen sections were taken out from the freezer at -80 °C and washed three times with PBS. The sections were then incubated with goat serum at room temperature for 1 hour, and then immunostained with primary antibodies at 4 °C overnight. After three washes with PBS every 5 minutes, the sections were incubated with secondary antibodies at room temperature for 1 hour, and then washed and fixed. Images were captured using an ECLIPSE 80i (Nikon Corporation Healthcare Business Unit) fluorescence microscope. 1.7. Measurement of serum cytokine level Blood samples were collected at endpoints in rats by cardiac puncture. Blood samples were left at room temperature for 40 minutes to clot and then centrifuged at 5000 rpm for 5 minutes at 4 °C. The serum was centrifuged again at 13000 rpm for 5 min at 4 °C and then stored in the freezer at -80 °C until being used. IL-1 P, TNF-a and IFN-y levels in serum were measured using a bead-based LEGENDplex multi-analyte flow assay kit (Biolegend, San Diego, USA) and a BD FACSVerse flow cytometer (BD Biosciences) according to the manufacturer’s instructions. 1.8. Enzyme-linked immunosorbent assay (ELISA) Rats anesthetized with isoflurane were perfused intracardially with 0.7% saline. The whole brain was removed, and the ipsilateral brain tissue was weighed and homogenized in ice-cold PBS (pH 7.4) containing a protease inhibitor cocktail, and then centrifuged at 13000 rpm for 30 minutes at 4 °C. The supernatant was collected and centrifuged again at 13000 rpm for 30 minutes at 4 °C. The supernatant was collected and used to assess the levels of IL-ip, TNF-a and IFN-y. For the measurement of IL-ip and IFN-y, a Peprotech ABTS ELISA development kit (New Jersey, USA) was used according to the manufacturer’s instructions. Cytokine concentrations were measured with an ELISA microplate reader at a wavelength of405 nm, with wavelength calibration set to 620 nm, and quantified using a standard curve. For TNF-a measurement, a Thermo uncoated ELISA kit was used according to the manufacturer’s instructions. Briefly, the captured antibodies were diluted with coating buffer in 1:250 and added to a 96-well microplate at a concentration of 100 pL / well. The plate was incubated overnight in the dark at 4 °C. After blocking the wells with dilution buffer for 2 hours at room temperature and washing 4 times, standards and samples were added to the wells and incubated for 2 hours at room temperature. After washing 4 times with washing buffer, the detection antibodies (diluted in 1:250 with coating buffer 1) were added to the wells and incubated for 1 hour at room temperature. The wells were then washed and avidin-HRP was added in sequence. Cytokine concentrations were measured with an ELISA plate reader at a wavelength of 450 nm, with wavelength calibration set to 570 nm, and quantified using a standard curve. 1.9. Statistical analysis Analysis was performed using GraphPad Prism 7.00 software. All data were presented as Mean ± SEM. Differences between two groups were determined using the two-tailed t-test, and the oneway Dunnett’s post hoc test was used for three or more groups. Two-Way ANOVA followed by a Bonferroni post hoc test was performed for multiple comparisons. Values of P < 0.05 were considered statistically significant. Example 2 2.1. Dose-dependent amelioration of neurological deficits in post-TBI rats by annexin A5 treatment The neurological function was assessed in post-TBI rats and rats of annexin A5 treatment using the modified neurological severity score (rnNSS), including motor (muscle status and abnormal movement), sensory (visual, tactile, and proprioceptive), reflex, and beam walking tests. All measurements were performed by observers blinded to individual treatment. The higher the rnNSS score was, the worse the sensorimotor function was. At 24 hours post-TBI, all rats in the model group had an rnNSS score higher than 11, indicating that the Feeney's weight-drop model in this study resulted in neurological deficits. At 24-72 hours post-TBI, the rnNSS scores of TBI rats treated with 0.02-0.2 mg / kg of A5 were significantly lower than those of the model group in a dosedependent manner (FIG. 1 A), indicating functional outcomes were improved. A rotarod test was performed to assess the motion and balance coordination. As shown in FIG. IB, the rotarod test results showed that the fall latency in the model group was significantly shorter than that in the sham group (p < 0.001) at 24-72 hours post-TBI. These results showed that the Feeney’s weight-drop model led to the motion and balance coordination deficits in this study. In contrast, TBI rats treated with 0.02 mg / kg to 0.2 mg / kg of A5 exhibited significantly longer fall latencies in a dose-dependent manner at 24 hours post-TBI (p < 0.05 or p < 0.001). At 48 hours and 72 hours post-TBI, the fall latencies of 0.06 mg / kg A5 and 0.2 mg / kg A5 treatment groups were significantly longer than that of the model group (p < 0.01 or p < 0.001). However, at 48 hours and 72 hours post-TBI, the lowest dose (0.02 mg / kg) of annexin A5 failed to show a significantly longer fall latency (p > 0.05) as compared to the model group (FIG. IB). These results showed that treatment with 0.06 mg / kg to 0.2 mg / kg A5 in the acute phase could rescue the motion and balance deficits caused by TBI. The above results showed that the annexin A5 treatment dose-dependently ameliorated the neurological deficits in post-TBI rats in the acute phase, and ameliorated the neurological deficits in post-TBI rats by about 60% at 0.2 mg / kg, indicating the clinical therapeutic efficacy of A5 on the TBI. 2.2. Alleviation of apoptosis of post-TBI brain tissue by annexin A5 Apoptotic cells in the post-TBI brain were assessed by TUNEL assay at 72 hours post-TBI. TUNEL staining on the brain operative side of sham-operated rats was negligible. A significant increase in apoptotic cells and intercellular apoptotic fragments was observed at 72 hours post-TBI in the model group (p < 0.001, as compared to the sham group), indicating that TBI induced significant apoptosis in brain tissue. In contrast, the number of apoptotic cells or fragments in the 0.2 mg / kg annexin A5 treatment group was significantly decreased (as compared to the model group, p < 0.05). Treatment with 0.2 mg / kg of annexin A5 resulted in about 42% reduction in apoptosis in brain tissue of post-TBI rats as characterized by TUNEL staining. These results showed that treatment with 0.2 mg / kg of annexin A5 could reduce TBI-induced brain apoptosis (FIG. 2). 