Networking in the hemostatic system. Integrin alphaiibbeta3 binds prothrombin and influences its activation.
Prothrombin activation is a pivotal event in thrombosis and hemostasis because thrombin can mediate fibrin formation and can activate and aggregate platelets. Platelet aggregation depends upon the binding of adhesive proteins to integrin alphaIIbbeta3 on the platelet surface. In the present study, a novel interface between the blood coagulation system and platelets is demonstrated by showing that 1) prothrombin binds to alphaIIbbeta3 and 2) this interaction accelerates prothrombin activation. Prothrombin bound to purified alphaIIbbeta3 in a specific, saturable, and divalent cation-dependent manner. This interaction was inhibited by certain monoclonal antibodies to alphaIIbbeta3, by the alphaIIbbeta3 ligands fibrinogen and RGD peptides, but not by thrombin or unrelated proteins. Prothrombin also interacted with alphaIIbbeta3 on resting and stimulated platelets as demonstrated by soluble ligand binding and platelet adhesion assays. Activation of prothrombin by Factor Xa alone or Factor Xa-Va was accelerated by alphaIIbbeta3, and this enhancement was blocked by a monoclonal antibody that inhibited prothrombin binding to the receptor. Taken together, these data identify a previously unrecognized linkage between platelets and the blood coagulation system that may have a significant regulatory consequence.
Byzova
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Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Plow
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D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001665:Binding Sites; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D005340:Fibrinogen / Q000494:pharmacology; D006487:Hemostasis; D006801:Humans; D007700:Kinetics; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000302:isolation & purification / Q000378:metabolism*; D011516:Prothrombin / Q000302:isolation & purification / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C047981:arginyl-glycyl-aspartic acid; D011516:Prothrombin; D005340:Fibrinogen; D013755:Tetradecanoylphorbol Acetate