Microthrombosis in sepsis.
Normal endothelial cells express several membrane components with anticoagulant properties, which include: 1) tissue factor pathway inhibitors (TFPI), i.e. surface molecules able to accelerate the action of antithrombin (AT) on coagulation proteases; 2) thrombomodulin (TM), a thrombin binding surface protein able to inhibit thrombin activity; the complex TM-thrombin, also, activates protein C (PC); 3) endothelium derived factors such as nitric oxide and prostacyclin, which have antiadhesive properties and activate plasminogen. Exposure to inflammatory and/or septic stimuli can rapidly lead to a procoagulant response, activated by bacterial endotoxins, and to a decrease of endothelial anticoagulant membrane components. Activation of coagulation concomitant to impaired fibrinolysis is associated with fibrin deposition, tissue ischemia and necrosis. This review presents the results of different strategies aimed at reducing organ dysfunction and mortality in septic shock by modulating coagulation activity. In various animal models and in phase II clinical studies, the treatment with TFPI, AT and activated PC reduced organ dysfunction and mortality. Two phase III trials showed no efficacy of AT and a reduction of the relative risk of death with activated PC. In animal studies, supplementation with l-arginine and administration of perindopril were able to prevent septic shock-associated endothelial injury. A marked reduction of endothelial injury and improved survival of treated animals were also seen with antiglycoprotein IIb/IIIa which attenuated the role of monocytes in the disseminated intravascular coagulation process.
Vallet
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Department of Anesthesiology and Intensive Care, University Hospital of Lille, Rue Michel Polonovski, 59037 Lille, France.
D000818:Animals; D000991:Antithrombins / Q000378:metabolism / Q000627:therapeutic use; D001777:Blood Coagulation; D017326:Clinical Trials, Phase III as Topic; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D011486:Protein C / Q000378:metabolism / Q000627:therapeutic use; D012772:Shock, Septic / Q000097:blood; D018180:Thrombomodulin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000991:Antithrombins; D008074:Lipoproteins; D011486:Protein C; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C051928:lipoprotein-associated coagulation inhibitor; D009569:Nitric Oxide; D013925:Thromboplastin