2.3. Inhibition against activation of post-TBI microglia by annexin A5 The expression of astrocyte activation marker, glial fibrillary acidic protein (GFAP), was detected using immunofluorescence assays. Only a few GFAP-positive cells were counted in the sham group. After a TBI model was established for 72 hours, as compared to the sham group, the number of GFAP-positive astrocytes of rats in the model group was increased, and the number of reactive astrocytes was remarkably increased (p < 0.001). Reactive astrocytes expressing GFAP in the model group also exhibited a morphology characterized by enlarged amoeba-shaped cell bodies. However, treatment with annexin A5 did not inhibit reactive astrocytes, and GFAP-expressing cells was not significantly reduced. The microglia-specific protein IBA-1 was detected by an immunofluorescence method to observe the activation of the microglia. A small amount of IBA-1 positive cells were visible in the sham group. The number of active microglia in the model group was significantly increased at 72 hours post-TBI. The cell bodies in the model group were enlarged like amoeba. Compared with the sham group, the expression of IBA-1 in the model group was significantly increased (p < 0.001), indicating TBI induced microglial activation. The treatment with 0.2 mg / kg of annexin A5 significantly reduced the expression of IBA-1 by about 60% in a dose-dependent manner at 72 hours post-TBI (p < 0.05, as compared to the model group), indicating that treatment with annexin A5 inhibited the activation of microglia (FIG. 3). 2.4. Time course of neurological deficits in post-TBI rats treated with annexin A5 TBI resulted in significant early deficits in mMNS test and fall latencies in the rotarod test, and both tests showed a gradual decrease in TBI-induced impairment over time. For the mNSS test, as shown at the top of FIG. 4, there was no difference in rnNSS scores among the A5 BID 7d, A5 QD 7d, and A5 QD 3d treatment groups. Two-Way ANOVA and Bonferroni adjusted multiple comparisons showed that all 3 treatments had significant group main effects as compared to the model group (p < 0.001). For the rotarod test shown at the bottom of FIG. 4, two-way ANOVA with Bonferroni-adjusted multiple comparisons on fall latencies showed that the A5 BID 7d group had a better performance as compared to the model group (p < 0.001). Compared with the model group, there was no significant improvement in the fall latency for the A5 QD 7d and A5 QD 3d treatment groups over time (p > 0.05). These results show that A5 BID treatment is a better method for treating TBI-induced neurological deficits in rats. 2.5. Up to 12 hours of the therapeutic time window for annexin A5 after onset of TBI in rats Most drugs used for TBI treatment would lose efficacy with increasing time interval between injury and first administration. For example, the N-type Ca2+ channel blocker ziconotide improved mitochondrial function when first administered at 15 minutes post-moderate TBI in rats, but rapidly lost efficacy when first administered at 1 hour post-TBI. Therefore, the assessment of therapeutic time windows with multiple outcome indicators is becoming a standard component of preclinical assessment of TBI therapeutics. TBI rats were dosed with a vehicle or 0.2 mg / kg A5 at 0 hours, 3 hours, 6 hours or 12 hours (n = 5) post-TBI, then dosed twice daily until 48 hours post-TBI. At 24 hours, 48 hours and 72 hours, the efficacy of the treatment was assessed by the mNSS test and the rotarod test. After the rotarod test, brain tissue was obtained for cytokine level testing according to the method described above. The mNSS score of the model group was significantly higher than that of the sham group, and the fall latency was significantly shorter than that of the sham group, indicating that the experimental TBI model resulted in neurological deficits. Two-Way ANOVA showed there was significant difference between groups (p < 0.001). The Bonferroni post hoc test showed there was a significant reduction in mNSS scores for Oh, 6h, and 12h groups as compared to the model group (top of FIG. 5). No significant difference in mNSS scores was observed between the 3h group and the model group, possibly due to the limited number of animals in the experiment (n = 5). Two-Way ANOVA showed that there were also significant differences for the fall latencies between the groups (p < 0.001). Further, Bonferroni post hoc tests also showed that the fall latencies were significantly prolonged for the Oh, 3h, 6h and 12h groups as compared to the model group (bottom of FIG. 5). The therapeutic time window experiment showed that 0.2 mg / kg of annexin A5 administered at 12 hours post-TBI could alleviate the neurological deficits in post-TBI rats by about 38%. These results showed that annexin A5 could be administered within 12 hours post-TBI and maintained a certain therapeutic effect in this TBI rat model. The above results showed that A5 alleviated TBI-induced neurological deficits and could exert a therapeutic effect when administered within 12 hours post-TBI. Therefore, the effect of A5 on the inflammatory response in TBI rats over 72 hours post-TBI was then investigated. The levels of cytokines IL-1 P, TNF-a and IFN-y in the ipsilateral cerebral hemisphere were detected using ELISA. Compared with the sham group, the expression level of IL-ip in the model group was significantly increased (p < 0.01), indicating that TBI induced the neuro inflammatory response