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6 Role of Thrombin In addition to its well known actions on the coagulation cascade, thrombin is a potent growth factor for mesenchymal cells [51–53], a proangiogenic factor [54] that stimulates endothelial cell mitogenesis and migration. The cellular effects of thrombin are mediated by the G-protein-coupled seven transmembranespanning protease-activated receptors (PARs)-1, -3 and -4. The unique mode of PAR-1 receptor activation results from cleavage of its N-terminal end which exposes a tethered ligand capable of binding to the second extracellular loop of the receptor.

These and other probable mechanisms for thrombosis in cancer patients have been examined in detail elsewhere [2, 28, 30]. Suffice it to say that the pathogenesis of thrombosis in cancer is complex and most likely involves multiple mechanisms that may differ dramatically from patient to patient. However, until recently, it has been presumed that all of these mechanisms are secondary and have no primary role in the molecular events leading to the development of cancer. 4 Molecular Pathogenesis of Thrombosis in Cancer – Direct Link to Oncogenesis Boccaccio and her colleagues developed a model for human liver carcinoma by targeting activated human MET oncogene to mouse liver with a lentiviral vector and liver-specific promoter [3].

J Thromb Haemost 2004;2:2107–14. Chapter 3 Activation of Clotting Factors in Cancer Frederick R. 1 Introduction Evidence for ‘‘hypercoagulability’’ is commonly found in patients with cancer and increases the risk of thromboembolism (TE) [1]. While the pathophysiology of TE in cancer is complex, it can be viewed classically as related to abnormalities of Virchow’s triad: stasis of the blood; vascular injury; hypercoagulability (or, as described by Virchow himself, as ‘‘abnormalities of the fixed elements of the blood’’) [2].