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Thrombotic and Hemorrhagic Conditions Due to a Gain of Function of Coagulation Proteins: A Special Type of Clotting Disorders

Coagulation disorders can be classified into 2 types, namely, type I and type II. In the former, there is a concomitant decrease in factor activity and antigen (activity–antigen ratio is 1), whereas in the latter, there is a discrepancy between factor activity which is always low and antigen which is normal or near normal (activity–antigen ratio is <1, eg, 0.5). Recently, several gain-of-function disorders have been described. These are characterized by an increased activity with respect to the antigen level. The condition involves polymorphisms of factor V and factor II, factor IX, von Willebrand disease, thrombomodulin, tissue factor pathway inhibitor, and thrombin activatable fibrinolysis inhibitor. The conditions could be subdivided into prothrombotic and prohemorrhagic. They should also be distinguished as cases of true gain of function (intrinsic increase activity without concomitant increase in protein level) and of “pseudo” gain of function (increase in both activity and protein level). This is a new concept of coagulation defects that has considerably enhanced our knowledge of blood coagulation and that should be familiar to all those interested in the mechanism of blood clotting and its disorders.