in rats. Compared with the model group, the levels of IL-ip in the 6h and 12h time window groups were significantly decreased. Treatment with 0.2 mg / kg of annexin A5 over 12 hours post-TBI reduced IL-1 P expression by about 100% in post-TBI rats. For TNF-a and IFN-y levels, there was no statistical difference between the two groups (FIG. 6). Example 3 Annexin A5 was derived from full-length annexin of human origin. By constructing a recombinant vector, it was expressed in prokaryotic Escherichia coli (E. coli) in large quantity. The expressed A5 protein was sequenced with the amino acid sequence as follows: AQVLRGTVTDFPGFDERADAETLRKAMKGLGTDEESILTLLTSRSNAQRQEISAAFKTLF GRDLLDDLKSELTGKFEKLIVALMKPSRLYDAYELKHALKGAGTNEKVLTEIIASRTPEEL RAIKQVYEEEYGSSLEDDWGDTSGYYQRMLWLLQANRDPDAGIDEAQVEQDAQALF QAGELKWGTDEEKFITIFGTRSVSHLRKVFDKYMTISGFQIEETIDRETSGNLEQLLLAVV KSIRSIPAYLAETLYYAMKGAGTDDHTLIRVMVSRSEIDLFNIRKEFRKNFATSLYSMIKGD TSGDYKKALLLLCGEDD (SEQ ID NO: 1). As shown in SEQ ID NO: 1, the A5 protein expressed by the E. coli expression system contained 319 amino acids, the complete cDNA sequence thereof was encoded by codons having 320 amino acid, and the N-terminus methionine was cleaved during the expression. The amino acid sequence of SEQ ID NO: 1 was identical to the amino acid sequence of native human annexin A5, except that the N-terminus amino acid of the A5 protein expressed by the system was alanine (A), whereas the N-terminus amino acid of native human annexin A5 was acetylated alanine. The following experiment was then performed using the A5 protein obtained in Example 3. Example 4 With reference to the content described in the literature “Behavioral deficits and recovery following transient focal cerebral ischemia in rats: glutamatergic and GABAergic receptor densities” (Jolkkonen J, Gallagher NP, Zilles K, Sivenius J. Behav Brain Res 2003; 138:187-200) and the literature “Reversible middle cerebral artery occlusion without craniectomy in rats” (Longa EZ, Weinstein PR, Carlson S, Cummins R. Stroke 1989; 20:84-91), a middle cerebral artery occlusion (MCAO) cerebral ischemia-reperfusion model was prepared by internal carotid artery thread embolization, the A5 0.1 mg / kg, A5 1.0 mg / kg, andA5 10.0 mg / kg groups were set, respectively, the group of intravenously administrating edaravone (6.0 mg / kg) was taken as the positive control group, and a model group and a sham group were additionally set. The model group and the sham group were given the same volume of 0.9% sodium chloride injection. Each dosage group of A5 protein was administered once at the time of reperfusion, and then administered again 1 hour after reperfusion, and the other groups were administered once immediately after reperfusion. After 24 hours of cerebral ischemia, neurobehavioral deficit symptom evaluation and cerebral infarction area measurement were performed. 1. Test materials (1) Experimental animals Sprague Dawley (SD) rats, SPF grade, male, age: about 6-8 weeks, weight: 250-280 g. Animals would be excluded if one of the following conditions occurred during the experiment: a) death during anesthesia; b) death during cerebral ischemia; c) death after reperfusion and before index evaluation; d) skull base hemorrhage after brain removal; and e) no infarct area in the right brain after TTC staining. (2) Reagents A5 protein solution was prepared by diluting the A5 protein prepared in Example 3 with 0.9% aqueous solution of sodium chloride. Control: edaravone injection (purchased from Nanjing Simcere Dongyuan Pharmaceutical Co., Ltd.); edaravone injection was mixed and diluted with 0.9% sodium chloride injection at a ratio of 1:1 to prepare a positive control. 2. Experimental design (1) Dose design Table 3. Dose list for A5 protein efficacy assay Group Test substance Dose of administration (mg / kg) Concentration for preparation (mg / mL) Administration volume (mL / kg) Number of main test animals A5 0.1 mg / kg group A5 protein 0.1 0.02 5 ~20 A5 1.0 mg / kg group A5 protein 1.0 0.2 5 ~20 A5 10.0 mg / kg group A5 protein 10.0 2 5 ~20 Edaravone Edaravone injection 6.0 1.0 6 ~20 Model group Model group - - 5 ~20 Sham group Sham group - - 5 ~10 (2) Administration Animals in each group were administered intravenously through the tail vein at the rate of intravenous administration of about 1.5-2.5 mL / min. For each treatment group, neurobehavioral deficit symptom evaluation and cerebral infarction area measurement were performed after 24 hours of cerebral ischemia. 3. Evaluation method (1) Neurological deficit symptom score With reference to the method in the literature “Rat middle cerebral artery occlusion, evaluation of the model and development of a neurologic examination” (Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. 1986. Stroke 17: 472-476), animals were evaluated for neurological deficit symptoms after 24 hours of ischemia by using the modified Bederson’s 5-point scale. (2) Determination of degree of cerebral infarction With reference to the content in the literature “Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats” (Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM. Stroke 1986;17:1304-8) and the literature “Quantification of infarct size on focal cerebral ischemia model of rats using a simple and economical method” (Yang Y, Shuaib A, Li Q. J Neurosci Methods 1998;84:9-16), the determination of the degree of cerebral infarction was carried out by TTC staining. Calculation of cerebral infarction area: the photos were processed by Image J software, the corresponding area of the left brain and the non-infarction area of the right brain were calculated according to the equation, and the percentage of infarction area was calculated. The equation for calculating infarct volume is: V=t (A1+A2+A3+.........