Appreciating and Mitigating Bleeding Risk

Excessive bleeding is a hazard that has been noted throughout history. As early as the 12th century, physicians identified males who died of uncontrollable bleeding and noted familial relationships. Although hemophilia was probably the source, over the past decade there has been a therapy-induced increase in hemorrhagic disorders. Until recently, treatment for obstructive cardiovascular disease has primarily focused on vessel patency and relief of the thrombosis. Although bleeding has been the accepted primary side effect of antithrombotics, the success and proliferation of novel antiplatelet and antithrombin therapies has tipped the hemorrhage-thrombosis scale. As has been appreciated in many recent clinical trials, the risk of bleeding has now limited efficacy for many of these therapies, leading to a reexamination of new and combinatorial therapeutic uses for antithrombotics.Although it seems evident that adding more powerful antithrombotic therapies would lead to greater bleeding, the increase in hemorrhage was not entirely anticipated. New antithrombotics typically have favorable bleeding/thrombotic profiles in preclinical models and are primarily evaluated singularly and, therefore, may or may not be directly applicable to clinical use.1 For example, warfarin treatment is associated with hematoma expansion after intracerebral hemorrhage, and it was hoped that direct thrombin inhibitors would mitigate this side effect. In the use of different animal models of intracerebral hemorrhage, warfarin-treated animals had enlarged cerebral hematomas and bleeding, but no difference was found between oral thrombin inhibitor–treated animals and controls.2 Although this is similar to clinical observations,3 other therapies have not had the same consistency in bleeding with preclinical trials.4 Potential inconsistencies between preclinical and clinical studies have made the development of …