Background: Sepsis-associated coagulopathy specifically refers to widespread systemic coagulation activation accompanied by a high risk of hemorrhage and organ damage, which in severe cases manifests as disseminated intravascular coagulation (DIC), or even develops into multiple organ dysfunction syndrome (MODS). The complement system and the coagulation system as the main columns of innate immunity and hemostasis, respectively, undergo substantial activation after sepsis. Summary: Dysfunction of the complement, coagulation/fibrinolytic cascades caused by sepsis leads to “thromboinflammation,” which ultimately amplifies the systemic inflammatory response and accelerates the development of MODS. Recent studies have revealed that massive activation of the complement system exacerbates sepsis-induced coagulation and even results in DIC, which suggests that inhibition of complement activation may have therapeutic potential in the treatment of septic coagulopathy. Key Messages: Sepsis-associated thrombosis involves the upregulation or activation of procoagulant factors, down-regulation or inactivation of anticoagulant factors, and impairment of the fibrinolytic mechanism. This review aims to summarize the latest literature and analyze the underlying molecular mechanisms of the activation of the complement system on the abnormal coagulation cascades in sepsis.

“Sepsis-3,” defined as a life-threatening organ dysfunction, is caused by dysregulated host responses to infection and subsequent impaired immune homeostasis [1]. The mechanisms of immune imbalance involved in sepsis are characterized by simultaneous hyperinflammation or immunosuppression in two opposite courses, the extent of which varies among individuals [2]. A large number of unsuccessful clinical trials with anti-inflammatory agents strongly suggest the necessity to increase knowledge of septic immune status to identify novel therapeutic strategies [2‒4]. In addition to the typical cytokine storm, the abnormal inflammatory responses during sepsis also involve the activation of the complement system, coagulation system, vascular endothelium, neutrophils, and platelets [1, 5, 6]. The disruption of the complement, coagulation, and fibrinolytic cascades caused by sepsis leads to systemic “thromboinflammation,” which ultimately leads to the development of multiple-organ dysfunction [6]. Central to thromboinflammation is the loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells, causing dysregulation of coagulation, complement, platelet activation, and leukocyte recruitment in the microvasculature [7]. A growing body of evidence indicates that thromboinflammation is an important pathogenic process linked to sepsis [7]. Therefore, defining the molecular mechanisms that regulate thromboinflammation is of great clinical interest in exploring novel anti-inflammatory therapy for sepsis.

Sepsis-associated coagulogenesis mainly involves upregulation or activation of procoagulant substances (e.g., tissue factor, TF), down-regulation or inactivation of anticoagulant substances (e.g., protein C, PC; antithrombin, AT; thrombomodulin, TM), and impairment of the fibrinolytic mechanism [8]. Therefore, the current primary therapeutic drugs for septic thrombosis include recombinant human-activated PC, TM, AT, and heparin [9]. However, the efficacy of anticoagulation therapy remains controversial because it can also cause bleeding tendencies and weaken host defenses against microbial dissemination [10]. International guidelines for the management of sepsis and septic shock have discouraged the application of recombinant human-activated PC, AT, and heparin in patients with sepsis due to the uncertainty of their therapeutic efficacies [11]. Therefore, an unmet need to find new approaches and strategies for the treatment of septic thrombosis is warranted.

Complement system is an important component of the innate immune system and plays an important role in defense against invasion by external pathogenic microorganisms [2, 5]. The complement system was activated in three ways: the classical, lectin, and alternative pathways (Fig. 1). The classical pathway is activated by the C1 complex, which consists of C1q and two serine proteases, C1r and C1s [12]. Then activated C1 cleaves C4 into C4a and C4b, and C2 into C2a and C2b. Subunits C4b and C2a will form C4b2a (a C3 convertase). In the lectin pathway (LP), pattern-recognizing mannose-binding lectins and ligands (such as mannose) together with mannose-binding lectin-associated serine protease 2 (MASP2) form a C1-like complex that cleaves C4 and C2 resulting in a C3 convertase C4b2a [13]. In the alternative pathway, stimulation occurs through spontaneous hydrolysis of C3. Hydrolyzed C3 named C3(H2O), with the help of factor D, binds cleaved factor B into C3(H2O)Bb. The C3(H2O)Bb complex will cleave plasma C3, resulting in C3a (a major anaphylatoxin) and C3b. C3b, an opsonin, will bind to Bb, resulting in C3bBb. C3bBb is the functional C3 convertase of the alternative pathway. C3 is the point of convergence between the three complement pathways; C3 convertase will also generate C5 convertase by binding to available C3b molecules. C5 convertase (C4b2a3b or C3bBb3b) cleaves C5 to generate C5a and C5b. C5b binds with C6, C7, C8, and multiple C9 to form the C5b-9 complex, also known as the membrane attack complex (MAC) or terminal complement complex (TCC). This may lead to the lysis of pathogens and the destruction of cells [14]. Besides these activated pathways, there are several regulatory mechanisms in place to ensure that the complement system does not become over-activated, thus causing harm to self-tissues. The soluble regulatory inhibitors include C1 inhibitor (C1-INH), C4b binding protein (C4BP), factor H (FH), and factor I. Moreover, another control mechanism called membrane-bound complement regulatory proteins that include CD35 (complement receptor 1, CR1) [15], CD46 (membrane cofactor protein), CD55 (decay acceleration factor), and CD59 (protectin) protects host cell membranes against the attack by over-activation of the complement system [6].

