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Abstract
Background
Septic shock-induced disseminated intravascular coagulation is responsible for increased occurrence of multiple organ dysfunction and mortality. Immunothrombosis-induced coagulopathy may contribute to hypercoagulability. We aimed at determining whether recombinant human thrombomodulin (rhTM) could control exaggerated immunothrombosis by studying procoagulant responses, fibrinolysis activity borne by microvesicles (MVs) and NETosis in septic shock.
Methods
In a septic shock model after a cecal ligation and puncture-induced peritonitis (H0), rats were treated with rhTM or a placebo at H18, resuscitated and monitored during 4 h. At H22, blood was sampled to perform coagulation tests, to characterize MVs and to detect neutrophils extracellular traps (NETs). Lungs were stained with hematoxylin–eosin for inflammatory injury assessment.
Results
Coagulopathy was attenuated in rhTM-treated septic rats compared to placebo-treated rats, as attested by a significant decrease in procoagulant annexin A5+-MVs and plasma procoagulant activity of phospholipids and by a significant increase in antithrombin levels (84 ± 8 vs. 64 ± 6%, p < 0.05), platelet count (582 ± 157 vs. 319 ± 91 × 109/L, p < 0.05) and fibrinolysis activity borne by MVs (2.9 ± 0.26 vs. 0.48 ± 0.29 U/mL urokinase, p < 0.05). Lung histological injury score showed significantly less leukocyte infiltration. Decreased procoagulant activity and lung injury were concomitant with decreased leukocyte activation as attested by plasma leukocyte-derived MVs and NETosis reduction after rhTM treatment (neutrophil elastase/DNA: 93 ± 33 vs. 227 ± 48 and citrullinated histones H3/DNA: 96 ± 16 vs. 242 ± 180, mOD for 109 neutrophils/L, p < 0.05).
Conclusion
Thrombomodulin limits procoagulant responses and NETosis and at least partly restores hemostasis control during immunothrombosis. Neutrophils might thus stand as a promising therapeutic target in septic shock-induced coagulopathy.
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Details
1 UMR INSERM 1176-Universite Paris Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Réanimation Médicale, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
2 Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, France; INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
3 UMR INSERM 1176-Universite Paris Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4 Service d’Accueil des Urgences, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France
5 INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
6 Réanimation Médicale, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
7 Laboratoire d’hématologie et hémostase, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France