Fig. 1
From: Immunohaemostasis: a new view on haemostasis during sepsis
Immunohaemostasis and infection. During infection, bacteria trigger platelet activation via PF4 and TLRs and can initiate neutrophil extracellular traps (NETs) release by neutrophils after chromatin decondensation and nuclear membrane disruption. Negatively charged DNA, decorated with histones, myeloperoxidase (MPO) and neutrophil elastase (NE), is a potent inducer of FXII auto-activation as well as polyphosphates (polyP150–200) released by bacteria. Both are “contact” activators, i.e. a negatively charged surface able to link and induce a conformational change in FXII that auto-activates FXII in α-FXIIa in the presence of Zn2+. Then α-FXIIa converts PK to kallikrein (KAL) that enables a reciprocal hetero-activation of α-FXII, leading to large amount of β-FXIIa and thereafter platelet GPIb-bound FXI activation. Large amount of FXIIa generated is able to convert platelet-bound FXI into FXIa involved in thrombin generation and fibrin generation. Interestingly, neutrophil elastase (NE) released with NETs is also able to enhance platelet adhesion and activation (inactivation of ADAMTS13) and coagulation with inhibition of tissue factor pathway inhibitor (prolonged tissue factor-induced initiation) and thrombomodulin (impaired activation of protein C). Moreover, polyP150–200 enhances activation of platelet-bound FXI by FXIIa and can be incorporated in the fibrin network, reinforcing its structure. On the other hand the kallikrein/kinin system (KKS) is also triggered. FXIIa and KAL convert high molecular weight kininogen (HK) in biologically active bradykinin (BK). BK is not involved in thrombin generation, but mainly in inflammatory response via two G-coupled receptors, B1R and B2R. BK results in increased vascular permeability, vasodilation (mediated by both PGI2 and nitric oxide after iNOS induction), oedema formation and ultimately hypotension