Anticoagulant activities of a monoclonal antibody that binds to exosite II of thrombin.
A monoclonal IgG isolated from a patient with multiple myeloma has been shown to bind to exosite II of thrombin, prolong both the thrombin time and the activated partial thromboplastin time (aPTT) when added to normal plasma, and alter the kinetics of hydrolysis of synthetic peptide substrates. Although the IgG does not affect cleavage of fibrinogen by thrombin, it increases the rate of inhibition of thrombin by purified antithrombin approximately 3-fold. Experiments with plasma immunodepleted of antithrombin or heparin cofactor II confirm that prolongation of the thrombin time requires antithrombin. By contrast, prolongation of the aPTT requires neither antithrombin nor heparin cofactor II. The IgG delays clotting of plasma initiated by purified factor IXa but has much less of an effect on clotting initiated by factor Xa. In a purified system, the IgG decreases the rate of activation of factor VIII by thrombin. These studies indicate that binding of a monoclonal IgG to exosite II prolongs the thrombin time indirectly by accelerating the thrombin-antithrombin reaction and may prolong the aPTT by interfering with activation of factor VIII, thereby diminishing the catalytic activity of the factor IXa/VIIIa complex.
Lian
F
F
Division of Hematology, Department of Internal Medicine, Washington University, St. Louis, Missouri 63110, USA.
He
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Colwell
N S
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Lollar
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Tollefsen
D M
DM
D000838:Anions / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000925:Anticoagulants / Q000378:metabolism*; D000991:Antithrombins / Q000378:metabolism*; D001666:Binding Sites, Antibody; D004306:Dose-Response Relationship, Immunologic; D015949:Factor IXa / Q000037:antagonists & inhibitors / Q000378:metabolism; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000378:metabolism; D015944:Factor VIIIa / Q000037:antagonists & inhibitors / Q000378:metabolism; D005340:Fibrinogen / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D010314:Partial Thromboplastin Time; D013917:Thrombin / Q000276:immunology* / Q000378:metabolism*; D013918:Thrombin Time
D000838:Anions; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D000991:Antithrombins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D015944:Factor VIIIa; D005169:Factor VIII; D005340:Fibrinogen; D015949:Factor IXa; D013917:Thrombin