Recombinant activated protein C attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke.
OBJECTIVE
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.


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 degrees C until systolic blood pressure fell below 90 mm Hg, which signaled severe heatstroke. rhAPC was administered intravenously (24 microg/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.
Bouchama
Abderrezak
A
Department of Comparative Medicine (MBC03), King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. abouchama@kfshrc.edu.sa
Kunzelmann
Corinne
C
Dehbi
Mohammed
M
Kwaasi
Aaron
A
Eldali
Abdelmoneim
A
Zobairi
Fatiha
F
Freyssinet
Jean-Marie
JM
de Prost
Dominique
D
D000818:Animals; D000990:Antithrombin III; D001777:Blood Coagulation / Q000187:drug effects*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018883:Heat Stroke / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000097:blood; D009102:Multiple Organ Failure / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D048529:Papio hamadryas; D010447:Peptide Hydrolases / Q000097:blood; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index; D018180:Thrombomodulin / Q000097:blood; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000097:blood; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism*
D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D015850:Interleukin-6; D011486:Protein C; D011994:Recombinant Proteins; D018180:Thrombomodulin; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D000990:Antithrombin III; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator