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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1318-1325
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number7
DOIs
Publication statusPublished - 1 Jul 2008
Externally publishedYes

Fingerprint

Heat Stroke
Papio
Protein C
Recombinant Proteins
Wounds and Injuries
Thrombomodulin
Hot Temperature
Control Groups
Interleukin-6
Blood Pressure
Incubators
Cytoprotection
Fibrinolysis
Tissue Plasminogen Activator
Fibrin
Thrombin
Survival

Keywords

  • APC
  • Heatstroke
  • Hyperthermia
  • Inflammation
  • Primates
  • Procoagulant microparticles

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Recombinant activated protein c attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke. / Bouchama, Abderrezak; Kunzelmann, Corinne; Dehbi, Mohammed; Kwaasi, Aaron; Eldali, Abdelmoneim; Zobairi, Fatiha; Freyssinet, Jean Marie; De Prost, Dominique.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 28, No. 7, 01.07.2008, p. 1318-1325.

Research output: Contribution to journalArticle

Bouchama, Abderrezak ; Kunzelmann, Corinne ; Dehbi, Mohammed ; Kwaasi, Aaron ; Eldali, Abdelmoneim ; Zobairi, Fatiha ; Freyssinet, Jean Marie ; De Prost, Dominique. / Recombinant activated protein c attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2008 ; Vol. 28, No. 7. pp. 1318-1325.
@article{740bb47bd69844d29c7e09350978bf54,
title = "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 (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.",
keywords = "APC, Heatstroke, Hyperthermia, Inflammation, Primates, Procoagulant microparticles",
author = "Abderrezak Bouchama and Corinne Kunzelmann and Mohammed Dehbi and Aaron Kwaasi and Abdelmoneim Eldali and Fatiha Zobairi and Freyssinet, {Jean Marie} and {De Prost}, Dominique",
year = "2008",
month = "7",
day = "1",
doi = "10.1161/ATVBAHA.107.161737",
language = "English",
volume = "28",
pages = "1318--1325",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Recombinant activated protein c attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke

AU - Bouchama, Abderrezak

AU - Kunzelmann, Corinne

AU - Dehbi, Mohammed

AU - Kwaasi, Aaron

AU - Eldali, Abdelmoneim

AU - Zobairi, Fatiha

AU - Freyssinet, Jean Marie

AU - De Prost, Dominique

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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.

AB - 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.

KW - APC

KW - Heatstroke

KW - Hyperthermia

KW - Inflammation

KW - Primates

KW - Procoagulant microparticles

UR - http://www.scopus.com/inward/record.url?scp=46249112459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=46249112459&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.107.161737

DO - 10.1161/ATVBAHA.107.161737

M3 - Article

VL - 28

SP - 1318

EP - 1325

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 7

ER -