Title: bloodBLD2020007208C.pdf

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Markdown Content:

Review Series THE INTERSECTION OF THE IMMUNE AND HEMOSTATIC SYSTEMS

Disseminated intravascular coagulation and its immune mechanisms

Narcis I. Popescu, 1 Cristina Lupu, 2 and Florea Lupu 2-5 1 Arthritis and Clinical Immunology Research and 2 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and 3 Department of Cell Biology, 4 Department of Pathology, and 5 Department of Internal Medicine, Oklahoma University Health Sciences Center, Oklahoma City, OK

Disseminated intravascular coagulation (DIC) is asyndrome triggered by infectious and noninfectious pathologies characterized by excessive generation of thrombin within the vasculature and widespread proteolytic conversion of fi brinogen. Despite diverse clinical manifestations ranging from thrombo-occlusive damage to bleeding diathesis, DIC etiology commonly involves excessive activation of blood coagulation and overlapping dysregulation of anticoagulants and

fi brinolysis. Initiation of blood coagulation follows intravascular expression of tissue factor or activation of the contact pathway in response to pathogen-associated or host-derived, damage-associated molecular patterns. The process is further ampli fi ed through in fl ammatory and immunothrombotic mechanisms. Consumption of anticoagulants and disruption of endothelial homeostasis lower the regulatory control and disseminate microvascular thrombosis. Clinical DIC development in patients is associated with worsening morbidities and increased mortality, regardless of the underlying pathology; therefore, timely recognition of DIC is critical for reducing the pathologic burden. Due to the diversity of triggers and pathogenic mechanisms leading to DIC, diagnosis is based on algorithms that quantify hemostatic imbalance, thrombocytopenia, and fi brinogen conversion. Because current diagnosis primarily assesses overt consumptive coagulopathies, there is a critical need for better recognition of nonovert DIC and/or pre-DIC states. Therapeutic strategies for patients with DIC involve resolution of the eliciting triggers and supportive care for the hemostatic imbalance. Despite medical care, mortality in patients with DIC remains high, and new strategies, tailored to the underlying pathologic mechanisms, are needed.

Introduction

Disseminated intravascular coagulation (DIC) is a life-threatening thrombohemorrhagic condition triggered by infectious and non-infectious causes. According to the International Society for Thrombosis and Hemostasis (ISTH), 1 DIC is an acquired syn-drome characterized by systemic activation of coagulation within the vasculature leading to microvascular damage and organ dys-function. The de fi nition emphasizes that DIC originates, devel-ops within, and affects the microvasculature and is not restricted to the site of insult, but spreads throughout the body.

Etiology

DIC is a complication of many disorders, such as severe systemic infections, malignancy, trauma, obstetrical complications, vascular malformations, severe immunological reactions, and heat stroke. Despite a heterogenous clinical presentation ranging from asymp-tomatic, to mild, to overwhelming thrombosis or bleeding, at its core, DIC follows exposure to or production of procoagulants insuf fi ciently balanced by endogenous anticoagulant and fi brino-lytic mechanisms. The excessive activation of thrombin, evidenced by elevated thrombin-antithrombin complexes or prothrombin activation fragments in the circulation, leads to proteolytic fi brino-gen conversion and intravascular formation of fi brin. If usage of clotting factors exceeds the synthetic hepatic output, a consump-tive coagulopathy develops that, in conjunction with thrombocy-topenia, predicts an elevated risk of bleeding. Intravascular fi brin is counterbalanced by plasmin-mediated fi brinolysis leading to increased fi brin degradation products ( D-dimers) in the circulation. When fi brinolysis cannot compensate for the excessive coagulop-athy, obstructive microthrombi formation may lead to hypoperfu-sion and hypoxia of peripheral organs.

Clinical features

Signs and symptoms of DIC include bleeding, bruising, low blood pressure, shortness of breath, and confusion. Clinical manifesta-tions comprise (1) microvascular thrombosis that leads to exten-sive organ dysfunction, gangrenes, acute kidney injury, and sometimes pulmonary and cerebral thrombosis; (2) bleeding such as petechiae, ecchymoses and necrotizing purpura in the skin; bleeding from vascular access sites; and mucosal bleeding into

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the gastrointestinal tract, pulmonary alveolae, adrenals, and cen-tral nervous system; and (3) shock due to blood loss, impaired endothelial permeability, and/or decreased vascular tone. Microvascular thrombosis and bleeding are the major causes of multiple organ failures, with lungs and kidneys being predomi-nantly sensitive to coagulopathic dysfunction. Pulmonary throm-bosis impairs gas exchanges, leading to hypoxemia, and damages the alveolar blood-air barrier, resulting in fl ooding of the alveolae with plasma (edema) and blood cells (hemor-rhages), which contribute to acute respiratory distress syndrome. Likewise, glomerular and peritubular microthrombosis causes hypoperfusion and subsequent ischemia-reperfusion damage, impairs urinary fi ltration, and induces acute kidney injury.

Epidemiology

The incidence of DIC is variable according to geographic loca-tion, clinical setting, underlying condition, and diagnostic crite-ria. 2 DIC incidence in various medical conditions is depicted in Figure 1. Mortality rates range from 31% to 86% despite sup-portive therapy, and are always higher than in patients without DIC. The presence of DIC is the strongest predictor of death within 28 days in patients with sepsis. 2

Diagnosis

Considering the multitude of causative factors, DIC diagnosis is always made in the context of the clinical presentation. Cur-rently, DIC cannot be diagnosed by any single laboratory test, and combinations of clinical biomarkers are used instead. Global coagulation tests, such as activated partial thromboplastin time and prothrombin time (PT) are routinely used in patients with sepsis to assess the consumptive coagulopathy. Although not yet validated for diagnostic use, viscoelastic point-of-care testing allows for rapid and concomitant monitoring of both coagulation and fi brinolysis in patients 3 treated for trauma and, in pilot stud-ies, 4 distinguished between critically ill patients with DIC and patients without DIC. Three diagnostic algorithms for DIC have been developed, 2 in Japan and 1 by the ISTH Standardization Committee. 5 The ISTH diagnostic score for overt DIC (Table 1) is calculated based on platelet count, PT, fi brinogen level, and fi brinogen/ fi brin degra-dation peptides ( D-dimer) in conjunction with clinical considera-tions. 1 A score of 5 or more indicates overt DIC. A simpler DIC score calculated in the fi rst 48 hours using platelet counts and PT could re fl ect the severity of the underlying disorder. 6There have been attempts to establish scoring algorithms to detect early (nonovert, compensated) DIC before it reaches a full-blown, frequently irreversible stage. 1,7 Biomarkers of throm-bin generation (TAT and prothrombin fragment-1 and -2), fi bri-nolysis activation (plasmin-antiplasmin and D-dimer), and suppression (plasminogen activator inhibitor 1 [PAI1]; tissue plas-minogen activator [t-PA]-PAI-1 complexes) are used to assess early stages of DIC, as well as its severity and progression. Mea-surement of damage-associated molecular patterns (DAMPs), such as high-mobility group box-1, nucleosomes, extracellular histones, and cell-free DNA, in correlation with scores of organ function (Sequential Organ Failure Assessment and Multiple Organ Dysfunction Score) and severity of disease (Acute Physiol-ogy and Chronic Health Evaluation II), could provide additional information, but their diagnostic and prognostic potential has not been demonstrated in large cohorts. Currently, the absence of algorithms with DIC prediction power greatly limits preventive therapeutic interventions.

Pathogenesis of DIC

As summarized in Figure 2, DIC pathophysiology is complex and multifactorial and involves overlapping host defense path-ways, such as uncontrolled activation of coagulation, platelets,

fi brinolysis, complement, innate immunity, and in fl ammation, within a dysfunctional microcirculation, characterized by wide-spread endotheliopathy.

Initiation of coagulation

Blood coagulation is primarily triggered by the exposure of tis-sue factor (TF) to coagulation factor (F) VII/VIIa 8 circulating in the plasma. In sepsis and likely other pathologies, activation of the contact pathway can also contribute to the initiation and

Cancers 26% Others 20% Obstretical complications 9% Liver diseases 5% Trauma and major surgeries 15% Infectious diseases 25%

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ampli fi cation of the coagulopathic and in fl ammatory responses. 9,10 TF is constitutively expressed outside vasculature where it forms a protective hemostatic envelope, but is normally repressed on vascular cells. Inducible TF expression in mono-cytes, 11,12 platelets, 13,14 granulocytes, 15,16 lymphocytes, 17 and endothelial cells 18,19 has been reported. Monocytes are consid-ered the primary source of intravascular TF in DIC, whereas TF transcription in other vascular cells has been challenged. 20 Multi-ple immune signaling networks promote intravascular TF expres-sion (Figure 3). During systemic infections, induction of monocyte TF is a primary immune response initiated by pattern recognition receptors (PRRs) binding pathogen-associated molecular patterns (PAMPs), 21-23 and/or host-derived DAMPs, 24,25 or by activating immunoglobulin Fc receptors. 26,27 PRR signaling supports over-lapping procoagulant and proin fl ammatory responses in human monocytes, 27 which augment TF expression. 27-30 Furthermore, intracellular immune sensors such as the in fl ammasome promote the release of TF from pyroptotic cells, 31 leading to the dissemi-nation of procoagulant triggers. Intravascular TF expression can be further ampli fi ed by thromboin fl ammatory signaling through protease-activated receptors (PARs), 32,33 complement media-tors, 34-36 P-selectin mediated leukocyte interactions, 37 and/or rec-ognition of DAMPs. 38-40 TF neutralization prevents thrombosis during experimental bacteremia 41 and viremia, 42,43 highlighting the critical role of TF-driven coagulation in DIC. In humans how-ever, the essential hemostatic function of TF may preclude the systemic use of neutralizing agents, as suggested by the increased bleeding and mortality observed in a sepsis trial of active site-inhibited FVIIa. 44 The hypercoagulant state in DIC is enhanced by dysregulation of endothelial homeostasis 45 and the anticoagulant networks that control the initiation, ampli fi cation, and termination of clot-ting reactions. Clotting initiation is controlled by TF pathway inhibitor (TFPI), a Kunitz type inhibitor primarily exposed on endothelium and to a lesser extent on platelets and mono-cytes. 20 In the presence of FXa, the quaternary TF-FVIIa-FXa-TFPI complex inhibits both FXa and FVIIa proteolytic activities. During the clinical course of DIC, cell-associated TFPI is cleaved by proteases, 46-48 leading to a progressive increase in plasma TFPI, 49 mostly truncated and devoid of anticoagulant activity. Lower active TFPI 46 and accumulation of TF on at risk endo-thelial surfaces, such as branching sites, sustain procoagulant environments in septic nonhuman primates. 19 Although adminis-tration of recombinant TFPI reduced DIC and mortality in experi-mental Gram-negative (G 2) sepsis, 50 TFPI supplementation in humans did not improve survival and exacerbated bleeding. 51 Serpins-like C1 inhibitor and antithrombin control coagulation initiation via contact pathway by making inhibitory complexes with FXIIa and FXIa. 10,12,52,53 Both serpins are consumed during DIC. Supplementation of C1 inhibitor was bene fi cial in preclini-cal sepsis models, 54 whereas in humans, it reduced organ failure without improving survival. 55 More recently, antibody neutraliza-tion of FXIIa or FXIa, key proteases of the contact pathway, dampened PAMP-induced coagulopathy in baboons. 10,53 This therapeutic approach has yet to be tested in sepsis patients with DIC.

Amplification of coagulation

This phase is primarily regulated by antithrombin, the circulating serpin that inhibits all coagulation serine proteases. 56 The anti-coagulant function of antithrombin is highly enhanced by heparan-sulfate proteoglycans within the endothelial glycocalyx. Independent of its anticoagulant role, antithrombin-syndecan-4 interactions promote anti-in fl ammatory outcomes, 57-59 reduce production of TF and proin fl ammatory cytokines, 60 and prevent endothelial glycocalyx shedding. 61 In DIC, antithrombin levels are depressed because of coagulopathic consumption, possible vascular leakage, and lower hepatic output, whereas the activity is impaired by degradation of the endothelial glycocalyx. 45 Anti-thrombin levels below 70% associate with worsening pathology and increased mortality. 56 In clinical trials, antithrombin supple-mentation in patients with sepsis did not improve the overall outcome, but post hoc analysis showed bene fi ts for patients with DIC who were not concomitantly treated with heparin. 62 Consequently, antithrombin supplementation was approved for sepsis-associated DIC in Japan. 63 Terminal clotting reactions are downregulated by activated pro-tein C (APC) through proteolytic inactivation of FVa and FVIIIa. 64 APC anticoagulant function is enhanced by protein S and binding to anionic phospholipids where tenase and prothrombinase complexes also concentrate. 65 Activation of PC requires formation of thrombin-thrombomodulin (TM) complexes on the endothelial surface and is enhanced by the endothelial PC receptor (EPCR). 66 EPCR-bound APC has

Table 1. ISTH diagnostic algorithm for the diagnosis of overt DIC Parameter/result Score* Underlying disease

Yes; proceed

Platelet count

.100 310 9 /L 0

,100 310 9 /L but .50 310 9 /L 1

,50 310 9 /L 2

Prolonged PT

,3 s 0

.3 s but ,6 s 1

.6 s 2

Elevated fi brin-related marker (eg, soluble fi brin monomer/ fi brin degradation products)

No increase 0Moderate increase 2Strong increase 3

Fibrinogen level

.1.0 g/L 0

,1.0 g/L 1Adapted from Taylor et al. 1*If $5, compatible with overt DIC, repeat scoring daily; if ,5, suggestive (not af fi rmative) of nonovert DIC, repeat next in 1 to 2 d.

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cytoprotective anti-in fl ammatory and antiapoptotic effects and prevents vascular permeability through PAR signaling. 64 The PC-TM pathway is dysregulated in DIC because of shedding of TM and EPCR from endothelium 67 and consumption of plasma PC. 68-70 Unsurprisingly, TM and APC supplementation has been bene fi cial in some clinical studies. Similar to antithrombin, recombinant TM decreased mortality in patients with sepsis and DIC, 71 but not in patients without DIC. 63 APC has been

Shedding: TM, EPCR WBP secretion: P-selectin, vWF GIycocaIyx Barrier function t-PA Opsonins: C3b Anaphylatoxins: C3a, C5a, C4a Terminal complex: C5b-9 PAMPs Phosphatidylserine exposure Procoagulants TF, FXlla Anticoagulants TFPI, AT, PC Coagulation Platelets Fibrinolysis Complement Inflammation Activation Adhesion Aggregation DAMPS NETs Cytokines PAI-1 D-Dimer

2-antiplasmin DIC Endotheliopathy

Figure 2. Interactions of cellular and molecular components of host defense in the pathogenesis of DIC.

Figure 3. Initiation of coagulation in DIC. Pathogens, dead cells, and their derived molecular pattern molecules (PAMPs and DAMPs) can signal through PRRs to induce TF expression and microparticle release from monocytes, and to promote synthesis of proin fl ammatory cytokines that further amplify TF expression, thus initiating coagulation via the extrinsic pathway. In parallel, contact activation with FXIIa generation can occur on the surface of the pathogens, PAMPs, DAMPs, and cell debris. In particular, bacteria-derived long-chain polyphosphates (LC-poly-Ps) and platelet-derived short-chain polyphosphates (SC-poly-P), and the extracellular nucleic acids (DNA/RNA) can induce contact-mediated autoactivation of FXII and trigger coagulation via the intrinsic pathway. Both pathways converge into the common coagulation mechanism, leading to thrombin generation and downstream platelet activation and fi brin and thrombus formation.

1976 blood 31 MARCH 2022 | VOLUME 139, NUMBER 13 POPESCU et al

bene fi cial in sepsis, despite an enhanced risk of bleeding, 72 and the drug has been in clinical use for 10 years. A subse-quent large clinical trial that did not show a survival bene fi t73 led to retraction of APC from clinical use, despite the proven advantage for patients with severe coagulopathy. 74 More recently, APC variants, with decreased anticoagulant but pre-served anti-in fl ammatory function, reduced death in murine models of sepsis and ischemic stroke 64 and reduced hemor-rhagic events in patients who had a stroke. 75 It remains to be determined whether these APC variants can provide protection in DIC.

Inflammation-induced amplification of DIC

Pathologies with associated DIC usually exhibit systemic in fl am-mation with pleiotropic pathophysiological effects. 76 The cross talk between in fl ammation and hemostatic dysregulation has been extensively investigated, especially in sepsis. Proin fl amma-tory cytokines overexpressed in DIC, 77 such as tumor necrosis fac-tor (TNF), interleukin (IL)1 b, and IL6, are all procoagulant, 28,30,78 whereas the regulatory IL10 attenuates clotting. 79 Proin fl amma-tory cytokines also downregulate anticoagulant mechanisms, 80 support endotheliopathies, 81 and modulate fi brinolysis, 82,83 with a net prothrombotic effect in experimental sepsis models. In con-trast to preclinical models, neither TNF 84 nor IL1 85 inhibition reduced the incidence of DIC in sepsis trials. Similarly, IL6 block-ade did not improve the coagulopathy associated with COVID-19 in a large observational cohort. 86 In localized prothrombotic environments, PAR signaling can be initiated by coagulation proteases involved in the TF-dependent pathway and by APC. The outcomes of these thromboin fl amma-tory events are complex and depend on the repertoire of PARs, the occupancy of associated receptors such as EPCRs, the differ-ential engagement of adaptor molecules, and costimulation by in fl ammatory cytokines. The concept of a PAR interactome on vascular cells was proposed recently. 64 In general, thrombin sig-naling induces proin fl ammatory and procoagulant responses, 87 whereas APC promotes cytoprotective and anti-in fl ammatory outcomes. 64 Of interest for DIC, thrombin induces platelet degranulation and release of procoagulant and proin fl ammatory proteins like FV and P-selectin, 88 the latter being a potent leuko-cyte adhesion molecule and inducer of TF in monocytes. 89 Thrombin also promotes conformational activation of integrin

Increased endothelial permeability (via PAR1) Classical pathway

via antigen-antibody complexes

Lectin pathway

via MBL-MASP complexes

Alternative pathway

via spontaneous C3 hydrolysis

C4 C4b C4a C3a C5a C5b C3b Amplification Triggers Initiating pathways Opsono-phagocytosis Host cell lysis and bacteriolysis C3 C5 Neutrophils and monocytes recruitment Platelet activation Tissue factor expression and microparticle release

Monocytes Tissue factor decription C5b-9 Self-amplification loop AP-C3 convertase CL/LP-C3 convertase Pathogens PAMPs DAMPs NETs and cell debris

DIC AND ITS IMMUNE MECHANISMS blood 31 MARCH 2022 | VOLUME 139, NUMBER 13 1977

IIb/IIIa, which is essential for platelet aggregation, 90 exposure of anionic phospholipids that enhance clotting reactions, 91 and release of platelet polyphosphates, 92,93 which support contact coagulation reactions. On endothelium, thrombin triggers degranulation of Weibel-Palade bodies (WPBs) and release of P-selectin and von Willebrand factor, 94 induces expression of proin fl ammatory and cell adhesion molecules, and enhances vascular permeability. 95 Inhibition of throm-boin fl ammatory PAR1 signaling in clinical trials, albeit not DIC, reduced ischemic events but elevated the risk of bleed-ing. 96 Biased PAR1 modulators that prevent thrombin but not APC signaling reduced thrombosis in experimental models 97 and may prove bene fi cial in DIC as well.