+An) wherein t is the slice thickness and A is the infarct size. %I=( Vc-ViJ / Vc x 100% %I is the percentage of the infarct area, Vc is the volume of the brain on the control side (left hemisphere), and Vl was the volume of the non-infarcted area on the infarct side (right hemisphere). (3) Evaluation indexes The cerebral infarct size and the neurobehavioral score were used as main evaluation indexes, and the clinical manifestations of the animals were observed at the same time. Quantitative data were expressed as mean ± standard errors. The efficacy indexes were analyzed using GraphPad Prism (6.01) software for one-way ANOVA. After the variance significance test was completed, the difference between groups was tested by using Fisher’s LSD test. P < 0.05 was defined as having a significant difference. 4. Experimental results (1) Effect of A5 protein on neurological deficit symptoms By means of one-way ANOVA, there were no statistical differences between groups (F (4.69) = 2.305, P = 0.0669). However, the T test was carried out between each group and the model group. The edaravone 6.0 mg / kg group (P < 0.01) and the A5 10.0 mg / kg group (P < 0.05) could significantly alleviate the neurobehavioral deficit symptoms of ischemic animals; the A5 1.0 mg / kg group and the A5 0.1 mg / kg group tended to alleviate the neurobehavioral deficit symptoms of ischemic animals, but there was no statistical difference. The effect of the A5 protein on neurobehavioral deficit symptoms is detailed in Table 4 and FIG. 7. Table 4. Effect of A5 protein on acute cerebral ischemia-reperfusion injury in rats (Mean ± SEM) Group Sample size Neurological deficit symptom score Cerebral infarct size (%) Sham group 10 0 0 Model group 15 2.47±0.22 42.53±3.27 Edaravone 6.0 mg / kg 15 1.60±0.25" 35.93±3.94 A5 10.0 mg / kg 14 1.64±0.20* 28.97±5.08# A5 1.0 mg / kg 14 1.86±0.27 38.37±3.61 A5 0.1 mg / kg 16 2.00±0.20 43.61±3.60 Compared with the model group, *P < 0.05, **P < 0.01, and #P < 0.05. (2) Effect of A5 protein on cerebral infarct size By means of one-way ANOVA, there were no statistical differences between groups (F (4.69) = 2.240, P = 0.0735). However, the T test was carried out between each group and the model group. The A5 10.0 mg / kg group (P < 0.05) could significantly reduce the cerebral infarction area of model animals; the edaravone 6.0 mg / kg group and the A5 1.0 mg / kg group tended to reduce the cerebral infarction area of model animals, but there was no statistical difference; the A5 0.1 mg / kg group had no effect of reducing the cerebral infarction area of model animals. The effect of the A5 protein on the cerebral infarction area is detailed in Table 4 and FIG. 8. In this experiment, the differences in the cerebral infarct size of the animals in the model group were basically within 1 / 3 of the mean value (Mean ± SD, 42.53 ± 12.65), and the model availability was 69.81% (excluding animals in the sham group). It can be seen that the experimental system was reliable and could be used for evaluating the drug efficacy. Compared with the model group, the A5 10.0 mg / kg group could significantly reduce the cerebral infarction area of model rats (P < 0.05); the edaravone 6.0 mg / kg group and the A5 1.0 mg / kg group tended to reduce the cerebral infarction area of model rats, but there was no statistical difference; the A5 0.1 mg / kg group had no effect of reducing the cerebral infarction area of model animals. Compared with the model group, the edaravone 6.0 mg / kg group and the A5 10.0 mg / kg group could significantly alleviate the neurobehavioral deficit symptoms of ischemic animals (p < 0.01, and p < 0.05); the other groups did not show significant improvement in this index. In this experiment, the A5 10.0 mg / kg group could significantly reduce the cerebral infarction area of ischemic rats and alleviate the neurobehavioral deficit symptoms of ischemic animals. There was no bleeding risk in the experimental groups treated with annexin A5. Example 5 Microglia plays an important role in the inflammatory process of the central nervous system. Moderate activation of microglia has a protective effect on neurons, but over-activated microglia can release a large number of neurotoxic factors, such as carbon monoxide, which will lead to the development of neurodegenerative diseases. Lipopolysaccharide (LPS) can activate microglia, resulting in overactivation of microglia, thereby causing damage to neurons. The effect of A5 on overactivation of microglia induced by LPS stimulation was observed. In the experimental process, primary purified microglia was stimulated by LPS as a control group, and was stimulated by LPS with adding A5 protein as an experimental group. For the above treatments, the cell viability was detected by MTT method, and the cell morphology change was observed by immunocytochemistry. The experimental results showed that LPS could significantly activate primary microglia without affecting cell viability. The A5 protein could inhibit the overactivation of microglia induced by LPS stimulation. Therefore, the A5 protein could be used to inhibit the overactivation of immune cells in the brain, such as the overactivation of microglia. Example 6 The oxygen-glucose deprivation (OGD) model is a stimulation model that simulates ischemia / hypoxia at the cellular level by altering the cell culture conditions, such as placing the cells in a hypoxic chamber or replacing sugar-free medium, to simulate the damage of the cells under ischemia / hypoxia conditions. The primary cortical neurons in a rat were taken to establish an OGD model, and the detection concentrations of A5 protein were 0 nM, 41.15 nM, 123.5 nM, 370.4 nM, 1,111 nM, 3,333 nM, and 10,000 nM, respectively. Cells in the cultured plate were washed 2 times with PBS, then sugar-free DMEM, previously replaced with 95% N2 + 5% CO2 for 30 min, was added, and the plate was rapidly placed in a hypoxic incubator (94% N2 + 1% O2 + 5% CO2) at 37 °C. After 8 hours of anaerobic culture, the corresponding drug-containing culture medium (i.e., DMEM culture medium containing A5) was added, and the plate was placed into a cell incubator (5% CO2) at 37 °C for reoxygenation culture for 24 hours. After returning to normal conditions and