Fig. 1.

Schematic overview of the normal complement pathway. The complement system can be activated by the classical, lectin, and alternative pathways. In the classical pathway, the cascade is initiated by the interaction between C1q and immunocomplexes. Activated C1 cleaves C4 to C4a and C4b, and C2 to C2a and C2b. The C4b fragment combines with C2a to form the C3 convertase of the classical pathway, C4b2a. The LP generates an identical C3 convertase (C4b2a), but its activation is MBL binding with MBL-associated serine proteases (MASP-1, MASP-2) and other ficolins. Then cleave intact C4 and C2 to generate the C4b2a convertase. The alternative pathway is capable of autoactivation by spontaneous hydrolysis of C3 to generate C3(H2O) with the help of FD and bind cleaved FB into C3(H2O)Bb. The C3 convertases continuously cleave C3 in a powerful amplification loop. The terminal complement cascade is initiated by the C5 convertase and ultimately generates the C5b-9/MAC/TCC that inserts pores into cell membranes to induce cell lysis. FB, factor B; FD, factor D; FH, factor H; FI, factor I; MAC, membrane attack complex; MBL, mannose-binding lectin; MASPs, MBL-associated serine proteases.

Fig. 1.

Schematic overview of the normal complement pathway. The complement system can be activated by the classical, lectin, and alternative pathways. In the classical pathway, the cascade is initiated by the interaction between C1q and immunocomplexes. Activated C1 cleaves C4 to C4a and C4b, and C2 to C2a and C2b. The C4b fragment combines with C2a to form the C3 convertase of the classical pathway, C4b2a. The LP generates an identical C3 convertase (C4b2a), but its activation is MBL binding with MBL-associated serine proteases (MASP-1, MASP-2) and other ficolins. Then cleave intact C4 and C2 to generate the C4b2a convertase. The alternative pathway is capable of autoactivation by spontaneous hydrolysis of C3 to generate C3(H2O) with the help of FD and bind cleaved FB into C3(H2O)Bb. The C3 convertases continuously cleave C3 in a powerful amplification loop. The terminal complement cascade is initiated by the C5 convertase and ultimately generates the C5b-9/MAC/TCC that inserts pores into cell membranes to induce cell lysis. FB, factor B; FD, factor D; FH, factor H; FI, factor I; MAC, membrane attack complex; MBL, mannose-binding lectin; MASPs, MBL-associated serine proteases.

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Systemic complement is markedly activated during sepsis [16, 17]; for example, factor Bb, C4d, C3a, C5a, and C5b-9 concentrations are significantly elevated in patients’ serum [18]. Moreover, complement activation in sepsis is considered to be a major driver of the thromboinflammatory response [19]. In a single-center prospective observational study to assess complement activation levels in patients with sepsis-induced disseminated intravascular coagulation (DIC), serum concentrations of soluble C5b-9 were significantly higher in patients with DIC than in those without DIC [20]. Higher C5b-9 level was associated with higher severity of sepsis, higher concomitant rates of DIC (including prolonged thrombocytopenia, increased prothrombin time, and elevated fibrin degradation products), and a relatively poorer outcome [20].

In addition, the early pathological process of sepsis involves a massive release of pro-inflammatory cytokines triggered by the activation of complement system (especially C5a) [21]. The complement system can synergize with inflammatory cytokines through interactions with the coagulation system, the kinin system, and the fibrinolytic system, forming an extremely complex network in vivo that amplifies and exacerbates the inflammatory response [21]. Abnormal complement activation can lead to thrombotic microangiopathy, characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage, often accompanied by coagulation dysfunction, suggesting a complex relationship between the complement system and the coagulation system [22]. Increasing evidence suggests that unconstrained activation of the complement system links to sepsis-associated coagulation dysfunction, suggesting the therapeutic potential by intervening in the activation of the complement system (Table 1; Fig. 2).

Table 1.

