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

AbstractOBJECTIVE:
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 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.
AuthorsAbderrezak Bouchama, Corinne Kunzelmann, Mohammed Dehbi, Aaron Kwaasi, Abdelmoneim Eldali, Fatiha Zobairi, Jean-Marie Freyssinet, Dominique de Prost
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 7 Pg. 1318-25 (Jul 2008) ISSN: 1524-4636 [Electronic] United States
PMID18451327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Fibrin Fibrinogen Degradation Products
  • Fibrinolytic Agents
  • Interleukin-6
  • Protein C
  • Recombinant Proteins
  • Thrombomodulin
  • antithrombin III-protease complex
  • fibrin fragment D
  • Antithrombin III
  • Peptide Hydrolases
  • Tissue Plasminogen Activator
Topics
  • Animals
  • Antithrombin III
  • Blood Coagulation (drug effects)
  • Cytoprotection
  • Disease Models, Animal
  • Endothelium, Vascular (drug effects, metabolism, pathology)
  • Fibrin Fibrinogen Degradation Products (metabolism)
  • Fibrinolysis (drug effects)
  • Fibrinolytic Agents (administration & dosage, pharmacology)
  • Heat Stroke (blood, complications, metabolism, pathology, prevention & control)
  • Humans
  • Infusions, Intravenous
  • Interleukin-6 (blood)
  • Multiple Organ Failure (etiology, metabolism, prevention & control)
  • Papio hamadryas
  • Peptide Hydrolases (blood)
  • Protein C (administration & dosage, pharmacology)
  • Recombinant Proteins (pharmacology)
  • Severity of Illness Index
  • Thrombomodulin (blood)
  • Time Factors
  • Tissue Plasminogen Activator (blood)
  • Transport Vesicles (drug effects, metabolism)

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