continuing to culture for 24 hours, the morphological changes of the cells were observed under an inverted microscope, the cell survival rate was detected by CCK-8 colorimetry, and the apoptosis rate was detected by flow cytometry. At the same time, a normal oxygen and glucose treatment group was set as a control group. The equation for calculating relative cell viability was as follows: Relative cell viability (%) = (administration group - background group ) / (control group -background group) x 100% Compared with the model group, the A5 protein did not show the protective effect on neuron damage caused by OGD within the concentration range of 41.15-1,111 nM (P > 0.05), and could significantly reduce the activity after the neuron damage caused by OGD at the concentration of 3,333-10,000 nM (P < 0.05, FIG. 9). The experimental results showed that the A5 protein could reduce the damage of oxygen-glucose deprivation to neuron cells, and had a neuroprotective effect at the concentration of 3,333-10,000 nM. Example 7 Example 7 studied the neuroprotective effect of A5 protein on the excitotoxic damage of rat cortical neurons induced by NMDA (N-methyl-D-aspartic acid). NMDA can activate NMDA receptors to increase the Ca2+ content in brain tissue, and a large amount of NOS is activated, leading to a series of physiological or pathological changes such as the synthesis of a large amount of NO, thereby resulting in damage to neurons in the brain. In the experiment, neurons were pretreated with A5 protein to observe the neuroprotective effect of A5 protein on neuronal damage caused by excitotoxicity. The 17-day embryos of SD rats were used in the experiment, and the cortical neurons were inoculated and cultured. Then the neurons were divided into a control group, an NMDA exposure group and an A5 pretreatment group. Neurons were exposed to NMDA in the NMDA exposure group; the control group did not receive any treatment; neurons were incubated with A5 protein for a period of time, and then exposed to NMDA in the A5 pretreatment group. For different treatment groups, the cell viability was evaluated by trypan blue staining, apoptotic cells were detected by TUNEL staining, and the neuronal morphology was determined by immunofluorescence cytochemistry. The equation for calculating relative cell viability was as follows: Relative cell viability (%) = (administration group - background group) / (control group -background group) x 100% As shown in FIG. 10, NMDA at the concentration of 100 pM could induce a decrease in activity of rat primary cortical neuronal cells (P < 0.001, as compared to normal control), indicating successful model establishment. No significant reduction effect of A5 protein on the excitatory damage of primary cortical neurons caused by NMDA was observed at the detection concentration of 41.15-3,333 nM (P > 0.05, as compared to the model group), and the A5 protein exhibited a significant reduction effect on the excitatory damage of primary cortical neurons caused by NMDA at the detection concentration of 10,000 nM (P < 0.05, as compared to the model group). The experimental results showed that compared with the NMDA exposure group, the A5 pretreatment group could reduce the damage of excitotoxicity to neurons at the detection concentration of 10,000 nM. Example 8 The blood-brain barrier is composed of three components: brain microvascular endothelial cells, astrocytes and basement membrane. The damage of the blood-brain barrier is one of the important pathologies of stroke brain injury. In the experimental process, an in-vitro blood-brain barrier model was established by co-culturing a spontaneously transformed endothelial cell line and an isolated and purified rat astrocyte. The in-vitro blood-brain barrier (BBB) model was damaged after being stimulated, and then the stimulated blood-brain barrier model was treated with A5 protein. The integrity of the blood-brain barrier was evaluated using a rat traumatic brain injury model induced by craniocerebral strike, and A5 10 mg / kg and A5 30 mg / kg groups and a model group were respectively set. Each A5 protein dose group and the model group were administered once 1 hour and 2 hours after modeling, twice in total. The administration method was tail vein injection. After 23 hours of modeling, the rats were anesthetized, and then injected with 2% EB (Evans blue) dye solution at a dose of 4 mL / kg through the tail vein, and the dye was allowed to circulate in the rat body for 1 hour before the rat was sacrificed. The heart of the rat was perfused with saline through the left ventricle until colorless perfusion was obtained. After being sacrificed, the brain was taken out, weighed, homogenized in formamide (3 pL / mg), and incubated at room temperature for 48 hours. After centrifugation, the supernatant was collected and the optical density was measured at 625 nm for determining the relative amount of EB dye. The results are shown in Table 5 and FIG. 11: Table 5. Effect of A5 protein on blood-brain barrier injury of rats induced by craniocerebral strike ________________________________(Mean ± SD)________________________________ Group Sample size EB content in brain tissue (pg / g) Model group 5 101.87±8.63 A5 10 mg / kg 5 96.08 ±4.33 A5 30 mg / kg 5 89.36 ±5.51* Compared with the model group, *P < 0.05. The results showed that compared with the model group, there was no significant difference in the EB content in the brain tissue of the A5 10 mg / kg group (P > 0.05), and the EB content in the brain tissue of the A5 30 mg / kg group was significantly decreased (P < 0.05). In this experiment, the A5 30 mg / kg group showed a repairing effect on the blood-brain barrier injury of rats caused by craniocerebral strike. The experimental results showed that after stimulation, the established blood-brain barrier would be significantly damaged, and A5 could repair the damaged blood-brain barrier. Example 9. Study on Immunotoxicity and Immunogenicity (Accompanying Repeat-Dose Toxicity Studies on SD