Introduction: New treatment strategies for thrombotic disorders

Abstract

THIS ISSUE OF Seminars reviews new drugs for thrombotic disorders that have been recently approved or are probably soon to be approved. Several articles also focus on the ways in which commonly used agents such as low molecular weight heparin (LMWH) and warfarin can be employed more safely for those patients who are at high risk for either thrombosis or bleeding. Stephan Moll and Harold Roberts provide the background and rationale for development of antithrombotic agents. They describe the benefits and disadvantages of current drugs and review our newer understanding of hemostasis, which provides the basis on which to develop drugs with specific targets, such as the tissue factor:factor VIIa complex. In addition, these authors provide an excellent summary of the pharmaceuticals that have been recently approved or are in development. Graham Turpie provides a thorough review of the preclinical and clinical trials that led to the recent approval by the Food and Drug Administration (FDA) of fondaparinux sodium (Arixtra, Sanofi-Synthelabo, Paris, France/Organon, Oss, The Netherlands) for prevention of venous thromboembolism after surgery for hip fracture or for hip or knee replacement. This pentasaccharide, which acts in conjunction with antithrombin to inhibit factor Xa, is synthesized rather than derived from animal origin; its long terminal half-life of 17 to 21 hours allows for once-daily dosing. The drug does not appear to inhibit platelet function or to interact with platelet factor 4, suggesting that it may have potential as alternative therapy in heparin-induced thrombocytopenia. Its disadvantages are that no antidote is available to neutralize its activity and it is cleared by the renal route, indicating cautious use in patients with any evidence of renal dysfunction. The FDA approval for the use of LMWH as treatment for acute venous thromboembolism has resulted in a revolution in the care ofmost patients with this disorder, with hospital days either completely eliminated or markedly reduced. However, many of the clinical trials that were designed to show efficacy of LMWH excluded patients with known underlying hypercoagulable states, or who were obese or had renal disease. These patients are now also receiving LMWH. SusanO’Shea and Thomas Ortel reviewwhat is known about the use of LMWH in patients who have renal insufficiency, cancer, or who are obese or pregnant. They also discuss the perioperative use of LMWH and the role of protamine in neutralizing the anticoagulant activity. The issues addressed in their article will also need to be considered for pentasaccharide. Jean Chai and Gail Macik discuss several factors that can affect the anticoagulant potency of warfarin. Polymorphisms in the cytochrome P450 CYP2C9 enzyme result in prolonged catabolism of the S enan-