First, the experiments of Wessler and Gitel over 40 years ago using a stasis model of thrombosis in rabbits showed that the antithrombotic effect of warfarin requires 6 days of treatment, whereas an anticoagulant effect develops in 2 days. The antithrombotic effect of warfarin requires the reduction of prothrombin (factor II), which has a relatively long half-life of about 60 to 72 h, compared with 6 to 24 h for other vitamin K-dependent factors that are responsible for the more rapid anticoagulant effect.
Second, in a rabbit model of tissue factor-induced intravascular coagulation the protective effect of warfarin was mainly a result of lowering prothrombin levels. Third, Patel and associates demonstrated that clots formed from umbilical cord plasma containing about half the prothrombin concentration of plasma from adult control subjects generated significantly less fibrinopeptide A than clots formed from maternal plasma. The view that warfarin exerts its antithrombotic effect by reducing prothrombin levels is consistent with observations that clot-bound thrombin is an important mediator of clot growth, and that reduction in prothrombin levels decreases the amount of thrombin generated and bound to fibrin, thereby reducing thrombogenicity.
The suggestion that the antithrombotic effect of warfarin is reflected in lower levels of prothrombin forms the basis for overlapping the administration of heparin with warfarin until the PT or INR is prolonged into the therapeutic range during the treatment of patients with thrombosis. Since the half-life of prothrombin is about 60 to 72 h, at least 4 days of overlap is necessary. Furthermore, the levels of native prothrombin antigen during warfarin therapy more closely reflect antithrombotic activity than the PT.
The PT test is the most common test used to monitor VKA therapy. The PT responds to a reduction of three of the four vitamin K-dependent procoagulant clotting factors (ie, II, VII, and X) that are reduced by warfarin at a rate proportional to their respective half-lives. Thus, during the first few days of warfarin therapy the PT reflects mainly a reduction of factor VII, the half-life of which is approximately 6 h. Subsequently, the reduction of factors X and II contributes to prolongation of the PT. The PT assay is performed by adding calcium and thromboplastin to citrated plasma.
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Thromboplastins vary in responsiveness to a reduction of the vitamin K-dependent coagulation factors. An unresponsive thromboplastin produces less prolongation of the PT for a given reduction in vitamin K-dependent clotting factors than a responsive one. The responsiveness of a thromboplastin can be measured by assessing its international sensitivity index (ISI) [see below]. Highly sensitive thromboplastins (ISI, approximately1.0) that are composed of human tissue factor produced by recombinant technology and defined phospholipid preparations are now available.