Angiogenesis Inhibitors, Cancer-Associated Thrombosis, and Bleeding

The development of cancer is dependent on new blood vessel formation, the process of angiogenesis (1). This process is stimulated by tumors through the release of angiogenic growth factors. Angiogenesis is required not only for tumor growth, but also for wound healing, growth, and the menstrual cycle (2). The coagulation cascade plays an important role in the angiogenic process (3,4). A clear correlation between tissue factor (TF), the main initiator of coagulation, and vascular endothelial growth factor (VEGF) has been recognized in both preclinical and clinical studies (5-7). In addition, platelets are transporters of angiogenesis factors, and activation of platelets stimulates new vessel formation (8-10). Taking these fi ndings together, the observation that angiogenesis inhibitors also affect coagulation could have been expected. In several clinical trials, various angiogenesis inhibitors caused venous and arterial thrombotic complications as well as delayed wound healing and bleeding complications. The fi rst severe thrombotic complications occurred in a dose-fi nding early clinical trial with SU5416, an antiangiogenic receptor tyrosine kinase inhibitor (RTKI), in combination with chemotherapy (11). This study contributed to the early termination of the clinical development of SU5416. In this chapter, we summarize the clinically observed coagulation abnormalities during antiangiogenic therapy.