Innate immune amplification of coagulopathy

DIC pathology is enhanced through immunothrombotic mechanisms that comprise primary immune responses that induce or enhance the hypercoagulant state. Excessive and/ or dysregulated complement activation and neutrophil extra-cellular traps (NETs) amplify the coagulopathy, including that in patients with COVID-19. 98 Complement is the innate pro-teolytic cascade tasked with recognition, extracellular killing, and clearance of invading pathogens or unprotected, dam-aged cells (Figure 4). Complement and coagulation pathways are closely linked through bidirectional cross talk, as detailed elsewhere. 99-101 Complement mediators with direct procoa-gulant effects include anaphylatoxins, opsonins, and inter-mediates of the terminal complement complex. In general, C3a and C5a anaphylatoxins promote in fl ammatory activation of vascular cells, whereas C4a may alter endothelial perme-ability through PARs. 102 C5a induces TF expression in endothelium, 103 monocytes, 35 and neutrophils, 34 whereas ter-minal complement complex intermediates promote TF decryption, 104,105 which is a procoagulant conformational change. Complement also activates platelets, 106 leading to aggregation, exposure of anionic phospholipids, degranula-tion, and release of prothrombotic factors. Furthermore, C5b-9 insertion into plasma membranes promotes shedding of prothrombotic microvesicles from vascular cells, 107,108 which disseminate the hypercoagulant state in DIC. 109 It comes as no surprise that complement inhibitors prevent DIC develop-ment in experimental sepsis models. 52,110 NETs are part of the innate immunity repertoire designed to trap and kill invading pathogens 111 (Figure 5). This process is aided by the generation of a local fi brin mesh 112 through activa-tion of clotting reactions, dysregulation of anticoagulant net-works and interaction with platelets and leukocytes. 113 NETs promote clotting through TF-dependent 98 and/or FXII-depen-dent 114 pathways, whereas anticoagulant depression is medi-ated by neutrophil proteases concentrated on NETs. 47,115 The cellular origin of TF accumulating on NETs is not always clear and may vary, depending on the underlying pathology. Expo-sure of P-selectin promotes NETosis, 116 induces TF transcription in monocytes, 37 and supports accumulation of TF 1 micropar-ticles in developing thrombi. 117 Thrombin generation is enhanced by cell-free DNA released from NETs, which amplify contact pathway reactions, 118 whereas histones induce platelet activation 119 and WPB exocytosis. 120 Not surprisingly, DNA breakdown 113,121 or histone neutralization 122,123 reduces the coagulopathy in experimental models. In interesting new devel-opments, histones can substitute FVa and form an alternative prothrombinase complex with FXa, 124 which escapes anticoagu-lant APC control. The elevated levels of circulating histones in patients with DIC 124 are thus likely contributors to pathology, and their neutralization should provide therapeutic bene fi ts.

1978 blood 31 MARCH 2022 | VOLUME 139, NUMBER 13 POPESCU et al

Fibrinolytic modulation of DIC

Intravascular fi brin initiates plasmin-mediated fi brinolysis and modulates phenotypic expression of DIC. Plasmin activation is controlled by the balanced expression of t-PA and its cognate regulator PAI-1. 125 Endothelial cells are the primary source of both t-PA and PAI-1, whose synthesis is modulated by in fl amma-tory mediators. Secretagogues such as thrombin, histamine, bra-dykinin, and TNF 82 trigger the acute release of t-PA from endothelium, which primes fi brinolysis, whereas delayed hyper-in fl ammatory cytokines such as IL6 induce PAI-1 83 expression and subsequent fi brinolytic suppression. Thrombin-stimulated platelets also release active PAI-1 126 and may augment the pro-thrombotic state in DIC. In sepsis, elevated PAI-1 levels correlate with coagulopathy, multiple organ failure, and mortality. 127 In contrast, lower PAI-1 expression 128 and/or its proteolytic inacti-vation 129 promote the hyper fi brinolytic phenotype associated with acute promyelocytic leukemia (APL). PAI-1 inhibition 130 or t-PA supplementation 131 attenuates thrombosis in experimental sepsis models and may be bene fi cial in cases of hypo fi brinolysis with extremely high levels of PAI-1. 132

DIC-associated pathologies

Clinical conditions with associated DIC include bacterial and viral infections and severe sterile organ damage/in fl ammation, such as in trauma, pancreatitis, cirrhosis, cancers, vascular abnormali-ties and vasculitis, heat stroke, and snake bites. 2 Cumulatively, infectious diseases, trauma, and malignant disorders account for more than two-thirds of DIC cases in North America and Europe. The pathological archetype in sepsis-associated DIC is overactive clotting with suppressed fi brinolysis leading to thrombo-occlusive organ damage. Consumption of clotting fac-tors increases the risk of bleeding in these patients. In DIC asso-ciated with trauma and obstetric calamities, severe consumption combines with abrupt hyper fi brinolysis, whereas APL and aortic aneurysms are usually associated with chronic increase of fi brino-lysis and primarily lead to bleeding complications (Figure 6).