Characterization of the regulation of coagulation by complement molecules

Complement moleculesProcoagulant propertiesReferences
Complement proteins 
 C1q Upregulates P-selectin on the platelet surface [23
Induces conformational changes in the integrins GPIIb–IIIa to support platelet adhesion and aggregation [24
Promotes platelet activation via circulating IC [25
 C3a Binds directly to fibrin, enhances clot stability, and increases clot resistance to fibrinolysis [26
As a component of NETs [27
 C4a Increases endothelial permeability through PAR signaling [28
Increases stress fiber formation and enhances endothelial permeability [28
 C5a Leads to the rapid expression of endothelial P-selectin, secretion of VWF, and adhesiveness for human neutrophils in a time- and dose-dependent manner [29
Mediates the expression of TF in neutrophils via the C5aR, which significantly enhances the procoagulant activity of neutrophils [30
Recombinant human C5a induces TF activity and its mRNA expression in human umbilical vein endothelial cells in a dose-dependent manner [31
A PDI-dependent thiol-disulfide exchange reaction occurs following C5 conversion, resulting in depletion of the membrane reductive equivalents and subsequent oxidation of PDI and TF [32
Induces the expression of PAI-1 in mast cells and basophils, leading to a procoagulant tendency [33
 C5b-9/TCC/MAC Increases vascular permeability and even promotes thrombosis by targeting the endothelium [34
Promotes the shedding of prothrombotic microvesicles from vascular cells [34
Induces vascular leakage via the release of bradykinin and platelet-activating factor [35
Attacks the platelet surface, triggering the release of α-granules and microparticles and stimulating the procoagulant activity by increasing prothrombinase [36‒39
Exposures of procoagulant lipids [40
Provides an extra surface or converts prothrombin to thrombin through prothrombinase (VaXa) [37
Enhances the exposure of prothrombinase assembly sites on the platelet surface by promoting the secretion of platelet FV and the assembly of functional FXa/FVa complex [34, 36
Mobilization of phosphatidylserine to the platelet surface to provide a catalytic surface for prothrombinase assembly [32, 41
Binds to thrombin to enhance platelet activation and aggregation [42
Upregulates TF activity by stimulating the oxidation of PDI [32, 43
Triggers NETosis, which in turn induces the release of the pro-inflammatory cytokine IL-17 [44
The intermediate C5b-7 initiation complex decrypts TF by a PDI-dependent mechanism, which is critical for TF activation and phosphatidylserine exposure [32
Complement regulators 
 FB As a component of NETs [27
 C1-INH Acts as a major regulator of the kinin system, neutralizing the effects of FXIIa, FXIa, kallikrein, HMWK-prekallikrein complexes, as well as plasmin, thereby affecting the fibrinolytic system [45‒47
 C4BP Leads to loss of PS cofactor activity, thereby reducing its anticoagulant effects [48‒50
 MASP-1 and MASP-2 MASP-2 cleaves prothrombin to thrombin; MASP-1 possesses thrombin-like properties and induces coagulation by cleavage of prothrombin, FXIII, HMWK, fibrinogen and activation of TAFI [51, 52
Complement receptors 
 gC1qR Activates the kallikrein-kinin-bradykinin system by binding to HMWK and FXII, thereby effectively driving the thrombo-inflammation [45
 C3aR Enabling the formation of NETs [53, 54
 CR3 Binds to the counter-receptor glycoprotein GPIb on platelets, thereby allowing leukocytes to adhere firmly to vascular thrombi [55
Complement moleculesProcoagulant propertiesReferences
Complement proteins 
 C1q Upregulates P-selectin on the platelet surface [23
Induces conformational changes in the integrins GPIIb–IIIa to support platelet adhesion and aggregation [24
Promotes platelet activation via circulating IC [25
 C3a Binds directly to fibrin, enhances clot stability, and increases clot resistance to fibrinolysis [26
As a component of NETs [27
 C4a Increases endothelial permeability through PAR signaling [28
Increases stress fiber formation and enhances endothelial permeability [28
 C5a Leads to the rapid expression of endothelial P-selectin, secretion of VWF, and adhesiveness for human neutrophils in a time- and dose-dependent manner [29
Mediates the expression of TF in neutrophils via the C5aR, which significantly enhances the procoagulant activity of neutrophils [30
Recombinant human C5a induces TF activity and its mRNA expression in human umbilical vein endothelial cells in a dose-dependent manner [31
A PDI-dependent thiol-disulfide exchange reaction occurs following C5 conversion, resulting in depletion of the membrane reductive equivalents and subsequent oxidation of PDI and TF [32
Induces the expression of PAI-1 in mast cells and basophils, leading to a procoagulant tendency [33
 C5b-9/TCC/MAC Increases vascular permeability and even promotes thrombosis by targeting the endothelium [34
Promotes the shedding of prothrombotic microvesicles from vascular cells [34
Induces vascular leakage via the release of bradykinin and platelet-activating factor [35
Attacks the platelet surface, triggering the release of α-granules and microparticles and stimulating the procoagulant activity by increasing prothrombinase [36‒39
Exposures of procoagulant lipids [40
Provides an extra surface or converts prothrombin to thrombin through prothrombinase (VaXa) [37
Enhances the exposure of prothrombinase assembly sites on the platelet surface by promoting the secretion of platelet FV and the assembly of functional FXa/FVa complex [34, 36
Mobilization of phosphatidylserine to the platelet surface to provide a catalytic surface for prothrombinase assembly [32, 41
Binds to thrombin to enhance platelet activation and aggregation [42
Upregulates TF activity by stimulating the oxidation of PDI [32, 43
Triggers NETosis, which in turn induces the release of the pro-inflammatory cytokine IL-17 [44
The intermediate C5b-7 initiation complex decrypts TF by a PDI-dependent mechanism, which is critical for TF activation and phosphatidylserine exposure [32
Complement regulators 
 FB As a component of NETs [27
 C1-INH Acts as a major regulator of the kinin system, neutralizing the effects of FXIIa, FXIa, kallikrein, HMWK-prekallikrein complexes, as well as plasmin, thereby affecting the fibrinolytic system [45‒47
 C4BP Leads to loss of PS cofactor activity, thereby reducing its anticoagulant effects [48‒50
 MASP-1 and MASP-2 MASP-2 cleaves prothrombin to thrombin; MASP-1 possesses thrombin-like properties and induces coagulation by cleavage of prothrombin, FXIII, HMWK, fibrinogen and activation of TAFI [51, 52
Complement receptors 
 gC1qR Activates the kallikrein-kinin-bradykinin system by binding to HMWK and FXII, thereby effectively driving the thrombo-inflammation [45
 C3aR Enabling the formation of NETs [53, 54
 CR3 Binds to the counter-receptor glycoprotein GPIb on platelets, thereby allowing leukocytes to adhere firmly to vascular thrombi [55

