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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1318.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Recombinant Activated Protein C Attenuates Endothelial Injury and Inhibits Procoagulant Microparticles Release in Baboon Heatstroke

Abderrezak Bouchama; Corinne Kunzelmann; Mohammed Dehbi; Aaron Kwaasi; Abdelmoneim Eldali; Fatiha Zobairi; Jean-Marie Freyssinet; Dominique de Prost

From the Department of Comparative Medicine (A.B., M.D., A.K.), King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Université Louis Pasteur, Faculté de Médecine (C.K., F.Z.), Institut d'Hématologie et d'Immunologie, Strasbourg, France; Biostatistics, Epidemiology, & Scientific Computing (A.E.), King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; INSERM U770 and Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre (J.-M.F.), le Kremlin-Bicêtre, France; and AP-HP, Hôpital Louis Mourier, Colombes and INSERM U698 (D.d.P.), Faculté Xavier Bichat, Paris, France.

Correspondence to Abderrezak Bouchama, MD, Department of Comparative Medicine (MBC03), King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. E-mail abouchama{at}kfshrc.edu.sa

Abstract

Objectives— We tested the hypothesis that the antithrombotic and cytoprotective effects of recombinant human activated protein C (rhAPC) protect baboons against the lethal effects of heatstroke.

Methods and Results— Fourteen anesthetized baboons assigned randomly to rhAPC (n=7) or control group (n=7) were heat-stressed in a prewarmed incubator at 44 to 47°C until systolic blood pressure fell below 90 mm Hg, which signaled severe heatstroke. rhAPC was administered intravenously (24 µg/kg/h) for 12 hours at onset of heatstroke. Heat stress induced coagulation and fibrinolysis activation as evidenced by a significant increase from baseline levels in plasma levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator, and D-dimer. Heat stress elicited cell activation/injury as assessed by the release of interleukin (IL)-6, soluble thrombomodulin, and procoagulant microparticles (MPs). rhAPC did not significantly reduce heatstroke-induced thrombin generation, and D-dimer and had no effect on fibrinolytic activity. In contrast, rhAPC infusion attenuated significantly the plasma rise of IL-6 and inhibited the release of soluble thrombomodulin and MPs as compared with control group. No difference in survival was observed between rhAPC-treated and control group.

Conclusions— rhAPC given to heatstroke baboons provided cytoprotection, but had no effect on heatstroke-induced coagulation activation and fibrin formation. Inhibition of MPs by rhAPC suggested a novel mechanism of action for this protein.

Key Words: APC • heatstroke • hyperthermia • inflammation • procoagulant microparticles • primates