DIC in infectious diseases

Infections leading to sepsis are among the most frequent medi-cal conditions that promote DIC. Sepsis is a life-threatening organ dysfunction syndrome caused by excessive and dysregu-lated host responses to microbial infection. 133 Sepsis-associated DIC is a major contributor to multiple organ failure and an inde-pendent predictor of mortality. 2,134

Bacterial infections Similar DIC incidences are observed in G2 and Gram-positive (G 1) infections. The pathogenesis of sep-sis in fl ammation, coagulopathy, and shock in G 2 bacteremia is driven by lipopolysaccharide (LPS), a speci fi c component of the G2 bacterial wall. LPS triggers TF expression in monocytes directly via CD14 - Toll-like receptor-4 (TLR4) signaling and indi-rectly via proin fl ammatory cytokines. Immunothrombotic ampli fi -cation by complement, 52,110 NETs, 47,113,121 and DAMPs 122,123 has been documented in preclinical models, but their contribu-tion to human pathology should be con fi rmed in clinical studies.

Infections, sepsis

DIC with thrombotic phenotype 2. DIC with fibrinolytic phenotype

Trauma, APL Anticoagulant mechanisms

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In G 1 bacteremia, proin fl ammatory and procoagulant monocyte responses are triggered by TLR2 interaction with acylated cell wall PAMPs 23 and/or by peptidoglycan 27 activation of intracellu-lar nucleotide-binding oligomerization domain sensors. Because of its polymeric structure, peptidoglycan also activates humoral proteolytic cascades, such as complement and the contact coagulation pathway, and impairs the anticoagulant function of antithrombin. 12 The hypercoagulant state is further ampli fi ed by the release of long-chain polyphosphates from inclusion bodies of both G 2 and G 1 bacteria. Polyphosphates can trigger the activation of FXII and downstream generation of thrombin and vasoactive bradykinin. 135 Attempting to subvert immune

Table 2. Bacteria-derived factors that modulate coagulation, fi brinolysis, and complement systems of the host Bacterial factor Bacteria species Host target Host effect

Staphylokinase Staphylococcus Plasminogen Activation of fi brinolysis Staphylocoagulase Staphylococcus Prothrombin Activation of coagulation via a nonproteolytic conformational change of prothrombin Clumping factors A and B (CLFA, CLFB)

Staphylococcus Fibrinogen and platelets Impairs pathogen clearance Extracellular fi brinogen binding (Efb) protein

Staphylococcus Fibrinogen, C3 Inhibits platelet aggregation, neutrophil binding to

fi brinogen and complement-mediated opsonization and phagocytosis Staphylococcal superantigen-like protein 10 (SSL10)

Staphylococcus Vitamin K dependent clotting factors Inhibits blood coagulation by targeting Gla domains of clotting factors Streptokinase Streptococcus Plasminogen Activation of fi brinolysis Streptococcal inhibitor of complement (SIC)

Streptococcus HK Inhibits complement and contact phase activation Surface collagen-like (Scl) proteins A and B Group A Streptococcus TAFI, thrombin and plasmin Promotes TAFI activation resulting in inhibition of

fi brinolysis Omptins G2 bacteria ( E coli , Salmonella

and Yersinia )TFPI Inhibit TFPI-mediated anticoagulation Phospholipases Multiple bacteria species GPI-anchored proteins Cleaves cell surface associated, GPI-anchored proteins (TFPI, uPAR, CD55, and CD59), thus decreasing anticoagulant, pro fi brinolytic, and anti-complement functions Glycosidases (hyaluronidases, sialidases, heparinases, chrondroitinases) Multiple bacteria species Hyaluronans, sialic acid, heparin/ heparan sulfate, and chondroitin sulfate residues Degradation of the glycocalyx leading to decreased anticoagulant activity and impaired cytoprotection against histone-induced toxicity DNAse Multiple bacterial species NETs, cell-free DNA Degradation of prothrombotic DNA and NETs Polyphosphates Multiple bacterial species FXII Trigger activation of contact pathway LPS G2 bacteria CD14-TLR4 signaling; complement and contact pathway Triggers production of proin fl ammatory cytokines, TF, and PAI-1 and activation of contact and alternative complement pathways Peptidoglycan G1 bacteria FcR, NOD and in fl ammasome signaling; complement and contact activation pathways; inhibits antithrombin Induces expression of cytokines and TF and the activation of complement and contact pathways

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defenses, many bacteria species secrete modulators of the host hemostasis, complement or fi brinolytic systems (Table 2), which can further in fl uence sepsis-associated DIC.