IC, immune complexes; PAR, protease-activated receptor; VWF, von Willebrand factor; FV, factor V; FB, factor B; TAFI, thrombin-activatable fibrinolysis inhibitor.

Fig. 2.

Involvement of components of the complement system in sepsis-associated coagulation. Complement is shown in the inner ring (dashed line), whereas the various components of sepsis-induced coagulation are shown in the outer ring (solid line). Pathogens induce inflammation and even development of sepsis, which in turn initiates an abnormal coagulation process in which C1q, C3, C3a, C4a, C4BP, C5, C5a, C5aR, C5b-9, MASP, and FI are involved in the activation of endothelial, platelet, and macrophage/neutrophil activation, as well as alterations of coagulation/anticoagulation and fibrinolytic systems.

Fig. 2.

Involvement of components of the complement system in sepsis-associated coagulation. Complement is shown in the inner ring (dashed line), whereas the various components of sepsis-induced coagulation are shown in the outer ring (solid line). Pathogens induce inflammation and even development of sepsis, which in turn initiates an abnormal coagulation process in which C1q, C3, C3a, C4a, C4BP, C5, C5a, C5aR, C5b-9, MASP, and FI are involved in the activation of endothelial, platelet, and macrophage/neutrophil activation, as well as alterations of coagulation/anticoagulation and fibrinolytic systems.

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C1-INH has been shown to protect mice against sepsis [56]. Neutralizing C5a [57] ameliorated lung function and hepatic injury in septic mice. C3aR antagonist (SB 290157) [58] or C5a antibody [59] ameliorated sepsis-associated cerebral dysfunction (including white matter alterations, disruption of the blood-brain barrier, and pituitary dysfunction) in septic rats. Application of the C3 inhibitor compstatin to septic baboon infected with Escherichia coli [60] down-regulated TF and plasminogen activator inhibitor-1 (PAI-1) to reduce the coagulation response, decreased overall coagulation markers (fibrinogen, fibrin degradation products, APTT), and preserved endothelial anticoagulant properties. It appears that complement inhibition is a promising therapeutic strategy for both sepsis and sepsis-related coagulopathy.

In sepsis, endothelial cells upon proinflammatory stimulation lose their anticoagulant function and promote coagulation by reducing the expression of TM and heparan sulfate and increasing the expression of TF [61]. In addition, pathogen-activated monocytes/macrophages, neutrophils, and neutrophil extracellular traps (NETs) also promote the release of TF, which initiates the coagulation cascades, leading to thrombosis [62‒64]. The interaction between NETs, platelets, and endothelium is essential for the formation of immunothrombosis during sepsis [65, 66], and this thromboinflammatory response leads to endothelial damage, which forms a vicious cycle and further increases thrombogenesis [64]. Moreover, anticoagulant proteins (e.g., AT) are significantly reduced due to increased consumption, decreased production, and excess extravasation caused by increased vascular permeability [64, 67]. Septic patients tend to exhibit a prothrombotic state through extrinsic pathway activation, cytokine-induced coagulation amplification, anticoagulant pathways suppression, and fibrinolysis impairment [68]. In the late stages of sepsis, hypo-coagulability ensues upon the establishment of DIC [68].

The newly introduced definition of sepsis-induced coagulopathy [68] is aimed at early identifying patients with reversible changes in coagulation status who have elevated levels of fibrin degradation products or D-dimers, reduced platelet counts, prolonged prothrombin time, and reduced fibrinogen levels consistent with overt DIC. However, by the time of clinical detection, patients are already at an irreversible stage of coagulopathy, beyond the timeframe for therapeutic intervention [68, 69]. Early identification of patients with sepsis-associated coagulopathy before progressing to the advanced stage of hemostatic derangement would be ideal for the initiation of anticoagulant treatment [9, 68]. Antithrombotic proteins in circulating plasma, such as AT, PC, and protein S (PS), play a crucial role in physiological hemostasis [66, 70]. These anticoagulant factors also regulate inflammation and protect vascular endothelial integrity [66]. However, the anticoagulation system of patients with sepsis is disrupted [66]. In addition, fibrinolysis is often suppressed in sepsis-induced coagulopathy/DIC by the excessive production of PAI-1, which increasingly forms fibrin clots in tissue microcirculation and leads to organ dysfunction [64, 67]. In addition, complement factors and damage-associated molecular patterns released from injured host cells activate the coagulation system [63] by modification of phospholipid membranes (which is required for the initiation of coagulation through TF), by activating platelets, and by inducing the expression of TF and PAI-1 by leukocytes [71‒73] further accelerating thrombogenic activity [63, 66].

In physiologic states, the coagulation and complement systems are tightly linked and regulate each other to effectively protect the host [74]. However, in severe sepsis, aberrant activation of these enzymatic cascades is, instead, the main cause of organ failure and mortality. Activation of the complement system not only directly enhances blood coagulation properties partly through damaging vascular endothelial cells but also releases anaphylatoxin indirect procoagulants, such as C3a and C5a released, which are powerful proinflammatory molecules that recruit and activate immune cells and platelets [2, 75]. C3a and C5a also regulate vascular flow by increasing vascular permeability and promoting leukocyte adhesion and mobility [2, 76]. Although local activation of these proinflammatory and procoagulant mechanisms after infection is part of protective innate immunity, their unrestrained activity leads to collateral damage and the pathogenesis of sepsis [2]. Similarly, unconstrained complement activation can cause tissue and organ damage [2, 75]. This review specifically focuses on the role of the activation of the complement system in septic coagulation.

Activation of the Endothelium by Complement Activation Products

C4a is a small protein released from complement component C4 upon activation of the classical and LPs of the complement system, which are important constituents of innate immune surveillance (Fig. 3) [77, 78]. Several studies linked complement C4 and its activation product C4a with sepsis [79, 80]. In human and animals with sepsis, the plasma level of C4a is increased [81]. Early studies demonstrated that human C4a causes erythma and edema formation when injected intradermally [82]. Furthermore, C4a was demonstrated to bind to thrombi formed following platelet activation. Interestingly, C4a was demonstrated to bind to both inactivated and activated platelet [83]. Recent studies revealed that C4a may alter/increase endothelial permeability through protease-activated receptor signaling [28, 84]. Another study revealed that mannose-binding lectin-associated serine protease-1 (MASP-1) can cause PAR4 activation, which may contribute endothelial cell inflammatory reaction [85]. All those data point to that C4a might interact with PAR1/4 to lead to permeability of endothelial cells and aggregation of platelets, which might enhance thrombosis during sepsis.

Fig. 3.

Complement activates the coagulation system during sepsis. (i) In platelet, C3a, C4a, and C5a induced P-selectin exposure marked as α-granule release; engagement of C1q with gC1q-R not only augments platelet activation via circulating immune complexes (IC) or P-selectin but also induces conformational changes of the integrin GpIIb–IIIa and modulates platelet-leukocyte aggregation in response to collagen. C3 that is hydrolyzed to C3(H2O) binds to soluble CR1 (CD35) on the surface of activated platelets and serves as a ligand for leukocyte cell surface receptor CR3(CD11b/CD18). CR3 binds to the counter-receptor glycoprotein GPIb on platelets, enabling the recruitment of CR3-bearing leukocytes to vascular injury sites. (ii) In endothelial cells, C3a, C5a, C4a, C5b-9, C4BPβ, and C1q induce the loss of endothelial barrier function and activate endothelium by different pathways as shown in the red area. (iii) C5a and its receptor C5aR mediate the expression of TF in neutrophils, which significantly enhances the procoagulant activity of neutrophils and fibrin formation during thrombosis. Complement activation triggers TF activation via C5-dependent thiol-disulfide exchange and/or oxidation of cell surface protein disulfide isomerase (PDI), whereas C5b-7 activates TF via phosphatidylserine exposure. C5a leads to the upregulation of PAI-1, resulting in higher expression than t-PA. C3 binds directly to fibrin, thereby enhancing clot stability and increasing clot resistance to fibrinolysis.

Fig. 3.

