Conundrums in the Combined Use of Anticoagulants and Antiplatelet Drugs

Medical pharmacological therapy typically targets a single process or agent. Examples include the selection of a specific antibiotic to suppress growth or viability of a specific bacterium, administration of a specific hormone to obviate a specific endocrinologic deficiency, and utilization of a specific chemotherapeutic agent selected to annihilate neoplastic cells of a specific type. By contrast, the use of anticoagulants and antiplatelet drugs deviates from this general principle because of several considerations: (1) inevitable interactions that link activation of platelets and activation of the coagulation cascade; (2) the effect of commonly used antithrombotics (eg, heparin and warfarin) on multiple factors in the coagulation cascade; and (3) profound amplification of a prothrombotic state of >5 orders of magnitude associated with activation. Accordingly, the concentration in blood of an antithrombotic agent that is sufficient to completely suppress its target under basal conditions may be totally insufficient in such suppression when the thrombotic system is activated. Conversely, if a concentration is sufficient to suppress the target under conditions of activation of the thrombotic system, a hemorrhagic diathesis may be induced under basal conditions. Thus, even when a patient has a single condition to be targeted with antithrombotic measures, the considerations that govern therapy are complex.Numerous positive and negative feedback loops in the prothrombotic process1 confer additional complexity. Important examples of positive loops include activation of coagulation factor (F) V and FVIII by thrombin with consequent augmentation of activation of generation of FXa through what has been called the intrinsic pathway, activation of FIX by the tissue factor/VIIa complex, and activation of FXI and consequently FIX by thrombin. Examples of negative feedback loops include inactivation of FVa and FVIIIa by activated protein C formed by the thrombin/thrombomodulin complex, inhibition of the tissue factor FVIIa complex by tissue factor pathway inhibitor, and inhibition …