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Immunohaemostasis: a new view on haemostasis during sepsis

Immunohaemostasis: a new view on haemostasis during sepsis 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 (antithrom - bin, 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 determina- tion of DIC scores. This is one of the clues to allocate the right treatment for the right patient at the right moment. Keywords: Infection, Septic shock, Disseminated intravascular coagulation (DIC), Host defence peptides (HDPs), Contact phase, Neutrophil extracellular traps (NETs) but also in vascular permeability and tone (via endothe- Background lial cell receptors and kinin pathways) [1–3]. The aim of this review is to describe the battle between a During infection, initiation of thrombin generation foreign pathogen and the host regarding thrombin gener- may occur through different pathways [ 35]: ation, one of the key molecules to win or to lose the war for surviving. Thrombin is involved in thrombus forma - tion (via fibrin network), in anticoagulation and fibrinol - i. Bacteria initiation with endothelial invasion [4] and ysis [via thrombomodulin and (activated) protein C], platelet activation (via FcγRIIa, αIIbβ3 and platelet focalisation (via glycosaminoglycans and antithrombin), factor 4) [5], ii. Bacterial polyphosphate (polyP) initiation through the “contact” pathway [6], *Correspondence: ferhat.meziani@chru-strasbourg.fr iii. Endothelial cell expression of encrypted tissue fac- Université de Strasbourg, Faculté de Médecine & Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, tor (TF), vascular cell recruitment and activation by France thrombin, cytokines and microparticles [1, 7, 8], Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 2 of 14 iv. fibrin network, neutrophil extracellular traps (NETs) Pathophysiology of thrombin and fibrin formation and histones [9, 10]. during infection The contact between a prokaryote and a eukaryote Haemostasis should therefore be considered as a non- can result in symbiosis or infection resulting in host or specific first line of host defence—at least when localised pathogen survival. To survive infection, the host initi- to a unique endothelial injury—considering the growing ates a complex inflammatory response including innate role of platelets as immune cells [11–13]. This immune immunity, complement and coagulation pathways. These response has been called “immunothrombosis” [14]. In two cascades have a unique origin, but many refinements this line, immunohaemostasis process may help to cap- over the past 500 million years improved their specifici - ture pathogens, prevent tissue invasion and concentrate ties [25, 26]. In this view, coagulation is fundamental to antimicrobial cells and peptides including thrombin- survive and the following section will highlight the role of derived host defence peptides. Therefore, when regu - contact activation system (not involved in “normal” hae- lated, a low-grade activation of thrombin generation may mostasis), the interplay between pathogens, coagulation help survive the bacterial challenge [14]. Yet, inhibition and fibrinolysis pathways, and the emerging role of anti - of thrombin generation by Dabigatran promotes bacterial microbial host defence peptides generated by proteolysis growth and spreading with increased mortality in experi- of “coagulation” proteins [17, 27, 28]. mental model of Klebsiella pneumoniae-induced murine pneumonia [15]. Initiation: the emerging role of contact activation system On the other hand, thrombin can become deleterious if (Fig. 1) ongoing activation of the coagulation, owing to defective Physiology or pathophysiology? natural anticoagulants, leads to excessive thrombin for- An old view of haemostasis distinguished two initiation mation. Combined with defective fibrinolysis, thrombin pathways: tissue factor (“extrinsic” pathway) and contact results in fibrin deposits in microvessels and eventually in activation system (CAS) (“intrinsic” pathway). The lat - disseminated intravascular coagulation (DIC) [16, 17]. DIC ter requires a “contact” activator, prekallikrein (PK), high thus represents a deregulation and/or an overwhelmed molecular weight kininogen (HK), factor XII (FXII) and haemostasis activation response triggered by pathogens FXI [29]. A deficit of one of these proteins results in pro - and/or host responses during septic shock [14]. DIC could longed aPTT although no haemorrhagic diathesis is evi- be classified in “asymptomatic”, “bleeding” (haemorrhagic), denced in patients. CAS does not seem to be involved in “thrombotic” (organ failure) and ultimately “massive “normal” haemostasis and may be restricted to pathologi- bleeding” (fibrinolytic) type, according to its clinical pres - cal conditions resulting in negatively charged surfaces, entation [18]. Except asymptomatic one, all types are char- including sepsis (via NETs and polyP), but also acute acterised by delayed clotting times (PT and aPTT), low respiratory distress syndrome (ARDS) [30] and blood fibrinogen and platelets count owing to their consump - contact with artificial surfaces (intravascular catheters, tion [19, 20]. Although known for many years, the role of extracorporeal circuits). DIC in the pathogenesis of septic shock remains a matter “Contact” activator is a negatively charged surface able of debate [21–23]. Since then, coagulation was considered to link and induce a conformational change in FXII that 2+ as a potential therapeutic target. The recognition of new auto-activates FXII in α-FXIIa in the presence of Zn . targets implied in thrombosis—but not in haemostasis— Then α-FXIIa converts PK to kallikrein (KAL) that enable opens a new window over innovative therapies. a reciprocal hetero-activation of α-FXII, leading to large amount of β-FXIIa and thereafter platelet GP -bound Ib Physiology of thrombin generation FXI activation. β-FXIIa is also able to activate the clas- For didactic settings, haemostasis can be separated into sic complement system pathway via C1r and to a lesser three phases: extent C1  s linking haemostasis and complement-medi- ated host defence [3]. i. Initiation, CAS and PK also activate fibrinolysis and tissue prote - ii. Propagation and regulation, olysis. HK linked to urokinase-type plasminogen activa- iii. Fibrinolysis. tor receptor (uPAR) is able to activate pro-uPA into uPA that in turn activates plasminogen into matrix-bound plasmin. Moreover, BK induces tPA release by endothe- A brief overview of haemostasis is available in Addi- lial cells when linked to B1R [2]. tional file  1 and Additional file  2: Figure S1 provides the Besides and related to CAS, the kallikrein/kinin sys- different steps of thrombin generation, fibrin formation tem (KKS) is also activated [3]. CAS and PK also activate and regulation [1, 24]. fibrinolysis and tissue proteolysis and are regulated by Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 3 of 14 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 (polyP ) released by bacteria. Both are “contact” activators, i.e. a negatively charged surface able to link and induce a conformational change in 150–200 2+ FXII that auto-activates FXII in α-FXIIa in the presence of Zn . 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 GP -bound FXI activation. Large amount of FXIIa generated is able to convert Ib 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, polyP enhances activation of 150–200 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 PGI and nitric oxide after iNOS induction), oedema formation and ultimately hypotension serpin C1 esterase inhibitor (C1-INH). A deficit (respon - further degradation, resulting in prolonged half-life. sible for hereditary angioedema) or consumption (during In the presence of fibrin polymers associated with septic shock but also after extracorporeal circulation) is polyP , α-FXIIa can activate fibrin-bound plasmino - 60–80 responsible for increased permeability syndrome [31]. gen in plasmin, resulting in “intrinsic” fibrinolytic activity overcoming antifibrinolytic properties [36, 37]. Interest- Polyphosphates (polyP) ingly, activated platelets could retain polyP on their 60–80 PolyP are negatively charged inorganic phosphorous surface assembled into insoluble spherical nanoparticles 2+ 2+ residue polymers, highly conserved in prokaryotes and with divalent metal ions (C a, Zn ). These nanoparti - eukaryotes. They are important source of energy, but are cles provide higher polymer size and become able to trig- also involved in cell response. Half-life of polyP is very ger contact system activation [38, 39]. short due to their degradation by phosphatases [32, 33]. On the other hand, large-sized insoluble p olyP 150–200 Medium-size soluble p olyP are released by acti- are released by bacteria and yeasts. P olyP are 60–80 150–200 vated platelets and mast cells. They are able to induce able to support auto-activation of FXIIa and to pro- FXII activation only if large amounts are present [34, mote thrombin generation independently of FXI activa- 35]. PolyP could also bind α-FXIIa preventing tion. PolyP can bind FM resulting in clots with reduced 60–80 Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 4 of 14 stiffness and increased deformability [40]. Moreover, a better activation by host proteases [51]. Interestingly, polyP are incorporated in fibrin mesh, inhibiting some bacteria use specific pathways to induce thrombin 150–200 fibrinolysis [34]. and fibrin generation [52–58]. Neutrophil extracellular traps (NETs) Degradation of fibrin clots Neutrophils have long been considered as suicidal cells Fibrin formation and pathogen entrapment are key fea- killing extracellular pathogens. Few years ago, biology tures of host defence during infection. Fibrin(ogen) is of neutrophils has evolved for a more complex network fundamental to survive infection [59]. To evade fibrin, linking innate immunity, adaptive immunity and haemo- many bacteria developed fibrinolysis activators or stasis [41–43]. Neutrophils do not only engulf pathogens expressed plasminogen receptors allowing activation by (phagocytosis) and release granules content, but also host tPA or uPA [60–76]. release their nuclear content, essentially histones and Outer membrane proteins (omptins) are surface- DNA fragments resulting in a net. These NETs support exposed, transmembrane β-barrel proteases exposed by histones and other granule enzymes like myeloperoxidase some gram-negative bacteria. They display fibrinolytic (MPO) and neutrophil elastase (NE). These fragments are and procoagulant activities required for pathogenic- called NETs for neutrophils extracellular traps, and they ity [71, 72]. Yersinia pestis is the agent of bubonic and enable to trap pathogens and blood cells, including plate- pneumonic plague. Both associate haemorrhagic and lets, in their meshes [44]. thrombotic disorders and the presence of Pla, a direct Two mechanisms of NETosis are described: a suicidal activator of host plasminogen, require rough LPS. Pla is one [44–46] and a vital one, with functional anucleated also able to promote fibrinolysis by activation of uPA, phagocytic cell survival [47]. Finally, the plasma mem- inactivation of serpins PAI-1 and α -antiplasmin and brane bursts and NETs are released [48]. by cleavage of C-terminal region of TAFI with reduced NETosis plays a critical role in host defence through activation by thrombin–thrombomodulin complex [73, innate immunity, but also through other procoagulant 74]. Pla is also able to cleave TFPI. Interestingly, dys- mechanisms:plasminogenemia (Ala   →  Thr), present in about 2% of the Chinese, Korean and Japanese populations, con- fers a protection against plague. Homozygous individu- i. Negatively charged DNA constitutes an activated als have a reduced plasminogen activity about 10% with surface for coagulation factors assembly, including fewer thrombotic events, but enhanced survival during contact phase; infection by Y. pestis but also by group A streptococci ii. Enzymatic inhibition of tissue factor pathway inhibi- and S. aureus requiring plasminogen activation for tor (TFPI) and thrombomodulin (TM) by neutrophil pathogenicity [75]. elastase; iii. Direct recruitment and activation of platelets by his- Inactivation of fibrinolysis tones [14]. Inhibition of fibrinolysis is another way to promote clot stabilisation [77, 78]. Recent data support a direct activation by DNA and his- tones more than NETs themselves [49]. High levels of Inhibition of coagulation circulating histones have been evidenced in septic shock. Bacteria can also block contact activation pathway [79, Histone infusion induces intravascular coagulation with 80] or thrombin generation [81] in order to prevent host thrombocytopenia and increased D-dimers. Antihistone defence. antibodies can prevent both lung and cardiac injuries in experimental models. C-reactive protein can bind his- Host defence peptides tones and reduce histone-induced endothelial cell injury. Innate immunity is mediated by cell activation via Toll- C-reactive protein infusion rescues histone-challenged like receptors (TLRs). Resulting cationic and amphip- mouse [50]. athic small peptides (15–30 amino acids, < 10 kDa) have many biological properties including direct bactericidal Pathogen‑induced modulation of blood coagulation effects, but also immunomodulation and angiogenesis. (Table 1) They have been named “host defence peptides” (HDPs) Initiation of coagulation or “antimicrobial peptides” (AMPs). All bacteria can induce blood coagulation in a polyP- In eukaryotes, we can identify defensins (disulphide- dependent pathway as seen above. High molecular weight stabilised peptides) and cathelicidins (α-helical or kininogen (HK) can also bind bacterial surface allowing Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 5 of 14 Table 1 Pathogen-induced modulation of blood coagulation Bacteria Protein Target Result References A—initiation of coagulation All bacteria PolyP FXII → FXIIa Contact phase activation (FXI) [51] S. aureus Coagulase FII → FIIa Non-proteolytic activation [52] von Willebrand binding protein (vWbp) vWF (endothelium) S. aureus anchorage to endothelium [53] FII → FIIa Non-proteolytic activation [52] vWbp-FIIa → FXIII Clot stabilisation [53] Clumping factor A (ClfA) and fibronectin- Fg S. aureus—platelet bridging and clot forma- [54] binding protein A (FnbpA) tion Staphopains A and B (ScpA, ScpB) HK → BK Vascular leakage [55, 56] Group G streptococci Fibrinogen-binding protein (FOG) and FXII → FXIIa Contact phase complex assembly and [57] protein G (PG) activation (FXI) at bacterial surface B. anthracis Zinc metalloprotease InhA1 FX → FXa/FII → FIIa Fibrin deposition [57, 58] ADAMTS13 inhibition Platelet adhesion/activation by UL-vWF [58] B—degradation of fibrin clot B. burgdorferi Outer surface proteins (OspA and OspC) and Plasmin(ogen) Plasminogen activation by tPA/uPA [62] Erp proteins (ErpA, ErpC and ErpP) H. influenzae Surface protein E (PE) Plasmin(ogen) Plasminogen activation by tPA/uPA [63] Streptococci spp. α-Enolase Plasmin(ogen) Plasminogen activation by tPA/uPA [64–67] B. anthracis α-Enolase and elongation factor tu Plasmin(ogen) Plasminogen activation by tPA/uPA [66] S. pyogenes Plasminogen-binding M-like protein (PAM) Plasminogen Direct non-enzymatic activation [51] and streptokinase (SK) Metalloprotease activation and tissue inva- [68, 69] sion by PAM-bound SK·PM S. agalactiae Skizzle (SkzL) tPA/uPA Enhanced plasminogen activation [70] Y. pestis Omptin Pla Plasminogen Direct activation in presence of LPS [71] PAI-1/TAFI/α -AP Inactivation of serpins [72–74] S. enterica Omptin PgtE PAI-1/α -AP Inactivation of serpins [76] C—inactivation of fibrinolysis Group A streptococci Collagen-like proteins (SclA and SclB) TAFI and FIIa TAFI → TAFIa [77, 78] D—Inhibition of coagulation Group A streptococci Streptococcal inhibitor of complement (SIC) HK Inhibition of HK binding and contact phase [79, 80] activation S. aureus Staphylococcal superantigen-like protein 10 FII Inhibition of platelet binding and activation [81] (SSLP-10) extended peptides). HDPs can be classified into three cat - Serine protease‑derived peptides egories regarding their target on prokaryotes: Human serine proteases (including vitamin K-dependent blood coagulation factors and kallikrein system peptides) i. Plasma membrane-active peptides disrupting mem- can be cleaved by proteases to generate C-terminal pep- brane integrity, tides with direct antimicrobial activities [84]. GKY25 is ii. Intracellular inhibitors of transcription or transla- released from FIIa, FXa and FXIa after cleavage by neu- tional factors and trophil elastase [85]. This peptide is able to slightly reduce iii. Cell wall-active peptides interfering with cell wall P. aeruginosa growth but also to significantly reduce both synthesis and bacterial replication [82]. inflammatory response and mortality [86]. Bacteria are also able, mainly by unknown mechanisms, to gener- ate HDPs from fibrinogen (GHR28) and high molecular Limited proteolysis of many proteins involved in blood weight kininogen (HKH20 and NAT26). coagulation (activators as well as inhibitors) is now rec- ognised as HDPs and may participate to host defence. Serpin‑derived peptides Interestingly, the development of synthetic HDPs is a Serpins (or serine protease inhibitors) can also gener- new therapeutic anti-infectious strategy regarding resist- ate HDPs. Heparin cofactor II (HCII) can be cleaved ance of pathogens to (conventional) antibiotics [83]. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 6 of 14 by neutrophil elastase after binding to glycosaminogly- Underlying disease can [87], and KYE28 displays antimicrobial properties In sepsis and septic shock, vascular injury is central and against gram-negative and gram-positive bacteria but prompted by different actors with overlapping kinetics, also against fungus [87]. Moreover, KYE28 can bind LPS leading to difficulties in deciphering a sequential order dampening inflammatory response [88]. FFF21 derived [97]. from antithrombin also shares antimicrobial activity after Acute kidney injury (AKI) is present in about half permeabilisation of bacterial membrane [89]. Protein C patients, one-third of non-DIC patients versus four-fifth inhibitor-derived SEK20 peptide displays antimicrobial in DIC patients. This association between AKI and low activity [90]. Interestingly, platelets can bind PCI under platelets may be symptomatic of thrombotic microangi- activation resulting in high concentration of PCI at site opathy (TMA) all the more that Ono et al. [98] reported of platelet recruitment as observed during infection [91]. low ADAMTS13 activity and high UL-vWF in septic shock-induced DIC. Nevertheless, there are two impor- Diagnosis tant differences: the presence of schizocytes and the Activation of the coagulation cascade is a physiologic, absence of prolonged clotting times in TMAs [99, 100]. innate and adaptive response during infection. This Hepatic injury is frequent, but remains mild to mod- response can be overwhelmed, becoming hazardous erate, with a slight increase in liver enzymes and bili- and referred to as DIC meaning disseminated intravas- rubin and decrease in PT. On the other hand, severe cular coagulation, as well as “death is coming” [92]. For hepatic ischaemia may lead to fulminant hypoxic hepa- many years, only two conditions were distinguished: titis with very low PT, but also inhibitors AT and PC “no DIC” and “DIC”. This “schizophrenic” view of hae - mimicking DIC with ischaemic limb gangrene with mostasis needs to be reissued, as proposed by Dutt and pulses [101]. Toh [93]: “The Ying-Yang of thrombin and protein C”. There is indeed a continuum from adaptive to noxious Cellular activation thrombin generation. Moreover, DIC remains a medical Only indirect markers of cellular activation are available; paradigm for critical care physicians: clinical diagnosis is most of them are not routinely assessed. These mark - often (too) late and biological diagnosis (too) frequent in ers could be soluble molecules (released by shedding or the absence of clinical signs or therapeutic opportunities by proteolytic cleavage) or cell-derived microvesicles, [94]. including microparticles (MPs). The role of MPs in sep - tic shock and infection has been discussed elsewhere Clinical diagnosis [102–104]. Most patients with sepsis and septic shock do not present any clinical sign of “coagulopathy”, while routine labo- Endothelial cells E-selectin (CD62E), or endothelial-leu- ratory tests are disturbed. Clinical examination should cocyte adhesion molecule-1 (ELAM-1), is only expressed focus on purpura, symmetric ischaemic limb gangrene by endothelial cells after cytokine stimulation. CD62E is (with pulses) [95] and diffuse oozing. A very specific sign involved in leucocyte recruitment at site of injury and is “retiform purpura”, which is a netlike purpura reminis- could be released in the blood stream as free, soluble mol- cent of livedo. However, unlike classic livedo, in which ecule (sCD62E) or membrane bound after MP shedding meshes are erythematous, meshes are here purpuric. The (CD62 -MPs). sCD62E is dramatically increased during absence of induced bleeding on retrieval when the skin is septic shock, especially in DIC patients [8], but was not punctured to a depth of 3 to 4 mm within a livid or pur- associated with DIC diagnosis in one study [105, 106]. puric area is a good indication of thrombotic microangi-Interestingly, CD62 -MPs were not increased in septic opathy [96]. shock due to proteolysis [8]. Endoglin (CD105, Eng) is a membrane protein Laboratory criteria expressed mainly by endothelial cells in the vascular A single test will never be able to diagnose and stratify repair and angiogenesis during inflammation [107]. It sepsis-induced coagulopathy. Only a combination of contains an arginine-glycine-aspartic acid (RGD) trip- the presence of underlying disease associated with evi- eptide sequence that enables cellular adhesion, through dence of cellular activation in the vascular compartment the binding of integrins or other RGD binding receptors (including endothelial cells, leucocytes and platelets), that are present in the extracellular matrix. Membrane- procoagulant activation, fibrinolytic activation, inhibitor bound CD105 is involved in leucocyte α5β1 activation, consumption and end-organ damage or failure will allow resulting in leucocyte recruitment and extravasation such diagnosis. on the one hand and in angiogenesis on the other hand, whereas MMP-14-cleaved soluble (s)CD105 abolishes Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 7 of 14 extravasation and inhibits angiogenesis [107]. CD105 Procoagulant activation plays a pivotal role in endothelial cell adhesion to mural Routine coagulation tests evidence a prolongation of cells [108]. Soluble CD105 overexpression is actually both prothrombin time (PT) and activated partial throm- linked to other typical systemic and vascular inflamma - boplastin time (aPTT). Nevertheless, PT is the more tion states, as pre-eclampsia and HELLP syndrome, that accurate. aPTT is only slightly elevated during DIC due are also characterised by a haemostatic activation/dereg- to inflammatory response and very high level of FVIII ulation [109] and podocyturia [108]. We evidenced the released by injured endothelial cells. presence of C D105 -MPs during septic shock, especially Evidence of thrombin generation can be evaluated by in DIC patients [8, 110]. quantification of prothrombin fragment 1  +  2 (F1  +  2) Endothelial cells also release soluble and microparticle- and/or thrombin–antithrombin (TAT) complexes. These bound EPCR. sEPCR is a marker of endothelial injury tests are not routinely available. Moreover, we evidenced and severity [111], while E PCR -MPs can display an anti- the lack of discrimination of F1  +  2 between DIC and coagulant and cytoprotective pattern in the bloodstream non-DIC patients despite significant differences [8]. [112, 113]. Fibrin formation is quantified by fibrinopeptide A (FpA) (with a 2:1 ratio), not available in routine [120]. Leucocytes Neutrophils and monocytes play a major Soluble fibrin monomers (FM) can be routinely quanti - role in sepsis-induced coagulopathy. After stimulation fied. They do not represent fibrin formation, but resting by thrombin and cytokines, monocytes could express TF fibrin monomers not yet polymerised by FXIIIa. High and promote thrombin generation after cell membrane FM can evidence increased production and/or defec- remodelling and phosphatidylserine (PhtdSer) exposition. tive polymerisation [121, 122]. The accuracy of this bio - Moreover, TF -MPs of monocyte origin have been identi- marker is still matter of debate (see below) [123, 124]. fied and could disseminate a procoagulant potential [7]. The role of neutrophils is more complex, involving both Fibrinolytic activation TF expression (fusion of TF -MPs) [114] and NETs [115]. Fibrin(ogen) degradation products (FDPs) are hetero- Direct evidence of the presence of NETs in bloodstream geneous small molecules generated by the action of is lacking, but histones (or nucleosomes), free DNA and plasmin on both fibrin network (secondary fibrinoly - myeloperoxidase could be detected in plasma and are sig- sis) and fibrinogen (primary fibrinogenolysis). D-dimers nificantly increased in septic shock-induced DIC [116]. (D-domain of two fibrin molecules stabilised by FXIIIa) Recently, our group showed cytological modification of are specific of fibrinolysis and must be preferred when neutrophils in blood smears of patients with DIC [117]. available [125–127]. D-dimers sign thrombin generation, Moreover, we evidenced neutrophil chromatin decon- fibrin formation and polymerisation then fibrinolysis, densation assessed by measuring neutrophil fluorescence while the absence of D-dimers could represent defective (NEUT-SFL) using a routine automated flow cytometer fibrinolysis despite the presence of fibrin. Other mark - Sysmex XN20 [118]. ers could be useful but are not available in routine labo- ratories: PAP (plasmin–antiplasmin complexes), tPA and Platelets Inflammation resulting in systemic inflamma - PAI-1 [128, 129]. Both tPA and PAI-1 are dramatically tory response syndrome (SIRS) is a potent inducer of both increased during septic shock, regardless of DIC diagno- fibrinogen synthesis and platelet circulating pool mobili - sis. Early inhibition of fibrinolysis during sepsis-induced sation. Platelet count can reach 700–800 G/L, but throm- coagulopathy may cause diagnostic delay regarding the bocytopenia can occur during sepsis. A “normal” value— importance of FDPs in DIC diagnosis. that is to say in the normal range—may be interpreted cautiously and represent patent consumption. Moreover, Inhibitors consumption enumeration is not function. During sepsis-induced coag- Sustained thrombin generation leads to activation, ulopathy, platelet activation follows thrombin generation then consumption, of regulatory mechanisms. TFPI is and does not support the propagation phase of haemosta- decreased during DIC [130]. Antithrombin can be—and 2+ sis with impaired P-selectin, ADP, Ca and cFXIII local should be—routinely assessed during sepsis-induced supply. coagulopathy. The absence of low AT level challenges the diagnosis of DIC [131]. Concerning the TM-APC Erythrocytes Schizocytes are fragmented erythrocytes pathway, assessment is complex. PC is decreased by con- and are the cornerstone of TMA diagnosis. They are fre - sumption, but APC is increased, at least at the begin- quently observed on blood smears during DIC and remain ning of sepsis. Moreover, soluble forms of EPCR (sEPCR) of poor value for DIC diagnosis [119]. [111] and TM (sTM) [132] can be found in plasma of sep- tic patients and are correlated to vascular injury. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 8 of 14 Global assessment of haemostasis In the following section, we will present an overview of Thromboelastography (TEG) and rotational thromboe - therapies focused on immunohaemostasis activation. lastometry (ROTEM ) are routinely used in operative theatres to monitor blood coagulation and “assess global Inhibition of contact pathway haemostasis” [133]. Interestingly, they can also evalu- Contact pathway is not necessary for “normal” haemosta- ate fibrinolysis at 30 and 60  min. Nevertheless, a recent sis. FXII(a) and FXI(a) are new targets to develop “safe” Cochrane review concluded that there was little or no evi- antithrombotic drugs without antihaemostatic effects dence of the accuracy of such devices, strongly suggesting [140–142]. Moreover, these drugs could improve hypo- that they should only be used for research [99, 100]. Few tension targeting bradykinin release. data are available regarding septic shock-induced coagu- lation/coagulopathy. A prospective study comparing C1‑inhibitor septic shock patients, surgical patients and healthy volun- C1-inhibitor regulates both complement activation teers evidences a hypocoagulability during DIC [134]. In and FXII and could improve both capillary leakage and this study, we may hypothesise that DIC patients were in hypotension on the one hand and contact phase-induced “fibrinolytic” phase. thrombin generation on the other. As other serpins, C1-inhibitor is dramatically reduced in septic shock and Scoring systems C1-inhibitor supplementation could improve patients or Different scoring systems have been developed to ensure renal function in short randomised trials [143–145]. Nev- DIC diagnosis and are discussed in supplementary data ertheless, no large randomised trial can support its use. (Additional file 1, Additional file 3: Table S1). Interestingly, bradykinin receptor antagonist icatibant had no effect on a porcine model of septic shock [146]. New therapeutic opportunities? A syllogism precludes anticoagulant therapy during FXII blockade severe sepsis and septic shock: “more severe is the infec- In a baboon model challenged with a lethal dose of E. coli, tion, more thrombin is generated”, “more thrombin is the monoclonal antibody C6B7 directed against FXIIa generated, more organ failure and death supervene”, so improved survival with higher blood pressure. In the “more you prevent thrombin generation, more you will treated group, the inflammatory response was reduced improve your patient with severe infection”. This view with lower IL-6 and neutrophil elastase release as well as forgets that haemostasis is mandatory to survive sepsis complement activation. Inhibition of FXIIa was obvious via many pathways, including newly recognised immu- with reduced BK released and fibrinolysis. Nevertheless, nothrombosis and HDPs. In fact, “anticoagulant” treat- both groups experiment DIC with low platelet count, low ments disrupt a tight equilibrium between pathogen and fibrinogen and low FV [147]. Another FXIIa monoclonal adaptive host response and may lead to more deaths in blocking antibody is 3F7. This antibody seems to be safe a group of patients (adaptive haemostasis) and to fewer as an anticoagulant in experimental extracorporeal mem- deaths in another group (noxious haemostasis). Recog- brane oxygenation model, with reduced bleeding com- nition of “noxious haemostasis” remains a medical para- pared to heparin, but no data are yet available regarding digm for critical care physicians. Negative therapeutic septic shock [148]. interventions [135, 136], drotrecogin alfa withdrawal [137], but also emerging concept of immunothrombo- FXI blockade sis [14] could argue for a radical “tabula rasa” regard- 14E11 is an anti-FXI monoclonal antibody that blocks ing coagulation during septic shock. The debate is still FXI activation by FXIIa but not by FIIa. 14E11 displays open and can be summarised in one question: “Should antithrombotic properties. This molecule was used in all patients with sepsis receive anticoagulation?” [138, mouse polymicrobial sepsis. Inflammation and coagu - 139]. Finally, whether immunohaemostasis/DIC clinical lopathy were improved as well as survival after 14E11 assessment is reliable remains a major issue (Fig. 2). treatment up to 12 h after bowel perforation onset. Clot- A mini-review of current (and past) therapies is pro- ting time was not modified, and no bleeding could be evi - vided in supplementary data (Additional file  1, Additional denced in this model [149]. −/− file  4: Table S2, Additional file  5: Table S3 and Additional Interestingly, FXI KO mice (FX I ) evidence increased file 6: Figure S2) regarding: inflammatory response with impaired neutrophil func - tions—but not haemorrhage in lungs—in a model of Klebsiella pneumoniae and Streptococcus pneumoniae i. limitation of thrombin and fibrin generation, pneumonia resulting in an increased mortality. Inhibition ii. DIC with thrombotic/multiple organ failure pattern, iii. DIC with haemorrhagic pattern. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 9 of 14 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 pol- ymerisation 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 of FXI activation by FXIIa does not reproduce this pat- of antiplatelet therapy or to transfuse platelets in the tern [150]. absence of obvious thrombocytopenia with bleeding. A genetically engineered fusion protein (MR1007) con- taining anti-CD14 antibody (to block LPS receptor) and Inhibition of polyP the modified second domain of bikunin (with anti-FXIa Targeting polyP is a new opportunity in the treatment of activity) improves survival in a rabbit model of sepsis contact phase-induced thrombosis, including immuno- without increasing spontaneous bleeding [151]. thrombosis, but some of them are toxic in vivo and can- not be used in humans (polymyxin B, polyethylenimine Inhibition of platelet functions in thrombus formation and polyamidoamine dendrimers) [157]. Platelets are important immune cells, and thrombocyto- penia is associated with an increased mortality in septic Universal heparin reversal agents (UHRAs) shock [152, 153]. Few data support a benefit of previous UHRAs have been developed to reverse heparin effects aspirin treatment in community-onset pneumonia with but also displayed anticoagulant effects. UHRA-9 and [154] or without septic shock [155]. In a retrospective UHRA-10 specifically inhibit polyP and prove antithrom - study of patients with septic shock, chronic antiplate- botic effects without increasing bleeding in a mouse model let treatment was not associated with reduced mor- of arterial thrombosis [158]. Nevertheless, these agents tality [156]. There are no data to support introduction have not been used in experimental septic shock to date. