Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective

Abstract

BackgroundCoagulation and innate immunity have been linked together for at least 450 million years of evolution. Sepsis, one of the world’s leading causes of death, is probably the condition in which this evolutionary link is more evident. However, the biological and the clinical relevance of this association have only recently gained the attention of the scientific community.DiscussionDuring sepsis, the host response to a pathogen is invariably associated with coagulation activation. For several years, coagulation activation has been solely regarded as a mechanism of tissue damage, a concept that led to several clinical trials of anticoagulant agents for sepsis. More recently, this paradigm has been challenged by the failure of these clinical trials, and by a growing bulk of evidence supporting the concept that coagulation activation is beneficial for pathogen clearance. In this article we discuss recent basic and clinical data that point to a more balanced view of the detrimental and beneficial consequences of coagulation activation in sepsis.SummaryReappraisal of the association between coagulation and immune activation from an evolutionary medicine perspective offers a unique opportunity to gain new insights about the pathogenesis of sepsis, paving the way to more successful approaches in both basic and clinical research in this field.

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

“…[1][2][3][4] The thrombotic process that occurs in the setting of infection or activation of the immune response is recognized as having distinct elements, which distinguish it from normal hemostasis or even other forms of arterial or venous thrombosis. 5 While agents such as antithrombin III and activated protein C (APC) initially held promise in treating sepsis, their clinical utility has been limited by a lack of efficacy and bleeding risks, 6,7 and the benefit of more standard anticoagulants such as heparin is uncertain.…”

The Emperor Has no Clothes? Searching for Dysregulation in Sepsis

“…These studies provide a clue that decreased protein C activity, and increased activity of the coagulation system, may be functional in sepsis. One proposed hypothesis is that increased activity of the coagulation cascade during infection promotes pathogen trapping and clearance [24].…”

Sepsis-Associated Coagulopathy

“…This was underlined in a study demonstrating that the activation of coagulation by the administration of recombinant factor VII triggers IL6 and 8 responses in healthy humans [52]. The proteaseactivated receptors (PARs) on immune cells activated by tissue factor and other coagulation factors modulate pro-and anti-inflammatory pathways, playing a pivotal role in the cross-talk between coagulation and inflammation [53]. Not only the coagulation factors but also other components of the coagulation process, like platelets or natural anticoagulants, have important effects on inflammation.…”