The Coagulation System in Sepsis

Abstract

Severe sepsis is consistently associated with systemic activation of the hemostatic system. There is abundant proof of a wide-ranging bidirectional cross talk between coagulation and inflammation, which is probably implicated in the pathogenesis of organ dysfunction in patients with sepsis. Inflammation not only leads to initiation and propagation of coagulation activity, but coagulation also markedly influences inflammation. Molecular mechanisms that play a role in inflammation-induced effects on the hemostatic system have been identified in much detail. Pro-inflammatory cells and cyto- and chemokines can activate the coagulation system and downregulate crucial physiological anticoagulant mechanisms. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and endothelial cells and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, are impaired by pro-inflammatory cytokines. Also, fibrin elimination is severely blocked by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Enhanced fibrin generation and insufficient breakdown lead to deposition of (micro)vascular clots, which may contribute to tissue ischemia and ensue organ dysfunction. The cornerstone of the management of coagulation in sepsis is the explicit and thorough treatment of the underlying disorder by appropriate antibiotic treatment and source control interventions. Adjunctive strategies focused at the control of coagulation, including anticoagulants and restoration of physiological anticoagulant mechanisms, may supposedly be indicated, and some of these interventions have been found advantageous in experimental and initial clinical trials, although a beneficial effect in 28-day mortality has not been show unequivocally.