Rats and Cynomolgus Monkeys) 1. Toxicity test study on SD rats SD rats were injected intravenously with A5 protein for 28 consecutive days, and a recovery period of 4 weeks was set to observe the toxic reaction generated by the rats and the severity thereof as well as the main toxic target organs and the reversible degree of damage. The doses were 0 pg / kg (blank adjuvant), 30 pg / kg, 150 pg / kg and 750 pg / kg, respectively. Blood was collected for immunotoxicity (CD4+, CD8+ T cells) and immunogenicity assays. In the experiment, the rats were divided into 4 groups, with 8 rats in each group, and samples were collected at 4 time points, that is, serum samples at 4 time points were collected from each rat. The immunotoxicity results showed that there was no statistically significant difference in the proportion and ratio (measured values of CD4+, CD8+ T cells) of peripheral blood T lymphocyte subsets of animals between each dose administration group and the control group in the test period. The immunogenicity results are shown in Table 6. In Table 6, the number of samples in each group represented 8 rats in each group, and serum was collected at 4 time points, for a total of 32 samples in each group. The number of positive individuals was the number of positive samples detected in the samples of each group. Table 6. Data of anti-drug antibodies of A5 protein in rat serum Group Control group 30 pg / kg dose group 150 pg / kg dose group 750 pg / kg dose group Administration dose 0 pg / kg 30 pg / kg 150 pg / kg 750 pg / kg Number of samples in each group 32 32 32 32 Number of positive samples 0 21 22 20 Total positive sample rate 0.0% 65.6% As could be seen from the results shown in Table 6, no anti-drug antibody (ADA) was detected after SD rats were intravenously injected with blank adjuvant of A5 protein. After intravenous injection of different doses of A5 protein, the detection rate of positive samples was 65.6%. There was no significant difference between the respective dose groups, and the positive samples were mainly concentrated after the last administration and at the end of the recovery period, which was consistent with the process of producing drug-resistant antibodies in vivo. 2. Toxicity test study on cynomolgus monkeys In this study, cynomolgus monkeys were injected intravenously with A5 protein for 28 consecutive days, and a recovery period of 4 weeks was set to observe the toxic reaction generated by the cynomolgus monkeys and the severity thereof as well as the main toxic target organs and the reversible degree of damage. The doses were 0 pg / kg (blank adjuvant), 15 pg / kg, 75 pg / kg and 375 pg / kg, respectively. Immunogenic blood sampling and immuno toxicity (CD4+, CD8+ T cells) assays were performed. The immunotoxicity results showed that there was no statistically significant difference in the proportion and the ratio (measured values of CD4+, CD8+ T cells) of peripheral blood T lymphocyte subsets of animals between each dose administration group and the control group in the test period. The immunogenicity results are shown in Table 7. The same grouping and processing methods as described above for rats were used, except that 2 more samples per group were taken, i.e., 2 more samples per group. Table 7. Data of anti-drug antibodies of A5 protein in monkey serum Group Control group 15 pg / kg dose group 75 pg / kg dose group 375 pg / kg dose group Administration dose 0 pg / kg 15 pg / kg 75 pg / kg 375 pg / kg Number of samples per group 34 34 34 34 Number of positive samples 0 7 6 13 Total sample positive rate 0.0% 25.5% As could be seen from the results shown in Table 7, no ADA was detected after cynomolgus monkeys were intravenously injected with A5 protein blank adjuvant. After intravenous injection of different doses of A5 protein, the detection rate of positive samples was 25.5%, and the positive samples were concentrated after 4 weeks of administration and at the end of the recovery period, which was consistent with the process of producing drug-resistant antibodies in vivo. The experimental results showed that no immuno toxicity was found in both rats and cynomolgus monkeys. In the immunogenicity test, the positive incidence rate of cynomolgus monkeys was significantly lower than that of rats. Considering that the A5 protein is a human protein, it was expected that the incidence rate of immunogenicity in humans was significantly reduced. Example 10. Toxicity Study of Single Administration of A5 Protein Intravenously Injected into SD Rats and Cynomolgus Monkeys 1. Single-dose toxicity study of intravenous injection of A5 protein in SD rats In this study, SD rats were injected intravenously with A5 protein once to observe the acute toxic reactions generated by animals and the severity thereof and the main toxic target organs. The doses were 0 pg / kg (blank adjuvant), 1000 pg / kg, 3000 pg / kg and 9000 pg / kg, respectively. Intravenous injection, continuous observation of the animal’s posture, gait, reaction state, nerve activity, appetite, hair, eyes, ears, mouth, nose, limbs, breath, defecation and other clinical symptoms after administration. The animals were then examined for recovery of toxic reactions by continued observation until day 14 after the administration. Animals were dissected for gross pathological examination 15 days after the administration. During the test period, no abnormalities were found in the clinical symptoms of all animals; no abnormalities were found in body weight changes of female and male animals in the administration group; no abnormalities were found in various tissues and organs in gross pathological examination. Under the conditions of this experiment, the tolerated dose (MTD) of single intravenous injection of A5 protein was above 9000 pg / kg. 2. Single-dose toxicity study of intravenous injection of A5 protein in cynomolgus monkeys In this study, cynomolgus monkeys were injected intravenously with A5 protein once to observe the acute toxic reactions generated by