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

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 (nϭ7) or control group (nϭ7) 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 g/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.

Heat Stroke

“…No pharmacological treatment has been found to be beneficial. Antipyretics have no role in heat stroke and may be toxic to the liver, whereas experimental findings in a primate classic heat stroke model do not support the clinical use of corticosteroids or activated protein C in the prevention or treatment of classic heat stroke (48,49).…”

Heat stroke: Role of the systemic inflammatory response

“…Recombinant human activated protein C (rhAPC) has been approved in the United States for the treatment of severe sepsis and has anti-inflammatory and anticoagulant properties that warrant consideration for the treatment of heat stroke. In heat stroke patients and experimental models, rhAPC attenuated inflammation, resolved multi-organ system dysfunction, and improved survival (5,10,23). However, the efficacy of rhAPC was dependent on the timing of administration and specific characteristics of the patient population and did not protect against mortality in all heat stroke models, indicating that additional studies are needed to warrant its use as a heat stroke treatment (10,23,87).…”

Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects

“…Early work by Satta and co-workers for example has demonstrated that LPS treatment increases TM activity on monocyte-derived MPs by up to 80% (135). Coelevated TM and MP levels in serum have also been observed during systemic inflammatory response syndrome (SIRS) in humans and during heat stroke in baboons (18,116), while recent work by Duchemin et al (40) points to an influence of circulating MPs on the "TM resistance" of patients suffering from myeloproliferative neoplasm.…”