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 10 of 14 Phosphatases shock, with many experimental data supporting it. Nev- Platelet-derived polyP are rapidly degraded by phos- ertheless, all clinical trials—with the exception of PROW- phatases. During septic shock, alkaline phosphatase activity ESS trial—failed to improve survival in unselected septic is dramatically decreased and could enhance polyP activity. shock patients. On the other hand, recent experimental A recombinant human alkaline phosphatase (RecAP) is and clinical data support a beneficial role of blood coagu - able to improve renal function due to acute kidney injury lation to survive sepsis, including immunohaemostasis. during septic shock [159–161]. Moreover, RecAP inhibits The first step to improve patients’ care is to stratify the platelet activation ex vivo by converting ADP in adenosine “coagulopathy”. A combination of biological tests must be and reverse hyperactivity of septic shock-derived platelets used daily, eventually combined in scores. We believe that [162]. Effects on polyP were not specifically studied in this JAAM 2006 and JAAM-DIC scores, taking into account experimental study but cannot be excluded. the inflammatory syndrome and evolution, are the most appropriate. New markers of cell activation may be of inter- Dabrafenib est. The second step is the choice of therapeutic interven - Dabrafenib is a B-Raf kinase inhibitor indicated in unre- tion. Treatment of both infection and shock without delay sectable or metastatic melanoma with BRAF V600E is mandatory. Then, anticoagulation may be considered. To mutation. This molecule has anti-inflammatory effects date, no recommendation can be made according to inter- on polyP-mediated vascular disruption and cytokine pro- national guidelines with a high level of proof. Nevertheless, duction. In a mouse model of CLP-induced septic shock, three different patterns could be recognised (Fig. 2 ): administration of Dabrafenib 12 and 50  h after ligation improves survival [163]. i. Absence of obvious coagulopathy with high platelet count, low D-dimers, subnormal PT and AT requir- Inhibition of NETs/histones ing only prevention of thrombosis by unfractionated or Deoxyribonuclease 1 (DNase 1) low molecular weight heparins. Deoxyribonuclease 1 or dornase alfa (Pulmo zyme ) is an ii. Thrombotic/multiple organ failure coagulopathy (also inhaled potent inhibitor of bacterial DNA used in patients referred as thrombotic DIC) with “low normal” platelet with cystic fibrosis. Few experimental data are available count, prolonged PT, decreased AT and mild to mod- regarding NETs. In a mouse model of thrombosis, DNase 1 erate D-dimers level; clinical presentation may combine infusion disassembles NETs and prevents thrombus forma- organ failure and cutaneous signs like symmetric limb tion [164]. Interestingly, in a CLP model of sepsis, DNase 1 gangrene with pulses and retiform purpura. Antithrom- delayed—but not early—infusion reduces organ failure and bin and recombinant soluble thrombomodulin must improves outcome [165]. More recently, DNase 1 infusion be considered. New treatments targeting FXIIa, FXIa, in mice challenged with LPS, E. coli or S. aureus reduces polyP and NETs preventing thrombosis are in develop- thrombin generation and platelet aggregation and improves ment and improve survival in experimental sepsis or microvascular perfusion [166] and survival [167]. septic shock. They have not yet been tested in humans. iii. Haemorrhagic/fibrinolytic coagulopathy with very low Interferon‑λ1/IL‑29 platelets, fibrinogen and AT, prolonged coagulation IFN-λ1/IL-29 is a potent antiviral cytokine able to prevent times and clinical oozing. Massive transfusion of fresh- NETs release induced by septic shock sera or platelet-derived frozen plasma, platelets and fibrinogen is required, polyP after phosphorylation of mammalian target of rapamy- with antifibrinolytic drugs. cin (mTOR) to downregulate autophagy. Moreover, IFN-λ1/ IL-29 does not alter neutrophil viability and ROS produc- New clinical trials are necessary to support this view and tion preserving phagocytosis. IFN-λ1/IL-29 has a strong to improve patients’ care. antithrombotic activity in experimental arterial thrombosis but could also regulate immunohaemostasis [168]. Additional files Conclusion: evidence-based versus pragmatic Additional file 1. Supplementary data. medicine Additional file 2: Figure S1. Physiology of thrombin generation. Up to date, it is not possible to propose a unique strategy to Additional file 3: Table S1. DIC scoring systems. diagnose and treat coagulation disorders during infection Additional file 4: Table S2. Efficacy of anticoagulants in septic shock. and septic shock. On the one hand, an “old view” consid- Additional file 5: Table S3. Eec ff t of antithrombin in pneumonia- ered activation of blood coagulation as one of the princi- induced septic shock with DIC (observational nationwide study) . pal ways to die and thrombin as the principal suspect. This Additional file 6: Figure S2. Timing of anticoagulant therapy. view was the rationale for anticoagulation during septic Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 11 of 14 5. Arman M, Krauel K, Tilley DO, et al. Amplification of bacteria-induced Abbreviations platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet ADAMTS13: a disintegrin and metalloprotease with thrombospondin type factor 4. Blood. 2014;123(20):3166–74. 1 motif; CAS: contact activation system; DIC: disseminated intravascular 6. Morrissey JH. Polyphosphate: a link between platelets, coagulation and coagulation; FDPs: fibrin(ogen) degradation products; HDPs: host defence inflammation. Int J Hematol. 2012;95(4):346–52. peptides; HK: high molecular weight kallikrein; ISTH: International Society for 7. Nieuwland R, Berckmans RJ, McGregor S, et al. Cellular origin and pro- Thrombosis and Haemostasis; JAAM: Japanese Association for Acute Medicine; coagulant properties of microparticles in meningococcal sepsis. Blood. KAL: kallikrein; KKS: kallikrein/kinin system; MPO: myeloperoxidase; MPs: 2000;95(3):930–5. microparticles; NE: neutrophil elastase; NETs: neutrophil extracellular traps; PCI: 8. Delabranche X, Boisrame-Helms J, Asfar P, et al. Microparticles are new protein C inhibitor; Pg: plasminogen; polyP: polyphosphates; SK: streptokinase; biomarkers of septic shock-induced disseminated intravascular coagu- TAFI: thrombin-activatable fibrinolysis inhibitor; TMAs: thrombotic microangi- lopathy. Intensive Care Med. 2013;39(10):1695–703. opathies; UL-vWF: ultralarge von Willebrand factor. 9. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318–21. Authors’ contributions 10. Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in XD was the primary author responsible for literature search and review. XD, JH thrombosis-the journey of TF through NETs. Front Immunol. 2012;3:385. and FM were involved in the generation of the first version of the manuscript 11. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. and then in critical revision, editing and generation of revised manuscript. All 2014;20(4):195–203. authors read and approved the final manuscript. 12. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: inter- national guidelines for management of severe sepsis and septic shock: Authors’ information 2012. Crit Care Med. 2013;41(2):580–637. XD (MD, Ph.D.), consultant, JH (MD, Ph.D.), consultant and lecturer and FM (MD, 13. Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated Ph.D.), consultant, professor and head, all in critical care medicine—service disseminated intravascular coagulation: the view from Japan. J Thromb de réanimation médicale, Nouvel Hôpital Civil—Hôpitaux Universitaires de Haemost. 2014;12(7):1010–9. Strasbourg, Strasbourg (France). 14. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13(1):34–45. Author details 15. Claushuis TA, de Stoppelaar SF, Stroo I, et al. Thrombin contributes to Université de Strasbourg, Faculté de Médecine & Hôpitaux Universitaires de protective immunity in pneumonia-derived sepsis via fibrin polym- Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, France. erization and platelet-neutrophil interactions. J Thromb Haemost. INSERM (French National Institute of Health and Medical Research), UMR 2017;15(4):744–57. 1260, Regenerative Nanomedicine (RNM), FMTS, Université de Strasbourg, 16. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. Strasbourg, France. INSERM, EFS Grand Est, BPPS UMR-S 949, Université de 2013;369(9):840–51. Strasbourg, Strasbourg, France. 17. van der Poll T, Herwald H. The coagulation system and its function in early immune defense. Thromb Haemost. 2014;112(4):640–8. Acknowledgements 18. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of dissemi- We want to thank Asaël BERGER (MD) for literature search. nated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014;2(1):15. Competing interests 19. Gando S, Wada H, Thachil J. Scientific and Standardization Committee The authors declare that they have no competing interests. on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) Availability of data and materials with the fibrinolytic phenotype from coagulopathy of trauma and Not applicable for this review. acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013;11(5):826–35. Consent for publication 20. Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic Not applicable for this review. disseminated intravascular coagulation in trauma and traumatic shock. Crit Care. 2015;19:72. Ethics approval and consent to participate 21. Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one Not applicable for this review. way? Crit Care Med. 2012;40(9):2704–8. 22. Levi M. The coagulant response in sepsis and inflammation. Hamosta- Funding seologie 2010; 30(1): 10–2, 4–6. No funding was obtained for the creation of this review. 23. Levi M, van der Poll T. Endothelial injury in sepsis. Intensive Care Med. 2013;39(10):1839–42. Publisher’s Note 24. Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in Springer Nature remains neutral with regard to jurisdictional claims in pub- hemostasis. Physiol Rev. 2013;93(1):327–58. lished maps and institutional affiliations. 25. Krem MM, Rose T, Di Cera E. Sequence determinants of function and evolution in serine proteases. Trends Cardiovasc Med. 2000;10(4):171–6. Received: 12 May 2017 Accepted: 20 November 2017 26. Davidson CJ, Tuddenham EG, McVey JH. 450 million years of hemosta- sis. J Thromb Haemost. 2003;1(7):1487–94. 27. Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD. Interactions between coagulation and complement–their role in inflammation. References Semin Immunopathol. 2012;34(1):151–65. 1. Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood. 28. Berends ET, Kuipers A, Ravesloot MM, Urbanus RT, Rooijakkers SH. 2005;106(8):2605–12. Bacteria under stress by complement and coagulation. FEMS Microbiol 2. Schmaier AH. The contact activation and kallikrein/kinin systems: Rev. 2014;38(6):1146–71. pathophysiologic and physiologic activities. J Thromb Haemost. 29. White GC 2nd. The partial thromboplastin time: defining an era in 2016;14(1):28–39. coagulation. J Thromb Haemost. 2003;1(11):2267–70. 3. Long AT, Kenne E, Jung R, Fuchs TA, Renne T. Contact system revisited: 30. Evans CE, Zhao YY. Impact of thrombosis on pulmonary endothelial an interface between inflammation, coagulation, and innate immunity. injury and repair following sepsis. Am J Physiol Lung Cell Mol Physiol. J Thromb Haemost. 2016;14(3):427–37. 2017;312(4):L441–51. 4. Lerolle N, Carlotti A, Melican K, et al. Assessment of the interplay 31. Frick IM, Bjorck L, Herwald H. The dual role of the contact system in between blood and skin vascular abnormalities in adult purpura fulmi- bacterial infectious disease. Thromb Haemost. 2007;98(3):497–502. nans. Am J Respir Crit Care Med. 2013;188(6):684–92. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 12 of 14 32. Brown MR, Kornberg A. Inorganic polyphosphate in the origin and 58. Kastrup CJ, Boedicker JQ, Pomerantsev AP, et al. Spatial localization of survival of species. Proc Natl Acad Sci USA. 2004;101(46):16085–7. bacteria controls coagulation of human blood by ‘quorum acting’. Nat 33. Kornberg A, Rao NN, Ault-Riche D. Inorganic polyphosphate: a mol- Chem Biol. 2008;4(12):742–50. ecule of many functions. Annu Rev Biochem. 1999;68:89–125. 59. Sun H, Wang X, Degen JL, Ginsburg D. Reduced thrombin generation 34. Smith SA, Choi SH, Davis-Harrison R, et al. Polyphosphate exerts dif- increases host susceptibility to group A streptococcal infection. Blood. ferential effects on blood clotting, depending on polymer size. Blood. 2009;113(6):1358–64. 2010;116(20):4353–9. 60. Rivera J, Vannakambadi G, Hook M, Speziale P. Fibrinogen-binding pro- 35. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis teins of Gram-positive bacteria. Thromb Haemost. 2007;98(3):503–11. and organ dysfunction. Thromb Res. 2012;129(3):290–5. 61. Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and 36. Mitchell JL, Lionikiene AS, Georgiev G, et al. Polyphosphate colocalizes host defense. J Thromb Haemost. 2007;5(Suppl 1):24–31. with factor XII on platelet-bound fibrin and augments its plasminogen 62. Brissette CA, Haupt K, Barthel D, et al. Borrelia burgdorferi infection- activator activity. Blood. 2016;128(24):2834–45. associated surface proteins ErpP, ErpA, and ErpC bind human plasmino- 37. Maas C. Polyphosphate strikes back. Blood. 2016;128(24):2754–6. gen. Infect Immun. 2009;77(1):300–6. 38. Verhoef JJ, Barendrecht AD, Nickel KF, et al. Polyphosphate nanopar- 63. Barthel D, Singh B, Riesbeck K, Zipfel PF. Haemophilus influenzae uses ticles on the platelet surface trigger contact system activation. Blood. the surface protein E to acquire human plasminogen and to evade 2017;129(12):1707–17. innate immunity. J Immunol. 2012;188(1):379–85. 39. Weitz JI, Fredenburgh JC. Platelet polyphosphate: the long and the 64. Pancholi V, Fischetti VA. alpha-enolase, a novel strong plasmin(ogen) short of it. Blood. 2017;129(12):1574–5. binding protein on the surface of pathogenic streptococci. J Biol Chem. 40. Whyte CS, Chernysh IN, Domingues MM, et al. Polyphosphate delays 1998;273(23):14503–15. fibrin polymerisation and alters the mechanical properties of the fibrin 65. Bergmann S, Rohde M, Chhatwal GS, Hammerschmidt S. Alpha-enolase network. Thromb Haemost. 2016;116(5):897–903. of Streptococcus pneumoniae is a plasmin(ogen)-binding protein dis- 41. Mocsai A. Diverse novel functions of neutrophils in immunity, inflam- played on the bacterial cell surface. Mol Microbiol. 2001;40(6):1273–87. mation, and beyond. J Exp Med. 2013;210(7):1283–99. 66. Chung MC, Tonry JH, Narayanan A, et al. Bacillus anthracis interacts with 42. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutro- plasmin(ogen) to evade C3b-dependent innate immunity. PLoS ONE. phil function: from mechanisms to disease. Annu Rev Immunol. 2011;6(3):0018119. 2012;30:459–89. 67. Floden AM, Watt JA, Brissette CA. Borrelia burgdorferi enolase is a 43. Stiel L, Meziani F, Helms J. Neutrophil activation during septic shock. surface-exposed plasminogen binding protein. PLoS ONE. 2011;6(11):8. Shock. 2017. https://doi.org/10.1097/SHK.0000000000000980. 68. Bisno AL, Brito MO, Collins CM. Molecular basis of group A streptococ- 44. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular cal virulence. Lancet Infect Dis. 2003;3(4):191–200. traps kill bacteria. Science. 2004;303(5663):1532–5. 69. Verhamme IM, Panizzi PR, Bock PE. Pathogen activators of plasminogen. 45. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to J Thromb Haemost. 2015;13(1):12939. neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41. 70. Wiles KG, Panizzi P, Kroh HK, Bock PE. Skizzle is a novel plasminogen- 46. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil and plasmin-binding protein from Streptococcus agalactiae that elastase and myeloperoxidase regulate the formation of neutrophil targets proteins of human fibrinolysis to promote plasmin generation. J extracellular traps. J Cell Biol. 2010;191(3):677–91. Biol Chem. 2010;285(27):21153–64. 47. Pilsczek FH, Salina D, Poon KK, et al. A novel mechanism of rapid nuclear 71. Stathopoulos C. Structural features, physiological roles, and biotechno- neutrophil extracellular trap formation in response to Staphylococcus logical applications of the membrane proteases of the OmpT bacterial aureus. J Immunol. 2010;185(12):7413–25. endopeptidase family: a micro-review. Membr Cell Biol. 1998;12(1):1–8. 48. Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat 72. Haiko J, Suomalainen M, Ojala T, Lahteenmaki K, Korhonen TK. Invited Med. 2011;17(11):1381–90. review: breaking barriers—attack on innate immune defences by 49. Noubouossie DF, Whelihan MF, Yu YB, et al. In vitro activation of omptin surface proteases of enterobacterial pathogens. Innate Immun. coagulation by human neutrophil DNA and histone proteins but not 2009;15(2):67–80. neutrophil extracellular traps. Blood. 2017;129(8):1021–9. 73. Korhonen TK, Haiko J, Laakkonen L, Jarvinen HM, Westerlund-Wikstrom 50. Abrams ST, Zhang N, Dart C, et al. Human CRP defends against the B. Fibrinolytic and coagulative activities of Yersinia pestis. Front Cell toxicity of circulating histones. J Immunol. 2013;191(5):2495–502. Infect Microbiol. 2013;3:35. 51. Smeesters PR, McMillan DJ, Sriprakash KS. The streptococcal M protein: 74. Korhonen TK. Fibrinolytic and procoagulant activities of Yersinia pestis a highly versatile molecule. Trends Microbiol. 2010;18(6):275–82. and Salmonella enterica. J Thromb Haemost. 2015;13(1):12932. 52. McAdow M, Missiakas DM, Schneewind O. Staphylococcus aureus 75. Ooe A, Kida M, Yamazaki T, et al. Common mutation of plasminogen secretes coagulase and von Willebrand factor binding protein to detected in three Asian populations by an amplification refractory modify the coagulation cascade and establish host infections. J Innate mutation system and rapid automated capillary electrophoresis. Immun. 2012;4(2):141–8. Thromb Haemost. 1999;82(4):1342–6. 53. Thomer L, Schneewind O, Missiakas D. Multiple ligands of von Wille- 76. Thomassin JL, Brannon JR, Gibbs BF, Gruenheid S, Le Moual H. OmpT brand factor-binding protein (vWbp) promote Staphylococcus aureus outer membrane proteases of enterohemorrhagic and enteropatho- clot formation in human plasma. J Biol Chem. 2013;288(39):28283–92. genic Escherichia coli contribute differently to the degradation of 54. Fitzgerald JR, Loughman A, Keane F, et al. Fibronectin-binding proteins human LL-37. Infect Immun. 