Abstract | 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. 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.
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Authors | Abderrezak Bouchama, Corinne Kunzelmann, Mohammed Dehbi, Aaron Kwaasi, Abdelmoneim Eldali, Fatiha Zobairi, Jean-Marie Freyssinet, Dominique de Prost |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 28
Issue 7
Pg. 1318-25
(Jul 2008)
ISSN: 1524-4636 [Electronic] United States |
PMID | 18451327
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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