Complement activates the coagulation system during sepsis. (i) In platelet, C3a, C4a, and C5a induced P-selectin exposure marked as α-granule release; engagement of C1q with gC1q-R not only augments platelet activation via circulating immune complexes (IC) or P-selectin but also induces conformational changes of the integrin GpIIb–IIIa and modulates platelet-leukocyte aggregation in response to collagen. C3 that is hydrolyzed to C3(H2O) binds to soluble CR1 (CD35) on the surface of activated platelets and serves as a ligand for leukocyte cell surface receptor CR3(CD11b/CD18). CR3 binds to the counter-receptor glycoprotein GPIb on platelets, enabling the recruitment of CR3-bearing leukocytes to vascular injury sites. (ii) In endothelial cells, C3a, C5a, C4a, C5b-9, C4BPβ, and C1q induce the loss of endothelial barrier function and activate endothelium by different pathways as shown in the red area. (iii) C5a and its receptor C5aR mediate the expression of TF in neutrophils, which significantly enhances the procoagulant activity of neutrophils and fibrin formation during thrombosis. Complement activation triggers TF activation via C5-dependent thiol-disulfide exchange and/or oxidation of cell surface protein disulfide isomerase (PDI), whereas C5b-7 activates TF via phosphatidylserine exposure. C5a leads to the upregulation of PAI-1, resulting in higher expression than t-PA. C3 binds directly to fibrin, thereby enhancing clot stability and increasing clot resistance to fibrinolysis.

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C5a has been found to activate endothelial cells and platelets, leading to the secretion of von Willebrand factor and enhancing exposure of prothrombinase assembly sites and P-selectin [29, 86]. Endothelial cells express receptors for C5a [53, 87, 88], which are involved in the upregulation of leukocyte adhesion molecules, P-selectin, von Willebrand factor, and TF [29, 53], inhibition of TM [53, 89], and destruction of glycocalyx [53, 90]. FH binds to endothelial cells and basement membranes and protects them from complement-mediated attack [91, 92]. C5 or C5aR1 deficiency or anti-C5 mAb treatment prevents macrovascular thrombosis in mice with a mutation in FH (W1206R) [93]. Heparan sulfate proteoglycans on the endothelial surface maintain the anticoagulant milieu by local activation of antithrombin III [94]. In the case of infection, the generation of C5a might amplify tissue injury by a mechanism involving endothelial cell activation and loss of heparan sulfate mediated by the combination of antibodies and C5a and natural antibody [95]. Therefore, C5a impairs endothelial glycocalyx function by shedding heparan sulfate from the surface of endothelial cells, thereby increasing the propensity for clotting and intravascular coagulation [5].

C5b-9 complex, also known as the MAC or the TCC, exposed to endothelial cells induces vesiculation of the endothelial cell with the expression of factor Va binding sites and prothrombinase activity [34, 78, 96]. The insertion of C5b-9 into the plasma membrane promotes the shedding of prothrombotic microvesicles from vascular cells, thereby disseminating the hypercoagulant state in DIC [78, 96]. The interaction of C5b-9 with endothelium causes increased vascular permeability, leading to thrombosis after exposure of the subendothelial matrix to blood [35, 48]. C5b-9-induced vascular leakage is mediated by the release of bradykinin and platelet-activating factor [35]. These together contributed to vascular permeability increasing even prothrombotic state through targeting endothelium.

Platelet Activation by the Complement System

Complement-mediated platelet activation leading to platelet aggregation, anionic phospholipids exposure, degranulation, and release of prothrombotic factors [78] supports thrombus formation and directly fights against microbial infection and inflammation [97]. On the other hand, activated platelets with or without bound antibodies undergo lysis by the complement system or phagocytosed after complement fragment conditioning. One of the significant characteristics of sepsis is excessive activation of platelets [98, 99]. Several complement factors participate in the platelet activation as described below.

C1q, known as the initiator molecule of the classical pathway, has been shown to induce upregulation of P-selectin on the platelet surface, which is associated with granule release [23, 97]. The interaction of platelets with C1q multimers or immobilized C1q results in activation of GPIIb–IIIa fibrinogen binding sites and expression of P-selectin, which contributes to platelet procoagulant activity, leading to thrombotic events associated with complement activation and inflammation [24]. C1q enhances the production of reactive oxygen species and modulating platelet-leukocyte aggregation in response to collagen [97, 100]. C1q also augments platelet activation via circulating immune complexes [25, 97]. C1q-enhanced platelet aggregation may not only support the immune functionality of platelets but also be a factor in excessive and pathological platelet activation, which may result in thrombus formation and thrombocytopenia during sepsis [25, 97].

Anaphylatoxins are known to activate human platelets [97, 101]. C3a and C5a interact with their respective cognate receptors to promote platelet activation and aggregation [77, 83]. Martel et al. [83] have reported the binding of C3a, C4a, and C5a to thrombi amplifies local platelet activation. Circulating quiescent platelets can become sensitized to stimulation by either C3a or C5a by minimal pre-activation, such as adhering to the subendothelium after vascular damage [53, 102]. C3a and C5a induce platelet activation and aggregation by binding to their receptors [53, 83, 101] and further triggering the release of C1q, C3a, C5a, and C5b-9 [53, 97]. Hydrolyzed C3 [C3(H2O)] binds to the surface of activated platelets in the presence of leukocyte-derived properdin to facilitate the formation of a platelet surface-localized alternative pathway C3(H2O)Bb convertase [53, 102, 103]. This platelet-bound C3(H2O) can also serve as a ligand for leukocyte cell surface receptor CR3(CD11b/CD18) to promote platelet-leukocyte interaction and recruitment of activated monocytes, which are TF bearing and prothrombotic [53]. Moreover, C3(H2O) binds to soluble CR1 (CD35) on the surface of activated platelets to facilitate interactions between platelets and leukocytes [97, 102].

