Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Dec 2;7(1):117.
doi: 10.1186/s13613-017-0339-5.

Immunohaemostasis: a new view on haemostasis during sepsis

Xavier Delabranche  1   2 , Julie Helms  1   3 , Ferhat Meziani  4   5
Affiliations
Review

Immunohaemostasis: a new view on haemostasis during sepsis

Xavier Delabranche et al. Ann Intensive Care. .

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.

Keywords: Contact phase; Disseminated intravascular coagulation (DIC); Host defence peptides (HDPs); Infection; Neutrophil extracellular traps (NETs); Septic shock.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
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
Fig. 2
Fig. 2
Natural history of coagulation during infection and potential therapeutics. The first step is “adaptive haemostasis” associated with the systemic inflammatory syndrome. Platelet count increases and fibrinogen production is dramatically increased (red curve). Thrombin generation is initiated with slight shortening of PT and aPTT (dark blue curve) resulting in fibrin monomers generation (green curve). Natural anticoagulants, antithrombin and protein C are decreased by consumption and downregulation (light blue curve). Inhibition of fibrinolysis by PAI-1 results in low D-dimers (yellow curve). Only low-dose heparin (unfractionated or low molecular weight) could be recommended to prevent thrombosis (inferior part of the graph). Reduction of anticoagulants and continuous thrombin generation results in prolonged clotting times (PT and aPTT) and platelet and fibrinogen consumption that remain in the high normal range. Fibrin monomers increased due to sustained fibrin formation and defective polymerisation by FXIIIa. D-dimers are moderately increased. This step can be called “thrombotic/multiple organ failure DIC” step and could be treated by natural anticoagulant infusion (antithrombin or soluble thrombomodulin) or fresh-frozen plasma. Later in the natural evolution of coagulation, consumption of all factors and platelets results in very low levels of fibrinogen, AT and PC, prolonged PT and aPTT and massive fibrinolysis with very high D-dimers. This “fibrinolytic DIC” step is characterised by oozing and massive bleeding, and supportive therapy associates fresh-frozen plasma and platelet transfusions, fibrinogen supply and tranexamic acid to prevent fibrinolysis
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood. 2005;106(8):2605–2612. doi: 10.1182/blood-2005-04-1710. - DOI - PubMed
    1. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost. 2016;14(1):28–39. doi: 10.1111/jth.13194. - DOI - PubMed
    1. Long AT, Kenne E, Jung R, Fuchs TA, Renne T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost. 2016;14(3):427–437. doi: 10.1111/jth.13235. - DOI - PubMed
    1. Lerolle N, Carlotti A, Melican K, et al. Assessment of the interplay between blood and skin vascular abnormalities in adult purpura fulminans. Am J Respir Crit Care Med. 2013;188(6):684–692. doi: 10.1164/rccm.201302-0228OC. - DOI - PubMed
    1. Arman M, Krauel K, Tilley DO, et al. Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4. Blood. 2014;123(20):3166–3174. doi: 10.1182/blood-2013-11-540526. - DOI - PMC - PubMed

LinkOut - more resources