Immunohaemostasis: a new view on haemostasis during sepsis

Abstract

Host infection by a micro-organism triggers systemic inflammation, innate immunity and complement pathways, but also haemostasis activation. The role of thrombin and fibrin generation in host defence is now recognised, and thrombin has become a partner for survival, while it was seen only as one of the “principal suspects” of multiple organ failure and death during septic shock. This review is first focused on pathophysiology. The role of contact activation system, polyphosphates and neutrophil extracellular traps has emerged, offering new potential therapeutic targets. Interestingly, newly recognised host defence peptides (HDPs), derived from thrombin and other “coagulation” factors, are potent inhibitors of bacterial growth. Inhibition of thrombin generation could promote bacterial growth, while HDPs could become novel therapeutic agents against pathogens when resistance to conventional therapies grows. In a second part, we focused on sepsis-induced coagulopathy diagnostic challenge and stratification from “adaptive” haemostasis to “noxious” disseminated intravascular coagulation (DIC) either thrombotic or haemorrhagic. Besides usual coagulation tests, we discussed cellular haemostasis assessment including neutrophil, platelet and endothelial cell activation. Then, we examined therapeutic opportunities to prevent or to reduce “excess” thrombin generation, while preserving “adaptive” haemostasis. The fail of international randomised trials involving anticoagulants during septic shock may modify the hypothesis considering the end of haemostasis as a target to improve survival. On the one hand, patients at low risk of mortality may not be treated to preserve “immunothrombosis” as a defence when, on the other hand, patients at high risk with patent excess thrombin and fibrin generation could benefit from available (antithrombin, soluble thrombomodulin) or ongoing (FXI and FXII inhibitors) therapies. We propose to better assess coagulation response during infection by an improved knowledge of pathophysiology and systematic testing including determination of DIC scores. This is one of the clues to allocate the right treatment for the right patient at the right moment.Electronic supplementary materialThe online version of this article (10.1186/s13613-017-0339-5) contains supplementary material, which is available to authorized users.

Networks that stop the flow: A fresh look at fibrin and neutrophil extracellular traps

“…While it is increasingly accepted that the intrinsic pathway is not required for physiological hemostasis, under pathological conditions, when DNA is released upon cellular damage (e.g. due to inflammation), this pathway can become crucial in initiating fibrin formation (reviewed in [41]). Interestingly, another example of a negatively charged trigger of clotting is relevant in the course of NET formation, namely, polyphosphates released from histone-activated platelets [42,43].…”

Flow Cytometry-Based Quantification of Neutrophil Extracellular Traps Shows an Association with Hypercoagulation in Septic Shock and Hypocoagulation in Postsurgical Systemic Inflammation—A Proof-of-Concept Study

“…However, despite innovative approaches, there is still no specific biomarker for the early detection of SAC available for clinical routine use [9][10][11][12][13]. By investigating the underlying interactions between the innate immune and coagulatory systems, immunothrombosis has been identified as an important trigger of systemic inflammation and offers new diagnostic and therapeutic approaches for the management of septic coagulopathy [14][15][16][17].…”

Toll‐like receptors 2 and 7 mediate coagulation activation and coagulopathy in murine sepsis

“…Sepsis is a clinical syndrome caused by a dysregulated host inflammatory response secondary to infection, and is often characterized by marked systemic inflammation and coagulation activation, the two key components that are inextricably linked in sepsis, leading to gross clotting dysfunction, a condition termed sepsis‐induced coagulopathy (SIC) …”

“…Sepsis is a clinical syndrome caused by a dysregulated host inflammatory response secondary to infection, 1 and is often characterized by marked systemic inflammation and coagulation activation, the two key components that are inextricably linked in sepsis, leading to gross clotting dysfunction, a condition termed sepsis-induced coagulopathy (SIC). [2][3][4][5][6] Under normal condition, tissue factor (TF), a potent initiator of the extrinsic coagulation cascade, binds factor VII to form the extrinsic tenase complex, leading to FX activation, thrombin and fibrin generation, and thrombus development. 7 Antithrombin III (ATIII) is a potent inhibitor of activated FX and thrombin, and functions to prevent further activation of coagulant proteases.…”