Published ahead of print on November 15, 2007, doi:10.1164/rccm.200706-840OC Am. J. Respir. Crit. Care Med., Volume 177, Number 5, March 2008, 536-543 A more recent version of this article appeared on March 1, 2008
Submitted on June 7, 2007 Procoagulant Membrane Microparticles Correlate with the Severity of Pulmonary Arterial HypertensionBabe Bakouboula1,1 Federation de Cardiologie, Hopitaux Universitaires de Strasbourg, Strasbourg, France; Institut d'Hematologie et d'Immunologie, Universite Louis Pasteur, Strasbourg, France; INSERM, U.770, Le Kremlin-Bicetre, France, 2 Federation de Cardiologie, Hopitaux Universitaires de Strasbourg, Strasbourg, France, 3 Institut d'Hematologie et d'Immunologie, Universite Louis Pasteur, Strasbourg, France; INSERM, U.770, Le Kremlin-Bicetre, France, 4 Departement de Pneumologie, Hopitaux Universitaires de Strasbourg, Strasbourg, France, 5 Hematologie Biologique, Service d'Hemostase, Hopitaux Universitaires de Strasbourg, Strasbourg, France, 6 Faculte de Medecine de Nancy, Nancy Universite, Vandoeuvre-les-Nancy, France; Faculte de Medecine de Nancy, INSERM, U.734, Vandoeuvre-les-Nancy, France, 7 Faculte de Medecine de Nancy, Nancy Universite, Vandoeuvre-les-Nancy, France; Faculte de Medecine de Nancy, INSERM, U.734, Vandoeuvre-les-Nancy, France; Service des Maladies Respiratoires et Reanimation Respiratoire, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France, 8 Departement de Pneumologie, Hopitaux Universitaires de Strasbourg, Strasbourg, France; Service des Maladies Respiratoires et Reanimation Respiratoire, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France, 9 Institut d'Hematologie et d'Immunologie, Universite Louis Pasteur, Strasbourg, France; INSERM, U.770, Le Kremlin-Bicetre, France; Faculte de Medecine, Universite Paris-Sud 11, Le Kremlin-Bicetre, France * To whom correspondence should be addressed. E-mail: a.chaouat{at}chu-nancy.fr.
Rationale: Procoagulant microparticles constitute valuable hallmarks of cell damage. Microparticles also behave as cellular effectors. Objectives: We hypothesized that the extent of the vascular cell damage measured by circulating microparticles could be related to the severity of pulmonary arterial hypertension (PAH). Methods: Circulating biomarkers of vascular damage and cell activation were measured in blood samples from 20 patients with PAH. Samples were withdrawn from occluded pulmonary artery and jugular vein. Peripheral venous blood samples were obtained in 23 control subjects. The microparticle procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin were determined. Results: Soluble vascular cellular adhesion molecule-1 and pro-inflammatory markers such as monocyte chemoattractant protein-1 and high-specific C-reactive protein were elevated in PAH patients compared to controls. Microparticles bearing active tissue factor and CD105 (endoglin) were also elevated in patients with PAH compared to controls (29 ± 13 fM versus 16 ± 6 fM, p<0.001 and 1.10 ± 0.46 nM PhtdSer Eq versus 0.49 ± 0.33 nM PhtdSer Eq, p<0.001, respectively). A further increase in endothelial-derived CD105 microparticles was observed in pulmonary arterial blood compared to venous blood in patients with PAH (1.73 ± 0.77, p=0.038). Microparticles bearing active tissue factor were at a higher level in patients in functional class III and IV and walking less than 380 meters at the 6-minute walk test. Conclusion: Circulating markers of endothelium damage, pro-inflammatory markers and cell stimulation estimated with circulating microparticles appear valuable tools in determining the severity of PAH. Key words: pulmonary hypertension, endothelium, tissue factor, VCAM-1, endoglin
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