Viral infections Coagulopathic complications commonly develop during acute infections with Ebola, Marburg, Crimean-Congo, Lassa, yellow fever, hantavirus, dengue, 136 and, more recently, the SARS-CoV-2 viruses. 137 Virus PAMPs activate endosomal TLRs, including TLR3 and TLR7, which also promote TF transcription. 22,138 Viruses trigger TF expression in endothe-lium 139,140 and monocytes, 141-143 and TF neutralization reduces coagulopathy and improves survival in Ebola 42 and HIV 43 infec-tions. Similar to bacteremia, TF 1 monocytes also express the proin fl ammatory cytokines TNF, IL1 b, and IL6. 43 These procoa-gulant and proin fl ammatory monocytes persist after virological suppression 43 and may support coagulopathic complications after treatment of the underlying disease. Enveloped viruses such as herpes simplex can also capture host-derived TF in their phospholipid envelope. The TF 1 virions exhibit enhanced infectivity, 144 whereas the exposed TF is procoagulant 145 and may disseminate the hypercoagulant state. Overall, viremia-associated DIC usually exhibits a thrombotic phenotype that can lead to hemorrhage due to consumption of clotting factors, thrombocytopenia, rapid decrease of TM-PC anticoagulants, and dysregulated fi brinolysis. The intravascular coagulopathy commonly observed in severe SARS-CoV-2 infections, which frequently exhibit nonovert DIC, can trigger both thrombotic and bleeding complications. 137 The progressive D-dimer elevation documented in nonsurviving patients with COVID-19 146 indicates active coagulopathy, associ-ates with hyperin fl ammatory markers, and predicts thrombotic complications and mortality. 137,146 Elevated D-dimer accompa-nied by thrombocytopenia predict an enhanced bleeding risk. 137 No signi fi cant changes in global coagulation test results and fi brinogen level were observed between patients with or without coagulopathic COVID-19, 137 indicating compensatory hepatic synthesis of clotting factors. The coagulopathic mecha-nisms in COVID-19 are under active investigation. Because endothelial cells harbor the ACE-2 receptor, 147 SARS-CoV-2 can directly infect the endothelium promoting endotheliopathy and microvascular thrombosis. 148,149 Unlike SARS-CoV-1, which repli-cates and triggers TF transcription in peripheral blood mononu-clear cells, 143 SARS-CoV-2 replication in monocytes has not been con fi rmed. Nevertheless, intravascular TF can be induced by platelet-monocyte aggregates in patients with COVID-19. 150 We learned that in fl ammatory mediators, 151 complement, 152 and autoimmune mechanisms 153 could amplify the coagulop-athy, but such fi ndings will require mechanistic con fi rmation in experimental models. Thus, anticoagulants can bene fi t patients with prothrombotic COVID-19, 154 but coagulopathic monitoring is still necessary to prevent bleeding. 137 At the moment, the American Society of Hematology recommends prophylactic-intensity anticoagulants for patients with COVID-19 who do not have con fi rmed venous thromboembolism. 155

DIC in noninfectious diseases

Coagulopathies associated with most cancers are TF depen-dent. 156,157 TF expression by malignant cells and cancer-derived microparticles contributes to tumor progression and metastasis. 158 Some tumors also express a cysteine endopeptidase, cancer procoagulant, which activates FX directly and impairs hemostasis. 159 In addition, circulating car-cinoma mucins activate platelets and support prothrombotic, selectin-mediated platelet-leukocyte interactions. 160,161 Cancer-associated coagulopathy usually exhibits a chronic asymptomatic progression, where clotting factors and plate-lets are compensated for. Thromboembolic manifestations are more commonly seen with solid tumors, whereas hemor-rhagic events predominate in hematologic malignancies. 157 Consumptive coagulopathy or dysregulated activation of plasminogen by annexin II 162 exacerbate bleeding in APL. Whereas patients with metastatic malignancies that display slow-onset thrombotic DIC can bene fi t from prophylactic hep-arins, anti fi brinolytic agents have been used to limit hemor-rhages in hyper fi brinolytic APL patients. 157 The coagulopathy of trauma is triggered by the exposure of peri-vascular TF after injury and is ampli fi ed by DAMPs, hemorrhagic shock, and potential superimposed infection resulting in thrombin generation, platelet activation, and fi brinolytic dysfunction. 163 In early trauma, DIC manifests a hyper fi brinolytic phenotype due to excessive t-PA release from endothelial cells. Consequently, anti fi -brinolytic agents, such as tranexamic acid, were bene fi cial when administered during the fi rst 3 hours. 164 At later stages, the hypo-

fi brinolytic shift caused by delayed PAI-1 expression promotes microvascular thrombosis and contributes to organ damage. Delayed administration of tranexamic acid exacerbated the thrombo-occlusive phenotype and increased the risk of death. 164 DIC complications are also observed in pregnancy and obstetric emergencies. 165 Abruptio placentae, amniotic fl uid embolism, and eclampsia lead to leakage of TF from the placenta into the maternal circulation during labor, which, coupled with reduced expression of TM 166 and elevation of PAI-1, can increase the risk of thrombotic complications. 167 Neonates are also predisposed to coagulopathies related to their incompletely developed hemostatic system. As a result, DIC incidence is higher in pre-mature babies with underlying conditions such as sepsis, acute respiratory distress syndrome, intravascular hemolysis, and nec-rotizing enterocolitis. 168