C5b-9 attacks the platelet’s surface and triggers the release of α-granules and microparticles from platelets and stimulates its procoagulant activity by increasing prothrombinase by up to fourfold [36‒39, 97]. The incorporation of C5b-9 into cell membranes activates platelets and results in the exposure of procoagulant lipids [40, 48]. The release of microparticles provides an extra surface or the conversion of prothrombin to thrombin through prothrombinase (VaXa) [37, 48]. Some early studies have also demonstrated that C5b-9/MAC is capable of enhancing the exposure of prothrombinase assembly sites on the platelet surface by promoting the secretion of platelet factor V and the assembly of functional FXa/FVa complex, thereby providing sites for thrombin propagation [34, 36, 45]. Complement activation and deposition of the MAC is highly effective in mobilizing phosphatidylserine to the surface of platelets, which will provide a catalytic surface for prothrombinase assembly [32, 37, 41, 104]. When combined with thrombin, the terminal pathway components C5b-9 result in enhanced activation and aggregation of platelets and the release of granules [42, 53]. Several upregulated adhesion molecules by C5b-9 and C1q can facilitate platelet adhesion to activated endothelial cells [48, 105, 106].

Apart from mutual complement-platelet activation, the complement receptor CR3 (Mac-1; CD11b/CD18) binds to the counter-receptor glycoprotein GPIb on platelets, enabling the recruitment of CR3-bearing leukocytes to vascular injury sites, where platelets and fibrin have already been deposited on endothelial cell lining [55]. This CR3-GPIb interaction allows leukocytes to adhere firmly to vascular thrombi and injured blood vessels as well as transplatelet migration [55, 97].

Induction of TF Expression by Complement Activation

Activation of complement, especially C5 as part of the inflammatory response, can lead to increased expression of functionally active TF in endothelium [31, 78] and leukocytes [48, 71]. For example, C5a binds to its receptor C5aR and mediates the expression of TF in neutrophils, thereby significantly enhancing the procoagulant activity of neutrophils [30]. Recombinant human C5a was reported to induce TF activity and its mRNA expression in human umbilical vein endothelial cells in a dose-dependent manner [31]. C5-dependent membrane perturbations in particular lead to prothrombotic TF activation on myeloid cells, thereby contributing to fibrin formation during thrombosis [43]. Complement activation triggers monocyte TF activation via C5-dependent thiol-disulfide exchange and initial membrane insertion of downstream complement components [43]. Lack of glycosylphosphatidylinositol-anchored complement regulatory proteins (CD55 and CD59) is associated with enhanced production of prothrombotic microparticles [43, 107] and attenuated regulation of TF by TF pathway inhibitor [43, 108, 109]. When chronic inflammation or acute infection results in elevated TF levels, the role of the complement cascade in activating monocyte-expressed TF may amplify this prothrombotic state and induce severe thrombosis [43]. C5 complement activation leads to the oxidation of cell surface protein disulfide isomerase (PDI), causing reduced PDI reductase activity [32], which represents a novel link between the complement system and cell surface PDI-mediated thiol-disulfide exchange [32]. A PDI-dependent thiol-disulfide exchange reaction occurs following C5 conversion through the engagement of complement regulatory proteins [32, 110], resulting in depletion of the membrane reductive equivalents (i.e., thioredoxin-1), with consecutive PDI and TF oxidation [32, 111].

The C5b-9 terminal complex also induces TF [106, 112], whereas the TCC intermediate C5b-7 initiation complex decrypts TF by a PDI-dependent mechanism [32, 104]. Complement activation and deposition of the MAC induce de novo expression of TF in endothelial cells [32, 112] and leukocytes [32, 71]. The clustering of the terminal components of the complement pathway on the cell membrane surfaces also upregulates TF activity by stimulating the oxidation of PDI [32, 43, 77]. Complement activation can induce these changes simultaneously through the delineated effects of C5 activation favoring oxidation and C7-dependent membrane alteration [53]. Even partial assembly to the extent of C5b-7, by attachment to the outer leaflet of the target membrane, is sufficient to trigger TF activation on monocytes without inducing anionic phospholipid (e.g., phosphatidyl serine) exposure but rather facilitating the enzymatic decryption of TF via PDI [32, 53]. The formation of the initial membrane insertion complex, C5b-7, is critical for TF activation and phosphatidylserine exposure. Cell membrane rearrangements caused by C5b-7 insertion may lead to phosphatidylserine exposure in raft domains, thereby facilitating the dissociation of TF from regulatory proteins and/or TF oxidation [32]. C7 promotes phosphatidylserine externalization and TF activation [32]. The binding of C7 to C5b6, the last proteolytic product of complement activation, is crucial for the generation of the first lipophilic intermediate – the C5b-7 complex – that stably associates with cell membranes [32]. Although the C5b-7 complex does not form pores that allow transmembrane flux, it appears to be sufficient to disrupt the cell membrane and thereby induce cell signaling [32, 113‒115]. It is therefore conceivable that targeted insertion of C5b-7 complexes into lipid rafts supports TF oxidation by inhibiting TF activity through perturbation of protein-protein interactions, including TF dimerization [32, 116] or association with β1 integrins [32, 117] and other chaperone proteins [32, 118].