2012;80(2):483–92. of Staphylococcus aureus mediate activation of human platelets via 77. Bengtson SH, Sanden C, Morgelin M, et al. Activation of TAFI on the fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG bind- surface of Streptococcus pyogenes evokes inflammatory reac- ing to the FcγRIIa receptor. Mol Microbiol. 2006;59(1):212–30. tions by modulating the kallikrein/kinin system. J Innate Immun. 55. Imamura T, Tanase S, Szmyd G, Kozik A, Travis J, Potempa J. Induction 2009;1(1):18–28. of vascular leakage through release of bradykinin and a novel kinin 78. Mook-Kanamori BB, Valls Seron M, Geldhoff M, et al. Thrombin- by cysteine proteinases from Staphylococcus aureus. J Exp Med. activatable fibrinolysis inhibitor influences disease severity in humans 2005;201(10):1669–76. and mice with pneumococcal meningitis. J Thromb Haemost. 56. Wollein Waldetoft K, Svensson L, Morgelin M, et al. Streptococcal sur- 2015;13(11):2076–86. face proteins activate the contact system and control its antibacterial 79. Akesson P, Herwald H, Rasmussen M, et al. Streptococcal inhibitor of activity. J Biol Chem. 2012;287(30):25010–8. complement-mediated lysis (SIC): an anti-inflammatory virulence deter - 57. Chung MC, Popova TG, Jorgensen SC, et al. Degradation of circulating minant. Microbiology. 2010;156(Pt 12):3660–8. von Willebrand factor and its regulator ADAMTS13 implicates secreted 80. Frick IM, Shannon O, Akesson P, et al. Antibacterial activity of the con- Bacillus anthracis metalloproteases in anthrax consumptive coagulopa- tact and complement systems is blocked by SIC, a protein secreted by thy. J Biol Chem. 2008;283(15):9531–42. Streptococcus pyogenes. J Biol Chem. 2011;286(2):1331–40. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 13 of 14 81. Itoh S, Yokoyama R, Kamoshida G, et al. Staphylococcal superantigen- 107. Rossi E, Sanz-Rodriguez F, Eleno N, et al. Endothelial endoglin is like protein 10 (SSL10) inhibits blood coagulation by binding to involved in inflammation: role in leukocyte adhesion and transmigra- prothrombin and factor Xa via their gamma-carboxyglutamic acid (Gla) tion. Blood. 2012;16:16. domain. J Biol Chem. 2013;288(30):21569–80. 108. Rossi E, Smadja DM, Boscolo E, et al. Endoglin regulates mural cell adhe- 82. Yount NY, Yeaman MR. Peptide antimicrobials: cell wall as a bacterial sion in the circulatory system. Cell Mol Life Sci. 2016;73(8):1715–39. target. Ann N Y Acad Sci. 2013;1277:127–38. 109. Ramma W, Ahmed A. Is inflammation the cause of pre-eclampsia? 83. Yount NY, Yeaman MR. Emerging themes and therapeutic prospects for Biochem Soc Trans. 2011;39(6):1619–27. anti-infective peptides. Annu Rev Pharmacol Toxicol. 2012;52:337–60. 110. Delabranche X, Quenot JP, Lavigne T, et al. Early detection of dis- 84. Kasetty G, Papareddy P, Kalle M, et al. The C-terminal sequence of sev- seminated intravascular coagulation during septic shock: a multicentre eral human serine proteases encodes host defense functions. J Innate prospective study. Crit Care Med. 2016;17:17. Immun. 2011;3(5):471–82. 111. Guitton C, Gerard N, Sebille V, et al. Early rise in circulating endothelial 85. Papareddy P, Rydengard V, Pasupuleti M, et al. Proteolysis of human protein C receptor correlates with poor outcome in severe sepsis. thrombin generates novel host defense peptides. PLoS Pathog. Intensive Care Med. 2011;37(6):950–6. 2010;6(4):1000857. 112. Perez-Casal M, Downey C, Fukudome K, Marx G, Toh CH. Activated 86. Kalle M, Papareddy P, Kasetty G, et al. Host defense peptides of throm- protein C induces the release of microparticle-associated endothelial bin modulate inflammation and coagulation in endotoxin-mediated protein C receptor. Blood. 2005;105(4):1515–22. shock and Pseudomonas aeruginosa sepsis. PLoS ONE. 2012;7(12):13. 113. Perez-Casal M, Thompson V, Downey C, et al. The clinical and functional 87. Kalle M, Papareddy P, Kasetty G, et al. Proteolytic activation trans- relevance of microparticles induced by activated protein C treatment in forms heparin cofactor II into a host defense molecule. J Immunol. sepsis. Crit Care. 2011;15(4):R195. 2013;190(12):6303–10. 114. Osterud B. Tissue factor expression in blood cells. Thromb Res. 88. Kalle M, Papareddy P, Kasetty G, et al. A peptide of heparin cofactor II 2010;125(1):10. inhibits endotoxin-mediated shock and invasive Pseudomonas aerugi- 115. Stakos DA, Kambas K, Konstantinidis T, et al. Expression of functional nosa infection. PLoS ONE. 2014;9(7):e102577. tissue factor by neutrophil extracellular traps in culprit artery of acute 89. Papareddy P, Kalle M, Bhongir RK, Morgelin M, Malmsten M, myocardial infarction. Eur Heart J. 2015;36(22):1405–14. Schmidtchen A. Antimicrobial effects of helix D-derived peptides of 116. Gould TJ, Lysov Z, Liaw PC. Extracellular DNA and histones: dou- human antithrombin III. J Biol Chem. 2014;289(43):29790–800. ble-edged swords in immunothrombosis. JJ Thromb Haemost. 90. Malmstrom E, Morgelin M, Malmsten M, et al. Protein C inhibitor–a 2015;13(Suppl 1):S82–91. novel antimicrobial agent. PLoS Pathog. 2009;5(12):18. 117. Delabranche X, Stiel L, Severac F, et al. Evidence of netosis in septic 91. Rieger D, Assinger A, Einfinger K, Sokolikova B, Geiger M. Protein C shock-induced disseminated intravascular coagulation. Shock. inhibitor (PCI) binds to phosphatidylserine exposing cells with implica- 2017;47(3):313–7. tions in the phagocytosis of apoptotic cells and activated platelets. 118. Stiel L, Delabranche X, Galoisy AC, et al. Neutrophil fluorescence: a new PLoS ONE. 2014;9(7):e101794. indicator of cell activation during septic shock-induced disseminated 92. Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. intravascular coagulation. Crit Care Med. 2016;44(11):e1132–6. Findings in 346 patients. Thromb Haemost. 1980;43(1):28–33. 119. Lesesve JF, Martin M, Banasiak C, et al. Schistocytes in disseminated 93. Dutt T, Toh CH. The Yin-Yang of thrombin and activated protein C. Br J intravascular coagulation. Int J Lab Hematol. 2014;36(4):439–43. Haematol. 2008;140(5):505–15. 120. Pfitzner SA, Dempfle CE, Matsuda M, Heene DL. Fibrin detected in 94. Wada H, Thachil J, Di Nisio M, et al. Guidance for diagnosis and treat- plasma of patients with disseminated intravascular coagulation by ment of DIC from harmonization of the recommendations from three fibrin-specific antibodies consists primarily of high molecular weight guidelines. J Thromb Haemost. 2013;4(10):12155. factor XIIIa-crosslinked and plasmin-modified complexes partially 95. Warkentin TE. Ischemic Limb Gangrene with Pulses. N Engl J Med. containing fibrinopeptide A. Thromb Haemost. 1997;78(3):1069–78. 2015;373(7):642–55. 121. Cauchie P, Cauchie C, Boudjeltia KZ, et al. Diagnosis and prognosis of 96. Lipsker D. Ischemic limb gangrene with pulses [Correspondance]. N overt disseminated intravascular coagulation in a general hospital— Engl J Med. 2015;373(24):2385–6. meaning of the ISTH score system, fibrin monomers, and lipoprotein-C- 97. Shapiro NI, Schuetz P, Yano K, et al. The association of endothelial cell reactive protein complex formation. Am J Hematol. 2006;81(6):414–9. signaling, severity of illness, and organ dysfunction in sepsis. Crit Care. 122. Dickneite G, Czech J, Keuper H. Formation of fibrin monomers in experi- 2010;14(5):R182. mental disseminated intravascular coagulation and its inhibition by 98. Ono T, Mimuro J, Madoiwa S, et al. Severe secondary deficiency of recombinant hirudin. Circ Shock. 1994;42(4):183–9. von Willebrand factor-cleaving protease (ADAMTS13) in patients with 123. Gris JC, Faillie JL, Cochery-Nouvellon E, Lissalde-Lavigne G, Lefrant JY. sepsis-induced disseminated intravascular coagulation: its correlation ISTH overt disseminated intravascular coagulation score in patients with development of renal failure. Blood. 2006;107(2):528–34. with septic shock: automated immunoturbidimetric soluble fibrin assay 99. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N vs. D-dimer assay. J Thromb Haemost. 2011;9(6):1252–5. Engl J Med. 2014;371(7):654–66. 124. Gris JC, Bouvier S, Cochery-Nouvellon E, Faillie JL, Lissalde-Lavigne 100. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. G, Lefrant JY. Fibrin-related markers in patients with septic shock: 2014;370(9):847–59. individual comparison of D-dimers and fibrin monomers impacts on 101. Warkentin TE, Pai M. Shock, acute disseminated intravascular coagula- prognosis. Thromb Haemost. 2011;106(6):1228–30. tion, and microvascular thrombosis: is ‘shock liver’ the unrecog- 125. Greenberg CS, Devine DV, McCrae KM. Measurement of plasma fibrin nized provocateur of ischemic limb necrosis? J Thromb Haemost. D-dimer levels with the use of a monoclonal antibody coupled to latex 2016;14(2):231–5. beads. Am J Clin Pathol. 1987;87(1):94–100. 102. Delabranche X, Berger A, Boisrame-Helms J, Meziani F. Microparticles 126. Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE. Plasma D-dimer and infectious diseases. Med Mal Infect. 2012;42(8):335–43. levels and their relationship to serum fibrinogen/fibrin degradation 103. Meziani F, Delabranche X, Asfar P, Toti F. Bench-to-bedside review: circu- products in hypercoagulable states. Br J Haematol. 1989;71(1):65–70. lating microparticles—a new player in sepsis? Crit Care. 2010;14(5):236. 127. Carr JM, McKinney M, McDonagh J. Diagnosis of disseminated intravas- 104. Reid VL, Webster NR. Role of microparticles in sepsis. Br J Anaesth. cular coagulation. Role of D-dimer. Am J Clin Pathol. 1989;91(3):280–7. 2012;109(4):503–13. 128. Boisclair MD, Ireland H, Lane DA. Assessment of hypercoagulable states 105. Okajima K, Uchiba M, Murakami K, Okabe H, Takatsuki K. Plasma levels by measurement of activation fragments and peptides. Blood Rev. of soluble E-selectin in patients with disseminated intravascular coagu- 1990;4(1):25–40. lation. Am J Hematol. 1997;54(3):219–24. 129. Boisclair MD, Lane DA, Wilde JT, Ireland H, Preston FE, Ofosu FA. A 106. Koyama K, Madoiwa S, Nunomiya S, et al. Combination of thrombin- comparative evaluation of assays for markers of activated coagulation antithrombin complex, plasminogen activator inhibitor-1, and protein and/or fibrinolysis: thrombin-antithrombin complex, D-dimer and C activity for early identification of severe coagulopathy in initial phase fibrinogen/fibrin fragment E antigen. Br J Haematol. 1990;74(4):471–9. of sepsis: a prospective observational study. Crit Care. 2014;18(1):R13. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 14 of 14 130. Fourrier F, Jourdain M, Tournois A, Caron C, Goudemand J, Chopin C. 150. Stroo I, Zeerleder S, Ding C, et al. Coagulation factor XI improves host Coagulation inhibitor substitution during sepsis. Intensive Care Med. defence during murine pneumonia-derived sepsis independent of 1995;21(2):S264–8. factor XII activation. Thromb Haemost. 2017;117(8):1601–14. 131. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ 151. Nakamura M, Takeuchi T, Kawahara T, et al. Simultaneous targeting of failure, and disseminated intravascular coagulation. Compared pat- CD14 and factor XIa by a fusion protein consisting of an anti-CD14 anti- terns of antithrombin III, protein C, and protein S deficiencies. Chest. body and the modified second domain of bikunin improves survival in 1992;101(3):816–23. rabbit sepsis models. Eur J Pharmacol. 2017;802:60–8. 132. Gando S, Kameue T, Matsuda N, Hayakawa M, Hoshino H, Kato H. Serial 152. Thiery-Antier N, Binquet C, Vinault S, et al. Is thrombocytopenia an early changes in neutrophil-endothelial activation markers during the course prognostic marker in septic shock? Crit Care Med. 2016;44(4):764–72. of sepsis associated with disseminated intravascular coagulation. 153. Tsirigotis P, Chondropoulos S, Frantzeskaki F, et al. Thrombocytopenia Thromb Res. 2005;116(2):91–100. in critically ill patients with severe sepsis/septic shock: prognostic 133. Hans GA, Besser MW. The place of viscoelastic testing in clinical prac- value and association with a distinct serum cytokine profile. J Crit Care. tice. Br J Haematol. 2016;173(1):37–48. 2016;32:9–15. 134. Brenner T, Schmidt K, Delang M, et al. Viscoelastic and aggregomet- 154. Falcone M, Russo A, Farcomeni A, et al. Septic shock from community- ric point-of-care testing in patients with septic shock—cross-links onset pneumonia: is there a role for aspirin plus macrolides combina- between inflammation and haemostasis. Acta Anaesthesiol Scand. tion? Intensive Care Med. 2016;42(2):301–2. 2012;56(10):1277–90. 155. Falcone M, Russo A, Cangemi R, et al. Lower mortality rate in elderly 135. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin patients with community-onset pneumonia on treatment with aspirin. (recombinant tissue factor pathway inhibitor) in severe sepsis: a rand- J Am Heart Assoc. 2015;4(1):e001595. omized controlled trial. JAMA. 2003;290(2):238–47. 156. Valerio-Rojas JC, Jaffer IJ, Kor DJ, Gajic O, Cartin-Ceba R. Outcomes of 136. Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient. High- severe sepsis and septic shock patients on chronic antiplatelet treat- dose antithrombin III in severe sepsis: a randomized controlled trial. ment: a historical cohort study. Crit Care Res Pract. 2013;2013:782573. JAMA. 2001;286(15):1869–78. 157. Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH. Inhibi- 137. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in tion of polyphosphate as a novel strategy for preventing thrombosis adults with septic shock. N Engl J Med. 2012;366(22):2055–64. and inflammation. Blood. 2012;120(26):5103–10. 138. Meziani F, Vincent JL, Gando S. Should all patients with sepsis receive 158. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey anticoagulation? Yes. Intensive Care Med. 2017;43:452–4. JH. Nontoxic polyphosphate inhibitors reduce thrombosis while spar- 139. van der Poll T, Opal SM. Should all septic patients be given systemic ing hemostasis. Blood. 2014;124(22):3183–90. anticoagulation? No. Intensive Care Med. 2017;43(3):455–7. 159. Heemskerk S, Masereeuw R, Moesker O, et al. Alkaline phosphatase 140. Kenne E, Renne T. Factor XII: a drug target for safe interference with treatment improves renal function in severe sepsis or septic shock thrombosis and inflammation. Drug Discov Today. 2014;19(9):1459–64. patients. Critical care medicine. 2009;37(2):417–23. 141. Chen Z, Seiffert D, Hawes B. Inhibition of Factor XI activity as a promis- 160. Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for ing antithrombotic strategy. Drug Discov Today. 2014;19(9):1435–9. treatment of sepsis-induced acute kidney injury: a prospective rand- 142. Labberton L, Kenne E, Renne T. New agents for thromboprotec- omized double-blind placebo-controlled trial. Crit Care. 2012;16(1):R14. tion. A role for factor XII and XIIa inhibition. Hamostaseologie. 161. Su F, Brands R, Wang Z, et al. Beneficial effects of alkaline phosphatase 2015;35(4):338–50. in septic shock. Crit Care Med. 2006;34(8):2182–7. 143. Caliezi C, Zeerleder S, Redondo M, et al. C1-inhibitor in patients with 162. Tunjungputri RN, Peters E, van der Ven A, de Groot PG, de Mast Q, severe sepsis and septic shock: beneficial effect on renal dysfunction. Pickkers P. Human recombinant alkaline phosphatase inhibits ex vivo Crit Care Med. 2002;30(8):1722–8. platelet activation in humans. Thromb Haemost. 2016;116(6):1111–21. 144. Zeerleder S, Caliezi C, van Mierlo G, et al. Administration of C1 inhibitor 163. Lee S, Ku SK, Bae JS. Anti-inflammatory effects of dabrafenib on reduces neutrophil activation in patients with sepsis. Clin Diag Lab polyphosphate-mediated vascular disruption. Chem Biol Interact. Immunol. 2003;10(4):529–35. 2016;256:266–73. 145. Igonin AA, Protsenko DN, Galstyan GM, et al. C1-esterase inhibitor 164. Brill A, Fuchs TA, Savchenko AS, et al. Neutrophil extracellular traps infusion increases survival rates for patients with sepsis. Crit Care Med. promote deep vein thrombosis in mice. Journal of thrombosis and 2012;40(3):770–7. haemostasis: JTH. 2012;10(1):136–44. 146. Barratt-Due A, Johansen HT, Sokolov A, et al. The role of bradykinin and 165. Mai SH, Khan M, Dwivedi DJ, et al. Delayed but not early treatment with the effect of the bradykinin receptor antagonist icatibant in porcine DNase reduces organ damage and improves outcome in a murine sepsis. Shock. 2011;36(5):517–23. model of sepsis. Shock. 2015;44(2):166–72. 147. Pixley RA, De La Cadena R, Page JD, et al. The contact system contrib- 166. McDonald B, Davis RP, Kim SJ, et al. Platelets and neutrophil extracellular utes to hypotension but not disseminated intravascular coagulation in traps collaborate to promote intravascular coagulation during sepsis in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody mice. Blood. 2017;129(10):1357–67. to block contact activation in baboons. J Clin Invest. 1993;91(1):61–8. 167. Laukova L, Konecna B, Babickova J, et al. Exogenous deoxyribonuclease 148. Worm M, Kohler EC, Panda R, et al. The factor XIIa blocking antibody has a protective effect in a mouse model of sepsis. Biomed Pharmaco - 3F7: a safe anticoagulant with anti-inflammatory activities. Ann Transl ther. 2017;93:8–16. Med. 2015;3(17):2305–5839. 168. Chrysanthopoulou A, Kambas K, Stakos D, et al. Interferon lambda1/ 149. Tucker EI, Verbout NG, Leung PY, et al. Inhibition of factor XI activa- IL-29 and inorganic polyphosphate are novel regulators of neutrophil- tion attenuates inflammation and coagulopathy while improving the driven thromboinflammation. J Pathol. 2017;243(1):111–22. survival of mouse polymicrobial sepsis. Blood. 2012;119(20):4762–8. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Intensive Care Springer Journals

Immunohaemostasis: a new view on haemostasis during sepsis

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Copyright © 2017 by The Author(s)
