Systemic versus localized coagulation activation contributing to organ failure in critically ill patients

Marcel Levi, Tom van der Poll, Marcus Schultz, Marcel Levi, Tom van der Poll, Marcus Schultz

Abstract

In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation but coagulation also considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may not only be relevant for vascular atherothrombotic disease in general but has in certain clinical settings considerable consequences, for example in the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Pro-inflammatory cytokines and other mediators are capable of activating the coagulation system and downregulating important physiological anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by physiological anticoagulant mechanisms and endogenous fibrinolysis. Interestingly, apart from the overall systemic responses, a differential local response in various vascular beds related to specific organs may occur.

Figures

Fig. 1
Fig. 1
Endothelium-associated mediators of coagulation and inflammation. Panel (a) depicts the normal situation in which the endothelium expresses thrombomodulin (TM) (activated by thrombin) and endothelial PC receptor (EPCR), which generate activated PC (APC). Other anticoagulant factors are tissue factor pathway inhibitor (TFPI) and antithrombin (AT) attached to the endothelial surface and from endothelium released tissue-type plasminogen activator (tPA), which promotes fibrinolysis. b Systemic activation of inflammation leads to cytokine release and endothelial perturbation, resulting in release of microparticles (MPs), apoptosis, detachment of endothelial cells, and loss of barrier function. Coagulation is activated by induction of tissue factor (TF) on monocytes, MPs, and endothelium and by release of von Willebrand factor (vWF), which adds to platelet adhesion to the subendothelial surface. Production of glycosaminoglycans (GAGs) is downregulated, and the anticoagulant proteins TFPI, AT, EPCR, and TM are cleaved from the endothelial surface and are impaired in action. Fibrinolysis is impaired as a result of a rise in the main inhibitor of the PA (PAI-1), which outweighs a rise in t-PA, and complement activation is enhanced by loss of activation of thrombin-activatable fibrinolysis inhibitor (TAFI), which normally inhibits complement factor C3a and C5a and bradykinin activity. Anticoagulant proteins in turn modulate cytokine release: tissue factor–factor VIIa (TF-FVIIa), factor (F) Xa, and thrombin exert pro-inflammatory activity by cleaving mainly protease activated receptor (PAR)-1 and PAR-2. APC cleaves PAR-1 in an EPCR-dependent manner and hereby modulates inflammation and apoptosis [27]

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Source: PubMed

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