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INTRODUCTION

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The association between cancer and thrombosis was first proposed by Armand Trousseau (Figure 19-1) when he recognized the condition of thrombophlebitis migrans, as a forewarning of occult malignancy (1). In 1865, he remarked, "Should you, when in doubt as to the nature of an affection of the stomach, should you when hesitating between chronic gastritis, simple ulcer, and cancer, observe a vein become infected in the arm or leg, you may dispel your doubt, and pronounce in a positive manner that there is a cancer …" (1). Although the association of hemostatic disorders and cancer has been studied extensively over the past 100 years, venous thromboembolism (VTE), defined herein as pulmonary embolus (PE) or deep vein thrombosis (DVT), remains a major cause of morbidity and mortality in cancer patients.

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This chapter will explore the pathogenesis of thrombosis in cancer as well as the epidemiology and risk factors. The chapter will also focus on novel risk assessment models and the emergence of new biomarkers to classify patients at high risk of developing VTE. Current diagnostic and management strategies for VTE in cancer patients and the challenges of antithrombotic therapy in this population will be examined. This update will evaluate the results of several randomized controlled trials aimed at assessing the clinical benefit of antithrombotic prophylaxis in cancer outpatients. Finally, new therapeutic developments in this area will be addressed.

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PATHOGENESIS

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The pathophysiological mechanisms of thrombosis in cancer patients are complex and involve multiple clinical and biological factors including tumor cells, the hemostatic system, inherited and acquired thrombophilia, and exogenous contributors such as chemotherapy and radiotherapy (2). Tumors contribute to thrombosis through the expression of procoagulant factors including tissue factor, cancer procoagulant, and adhesion molecules. Recent experimental models of human cancers have shown that an integral feature of neoplastic transformation from cancer cells is through activation of clotting proteins (3,4,5,6). The role of tissue factor-bearing microparticles (MP) contributing to thrombin generation has also been explored in vitro and in vivo studies. Zwicker et al. found that VTE developed in 34.8% of cancer patients with elevated levels of MP compared to 0% in those without detectable levels (7). Tumor cells can also induce platelet activation and aggregation through secretion of proteases. Tumor-related release of various cytokines, growth factors, and proteases including tumor necrosis factor α (TNFα), interleukin 1β, and vascular endothelial growth factor (VEGF) contribute not only to angiogenesis and inflammation but also to the activation of the hemostatic system. Furthermore, tumor cells interact directly with the host blood vessels, endothelial cells, leukocytes, and monocytes leading to host cell inflammatory responses (2). These many and varied interactions lead to both a direct and an indirect ...

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