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Medicine & Public Health; Intensive / Critical Care Medicine; Emergency Medicine; Anesthesiology
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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 (antithrom - bin, 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 determina- tion of DIC scores. This is one of the clues to allocate the right treatment for the right patient at the right moment. Keywords: Infection, Septic shock, Disseminated intravascular coagulation (DIC), Host defence peptides (HDPs), Contact phase, Neutrophil extracellular traps (NETs) but also in vascular permeability and tone (via endothe- Background lial cell receptors and kinin pathways) [1–3]. The aim of this review is to describe the battle between a During infection, initiation of thrombin generation foreign pathogen and the host regarding thrombin gener- may occur through different pathways [ 35]: ation, one of the key molecules to win or to lose the war for surviving. Thrombin is involved in thrombus forma - tion (via fibrin network), in anticoagulation and fibrinol - i. Bacteria initiation with endothelial invasion [4] and ysis [via thrombomodulin and (activated) protein C], platelet activation (via FcγRIIa, αIIbβ3 and platelet focalisation (via glycosaminoglycans and antithrombin), factor 4) [5], ii. Bacterial polyphosphate (polyP) initiation through the “contact” pathway [6], *Correspondence: ferhat.meziani@chru-strasbourg.fr iii. Endothelial cell expression of encrypted tissue fac- Université de Strasbourg, Faculté de Médecine & Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, tor (TF), vascular cell recruitment and activation by France thrombin, cytokines and microparticles [1, 7, 8], Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 2 of 14 iv. fibrin network, neutrophil extracellular traps (NETs) Pathophysiology of thrombin and fibrin formation and histones [9, 10]. during infection The contact between a prokaryote and a eukaryote Haemostasis should therefore be considered as a non- can result in symbiosis or infection resulting in host or specific first line of host defence—at least when localised pathogen survival. To survive infection, the host initi- to a unique endothelial injury—considering the growing ates a complex inflammatory response including innate role of platelets as immune cells [11–13]. This immune immunity, complement and coagulation pathways. These response has been called “immunothrombosis” [14]. In two cascades have a unique origin, but many refinements this line, immunohaemostasis process may help to cap- over the past 500 million years improved their specifici - ture pathogens, prevent tissue invasion and concentrate ties [25, 26]. In this view, coagulation is fundamental to antimicrobial cells and peptides including thrombin- survive and the following section will highlight the role of derived host defence peptides. Therefore, when regu - contact activation system (not involved in “normal” hae- lated, a low-grade activation of thrombin generation may mostasis), the interplay between pathogens, coagulation help survive the bacterial challenge [14]. Yet, inhibition and fibrinolysis pathways, and the emerging role of anti - of thrombin generation by Dabigatran promotes bacterial microbial host defence peptides generated by proteolysis growth and spreading with increased mortality in experi- of “coagulation” proteins [17, 27, 28]. mental model of Klebsiella pneumoniae-induced murine pneumonia [15]. Initiation: the emerging role of contact activation system On the other hand, thrombin can become deleterious if (Fig. 1) ongoing activation of the coagulation, owing to defective Physiology or pathophysiology? natural anticoagulants, leads to excessive thrombin for- An old view of haemostasis distinguished two initiation mation. Combined with defective fibrinolysis, thrombin pathways: tissue factor (“extrinsic” pathway) and contact results in fibrin deposits in microvessels and eventually in activation system (CAS) (“intrinsic” pathway). The lat - disseminated intravascular coagulation (DIC) [16, 17]. DIC ter requires a “contact” activator, prekallikrein (PK), high thus represents a deregulation and/or an overwhelmed molecular weight kininogen (HK), factor XII (FXII) and haemostasis activation response triggered by pathogens FXI [29]. A deficit of one of these proteins results in pro - and/or host responses during septic shock [14]. DIC could longed aPTT although no haemorrhagic diathesis is evi- be classified in “asymptomatic”, “bleeding” (haemorrhagic), denced in patients. CAS does not seem to be involved in “thrombotic” (organ failure) and ultimately “massive “normal” haemostasis and may be restricted to pathologi- bleeding” (fibrinolytic) type, according to its clinical pres - cal conditions resulting in negatively charged surfaces, entation [18]. Except asymptomatic one, all types are char- including sepsis (via NETs and polyP), but also acute acterised by delayed clotting times (PT and aPTT), low respiratory distress syndrome (ARDS) [30] and blood fibrinogen and platelets count owing to their consump - contact with artificial surfaces (intravascular catheters, tion [19, 20]. Although known for many years, the role of extracorporeal circuits). DIC in the pathogenesis of septic shock remains a matter “Contact” activator is a negatively charged surface able of debate [21–23]. Since then, coagulation was considered to link and induce a conformational change in FXII that 2+ as a potential therapeutic target. The recognition of new auto-activates FXII in α-FXIIa in the presence of Zn . targets implied in thrombosis—but not in haemostasis— Then α-FXIIa converts PK to kallikrein (KAL) that enable opens a new window over innovative therapies. a reciprocal hetero-activation of α-FXII, leading to large amount of β-FXIIa and thereafter platelet GP -bound Ib Physiology of thrombin generation FXI activation. β-FXIIa is also able to activate the clas- For didactic settings, haemostasis can be separated into sic complement system pathway via C1r and to a lesser three phases: extent C1  s linking haemostasis and complement-medi- ated host defence [3]. i. Initiation, CAS and PK also activate fibrinolysis and tissue prote - ii. Propagation and regulation, olysis. HK linked to urokinase-type plasminogen activa- iii. Fibrinolysis. tor receptor (uPAR) is able to activate pro-uPA into uPA that in turn activates plasminogen into matrix-bound plasmin. Moreover, BK induces tPA release by endothe- A brief overview of haemostasis is available in Addi- lial cells when linked to B1R [2]. tional file  1 and Additional file  2: Figure S1 provides the Besides and related to CAS, the kallikrein/kinin sys- different steps of thrombin generation, fibrin formation tem (KKS) is also activated [3]. CAS and PK also activate and regulation [1, 24]. fibrinolysis and tissue proteolysis and are regulated by Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 3 of 14 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 (polyP ) released by bacteria. Both are “contact” activators, i.e. a negatively charged surface able to link and induce a conformational change in 150–200 2+ FXII that auto-activates FXII in α-FXIIa in the presence of Zn . 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 GP -bound FXI activation. Large amount of FXIIa generated is able to convert Ib 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, polyP enhances activation of 150–200 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 PGI and nitric oxide after iNOS induction), oedema formation and ultimately hypotension serpin C1 esterase inhibitor (C1-INH). A deficit (respon - further degradation, resulting in prolonged half-life. sible for hereditary angioedema) or consumption (during In the presence of fibrin polymers associated with septic shock but also after extracorporeal circulation) is polyP , α-FXIIa can activate fibrin-bound plasmino - 60–80 responsible for increased permeability syndrome [31]. gen in plasmin, resulting in “intrinsic” fibrinolytic activity overcoming antifibrinolytic properties [36, 37]. Interest- Polyphosphates (polyP) ingly, activated platelets could retain polyP on their 60–80 PolyP are negatively charged inorganic phosphorous surface assembled into insoluble spherical nanoparticles 2+ 2+ residue polymers, highly conserved in prokaryotes and with divalent metal ions (C a, Zn ). These nanoparti - eukaryotes. They are important source of energy, but are cles provide higher polymer size and become able to trig- also involved in cell response. Half-life of polyP is very ger contact system activation [38, 39]. short due to their degradation by phosphatases [32, 33]. On the other hand, large-sized insoluble p olyP 150–200 Medium-size soluble p olyP are released by acti- are released by bacteria and yeasts. P olyP are 60–80 150–200 vated platelets and mast cells. They are able to induce able to support auto-activation of FXIIa and to pro- FXII activation only if large amounts are present [34, mote thrombin generation independently of FXI activa- 35]. PolyP could also bind α-FXIIa preventing tion. PolyP can bind FM resulting in clots with reduced 60–80 Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 4 of 14 stiffness and increased deformability [40]. Moreover, a better activation by host proteases [51]. Interestingly, polyP are incorporated in fibrin mesh, inhibiting some bacteria use specific pathways to induce thrombin 150–200 fibrinolysis [34]. and fibrin generation [52–58]. Neutrophil extracellular traps (NETs) Degradation of fibrin clots Neutrophils have long been considered as suicidal cells Fibrin formation and pathogen entrapment are key fea- killing extracellular pathogens. Few years ago, biology tures of host defence during infection. Fibrin(ogen) is of neutrophils has evolved for a more complex network fundamental to survive infection [59]. To evade fibrin, linking innate immunity, adaptive immunity and haemo- many bacteria developed fibrinolysis activators or stasis [41–43]. Neutrophils do not only engulf pathogens expressed plasminogen receptors allowing activation by (phagocytosis) and release granules content, but also host tPA or uPA [60–76]. release their nuclear content, essentially histones and Outer membrane proteins (omptins) are surface- DNA fragments resulting in a net. These NETs support exposed, transmembrane β-barrel proteases exposed by histones and other granule enzymes like myeloperoxidase some gram-negative bacteria. They display fibrinolytic (MPO) and neutrophil elastase (NE). These fragments are and procoagulant activities required for pathogenic- called NETs for neutrophils extracellular traps, and they ity [71, 72]. Yersinia pestis is the agent of bubonic and enable to trap pathogens and blood cells, including plate- pneumonic plague. Both associate haemorrhagic and lets, in their meshes [44]. thrombotic disorders and the presence of Pla, a direct Two mechanisms of NETosis are described: a suicidal activator of host plasminogen, require rough LPS. Pla is one [44–46] and a vital one, with functional anucleated also able to promote fibrinolysis by activation of uPA, phagocytic cell survival [47]. Finally, the plasma mem- inactivation of serpins PAI-1 and α -antiplasmin and brane bursts and NETs are released [48]. by cleavage of C-terminal region of TAFI with reduced NETosis plays a critical role in host defence through activation by thrombin–thrombomodulin complex [73, innate immunity, but also through other procoagulant 74]. Pla is also able to cleave TFPI. Interestingly, dys- mechanisms:plasminogenemia (Ala   →  Thr), present in about 2% of the Chinese, Korean and Japanese populations, con- fers a protection against plague. Homozygous individu- i. Negatively charged DNA constitutes an activated als have a reduced plasminogen activity about 10% with surface for coagulation factors assembly, including fewer thrombotic events, but enhanced survival during contact phase; infection by Y. pestis but also by group A streptococci ii. Enzymatic inhibition of tissue factor pathway inhibi- and S. aureus requiring plasminogen activation for tor (TFPI) and thrombomodulin (TM) by neutrophil pathogenicity [75]. elastase; iii. Direct recruitment and activation of platelets by his- Inactivation of fibrinolysis tones [14]. Inhibition of fibrinolysis is another way to promote clot stabilisation [77, 78]. Recent data support a direct activation by DNA and his- tones more than NETs themselves [49]. High levels of Inhibition of coagulation circulating histones have been evidenced in septic shock. Bacteria can also block contact activation pathway [79, Histone infusion induces intravascular coagulation with 80] or thrombin generation [81] in order to prevent host thrombocytopenia and increased D-dimers. Antihistone defence. antibodies can prevent both lung and cardiac injuries in experimental models. C-reactive protein can bind his- Host defence peptides tones and reduce histone-induced endothelial cell injury. Innate immunity is mediated by cell activation via Toll- C-reactive protein infusion rescues histone-challenged like receptors (TLRs). Resulting cationic and amphip- mouse [50]. athic small peptides (15–30 amino acids, < 10 kDa) have many biological properties including direct bactericidal Pathogen‑induced modulation of blood coagulation effects, but also immunomodulation and angiogenesis. (Table 1) They have been named “host defence peptides” (HDPs) Initiation of coagulation or “antimicrobial peptides” (AMPs). All bacteria can induce blood coagulation in a polyP- In eukaryotes, we can identify defensins (disulphide- dependent pathway as seen above. High molecular weight stabilised peptides) and cathelicidins (α-helical or kininogen (HK) can also bind bacterial surface allowing Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 5 of 14 Table 1 Pathogen-induced modulation of blood coagulation Bacteria Protein Target Result References A—initiation of coagulation All bacteria PolyP FXII → FXIIa Contact phase activation (FXI) [51] S. aureus Coagulase FII → FIIa Non-proteolytic activation [52] von Willebrand binding protein (vWbp) vWF (endothelium) S. aureus anchorage to endothelium [53] FII → FIIa Non-proteolytic activation [52] vWbp-FIIa → FXIII Clot stabilisation [53] Clumping factor A (ClfA) and fibronectin- Fg S. aureus—platelet bridging and clot forma- [54] binding protein A (FnbpA) tion Staphopains A and B (ScpA, ScpB) HK → BK Vascular leakage [55, 56] Group G streptococci Fibrinogen-binding protein (FOG) and FXII → FXIIa Contact phase complex assembly and [57] protein G (PG) activation (FXI) at bacterial surface B. anthracis Zinc metalloprotease InhA1 FX → FXa/FII → FIIa Fibrin deposition [57, 58] ADAMTS13 inhibition Platelet adhesion/activation by UL-vWF [58] B—degradation of fibrin clot B. burgdorferi Outer surface proteins (OspA and OspC) and Plasmin(ogen) Plasminogen activation by tPA/uPA [62] Erp proteins (ErpA, ErpC and ErpP) H. influenzae Surface protein E (PE) Plasmin(ogen) Plasminogen activation by tPA/uPA [63] Streptococci spp. α-Enolase Plasmin(ogen) Plasminogen activation by tPA/uPA [64–67] B. anthracis α-Enolase and elongation factor tu Plasmin(ogen) Plasminogen activation by tPA/uPA [66] S. pyogenes Plasminogen-binding M-like protein (PAM) Plasminogen Direct non-enzymatic activation [51] and streptokinase (SK) Metalloprotease activation and tissue inva- [68, 69] sion by PAM-bound SK·PM S. agalactiae Skizzle (SkzL) tPA/uPA Enhanced plasminogen activation [70] Y. pestis Omptin Pla Plasminogen Direct activation in presence of LPS [71] PAI-1/TAFI/α -AP Inactivation of serpins [72–74] S. enterica Omptin PgtE PAI-1/α -AP Inactivation of serpins [76] C—inactivation of fibrinolysis Group A streptococci Collagen-like proteins (SclA and SclB) TAFI and FIIa TAFI → TAFIa [77, 78] D—Inhibition of coagulation Group A streptococci Streptococcal inhibitor of complement (SIC) HK Inhibition of HK binding and contact phase [79, 80] activation S. aureus Staphylococcal superantigen-like protein 10 FII Inhibition of platelet binding and activation [81] (SSLP-10) extended peptides). HDPs can be classified into three cat - Serine protease‑derived peptides egories regarding their target on prokaryotes: Human serine proteases (including vitamin K-dependent blood coagulation factors and kallikrein system peptides) i. Plasma membrane-active peptides disrupting mem- can be cleaved by proteases to generate C-terminal pep- brane integrity, tides with direct antimicrobial activities [84]. GKY25 is ii. Intracellular inhibitors of transcription or transla- released from FIIa, FXa and FXIa after cleavage by neu- tional factors and trophil elastase [85]. This peptide is able to slightly reduce iii. Cell wall-active peptides interfering with cell wall P. aeruginosa growth but also to significantly reduce both synthesis and bacterial replication [82]. inflammatory response and mortality [86]. Bacteria are also able, mainly by unknown mechanisms, to gener- ate HDPs from fibrinogen (GHR28) and high molecular Limited proteolysis of many proteins involved in blood weight kininogen (HKH20 and NAT26). coagulation (activators as well as inhibitors) is now rec- ognised as HDPs and may participate to host defence. Serpin‑derived peptides Interestingly, the development of synthetic HDPs is a Serpins (or serine protease inhibitors) can also gener- new therapeutic anti-infectious strategy regarding resist- ate HDPs. Heparin cofactor II (HCII) can be cleaved ance of pathogens to (conventional) antibiotics [83]. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 6 of 14 by neutrophil elastase after binding to glycosaminogly- Underlying disease can [87], and KYE28 displays antimicrobial properties In sepsis and septic shock, vascular injury is central and against gram-negative and gram-positive bacteria but prompted by different actors with overlapping kinetics, also against fungus [87]. Moreover, KYE28 can bind LPS leading to difficulties in deciphering a sequential order dampening inflammatory response [88]. FFF21 derived [97]. from antithrombin also shares antimicrobial activity after Acute kidney injury (AKI) is present in about half permeabilisation of bacterial membrane [89]. Protein C patients, one-third of non-DIC patients versus four-fifth inhibitor-derived SEK20 peptide displays antimicrobial in DIC patients. This association between AKI and low activity [90]. Interestingly, platelets can bind PCI under platelets may be symptomatic of thrombotic microangi- activation resulting in high concentration of PCI at site opathy (TMA) all the more that Ono et al. [98] reported of platelet recruitment as observed during infection [91]. low ADAMTS13 activity and high UL-vWF in septic shock-induced DIC. Nevertheless, there are two impor- Diagnosis tant differences: the presence of schizocytes and the Activation of the coagulation cascade is a physiologic, absence of prolonged clotting times in TMAs [99, 100]. innate and adaptive response during infection. This Hepatic injury is frequent, but remains mild to mod- response can be overwhelmed, becoming hazardous erate, with a slight increase in liver enzymes and bili- and referred to as DIC meaning disseminated intravas- rubin and decrease in PT. On the other hand, severe cular coagulation, as well as “death is coming” [92]. For hepatic ischaemia may lead to fulminant hypoxic hepa- many years, only two conditions were distinguished: titis with very low PT, but also inhibitors AT and PC “no DIC” and “DIC”. This “schizophrenic” view of hae - mimicking DIC with ischaemic limb gangrene with mostasis needs to be reissued, as proposed by Dutt and pulses [101]. Toh [93]: “The Ying-Yang of thrombin and protein C”. There is indeed a continuum from adaptive to noxious Cellular activation thrombin generation. Moreover, DIC remains a medical Only indirect markers of cellular activation are available; paradigm for critical care physicians: clinical diagnosis is most of them are not routinely assessed. These mark - often (too) late and biological diagnosis (too) frequent in ers could be soluble molecules (released by shedding or the absence of clinical signs or therapeutic opportunities by proteolytic cleavage) or cell-derived microvesicles, [94]. including microparticles (MPs). The role of MPs in sep - tic shock and infection has been discussed elsewhere Clinical diagnosis [102–104]. Most patients with sepsis and septic shock do not present any clinical sign of “coagulopathy”, while routine labo- Endothelial cells E-selectin (CD62E), or endothelial-leu- ratory tests are disturbed. Clinical examination should cocyte adhesion molecule-1 (ELAM-1), is only expressed focus on purpura, symmetric ischaemic limb gangrene by endothelial cells after cytokine stimulation. CD62E is (with pulses) [95] and diffuse oozing. A very specific sign involved in leucocyte recruitment at site of injury and is “retiform purpura”, which is a netlike purpura reminis- could be released in the blood stream as free, soluble mol- cent of livedo. However, unlike classic livedo, in which ecule (sCD62E) or membrane bound after MP shedding meshes are erythematous, meshes are here purpuric. The (CD62 -MPs). sCD62E is dramatically increased during absence of induced bleeding on retrieval when the skin is septic shock, especially in DIC patients [8], but was not punctured to a depth of 3 to 4 mm within a livid or pur- associated with DIC diagnosis in one study [105, 106]. puric area is a good indication of thrombotic microangi-Interestingly, CD62 -MPs were not increased in septic opathy [96]. shock due to proteolysis [8]. Endoglin (CD105, Eng) is a membrane protein Laboratory criteria expressed mainly by endothelial cells in the vascular A single test will never be able to diagnose and stratify repair and angiogenesis during inflammation [107]. It sepsis-induced coagulopathy. Only a combination of contains an arginine-glycine-aspartic acid (RGD) trip- the presence of underlying disease associated with evi- eptide sequence that enables cellular adhesion, through dence of cellular activation in the vascular compartment the binding of integrins or other RGD binding receptors (including endothelial cells, leucocytes and platelets), that are present in the extracellular matrix. Membrane- procoagulant activation, fibrinolytic activation, inhibitor bound CD105 is involved in leucocyte α5β1 activation, consumption and end-organ damage or failure will allow resulting in leucocyte recruitment and extravasation such diagnosis. on the one hand and in angiogenesis on the other hand, whereas MMP-14-cleaved soluble (s)CD105 abolishes Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 7 of 14 extravasation and inhibits angiogenesis [107]. CD105 Procoagulant activation plays a pivotal role in endothelial cell adhesion to mural Routine coagulation tests evidence a prolongation of cells [108]. Soluble CD105 overexpression is actually both prothrombin time (PT) and activated partial throm- linked to other typical systemic and vascular inflamma - boplastin time (aPTT). Nevertheless, PT is the more tion states, as pre-eclampsia and HELLP syndrome, that accurate. aPTT is only slightly elevated during DIC due are also characterised by a haemostatic activation/dereg- to inflammatory response and very high level of FVIII ulation [109] and podocyturia [108]. We evidenced the released by injured endothelial cells. presence of C D105 -MPs during septic shock, especially Evidence of thrombin generation can be evaluated by in DIC patients [8, 110]. quantification of prothrombin fragment 1  +  2 (F1  +  2) Endothelial cells also release soluble and microparticle- and/or thrombin–antithrombin (TAT) complexes. These bound EPCR. sEPCR is a marker of endothelial injury tests are not routinely available. Moreover, we evidenced and severity [111], while E PCR -MPs can display an anti- the lack of discrimination of F1  +  2 between DIC and coagulant and cytoprotective pattern in the bloodstream non-DIC patients despite significant differences [8]. [112, 113]. Fibrin formation is quantified by fibrinopeptide A (FpA) (with a 2:1 ratio), not available in routine [120]. Leucocytes Neutrophils and monocytes play a major Soluble fibrin monomers (FM) can be routinely quanti - role in sepsis-induced coagulopathy. After stimulation fied. They do not represent fibrin formation, but resting by thrombin and cytokines, monocytes could express TF fibrin monomers not yet polymerised by FXIIIa. High and promote thrombin generation after cell membrane FM can evidence increased production and/or defec- remodelling and phosphatidylserine (PhtdSer) exposition. tive polymerisation [121, 122]. The accuracy of this bio - Moreover, TF -MPs of monocyte origin have been identi- marker is still matter of debate (see below) [123, 124]. fied and could disseminate a procoagulant potential [7]. The role of neutrophils is more complex, involving both Fibrinolytic activation TF expression (fusion of TF -MPs) [114] and NETs [115]. Fibrin(ogen) degradation products (FDPs) are hetero- Direct evidence of the presence of NETs in bloodstream geneous small molecules generated by the action of is lacking, but histones (or nucleosomes), free DNA and plasmin on both fibrin network (secondary fibrinoly - myeloperoxidase could be detected in plasma and are sig- sis) and fibrinogen (primary fibrinogenolysis). D-dimers nificantly increased in septic shock-induced DIC [116]. (D-domain of two fibrin molecules stabilised by FXIIIa) Recently, our group showed cytological modification of are specific of fibrinolysis and must be preferred when neutrophils in blood smears of patients with DIC [117]. available [125–127]. D-dimers sign thrombin generation, Moreover, we evidenced neutrophil chromatin decon- fibrin formation and polymerisation then fibrinolysis, densation assessed by measuring neutrophil fluorescence while the absence of D-dimers could represent defective (NEUT-SFL) using a routine automated flow cytometer fibrinolysis despite the presence of fibrin. Other mark - Sysmex XN20 [118]. ers could be useful but are not available in routine labo- ratories: PAP (plasmin–antiplasmin complexes), tPA and Platelets Inflammation resulting in systemic inflamma - PAI-1 [128, 129]. Both tPA and PAI-1 are dramatically tory response syndrome (SIRS) is a potent inducer of both increased during septic shock, regardless of DIC diagno- fibrinogen synthesis and platelet circulating pool mobili - sis. Early inhibition of fibrinolysis during sepsis-induced sation. Platelet count can reach 700–800 G/L, but throm- coagulopathy may cause diagnostic delay regarding the bocytopenia can occur during sepsis. A “normal” value— importance of FDPs in DIC diagnosis. that is to say in the normal range—may be interpreted cautiously and represent patent consumption. Moreover, Inhibitors consumption enumeration is not function. During sepsis-induced coag- Sustained thrombin generation leads to activation, ulopathy, platelet activation follows thrombin generation then consumption, of regulatory mechanisms. TFPI is and does not support the propagation phase of haemosta- decreased during DIC [130]. Antithrombin can be—and 2+ sis with impaired P-selectin, ADP, Ca and cFXIII local should be—routinely assessed during sepsis-induced supply. coagulopathy. The absence of low AT level challenges the diagnosis of DIC [131]. Concerning the TM-APC Erythrocytes Schizocytes are fragmented erythrocytes pathway, assessment is complex. PC is decreased by con- and are the cornerstone of TMA diagnosis. They are fre - sumption, but APC is increased, at least at the begin- quently observed on blood smears during DIC and remain ning of sepsis. Moreover, soluble forms of EPCR (sEPCR) of poor value for DIC diagnosis [119]. [111] and TM (sTM) [132] can be found in plasma of sep- tic patients and are correlated to vascular injury. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 8 of 14 Global assessment of haemostasis In the following section, we will present an overview of Thromboelastography (TEG) and rotational thromboe - therapies focused on immunohaemostasis activation. lastometry (ROTEM ) are routinely used in operative theatres to monitor blood coagulation and “assess global Inhibition of contact pathway haemostasis” [133]. Interestingly, they can also evalu- Contact pathway is not necessary for “normal” haemosta- ate fibrinolysis at 30 and 60  min. Nevertheless, a recent sis. FXII(a) and FXI(a) are new targets to develop “safe” Cochrane review concluded that there was little or no evi- antithrombotic drugs without antihaemostatic effects dence of the accuracy of such devices, strongly suggesting [140–142]. Moreover, these drugs could improve hypo- that they should only be used for research [99, 100]. Few tension targeting bradykinin release. data are available regarding septic shock-induced coagu- lation/coagulopathy. A prospective study comparing C1‑inhibitor septic shock patients, surgical patients and healthy volun- C1-inhibitor regulates both complement activation teers evidences a hypocoagulability during DIC [134]. In and FXII and could improve both capillary leakage and this study, we may hypothesise that DIC patients were in hypotension on the one hand and contact phase-induced “fibrinolytic” phase. thrombin generation on the other. As other serpins, C1-inhibitor is dramatically reduced in septic shock and Scoring systems C1-inhibitor supplementation could improve patients or Different scoring systems have been developed to ensure renal function in short randomised trials [143–145]. Nev- DIC diagnosis and are discussed in supplementary data ertheless, no large randomised trial can support its use. (Additional file 1, Additional file 3: Table S1). Interestingly, bradykinin receptor antagonist icatibant had no effect on a porcine model of septic shock [146]. New therapeutic opportunities? A syllogism precludes anticoagulant therapy during FXII blockade severe sepsis and septic shock: “more severe is the infec- In a baboon model challenged with a lethal dose of E. coli, tion, more thrombin is generated”, “more thrombin is the monoclonal antibody C6B7 directed against FXIIa generated, more organ failure and death supervene”, so improved survival with higher blood pressure. In the “more you prevent thrombin generation, more you will treated group, the inflammatory response was reduced improve your patient with severe infection”. This view with lower IL-6 and neutrophil elastase release as well as forgets that haemostasis is mandatory to survive sepsis complement activation. Inhibition of FXIIa was obvious via many pathways, including newly recognised immu- with reduced BK released and fibrinolysis. Nevertheless, nothrombosis and HDPs. In fact, “anticoagulant” treat- both groups experiment DIC with low platelet count, low ments disrupt a tight equilibrium between pathogen and fibrinogen and low FV [147]. Another FXIIa monoclonal adaptive host response and may lead to more deaths in blocking antibody is 3F7. This antibody seems to be safe a group of patients (adaptive haemostasis) and to fewer as an anticoagulant in experimental extracorporeal mem- deaths in another group (noxious haemostasis). Recog- brane oxygenation model, with reduced bleeding com- nition of “noxious haemostasis” remains a medical para- pared to heparin, but no data are yet available regarding digm for critical care physicians. Negative therapeutic septic shock [148]. interventions [135, 136], drotrecogin alfa withdrawal [137], but also emerging concept of immunothrombo- FXI blockade sis [14] could argue for a radical “tabula rasa” regard- 14E11 is an anti-FXI monoclonal antibody that blocks ing coagulation during septic shock. The debate is still FXI activation by FXIIa but not by FIIa. 14E11 displays open and can be summarised in one question: “Should antithrombotic properties. This molecule was used in all patients with sepsis receive anticoagulation?” [138, mouse polymicrobial sepsis. Inflammation and coagu - 139]. Finally, whether immunohaemostasis/DIC clinical lopathy were improved as well as survival after 14E11 assessment is reliable remains a major issue (Fig. 2). treatment up to 12 h after bowel perforation onset. Clot- A mini-review of current (and past) therapies is pro- ting time was not modified, and no bleeding could be evi - vided in supplementary data (Additional file  1, Additional denced in this model [149]. −/− file  4: Table S2, Additional file  5: Table S3 and Additional Interestingly, FXI KO mice (FX I ) evidence increased file 6: Figure S2) regarding: inflammatory response with impaired neutrophil func - tions—but not haemorrhage in lungs—in a model of Klebsiella pneumoniae and Streptococcus pneumoniae i. limitation of thrombin and fibrin generation, pneumonia resulting in an increased mortality. Inhibition ii. DIC with thrombotic/multiple organ failure pattern, iii. DIC with haemorrhagic pattern. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 9 of 14 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 pol- ymerisation 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 of FXI activation by FXIIa does not reproduce this pat- of antiplatelet therapy or to transfuse platelets in the tern [150]. absence of obvious thrombocytopenia with bleeding. A genetically engineered fusion protein (MR1007) con- taining anti-CD14 antibody (to block LPS receptor) and Inhibition of polyP the modified second domain of bikunin (with anti-FXIa Targeting polyP is a new opportunity in the treatment of activity) improves survival in a rabbit model of sepsis contact phase-induced thrombosis, including immuno- without increasing spontaneous bleeding [151]. thrombosis, but some of them are toxic in vivo and can- not be used in humans (polymyxin B, polyethylenimine Inhibition of platelet functions in thrombus formation and polyamidoamine dendrimers) [157]. Platelets are important immune cells, and thrombocyto- penia is associated with an increased mortality in septic Universal heparin reversal agents (UHRAs) shock [152, 153]. Few data support a benefit of previous UHRAs have been developed to reverse heparin effects aspirin treatment in community-onset pneumonia with but also displayed anticoagulant effects. UHRA-9 and [154] or without septic shock [155]. In a retrospective UHRA-10 specifically inhibit polyP and prove antithrom - study of patients with septic shock, chronic antiplate- botic effects without increasing bleeding in a mouse model let treatment was not associated with reduced mor- of arterial thrombosis [158]. Nevertheless, these agents tality [156]. There are no data to support introduction have not been used in experimental septic shock to date. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 10 of 14 Phosphatases shock, with many experimental data supporting it. Nev- Platelet-derived polyP are rapidly degraded by phos- ertheless, all clinical trials—with the exception of PROW- phatases. During septic shock, alkaline phosphatase activity ESS trial—failed to improve survival in unselected septic is dramatically decreased and could enhance polyP activity. shock patients. On the other hand, recent experimental A recombinant human alkaline phosphatase (RecAP) is and clinical data support a beneficial role of blood coagu - able to improve renal function due to acute kidney injury lation to survive sepsis, including immunohaemostasis. during septic shock [159–161]. Moreover, RecAP inhibits The first step to improve patients’ care is to stratify the platelet activation ex vivo by converting ADP in adenosine “coagulopathy”. A combination of biological tests must be and reverse hyperactivity of septic shock-derived platelets used daily, eventually combined in scores. We believe that [162]. Effects on polyP were not specifically studied in this JAAM 2006 and JAAM-DIC scores, taking into account experimental study but cannot be excluded. the inflammatory syndrome and evolution, are the most appropriate. New markers of cell activation may be of inter- Dabrafenib est. The second step is the choice of therapeutic interven - Dabrafenib is a B-Raf kinase inhibitor indicated in unre- tion. Treatment of both infection and shock without delay sectable or metastatic melanoma with BRAF V600E is mandatory. Then, anticoagulation may be considered. To mutation. This molecule has anti-inflammatory effects date, no recommendation can be made according to inter- on polyP-mediated vascular disruption and cytokine pro- national guidelines with a high level of proof. Nevertheless, duction. In a mouse model of CLP-induced septic shock, three different patterns could be recognised (Fig. 2 ): administration of Dabrafenib 12 and 50  h after ligation improves survival [163]. i. Absence of obvious coagulopathy with high platelet count, low D-dimers, subnormal PT and AT requir- Inhibition of NETs/histones ing only prevention of thrombosis by unfractionated or Deoxyribonuclease 1 (DNase 1) low molecular weight heparins. Deoxyribonuclease 1 or dornase alfa (Pulmo zyme ) is an ii. Thrombotic/multiple organ failure coagulopathy (also inhaled potent inhibitor of bacterial DNA used in patients referred as thrombotic DIC) with “low normal” platelet with cystic fibrosis. Few experimental data are available count, prolonged PT, decreased AT and mild to mod- regarding NETs. In a mouse model of thrombosis, DNase 1 erate D-dimers level; clinical presentation may combine infusion disassembles NETs and prevents thrombus forma- organ failure and cutaneous signs like symmetric limb tion [164]. Interestingly, in a CLP model of sepsis, DNase 1 gangrene with pulses and retiform purpura. Antithrom- delayed—but not early—infusion reduces organ failure and bin and recombinant soluble thrombomodulin must improves outcome [165]. More recently, DNase 1 infusion be considered. New treatments targeting FXIIa, FXIa, in mice challenged with LPS, E. coli or S. aureus reduces polyP and NETs preventing thrombosis are in develop- thrombin generation and platelet aggregation and improves ment and improve survival in experimental sepsis or microvascular perfusion [166] and survival [167]. septic shock. They have not yet been tested in humans. iii. Haemorrhagic/fibrinolytic coagulopathy with very low Interferon‑λ1/IL‑29 platelets, fibrinogen and AT, prolonged coagulation IFN-λ1/IL-29 is a potent antiviral cytokine able to prevent times and clinical oozing. Massive transfusion of fresh- NETs release induced by septic shock sera or platelet-derived frozen plasma, platelets and fibrinogen is required, polyP after phosphorylation of mammalian target of rapamy- with antifibrinolytic drugs. cin (mTOR) to downregulate autophagy. Moreover, IFN-λ1/ IL-29 does not alter neutrophil viability and ROS produc- New clinical trials are necessary to support this view and tion preserving phagocytosis. IFN-λ1/IL-29 has a strong to improve patients’ care. antithrombotic activity in experimental arterial thrombosis but could also regulate immunohaemostasis [168]. Additional files Conclusion: evidence-based versus pragmatic Additional file 1. Supplementary data. medicine Additional file 2: Figure S1. Physiology of thrombin generation. Up to date, it is not possible to propose a unique strategy to Additional file 3: Table S1. DIC scoring systems. diagnose and treat coagulation disorders during infection Additional file 4: Table S2. Efficacy of anticoagulants in septic shock. and septic shock. On the one hand, an “old view” consid- Additional file 5: Table S3. Eec ff t of antithrombin in pneumonia- ered activation of blood coagulation as one of the princi- induced septic shock with DIC (observational nationwide study) . pal ways to die and thrombin as the principal suspect. This Additional file 6: Figure S2. Timing of anticoagulant therapy. view was the rationale for anticoagulation during septic Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 11 of 14 5. Arman M, Krauel K, Tilley DO, et al. Amplification of bacteria-induced Abbreviations platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet ADAMTS13: a disintegrin and metalloprotease with thrombospondin type factor 4. Blood. 2014;123(20):3166–74. 1 motif; CAS: contact activation system; DIC: disseminated intravascular 6. Morrissey JH. Polyphosphate: a link between platelets, coagulation and coagulation; FDPs: fibrin(ogen) degradation products; HDPs: host defence inflammation. Int J Hematol. 2012;95(4):346–52. peptides; HK: high molecular weight kallikrein; ISTH: International Society for 7. Nieuwland R, Berckmans RJ, McGregor S, et al. Cellular origin and pro- Thrombosis and Haemostasis; JAAM: Japanese Association for Acute Medicine; coagulant properties of microparticles in meningococcal sepsis. Blood. KAL: kallikrein; KKS: kallikrein/kinin system; MPO: myeloperoxidase; MPs: 2000;95(3):930–5. microparticles; NE: neutrophil elastase; NETs: neutrophil extracellular traps; PCI: 8. Delabranche X, Boisrame-Helms J, Asfar P, et al. Microparticles are new protein C inhibitor; Pg: plasminogen; polyP: polyphosphates; SK: streptokinase; biomarkers of septic shock-induced disseminated intravascular coagu- TAFI: thrombin-activatable fibrinolysis inhibitor; TMAs: thrombotic microangi- lopathy. Intensive Care Med. 2013;39(10):1695–703. opathies; UL-vWF: ultralarge von Willebrand factor. 9. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318–21. Authors’ contributions 10. Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in XD was the primary author responsible for literature search and review. XD, JH thrombosis-the journey of TF through NETs. Front Immunol. 2012;3:385. and FM were involved in the generation of the first version of the manuscript 11. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. and then in critical revision, editing and generation of revised manuscript. All 2014;20(4):195–203. authors read and approved the final manuscript. 12. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: inter- national guidelines for management of severe sepsis and septic shock: Authors’ information 2012. Crit Care Med. 2013;41(2):580–637. XD (MD, Ph.D.), consultant, JH (MD, Ph.D.), consultant and lecturer and FM (MD, 13. Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated Ph.D.), consultant, professor and head, all in critical care medicine—service disseminated intravascular coagulation: the view from Japan. J Thromb de réanimation médicale, Nouvel Hôpital Civil—Hôpitaux Universitaires de Haemost. 2014;12(7):1010–9. Strasbourg, Strasbourg (France). 14. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13(1):34–45. Author details 15. Claushuis TA, de Stoppelaar SF, Stroo I, et al. Thrombin contributes to Université de Strasbourg, Faculté de Médecine & Hôpitaux Universitaires de protective immunity in pneumonia-derived sepsis via fibrin polym- Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, France. erization and platelet-neutrophil interactions. J Thromb Haemost. INSERM (French National Institute of Health and Medical Research), UMR 2017;15(4):744–57. 1260, Regenerative Nanomedicine (RNM), FMTS, Université de Strasbourg, 16. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. Strasbourg, France. INSERM, EFS Grand Est, BPPS UMR-S 949, Université de 2013;369(9):840–51. Strasbourg, Strasbourg, France. 17. van der Poll T, Herwald H. The coagulation system and its function in early immune defense. Thromb Haemost. 2014;112(4):640–8. Acknowledgements 18. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of dissemi- We want to thank Asaël BERGER (MD) for literature search. nated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014;2(1):15. Competing interests 19. Gando S, Wada H, Thachil J. Scientific and Standardization Committee The authors declare that they have no competing interests. on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) Availability of data and materials with the fibrinolytic phenotype from coagulopathy of trauma and Not applicable for this review. acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013;11(5):826–35. Consent for publication 20. Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic Not applicable for this review. disseminated intravascular coagulation in trauma and traumatic shock. Crit Care. 2015;19:72. Ethics approval and consent to participate 21. Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one Not applicable for this review. way? Crit Care Med. 2012;40(9):2704–8. 22. Levi M. The coagulant response in sepsis and inflammation. Hamosta- Funding seologie 2010; 30(1): 10–2, 4–6. No funding was obtained for the creation of this review. 23. Levi M, van der Poll T. Endothelial injury in sepsis. Intensive Care Med. 2013;39(10):1839–42. Publisher’s Note 24. Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in Springer Nature remains neutral with regard to jurisdictional claims in pub- hemostasis. Physiol Rev. 2013;93(1):327–58. lished maps and institutional affiliations. 25. Krem MM, Rose T, Di Cera E. Sequence determinants of function and evolution in serine proteases. Trends Cardiovasc Med. 2000;10(4):171–6. Received: 12 May 2017 Accepted: 20 November 2017 26. Davidson CJ, Tuddenham EG, McVey JH. 450 million years of hemosta- sis. J Thromb Haemost. 2003;1(7):1487–94. 27. Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD. Interactions between coagulation and complement–their role in inflammation. References Semin Immunopathol. 2012;34(1):151–65. 1. Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood. 28. Berends ET, Kuipers A, Ravesloot MM, Urbanus RT, Rooijakkers SH. 2005;106(8):2605–12. Bacteria under stress by complement and coagulation. FEMS Microbiol 2. Schmaier AH. The contact activation and kallikrein/kinin systems: Rev. 2014;38(6):1146–71. pathophysiologic and physiologic activities. J Thromb Haemost. 29. White GC 2nd. The partial thromboplastin time: defining an era in 2016;14(1):28–39. coagulation. J Thromb Haemost. 2003;1(11):2267–70. 3. Long AT, Kenne E, Jung R, Fuchs TA, Renne T. Contact system revisited: 30. Evans CE, Zhao YY. Impact of thrombosis on pulmonary endothelial an interface between inflammation, coagulation, and innate immunity. injury and repair following sepsis. Am J Physiol Lung Cell Mol Physiol. J Thromb Haemost. 2016;14(3):427–37. 2017;312(4):L441–51. 4. Lerolle N, Carlotti A, Melican K, et al. Assessment of the interplay 31. Frick IM, Bjorck L, Herwald H. The dual role of the contact system in between blood and skin vascular abnormalities in adult purpura fulmi- bacterial infectious disease. Thromb Haemost. 2007;98(3):497–502. nans. Am J Respir Crit Care Med. 2013;188(6):684–92. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 12 of 14 32. Brown MR, Kornberg A. Inorganic polyphosphate in the origin and 58. Kastrup CJ, Boedicker JQ, Pomerantsev AP, et al. Spatial localization of survival of species. Proc Natl Acad Sci USA. 2004;101(46):16085–7. bacteria controls coagulation of human blood by ‘quorum acting’. Nat 33. Kornberg A, Rao NN, Ault-Riche D. Inorganic polyphosphate: a mol- Chem Biol. 2008;4(12):742–50. ecule of many functions. Annu Rev Biochem. 1999;68:89–125. 59. Sun H, Wang X, Degen JL, Ginsburg D. Reduced thrombin generation 34. Smith SA, Choi SH, Davis-Harrison R, et al. Polyphosphate exerts dif- increases host susceptibility to group A streptococcal infection. Blood. ferential effects on blood clotting, depending on polymer size. Blood. 2009;113(6):1358–64. 2010;116(20):4353–9. 60. Rivera J, Vannakambadi G, Hook M, Speziale P. Fibrinogen-binding pro- 35. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis teins of Gram-positive bacteria. Thromb Haemost. 2007;98(3):503–11. and organ dysfunction. Thromb Res. 2012;129(3):290–5. 61. Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and 36. Mitchell JL, Lionikiene AS, Georgiev G, et al. Polyphosphate colocalizes host defense. J Thromb Haemost. 2007;5(Suppl 1):24–31. with factor XII on platelet-bound fibrin and augments its plasminogen 62. Brissette CA, Haupt K, Barthel D, et al. Borrelia burgdorferi infection- activator activity. Blood. 2016;128(24):2834–45. associated surface proteins ErpP, ErpA, and ErpC bind human plasmino- 37. Maas C. Polyphosphate strikes back. Blood. 2016;128(24):2754–6. gen. Infect Immun. 2009;77(1):300–6. 38. Verhoef JJ, Barendrecht AD, Nickel KF, et al. Polyphosphate nanopar- 63. Barthel D, Singh B, Riesbeck K, Zipfel PF. Haemophilus influenzae uses ticles on the platelet surface trigger contact system activation. Blood. the surface protein E to acquire human plasminogen and to evade 2017;129(12):1707–17. innate immunity. J Immunol. 2012;188(1):379–85. 39. Weitz JI, Fredenburgh JC. Platelet polyphosphate: the long and the 64. Pancholi V, Fischetti VA. alpha-enolase, a novel strong plasmin(ogen) short of it. Blood. 2017;129(12):1574–5. binding protein on the surface of pathogenic streptococci. J Biol Chem. 40. Whyte CS, Chernysh IN, Domingues MM, et al. Polyphosphate delays 1998;273(23):14503–15. fibrin polymerisation and alters the mechanical properties of the fibrin 65. Bergmann S, Rohde M, Chhatwal GS, Hammerschmidt S. Alpha-enolase network. Thromb Haemost. 2016;116(5):897–903. of Streptococcus pneumoniae is a plasmin(ogen)-binding protein dis- 41. Mocsai A. Diverse novel functions of neutrophils in immunity, inflam- played on the bacterial cell surface. Mol Microbiol. 2001;40(6):1273–87. mation, and beyond. J Exp Med. 2013;210(7):1283–99. 66. Chung MC, Tonry JH, Narayanan A, et al. Bacillus anthracis interacts with 42. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutro- plasmin(ogen) to evade C3b-dependent innate immunity. PLoS ONE. phil function: from mechanisms to disease. Annu Rev Immunol. 2011;6(3):0018119. 2012;30:459–89. 67. Floden AM, Watt JA, Brissette CA. Borrelia burgdorferi enolase is a 43. Stiel L, Meziani F, Helms J. Neutrophil activation during septic shock. surface-exposed plasminogen binding protein. PLoS ONE. 2011;6(11):8. Shock. 2017. https://doi.org/10.1097/SHK.0000000000000980. 68. Bisno AL, Brito MO, Collins CM. Molecular basis of group A streptococ- 44. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular cal virulence. Lancet Infect Dis. 2003;3(4):191–200. traps kill bacteria. Science. 2004;303(5663):1532–5. 69. Verhamme IM, Panizzi PR, Bock PE. Pathogen activators of plasminogen. 45. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to J Thromb Haemost. 2015;13(1):12939. neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41. 70. Wiles KG, Panizzi P, Kroh HK, Bock PE. Skizzle is a novel plasminogen- 46. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil and plasmin-binding protein from Streptococcus agalactiae that elastase and myeloperoxidase regulate the formation of neutrophil targets proteins of human fibrinolysis to promote plasmin generation. J extracellular traps. J Cell Biol. 2010;191(3):677–91. Biol Chem. 2010;285(27):21153–64. 47. Pilsczek FH, Salina D, Poon KK, et al. A novel mechanism of rapid nuclear 71. Stathopoulos C. Structural features, physiological roles, and biotechno- neutrophil extracellular trap formation in response to Staphylococcus logical applications of the membrane proteases of the OmpT bacterial aureus. J Immunol. 2010;185(12):7413–25. endopeptidase family: a micro-review. Membr Cell Biol. 1998;12(1):1–8. 48. Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat 72. Haiko J, Suomalainen M, Ojala T, Lahteenmaki K, Korhonen TK. Invited Med. 2011;17(11):1381–90. review: breaking barriers—attack on innate immune defences by 49. Noubouossie DF, Whelihan MF, Yu YB, et al. In vitro activation of omptin surface proteases of enterobacterial pathogens. Innate Immun. coagulation by human neutrophil DNA and histone proteins but not 2009;15(2):67–80. neutrophil extracellular traps. Blood. 2017;129(8):1021–9. 73. Korhonen TK, Haiko J, Laakkonen L, Jarvinen HM, Westerlund-Wikstrom 50. Abrams ST, Zhang N, Dart C, et al. Human CRP defends against the B. Fibrinolytic and coagulative activities of Yersinia pestis. Front Cell toxicity of circulating histones. J Immunol. 2013;191(5):2495–502. Infect Microbiol. 2013;3:35. 51. Smeesters PR, McMillan DJ, Sriprakash KS. The streptococcal M protein: 74. Korhonen TK. Fibrinolytic and procoagulant activities of Yersinia pestis a highly versatile molecule. Trends Microbiol. 2010;18(6):275–82. and Salmonella enterica. J Thromb Haemost. 2015;13(1):12932. 52. McAdow M, Missiakas DM, Schneewind O. Staphylococcus aureus 75. Ooe A, Kida M, Yamazaki T, et al. Common mutation of plasminogen secretes coagulase and von Willebrand factor binding protein to detected in three Asian populations by an amplification refractory modify the coagulation cascade and establish host infections. J Innate mutation system and rapid automated capillary electrophoresis. Immun. 2012;4(2):141–8. Thromb Haemost. 1999;82(4):1342–6. 53. Thomer L, Schneewind O, Missiakas D. Multiple ligands of von Wille- 76. Thomassin JL, Brannon JR, Gibbs BF, Gruenheid S, Le Moual H. OmpT brand factor-binding protein (vWbp) promote Staphylococcus aureus outer membrane proteases of enterohemorrhagic and enteropatho- clot formation in human plasma. J Biol Chem. 2013;288(39):28283–92. genic Escherichia coli contribute differently to the degradation of 54. Fitzgerald JR, Loughman A, Keane F, et al. Fibronectin-binding proteins human LL-37. Infect Immun. 