animals and the severity thereof and the main toxic target organs. The doses were 0 pg / kg (blank adjuvant), 500 pg / kg, 1500 pg / kg and 4500 pg / kg, respectively. After a single intravenous injection, the animal’s clinical symptoms (including defecation, appearance, breath, neural response, activity status, etc.) were observed until day 15 after the administration. After administration, the food intake was measured once a day, and the body weight was measured once a week. On the day of administration, the body temperature, blood pressure and electrocardiogram of the animals were measured before and after administration, and again on days 1, 7, and 15 of administration. All animals were subjected to hematological (including blood coagulation) and serum biochemical examinations on days 1, 7, and 15 after administration, and urine tests on day 14 after administration. On day 15 after administration, the animals were dissected for gross pathological examination and, if necessary, histopathological examination. The results showed that there were no obvious changes associated with the test substances in the clinical symptoms, observation of injection sites, body weight, food intake, body temperature, blood pressure, electrocardiogram, urine test, serum biochemical and pathological examination of animals in each group. On day 13 of the quarantine period, from day 1 after administration to day 15 after administration, the prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) of animals in each group did not change significantly. Under the test condition, the tolerated dose (MTD) of the cynomolgus monkeys was above 4500 pg / kg. The above experimental results showed that, whether in SD rats or in cynomolgus monkeys, the tolerated dose of A5 protein was above 4500 pg / kg, and the tolerated dose of A5 protein in SD rats was even above 9000 pg / kg. The results showed that at the equivalent dose of A5 protein to exert the protective effect on cerebral apoplexy, no obvious toxicity was seen in rats and monkeys. Therefore, this reminds us that the protein A5 is safe for treating cerebral apoplexy, and even in the case of higher doses, it will not or hardly bring drug risks. Although the examples of the present disclosure have been shown and described above, it should be understood that the above examples are exemplary and should not be construed as limiting the protection scope of the present disclosure. Those skilled in the art can make changes, modifications, substitutions and alterations to the above examples within the scope of the present disclosure, and these changes, modifications, substitutions and alterations should be covered within the protection scope of the claims of the present disclosure.

Claims

1. A method for treating a traumatic brain injury in a patient in need thereof, comprising determining a patient having a traumatic brain injury or suspected of having a traumatic brain injury; andadministering to the patient a therapeutically effective amount of annexin A5 or a variant thereof or a pharmaceutical composition comprising the therapeutically effective amount of annexin A5 or the variant thereof; whereinfor example, in the method according to claim 1, the annexin A5 or the variant thereof comprises an amino acid sequence having at least 90% sequence identity to an amino acid sequence of SEQ ID NO: 1 or comprises the amino acid sequence of SEQ ID NO: 1;for example, the traumatic brain injury is a mild, moderate or severe traumatic brain injury;for example, the traumatic brain injury is caused by a head impact, a penetrating head injury, a nonpenetrating head injury, a fall, a skull fracture, a sudden acceleration or deceleration, a concussion, or a contusion;for example, the patient is a human.

2. The method according to claim 1, wherein the annexin A5 or the variant thereof:(i) reduces diffuse axonal injury, behavioral disorder, brain tissue injury, brain atrophy, neuronal cell death or apoptosis, microglial activation, or neuronal tissue loss in the patient having the traumatic brain injury; or(ii) increases a cerebral blood flow or a cerebral glucose uptake in the patient having the traumatic brain injury;or, the annexin A5 alleviates one or more symptoms associated with the traumatic brain injury in the patient;for example, the one or more symptoms associated with the traumatic brain injury include impaired level of consciousness, cognitive impairment, cognitive processing speed impairment, language impairment, motor activity impairment, memory impairment, motor skills impairment, sensory skills impairment, cerebral ischemia, edema, intracranial pressure, hearing loss, tinnitus, headache, seizures, dizziness, nausea, vomiting, blurred vision, decreased sense of smell or taste, decreasedphysical strength, or decreased coordination.

3. The method according to claim 1, wherein a first agent, such as the annexin A5 or the variant thereof, or the pharmaceutical composition is administered over a period of time from the time of the traumatic brain injury to 4 weeks;for example, the first agent is administered within about 0 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the occurrence of the traumatic brain injury;for example, the therapeutically effective amount of the annexin A5 or the variant thereof is between about 0.01 mg / kg and about 10 mg / kg, such as between about 0.01 mg / kg and about 0.5 mg / kg, e.g., about 0.02 mg / kg, 0.06 mg / kg, or 0.2 mg / kg.

4. The method according to claim 1, wherein the method further comprises administering to the patient a second agent or therapy;wherein the second agent or therapy is a cardioprotective medicament or therapy, wherein the cardioprotective medicament or therapy comprises one of beta blockers, diuretics, angiotensinconverting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering therapies, statins, nitrates, antiplatelet drugs, anticlotting agents, and anticoagulation agents or a combination thereof, and the above medicaments are used in therapies.

