424 American Society of Hematology Thrombophilia and New Anticoagulant Drugs Jeffrey I. Weitz, Saskia Middeldorp, William Geerts, and John A. Heit 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 throm- boembolism 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 pa- tients with unprovoked venous thromboembo- lism 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 thromboem- bolism. In Section III, Dr. John Heit focuses on direct thrombin inhibitors. He discusses their mecha- nism 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. * Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands I. THROMBOPHILIC DEFECTS Saskia Middeldorp, MD* Deep vein thrombosis (DVT) and pulmonary embo- lism (PE) are manifestations of a single disease, venous thromboembolism (VTE). The pathogenesis of VTE is multifactorial, often involving acquired or environmental risk factors, as well as a genetic predisposition. Patients whose VTE occurs in conjunction with a self-limited risk factor, such as surgery, have a low risk of recur- rence when anticoagulant treatment is stopped. In con- trast, approximately one-third of those with unprovoked VTE will suffer a recurrence over the subsequent de- cade once anticoagulant therapy is stopped. Given this high risk of recurrent VTE, some experts recommend long-term anticoagulant therapy after a first episode of unprovoked VTE. This approach is suboptimal because the risk of major bleeding with coumarin derivatives is 2% per year. Consequently, there is a need for patient- specific markers that predict the risk of recurrent VTE so that those at highest risk can be targeted for long- term anticoagulation therapy. At least 50% of patients presenting with unpro- voked VTE have an underlying thrombophilic defect. The prevalence of common thrombophilic defects, such as the factor V Leiden and the prothrombin G20210A mutation, varies according to ethnicity. Thus, in Cau- casians, these mutations are found in 2%–7% and 1%– 3% of the population, respectively. In contrast, both mu-