Role of current and emerging antithrombotics in thrombosis and cancer.

Abstract

In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy. The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa activity impairs the activation of tissue factor/factor VIIa complex leading to downregulation of procoagulant state, pro-angiogenesis, and proinflammatory factors induced by tissue factor/factor VIIa. Furthermore, a number of orally active direct antithrombin and anti-factor Xa are in advanced clinical development for various thromboembolic disorders.