title: Cartilage oligomeric matrix protein is a natural inhibitor of thrombin.
abstract: Thrombin is an effector enzyme for hemostasis and thrombosis; however, endogenous regulators of thrombin remain elusive. Cartilage oligomeric matrix protein (COMP), a matricellular protein also known as thrombospondin-5, is essential for maintaining vascular homeostasis. Here, we asked whether COMP is involved in the process of blood coagulation. COMP deficiency shortened tail-bleeding and clotting time and accelerated ferric-chloride-induced thrombosis in mice. The absence of COMP had no effect on platelet count. In contrast, COMP specifically inhibited thrombin-induced platelet aggregation, activation, and retraction and the thrombin-mediated cleavage of fibrinogen. Furthermore, surface plasmon resonance analysis revealed direct thrombin-COMP binding (KD = 1.38 ± 0.24 μM). In particular, blockage of thrombin exosites with compounds specific for exosite I (hirudin and HD1 aptamer) or exosite II (heparin and HD22 aptamer) impaired the COMP-thrombin interaction, indicating a 2-site binding mechanism. Additionally, epidermal growth factor-like repeats (amino acids 84-261) were identified as a COMP binding site for thrombin. Moreover, COMP was expressed in and secreted by platelets. Using bone marrow transplantation and platelet transfusion to create chimeric mice, platelet-derived but not vessel-wall-derived COMP was demonstrated to inhibit coagulation. Taken together, COMP is an endogenous thrombin inhibitor and negative regulator of hemostasis and thrombosis.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, People's Republic of China;
authors.forename: Ruomei
authors.initials: R
authors.lastname: Qi
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Meili
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China;
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, People's Republic of China; and.
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Yun
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai, People's Republic of China.
authors.forename: Junling
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Peking, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China;
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000097:blood*; D052157:Aptamers, Nucleotide / Q000378:metabolism; D001665:Binding Sites; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000097:blood; D064236:Cartilage Oligomeric Matrix Protein / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D006487:Hemostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation; D011485:Protein Binding; D011828:Radiation Chimera / Q000097:blood; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood
chemical_list: D000991:Antithrombins; D052157:Aptamers, Nucleotide; D064236:Cartilage Oligomeric Matrix Protein; D013917:Thrombin