Thrombosis is responsible for 10 million deaths each year, accounting for one in four deaths worldwide. Arterial thrombosis is the most common cause of myocardial infarction, ischemic stroke, and acute limb ischemia, whereas on the venous side, it causes deep-vein thrombosis and pulmonary embolism, collectively known as venous thromboembolism.
Anticoagulation therapy is the cornerstone of prevention and treatment of thrombosis. Blood coagulation is triggered by tissue factor exposed at sites of vascular injury, which initiates a series of activation events that culminate in thrombin generation. Thrombin converts fibrinogen to fibrin, serves as a potent platelet agonist, and activates several clotting factors to amplify its own generation and stabilize the fibrin clot.
For years, the mainstays of anticoagulation therapy were heparin and warfarin, which target multiple reactions in the coagulation cascade to suppress thrombin generation. Although effective, heparin must be given parenterally, and both agents require frequent monitoring to ensure therapeutic anticoagulation. The newer direct oral anticoagulants (DOACs) include the thrombin inhibitor dabigatran, and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. The DOACs, specific inhibitors of catalytic function, are designed to be given in fixed doses without routine coagulation monitoring. Because of their similar efficacy to warfarin but greater safety and convenience, DOACs are now preferred for prevention and treatment of many thrombotic disorders.
Although the DOACs come closer to the goal of attenuating thrombosis without perturbing hemostasis, bleeding remains the major side effect. By deciphering the mechanisms through which membrane-bound clotting factor complexes function, new ways to modulate coagulation reactions without ablating protease activity have been identified. Furthermore, as a result of better understanding the regulatory interconnectivity between the activation steps in coagulation, factor XI and factor XII have been identified as potentially safer targets for new anticoagulants, because they have little or no role in hemostasis but are implicated in thrombosis.
Dr. Krishnaswamy will describe how incorporation of factor Xa into the prothrombinase complex modulates its specificity and efficiency to promote thrombin generation and how this information can inform novel strategies for attenuating this process.
Dr. Weitz will describe how the DOACs have transformed anticoagulation therapy and how the results of trials with factor XI inhibitors provide new insights into the pathogenesis of thrombosis and pave the way for safer therapies.