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Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients

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Author: Kuenen, B.C. · Levi, M. · Meijers, J.C.M. · Kakkar, A.K. · Hinsbergh, V.W.M. van · Kostense, P.J. · Pinedo, H.M. · Hoekman, K.
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 9, 22, 1500-1505
Identifier: 236675
doi: doi:10.1161/01.ATV.0000030186.66672.36
Keywords: Angiogenesis Inhibitors · Blood Coagulation · Blood Platelets · Carcinoma, Renal Cell · Cell Division · Cell Membrane Permeability · Cell Movement · Drug Administration Schedule · Endothelium, Vascular · Fibrinolysis · Hemostasis · Indoles · Kidney Neoplasms · Melanoma · Neovascularization, Pathologic · Protein C · Proto-Oncogene Proteins · Pyrroles · Receptor Protein-Tyrosine Kinases · Receptors, Growth Factor · Receptors, Vascular Endothelial Growth Factor · Sarcoma · Thrombin · Vascular Endothelial Growth Factor Receptor-1


Objective - The angiogenesis inhibitor SU5416 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor-1 and -2. VEGF may be involved in hemostasis by altering the hemostatic properties of endothelial cells. We analyzed the effects of SU5416 on the coagulation cascade and the vessel wall in patients with advanced cancer. Methods and Results - Markers for thrombin generation, activation of the protein C pathway, fibrinolysis, and endothelial cell activation were measured in patients with renal cell carcinoma, soft tissue sarcoma, or melanoma on days 0, 14, and 28 of treatment with SU5416. Three of 17 sampled patients developed a thromboembolic event in the fifth week of treatment. Markers for thrombin generation and fibrinolysis did not show significant changes. We observed a significant increase in endogenous thrombin potential and of parameters reflecting endothelial cell activation (von Willebrand antigen, soluble tissue factor, and soluble E-selectin) in all patients (P≤0.001). In patients experiencing a thromboembolic event, endogenous thrombin potential, soluble tissue factor, and soluble E-selectin increased to a significantly greater extent (P=0.029, P=0.021, and P=0.007, respectively). Conclusions - VEGF is not only a permeability, proliferation, and migration factor, but it is also a maintenance and protection factor for endothelial cells. Chemicals/CAS: Angiogenesis Inhibitors; Indoles; Protein C; Proto-Oncogene Proteins; Pyrroles; Receptor Protein-Tyrosine Kinases, EC; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor, EC; SU 5416; Thrombin, EC; Vascular Endothelial Growth Factor Receptor-1, EC