5. The method according to claim 1, wherein the step of determining a patient having a traumatic brain injury comprises performing a computed tomography (CT) scan or magnetic resonance imaging (MRI) on the patient;for example, the patient is identified as having the traumatic brain injury according to a modified neurological severity score (mNSS), rotarod test, Glasgow Coma Scale score, or Glasgow Outcome Scale score;for example, the mNSS or Glasgow Coma Scale score is between 3 and 8, 9 and 12, or 13 and 15; for example, if the mNSS or Glasgow Coma Scale score is below a reference level, the patient is identified as having the traumatic brain injury;for example, the reference level is obtained from a reference subject who has not suffered a headinjury.

6. The method according to claim 1, wherein the step of determining a patient having a traumatic brain injury comprises:determining a level of a biomarker in a sample from the patient;comparing the level of the biomarker with a reference level of the biomarker; andidentifying the patient as having the traumatic brain injury if the determined level of the biomarker is increased as compared to the reference level of the biomarker.

7. The method according to claim 6, wherein the biomarker comprises a cytokine selected from: IL-ip, TNF-a, IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, or phosphorylated Tau;for example, the sample is obtained after a patient's head is subjected to a physical shock, a blunt impact of an external mechanical force or other forces resulting in closed or open head trauma, one or more falls, explosions, blasts, solid explosions, gas explosions or other types of blunt trauma;for example, the sample is selected from a whole blood sample, a serum sample, a cerebrospinal fluid sample, and a plasma sample.

8. A method for reducing a level of a biomarker in a patient having a traumatic brain injury, comprising:(a) determining a patient having a traumatic brain injury; and(b) administering to the patient a therapeutically effective amount of annexin A5 or a variant thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the annexin A5 or the variant thereof,wherein the biomarker comprises a cytokine selected from: IL-1P, TNF-a and IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, and phosphorylated Tau;for example, the therapeutically effective amount of the annexin A5 or the variant thereof is an amount that causes the annexin A5 or the variant thereof to increase or decrease the level of the biomarker by at least 5%, 10%, 20%, 30%, 40%, or 50%.

9. Use of annexin A5 or a variant thereof for the manufacturing of a medicament, wherein the medicament is for use in one, two or more of the following uses selected from:treating and / or preventing a traumatic brain injury, for example a mild, moderate or severe traumatic brain injury;reducing diffuse axonal injury, behavioral disorder, brain tissue injury, brain atrophy, neuronal cell death or apoptosis, microglial activation, or neuronal tissue loss in a patient having the traumatic brain injury;increasing a cerebral blood flow or a cerebral glucose uptake in a patient having the traumatic brain injury;alleviating one or more symptoms associated with the traumatic brain injury in a patient, for example, the one or more symptoms associated with the traumatic brain injury include impaired level of consciousness, cognitive impairment, cognitive processing speed impairment, language impairment, motor activity impairment, memory impairment, motor skills impairment, sensory skills impairment, cerebral ischemia, edema, intracranial pressure, hearing loss, tinnitus, headache, seizures, dizziness, nausea, vomiting, blurred vision, decreased sense of smell or taste, decreased physical strength, or decreased coordination; andreducing a level of a biomarker in a patient having a traumatic brain injury; for example, wherein the biomarker comprises a cytokine selected from: IL-1 p, TNF-a and IFN-y, IL-6, IL-10, IL-8, HMGB1, TGFp, UCH-L1, NSE, GFAP, SIOOB, NF proteins (L and H), MBP, Tau, and phosphorylated Tau; for example, the medicament increases or decreases the level of the biomarker by an amount of at least 5%, 10%, 20%, 30%, 40%, or 50%;for example, the annexin A5 or the variant thereof comprises an amino acid sequence having at least 90% sequence identity to an amino acid sequence of SEQ ID NO: 1 or comprises the amino acid sequence of SEQ ID NO: 1.

10. The use according to claim 9, wherein the traumatic brain injury is a mild, moderate or severe traumatic brain injury;for example, the traumatic brain injury is caused by a head impact, a penetrating head injury, a nonpenetrating head injury, a fall, a skull fracture, a sudden acceleration or deceleration, a concussion,or a contusion;for example, the patient is a human;preferably, the medicament is in a unit dosage form;for example, the amount of the annexin A5 or the variant thereof in the medicament is between about 0.01 mg / kg and about 10 mg / kg of a patient's body weight, such as between about 0.01 mg / kg and about 0.5 mg / kg of the patient's body weight, e.g., about 0.02 mg / kg, 0.06 mg / kg, or 0.2 mg / kg of the patient's body weight;for example, the medicament is in a unit dosage form, and the amount of the annexin A5 or the variant thereof in the unit dosage form is 0.025 mg to 250 mg, such as 0.1 mg to 50 mg, 0.1 mg to 100 mg, 0.1 mg to 200 mg, or 0.1 mg to 250 mg, or 1 mg to 50 mg, 1 mg to 100 mg, 1 mg to 200 mg, or 1 mg to 250 mg.

11. The use according to claim 10, wherein the medicament is administered over a period of time from the time of the traumatic brain injury to 4 weeks, preferably within about 0 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the occurrence of the traumatic brain injury, more preferably, a first agent is administered to the patient within about 12 hours after the occurrence of the traumatic brain injury;for example, the medicament further comprises a cardioprotective medicament;for example, the cardioprotective medicament is selected from beta blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering therapies, statins, nitrates, antiplatelet drugs, anticlotting agents, and anticoagulation agents or a combination thereof.

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