Thrombophilia and New Anticoagulant Drugs

Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is the result of an imbalance among procoagulant, anticoagulant and profibrinolytic processes. This imbalance reflects a complex interplay between genetic and environmental or acquired risk factors. Genetic thrombophilic defects influence the risk of a first episode of thrombosis. How these defects influence the risk of recurrence in patients whose first episode of venous thromboembolism was unprovoked is less certain. Thus, when anticoagulants are stopped, patients with unprovoked venous thromboembolism have a risk of recurrence of at least 7% to 10% per year, even in the absence of an underlying thrombophilic defect. Consequently, there is a trend toward longer durations of anticoagulation therapy for these patients, which is problematic given the limitation of existing anticoagulants. This chapter provides an overview of the thrombophilic defects and how they influence the risk of venous thromboembolism. The chapter also details advances in anticoagulant therapy, focusing on new inhibitors of factor Xa and thrombin. In Section I, Dr. Saskia Middeldorp describes the various thrombophilic defects and reviews their relative importance in the pathogenesis of a first episode of venous thromboembolism. She then discusses the influence of these defects on the risk of recurrent thrombotic events in patients with unprovoked venous thromboembolism and in those whose thrombosis occurred in association with a known risk factor, such as surgery. In Section II, Dr. William Geerts reviews the pharmacology of new parenteral and oral factor Xa inhibitors and describes the results of the Phase II and III clinical trials with these agents. He then provides perspective on the potential advantages and drawbacks of these drugs for the prevention and treatment of venous thromboembolism. In Section III, Dr. John Heit focuses on direct thrombin inhibitors. He discusses their mechanism of action and compares and contrasts their pharmacological profiles prior to describing the results of Phase II and III clinical trials. Dr. Heit then provides perspective on the potential advantages and limitations of these drugs relative to existing anticoagulants.