Defective Thrombin Binding by Abnormal Fibrin Associated with Recurrent Thrombosis

Studies of clotting activity and radioactivity (with ¹²⁵I-thrombin) indicated that binding of human thrombin to fibrin depends upon the initial concentrations of the reactants. Scatchard analysis suggests two classes of binding site: a high affinity site with a Ka 5.8±0.9 x 10⁵M^-1 and a maximum molar binding ratio of thrombin to fibrin 0.4±0.2, and a low affinity site with a Ka 6.8±0.6 x 10⁴M^-1 and a maximum molar binding ratio of 1.6±0.5. The active site of thrombin is not required for binding since neutralization with phenylmethyl sulfonyl fluoride does not affect the binding. Thrombin also binds to fibrin formed in whole blood and can be recovered with full clotting activity when the clot is dissolved by plasmin, suggesting that binding of thrombin to fibrin is a potential mechanism for limiting thrombosis. Fibrinogen New York I, in a patient with recurrent venous and arterial thrombosis, was characterized by abnormalities in fibrinopeptide release by thrombin and fibrin polymerization. The patient’s plasma contained equal amounts of normal and abnormal fibrinogen. Thrombin was bound normally by fibrin derived from the normal fibrinogen but was not bound at all by fibrin from the abnormal fibrinogen. Fibrinogen New York II, in an asymptomatic patient, was characterized by delayed fibrinopeptide release and fibrin polymerization. Thrombin was bound normally by this fibrin. Thus defective binding of thrombin by fibrin is suggested as a new mechanism predisposing to recurrent thrombosis.