2012;80(2):483–92. of Staphylococcus aureus mediate activation of human platelets via 77. Bengtson SH, Sanden C, Morgelin M, et al. Activation of TAFI on the fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG bind- surface of Streptococcus pyogenes evokes inflammatory reac- ing to the FcγRIIa receptor. Mol Microbiol. 2006;59(1):212–30. tions by modulating the kallikrein/kinin system. J Innate Immun. 55. Imamura T, Tanase S, Szmyd G, Kozik A, Travis J, Potempa J. Induction 2009;1(1):18–28. of vascular leakage through release of bradykinin and a novel kinin 78. Mook-Kanamori BB, Valls Seron M, Geldhoff M, et al. Thrombin- by cysteine proteinases from Staphylococcus aureus. J Exp Med. activatable fibrinolysis inhibitor influences disease severity in humans 2005;201(10):1669–76. and mice with pneumococcal meningitis. J Thromb Haemost. 56. Wollein Waldetoft K, Svensson L, Morgelin M, et al. Streptococcal sur- 2015;13(11):2076–86. face proteins activate the contact system and control its antibacterial 79. Akesson P, Herwald H, Rasmussen M, et al. Streptococcal inhibitor of activity. J Biol Chem. 2012;287(30):25010–8. complement-mediated lysis (SIC): an anti-inflammatory virulence deter - 57. Chung MC, Popova TG, Jorgensen SC, et al. Degradation of circulating minant. Microbiology. 2010;156(Pt 12):3660–8. von Willebrand factor and its regulator ADAMTS13 implicates secreted 80. Frick IM, Shannon O, Akesson P, et al. Antibacterial activity of the con- Bacillus anthracis metalloproteases in anthrax consumptive coagulopa- tact and complement systems is blocked by SIC, a protein secreted by thy. J Biol Chem. 2008;283(15):9531–42. Streptococcus pyogenes. J Biol Chem. 2011;286(2):1331–40. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 13 of 14 81. Itoh S, Yokoyama R, Kamoshida G, et al. Staphylococcal superantigen- 107. Rossi E, Sanz-Rodriguez F, Eleno N, et al. Endothelial endoglin is like protein 10 (SSL10) inhibits blood coagulation by binding to involved in inflammation: role in leukocyte adhesion and transmigra- prothrombin and factor Xa via their gamma-carboxyglutamic acid (Gla) tion. Blood. 2012;16:16. domain. J Biol Chem. 2013;288(30):21569–80. 108. Rossi E, Smadja DM, Boscolo E, et al. Endoglin regulates mural cell adhe- 82. Yount NY, Yeaman MR. Peptide antimicrobials: cell wall as a bacterial sion in the circulatory system. Cell Mol Life Sci. 2016;73(8):1715–39. target. Ann N Y Acad Sci. 2013;1277:127–38. 109. Ramma W, Ahmed A. Is inflammation the cause of pre-eclampsia? 83. Yount NY, Yeaman MR. Emerging themes and therapeutic prospects for Biochem Soc Trans. 2011;39(6):1619–27. anti-infective peptides. Annu Rev Pharmacol Toxicol. 2012;52:337–60. 110. Delabranche X, Quenot JP, Lavigne T, et al. Early detection of dis- 84. Kasetty G, Papareddy P, Kalle M, et al. The C-terminal sequence of sev- seminated intravascular coagulation during septic shock: a multicentre eral human serine proteases encodes host defense functions. J Innate prospective study. Crit Care Med. 2016;17:17. Immun. 2011;3(5):471–82. 111. Guitton C, Gerard N, Sebille V, et al. Early rise in circulating endothelial 85. Papareddy P, Rydengard V, Pasupuleti M, et al. Proteolysis of human protein C receptor correlates with poor outcome in severe sepsis. thrombin generates novel host defense peptides. PLoS Pathog. Intensive Care Med. 2011;37(6):950–6. 2010;6(4):1000857. 112. Perez-Casal M, Downey C, Fukudome K, Marx G, Toh CH. Activated 86. Kalle M, Papareddy P, Kasetty G, et al. Host defense peptides of throm- protein C induces the release of microparticle-associated endothelial bin modulate inflammation and coagulation in endotoxin-mediated protein C receptor. Blood. 2005;105(4):1515–22. shock and Pseudomonas aeruginosa sepsis. PLoS ONE. 2012;7(12):13. 113. Perez-Casal M, Thompson V, Downey C, et al. The clinical and functional 87. Kalle M, Papareddy P, Kasetty G, et al. Proteolytic activation trans- relevance of microparticles induced by activated protein C treatment in forms heparin cofactor II into a host defense molecule. J Immunol. sepsis. Crit Care. 2011;15(4):R195. 2013;190(12):6303–10. 114. Osterud B. Tissue factor expression in blood cells. Thromb Res. 88. Kalle M, Papareddy P, Kasetty G, et al. A peptide of heparin cofactor II 2010;125(1):10. inhibits endotoxin-mediated shock and invasive Pseudomonas aerugi- 115. Stakos DA, Kambas K, Konstantinidis T, et al. Expression of functional nosa infection. PLoS ONE. 2014;9(7):e102577. tissue factor by neutrophil extracellular traps in culprit artery of acute 89. Papareddy P, Kalle M, Bhongir RK, Morgelin M, Malmsten M, myocardial infarction. Eur Heart J. 2015;36(22):1405–14. Schmidtchen A. Antimicrobial effects of helix D-derived peptides of 116. Gould TJ, Lysov Z, Liaw PC. Extracellular DNA and histones: dou- human antithrombin III. J Biol Chem. 2014;289(43):29790–800. ble-edged swords in immunothrombosis. JJ Thromb Haemost. 90. Malmstrom E, Morgelin M, Malmsten M, et al. Protein C inhibitor–a 2015;13(Suppl 1):S82–91. novel antimicrobial agent. PLoS Pathog. 2009;5(12):18. 117. Delabranche X, Stiel L, Severac F, et al. Evidence of netosis in septic 91. Rieger D, Assinger A, Einfinger K, Sokolikova B, Geiger M. Protein C shock-induced disseminated intravascular coagulation. Shock. inhibitor (PCI) binds to phosphatidylserine exposing cells with implica- 2017;47(3):313–7. tions in the phagocytosis of apoptotic cells and activated platelets. 118. Stiel L, Delabranche X, Galoisy AC, et al. Neutrophil fluorescence: a new PLoS ONE. 2014;9(7):e101794. indicator of cell activation during septic shock-induced disseminated 92. Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. intravascular coagulation. Crit Care Med. 2016;44(11):e1132–6. Findings in 346 patients. Thromb Haemost. 1980;43(1):28–33. 119. Lesesve JF, Martin M, Banasiak C, et al. Schistocytes in disseminated 93. Dutt T, Toh CH. The Yin-Yang of thrombin and activated protein C. Br J intravascular coagulation. Int J Lab Hematol. 2014;36(4):439–43. Haematol. 2008;140(5):505–15. 120. Pfitzner SA, Dempfle CE, Matsuda M, Heene DL. Fibrin detected in 94. Wada H, Thachil J, Di Nisio M, et al. Guidance for diagnosis and treat- plasma of patients with disseminated intravascular coagulation by ment of DIC from harmonization of the recommendations from three fibrin-specific antibodies consists primarily of high molecular weight guidelines. J Thromb Haemost. 2013;4(10):12155. factor XIIIa-crosslinked and plasmin-modified complexes partially 95. Warkentin TE. Ischemic Limb Gangrene with Pulses. N Engl J Med. containing fibrinopeptide A. Thromb Haemost. 1997;78(3):1069–78. 2015;373(7):642–55. 121. Cauchie P, Cauchie C, Boudjeltia KZ, et al. Diagnosis and prognosis of 96. Lipsker D. Ischemic limb gangrene with pulses [Correspondance]. N overt disseminated intravascular coagulation in a general hospital— Engl J Med. 2015;373(24):2385–6. meaning of the ISTH score system, fibrin monomers, and lipoprotein-C- 97. Shapiro NI, Schuetz P, Yano K, et al. The association of endothelial cell reactive protein complex formation. Am J Hematol. 2006;81(6):414–9. signaling, severity of illness, and organ dysfunction in sepsis. Crit Care. 122. Dickneite G, Czech J, Keuper H. Formation of fibrin monomers in experi- 2010;14(5):R182. mental disseminated intravascular coagulation and its inhibition by 98. Ono T, Mimuro J, Madoiwa S, et al. Severe secondary deficiency of recombinant hirudin. Circ Shock. 1994;42(4):183–9. von Willebrand factor-cleaving protease (ADAMTS13) in patients with 123. Gris JC, Faillie JL, Cochery-Nouvellon E, Lissalde-Lavigne G, Lefrant JY. sepsis-induced disseminated intravascular coagulation: its correlation ISTH overt disseminated intravascular coagulation score in patients with development of renal failure. Blood. 2006;107(2):528–34. with septic shock: automated immunoturbidimetric soluble fibrin assay 99. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N vs. D-dimer assay. J Thromb Haemost. 2011;9(6):1252–5. Engl J Med. 2014;371(7):654–66. 124. Gris JC, Bouvier S, Cochery-Nouvellon E, Faillie JL, Lissalde-Lavigne 100. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. G, Lefrant JY. Fibrin-related markers in patients with septic shock: 2014;370(9):847–59. individual comparison of D-dimers and fibrin monomers impacts on 101. Warkentin TE, Pai M. Shock, acute disseminated intravascular coagula- prognosis. Thromb Haemost. 2011;106(6):1228–30. tion, and microvascular thrombosis: is ‘shock liver’ the unrecog- 125. Greenberg CS, Devine DV, McCrae KM. Measurement of plasma fibrin nized provocateur of ischemic limb necrosis? J Thromb Haemost. D-dimer levels with the use of a monoclonal antibody coupled to latex 2016;14(2):231–5. beads. Am J Clin Pathol. 1987;87(1):94–100. 102. Delabranche X, Berger A, Boisrame-Helms J, Meziani F. Microparticles 126. Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE. Plasma D-dimer and infectious diseases. Med Mal Infect. 2012;42(8):335–43. levels and their relationship to serum fibrinogen/fibrin degradation 103. Meziani F, Delabranche X, Asfar P, Toti F. Bench-to-bedside review: circu- products in hypercoagulable states. Br J Haematol. 1989;71(1):65–70. lating microparticles—a new player in sepsis? Crit Care. 2010;14(5):236. 127. Carr JM, McKinney M, McDonagh J. Diagnosis of disseminated intravas- 104. Reid VL, Webster NR. Role of microparticles in sepsis. Br J Anaesth. cular coagulation. Role of D-dimer. Am J Clin Pathol. 1989;91(3):280–7. 2012;109(4):503–13. 128. Boisclair MD, Ireland H, Lane DA. Assessment of hypercoagulable states 105. Okajima K, Uchiba M, Murakami K, Okabe H, Takatsuki K. Plasma levels by measurement of activation fragments and peptides. Blood Rev. of soluble E-selectin in patients with disseminated intravascular coagu- 1990;4(1):25–40. lation. Am J Hematol. 1997;54(3):219–24. 129. Boisclair MD, Lane DA, Wilde JT, Ireland H, Preston FE, Ofosu FA. A 106. Koyama K, Madoiwa S, Nunomiya S, et al. Combination of thrombin- comparative evaluation of assays for markers of activated coagulation antithrombin complex, plasminogen activator inhibitor-1, and protein and/or fibrinolysis: thrombin-antithrombin complex, D-dimer and C activity for early identification of severe coagulopathy in initial phase fibrinogen/fibrin fragment E antigen. Br J Haematol. 1990;74(4):471–9. of sepsis: a prospective observational study. Crit Care. 2014;18(1):R13. Delabranche et al. Ann. Intensive Care (2017) 7:117 Page 14 of 14 130. Fourrier F, Jourdain M, Tournois A, Caron C, Goudemand J, Chopin C. 150. Stroo I, Zeerleder S, Ding C, et al. Coagulation factor XI improves host Coagulation inhibitor substitution during sepsis. Intensive Care Med. defence during murine pneumonia-derived sepsis independent of 1995;21(2):S264–8. factor XII activation. Thromb Haemost. 2017;117(8):1601–14. 131. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ 151. Nakamura M, Takeuchi T, Kawahara T, et al. Simultaneous targeting of failure, and disseminated intravascular coagulation. Compared pat- CD14 and factor XIa by a fusion protein consisting of an anti-CD14 anti- terns of antithrombin III, protein C, and protein S deficiencies. Chest. body and the modified second domain of bikunin improves survival in 1992;101(3):816–23. rabbit sepsis models. Eur J Pharmacol. 2017;802:60–8. 132. Gando S, Kameue T, Matsuda N, Hayakawa M, Hoshino H, Kato H. Serial 152. Thiery-Antier N, Binquet C, Vinault S, et al. Is thrombocytopenia an early changes in neutrophil-endothelial activation markers during the course prognostic marker in septic shock? Crit Care Med. 2016;44(4):764–72. of sepsis associated with disseminated intravascular coagulation. 153. Tsirigotis P, Chondropoulos S, Frantzeskaki F, et al. Thrombocytopenia Thromb Res. 2005;116(2):91–100. in critically ill patients with severe sepsis/septic shock: prognostic 133. Hans GA, Besser MW. The place of viscoelastic testing in clinical prac- value and association with a distinct serum cytokine profile. J Crit Care. tice. Br J Haematol. 2016;173(1):37–48. 2016;32:9–15. 134. Brenner T, Schmidt K, Delang M, et al. Viscoelastic and aggregomet- 154. Falcone M, Russo A, Farcomeni A, et al. Septic shock from community- ric point-of-care testing in patients with septic shock—cross-links onset pneumonia: is there a role for aspirin plus macrolides combina- between inflammation and haemostasis. Acta Anaesthesiol Scand. tion? Intensive Care Med. 2016;42(2):301–2. 2012;56(10):1277–90. 155. Falcone M, Russo A, Cangemi R, et al. Lower mortality rate in elderly 135. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin patients with community-onset pneumonia on treatment with aspirin. (recombinant tissue factor pathway inhibitor) in severe sepsis: a rand- J Am Heart Assoc. 2015;4(1):e001595. omized controlled trial. JAMA. 2003;290(2):238–47. 156. Valerio-Rojas JC, Jaffer IJ, Kor DJ, Gajic O, Cartin-Ceba R. Outcomes of 136. Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient. High- severe sepsis and septic shock patients on chronic antiplatelet treat- dose antithrombin III in severe sepsis: a randomized controlled trial. ment: a historical cohort study. Crit Care Res Pract. 2013;2013:782573. JAMA. 2001;286(15):1869–78. 157. Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH. Inhibi- 137. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in tion of polyphosphate as a novel strategy for preventing thrombosis adults with septic shock. N Engl J Med. 2012;366(22):2055–64. and inflammation. Blood. 2012;120(26):5103–10. 138. Meziani F, Vincent JL, Gando S. Should all patients with sepsis receive 158. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey anticoagulation? Yes. Intensive Care Med. 2017;43:452–4. JH. Nontoxic polyphosphate inhibitors reduce thrombosis while spar- 139. van der Poll T, Opal SM. Should all septic patients be given systemic ing hemostasis. Blood. 2014;124(22):3183–90. anticoagulation? No. Intensive Care Med. 2017;43(3):455–7. 159. Heemskerk S, Masereeuw R, Moesker O, et al. Alkaline phosphatase 140. Kenne E, Renne T. Factor XII: a drug target for safe interference with treatment improves renal function in severe sepsis or septic shock thrombosis and inflammation. Drug Discov Today. 2014;19(9):1459–64. patients. Critical care medicine. 2009;37(2):417–23. 141. Chen Z, Seiffert D, Hawes B. Inhibition of Factor XI activity as a promis- 160. Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for ing antithrombotic strategy. Drug Discov Today. 2014;19(9):1435–9. treatment of sepsis-induced acute kidney injury: a prospective rand- 142. Labberton L, Kenne E, Renne T. New agents for thromboprotec- omized double-blind placebo-controlled trial. Crit Care. 2012;16(1):R14. tion. A role for factor XII and XIIa inhibition. Hamostaseologie. 161. Su F, Brands R, Wang Z, et al. Beneficial effects of alkaline phosphatase 2015;35(4):338–50. in septic shock. Crit Care Med. 2006;34(8):2182–7. 143. Caliezi C, Zeerleder S, Redondo M, et al. C1-inhibitor in patients with 162. Tunjungputri RN, Peters E, van der Ven A, de Groot PG, de Mast Q, severe sepsis and septic shock: beneficial effect on renal dysfunction. Pickkers P. Human recombinant alkaline phosphatase inhibits ex vivo Crit Care Med. 2002;30(8):1722–8. platelet activation in humans. Thromb Haemost. 2016;116(6):1111–21. 144. Zeerleder S, Caliezi C, van Mierlo G, et al. Administration of C1 inhibitor 163. Lee S, Ku SK, Bae JS. Anti-inflammatory effects of dabrafenib on reduces neutrophil activation in patients with sepsis. Clin Diag Lab polyphosphate-mediated vascular disruption. Chem Biol Interact. Immunol. 2003;10(4):529–35. 2016;256:266–73. 145. Igonin AA, Protsenko DN, Galstyan GM, et al. C1-esterase inhibitor 164. Brill A, Fuchs TA, Savchenko AS, et al. Neutrophil extracellular traps infusion increases survival rates for patients with sepsis. Crit Care Med. promote deep vein thrombosis in mice. Journal of thrombosis and 2012;40(3):770–7. haemostasis: JTH. 2012;10(1):136–44. 146. Barratt-Due A, Johansen HT, Sokolov A, et al. The role of bradykinin and 165. Mai SH, Khan M, Dwivedi DJ, et al. Delayed but not early treatment with the effect of the bradykinin receptor antagonist icatibant in porcine DNase reduces organ damage and improves outcome in a murine sepsis. Shock. 2011;36(5):517–23. model of sepsis. Shock. 2015;44(2):166–72. 147. Pixley RA, De La Cadena R, Page JD, et al. The contact system contrib- 166. McDonald B, Davis RP, Kim SJ, et al. Platelets and neutrophil extracellular utes to hypotension but not disseminated intravascular coagulation in traps collaborate to promote intravascular coagulation during sepsis in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody mice. Blood. 2017;129(10):1357–67. to block contact activation in baboons. J Clin Invest. 1993;91(1):61–8. 167. Laukova L, Konecna B, Babickova J, et al. Exogenous deoxyribonuclease 148. Worm M, Kohler EC, Panda R, et al. The factor XIIa blocking antibody has a protective effect in a mouse model of sepsis. Biomed Pharmaco - 3F7: a safe anticoagulant with anti-inflammatory activities. Ann Transl ther. 2017;93:8–16. Med. 2015;3(17):2305–5839. 168. Chrysanthopoulou A, Kambas K, Stakos D, et al. Interferon lambda1/ 149. Tucker EI, Verbout NG, Leung PY, et al. Inhibition of factor XI activa- IL-29 and inorganic polyphosphate are novel regulators of neutrophil- tion attenuates inflammation and coagulopathy while improving the driven thromboinflammation. J Pathol. 2017;243(1):111–22. survival of mouse polymicrobial sepsis. Blood. 2012;119(20):4762–8.

Journal

Annals of Intensive Care – Springer Journals

Published: Dec 2, 2017

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