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Potential Role of Platelets in Endothelial Damage Observed During Treatment With Cisplatin, Gemcitabine, and the Angiogenesis Inhibitor SU5416

B.C. Kuenen, M. Levi, J.C.M. Meijers, V.W.M. van Hinsbergh, J. Berkhof, A.K. Kakkar, K. Hoekman, H.M. Pinedo

From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom.

Address reprint requests to H.M. Pinedo, MD, Department of Medical Oncology, VU Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; email: HM.Pinedo{at}vumc.nl.

Purpose: An increased incidence of thromboembolic events was observed during treatment with cisplatin-gemcitabine plus SU5416 (CG+SU5416), a tyrosine kinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor-1 and -2. Nine thromboembolic events occurred in eight of 19 patients. We performed an analysis of parameters of the coagulation cascade and vessel wall activation.

Materials and Methods: Markers for thrombin generation and endothelial cell activation were measured in three patients treated with CG+SU5416, two of whom developed a thromboembolic event. The results were compared with measurements in six patients treated with CG alone, and in 17 patients treated with SU5416 alone.

Results: During cycles 1 and 2 of treatment with CG+SU5416, a significant cycle-dependent activation of both the coagulation cascade and endothelial cells occurred, whereas platelet counts decreased. Change in platelet number had a significant negative predictive effect on soluble (s)-E-selectin levels. Significant activation of the coagulation cascade only was observed in the patients treated with CG alone, whereas in patients treated with SU5416 alone, significant endothelial cell activation was observed.

Conclusion: We hypothesize that endothelial cells deprived of VEGF after exposure to SU5416 became activated and more susceptible to damage during treatment with CG+SU5416, which was aggravated by a transient decrease in platelets, which are, among other things, carriers of VEGF. These results suggests that VEGF, in addition to being a permeability, proliferation, and migration factor, also is a maintenance and protection factor for endothelial cells, and that platelets may have a role in maintaining vascular integrity.

Supported by grant D96.021 from the Netherlands Heart Foundation (J.C.M.M.).

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