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A Comparative Study of the Protein C Pathway in Septic and Nonseptic Patients with Organ Failure

¹ INSERM Unité 765, Paris, France; ² AP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France; ³ Université Paris-Descartes, Paris, France; ⁴ AP-HP, Hôpital Européen Georges Pompidou, Service de Réanimation Médicale, Paris, France; ⁵ Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; and ⁶ Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, The Howard Hughes Medical Institute, Oklahoma City, Oklahoma

Correspondence and requests for reprints should be addressed to Pr. Jean-Luc Diehl, M.D., INSERM U765, Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris, Cedex 15, France. E-mail: jldiehl{at}invivo.edu

Rationale: Severe sepsis is associated with an exacerbated procoagulant state with protein C (PC) system impairment. In contrast, the inflammatory and coagulation status of nonseptic patients with organ failure (OF) is less documented.

Objectives: To compare coagulation activation, focusing on the PC system, and inflammatory status in septic and nonseptic patients with OF.

Methods: Thirty patients with severe sepsis and 30 nonseptic patients were recruited at the onset of OF and compared with 30 matched healthy subjects. We performed an extensive analysis of the PC pathway, including plasma protein measurements and quantification of leukocyte expression of PC system receptors. In addition, we analyzed the inflammatory status, based on inflammation-related gene leukocyte expression.

Measurements and Main Results: We observed coagulation activation, reflected by a similar increase in tissue factor mRNA expression, in the two patient groups when compared with the healthy subjects. Soluble thrombomodulin levels were higher in septic patients than in healthy control subjects, whereas PC, protein S, and soluble endothelial cell PC receptor levels were lower. Similar results were obtained in nonseptic patients with OF. Monocyte thrombomodulin overexpression, together with increased circulating levels of activated PC, suggests that the capacity for PC activation is at least partly preserved in both settings. No difference in the inflammatory profile was found between septic and nonseptic patients.

Conclusions: The pathogenesis of OF in critical care patients is characterized by an overwhelming systemic inflammatory response and by exacerbated coagulation activation, independently of whether or not infection is the triggering event.

Clinical trial registered with www.clinicaltrials.gov (NCT 00361725).

Key Words: protein C • organ failure • coagulation • inflammatory profile

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Patients with severe sepsis and organ failure have abnormalities of coagulation and protein C pathways, but little is known about these pathways in patients with organ failure who are not septic. What This Study Adds to the Field Severely ill patients with organ failure have similar coagulation and protein C pathway abnormalities, whether or not sepsis is present, suggesting that common mechanisms are involved in the pathogenesis of organ failure.

 

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