Future perspectives

The diversity of DIC, in terms of underlying conditions, pro-thrombotic triggers, anticoagulant dysregulation, and the gamut of hemostatic complications from thrombosis to bleeding that can sometimes occur in the same patient during the course of disease, makes it challenging to assess this broad pathology in clinical settings. As a result, nonovert DIC states are harder to diagnose accurately, and overt DIC diagnosis is usually con-

fi rmed when physiologic compensatory mechanisms are long overcome. Better biomarker de fi nitions and strati fi cation of DIC subtypes and patients are needed. Ideally, combinations of bio-markers that de fi ne DIC subtypes would re fl ect the underlying pathologic mechanisms and allow for targeted therapeutic approaches, unlike the global anticoagulant strategies used so far. This need is painfully obvious from retrospective analyses of anticoagulant trials in sepsis, where bene fi ts observed ex post facto in subgroups of patients are drowned by the overall het-erogeneity of these studies. Furthermore, we need a better understanding of the pre-DIC state along with predictive assess-ments of clinical developments. This knowledge would greatly

blood 31 MARCH 2022 | VOLUME 139, NUMBER 13 1981

expand the therapeutic repertoire, adding preventive interven-tions with fewer side effects. Current therapeutic approaches in patients with DIC target the resolution of the underlying trigger (infection, trauma, and malignancy) and are mostly compensatory in nature, being restricted to supplementation of the missing components (clot-ting factors, anticoagulants, and platelets) necessary to restore hemostatic balance. Targeting the TF pathway directly or by TFPI supplementation signi fi cantly increases the risk of bleeding due to hemostatic impairment. Unless the inhibitors can be spatially and/or tempo-rally aimed toward the developing thrombi, they are unlikely to be useful systemically. In contrast, limiting clotting ampli fi cation through inhibition of the contact/intrinsic pathways and/or mod-ulation of terminal reactions seems to have better potential. We and others have shown that contact pathway inhibition reduces sepsis-associated coagulopathy and improves organ function in experimental bacteremia. 10,53 De fi ning the role of the contact pathway in DIC associated with other pathologies is needed to identify additional patients for whom the strategy may be useful. Likewise, inhibitors of terminal clotting reactions have long been used for thromboprophylaxis. They usually have relatively long half-lives in circulation, and, as such, their use is problematic in fast-progressing acute coagulopathies with the potential for bleeding. In contrast, short-lived inhibitors of FXa and thrombin attenuated DIC and protected organ function in Escherichia coli

sepsis in baboons, 169 and may be useful in clinical settings. These strategies nevertheless require further clinical validation. Last, the role of genomic variation in the incidence and pheno-typic expression of DIC has been underinvestigated to date. With the expansion of genomic sequencing, we expect associa-tions between polymorphisms and DIC to multiply during the next decade, at least in cancer-associated DIC. Integration of genetic data, biomarker dynamics, and clinical outcomes will not be trivial and is likely to require machine learning algorithms and collaboration of computer and basic science and clinical researchers to tailor individualized therapies for patients.

Acknowledgments

The authors thank Fletcher B. Taylor and Gary Kinasewitz for critical reading of the manuscript. The authors apologize to colleagues whose work could not be cited because of space constraints. The Illustrations were created with BioRender.com. Investigations of coagulopathies by our group were supported by grants from the National Institutes of Health, National Institute of General Medical Sciences (GM116184, GM12160, and GM122725) (F.L.), and by National Institute of Allergy and Infectious Diseases grants AI157037 (F.L.) and U19AI062629 (F.L. and N.I.P.).

Authorship

Contribution: All authors drafted the fi rst version of different sections of the manuscript and critically reviewed the fi nal manuscript. Con fl ict-of-interest disclosure: F.L. has received research contract funding from Bayer and Ra Pharma. The remaining authors declare no competing

fi nancial interests. ORCID pro fi les: N.I.P., 0000-0002-4809-9885; C.L., 0000-0001-8619-0893; F.L., 0000-0003-1249-9278. Correspondence: Florea Lupu, Cardiovascular Biology Research Pro-gram, Oklahoma Medical Research Foundation, 825 NE13th St, Okla-homa City, OK 73104; e-mail: fl [email protected].

Footnote

Submitted 18 February 2021; accepted 2 June 2021; prepublished online on Blood First Edition 24 August 2021; DOI 10.1182/blood.2020007208.

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