Role of Complement on the Fibrinolysis System

C5a/C5aR signaling is thought to play an important role in the fibrinolysis system [119, 120]. C5a induces the expression of PAI-1 in human mast cells and basophils, thereby affecting the balance between pro- and antifibrinolytic proteins [30, 72]. In vitro stimulation of mast cells with C5a leads to upregulation of PAI-1, resulting in higher expression of PAI-1 than tissue plasminogen activator (t-PA) [48, 121]. This phenotype regarding the reversal of t-PA and PAI-1 expression abolishes the fibrinolytic activity of mast cells, resulting in an inclination of pro-coagulation [48]. In vivo, blockade with anti-C5a IgG ameliorates several fibrinolytic/coagulation protein changes seen in sepsis [30, 33]. In this paper [33], to determine the effects of rabbit-rat polyclonal anti-C5a IgG on changes in the coagulation/fibrinolytic responses in experimental sepsis, a rat cecal ligation and puncture model of septic shock was used. This model closely mimics the pathophysiology of sepsis in humans [122, 123]. Anti-C5a therapy not only reduced the frequency of death in cecal ligation and puncture-treated animals but also attenuated the development of DIC. That is to say, anti-C5a markedly ameliorates coagulation/fibrinolytic changes in platelet counts, fibrinogen, factor VII, AT, plasminogen, plasma t-PA, and plasminogen activator inhibitor as well as the plasma thrombin-antithrombin complexes and D-dimer. C3 binds directly to fibrin, thereby enhancing clot stability and increasing clot resistance to fibrinolysis [53]. Mice deficient in C3 have prolonged bleeding time and delayed thrombosis post-injury [26, 53]. Both the C3- and C4-deficient mice were significantly more sensitive to endotoxin than wild-type controls [79]. Notably, few studies have further explored the molecular mechanisms by which these complement factors alter fibrin clot structure [53].

MASP-2and MASP-1 are the serine protease pattern recognition molecules, as important components of the LP complement activation [45]. MASP-1 is the key initiator protease of the LP while MASP-2 is the main protease cleaving C4, and some C2, to generate C3 convertase [45]. MASP-2 cleaves prothrombin to thrombin, whereas MASP-1 appears to possess thrombin-like properties, in terms of structure and substrate specificity, and induces coagulation by cleavage of prothrombin [45, 51], FXIII, high-molecular weight kininogen (HMWK), fibrinogen and activation of thrombin-activatable fibrinolysis inhibitor [45, 52]. In vivo, MASP-1 appears to be involved in thrombogenesis both in animal models and in human plasma [45, 51, 124].

Inhibition of Anticoagulant Mechanisms by Complement

Complement also augments the thrombogenic properties of blood by inhibiting the anticoagulation mechanism [48]. PS functions as a cofactor for the degradation of coagulation factors Va and VIIIa by APC and has a high binding affinity for negatively charged phospholipids on cell membranes [48]. C4b-binding protein (C4BP) is an important cofactor in the degradation of C4b by serine protease factor I in the classic complement pathway, acting as an acute phase protein whose levels in the blood can increase by up to 400% during the inflammatory response [49, 125]. It is generally accepted that only the free PS fraction in plasma has an active anticoagulant function [49]. C4BP directly inhibits PS activity due to the fact that the formation of PS-C4BP complex results in a loss of PS cofactor activity, thus reducing its anticoagulant effects [48‒50]. Increased formation of C4BP-PS complex in septic patients leads to a relative decrease in plasma PS levels, which can contribute to an increased risk of microthrombosis during sepsis [126].

Role of Complement on the Contact Pathway/Kinin System

There are several notable associations between the contact pathway and complement, including kallikrein, the gC1qR protein, and C1-INH [45]. gC1qR can directly activate the classical complement pathway by binding to C1q, as well as the kallikrein-kinin-bradykinin system by binding to HMWK and FXII, thereby effectively driving the thrombo-inflammation and the production of vasoactive molecules [45]. In contrast, C1-INH is a potent inhibitor of the classical complement pathway and a major regulator of the kinin system, neutralizing the effects of FXIIa, FXIa, kallikrein, and HMWK-prekallikrein complexes [45‒47]. The contact system can be activated during sepsis [127]. Salmonella typhimurium-induced lung injury in rats is accompanied by a massive release of bradykinin, and inhibitors of FXII or bradykinin alleviate lung lesions in this model [128]. In baboons with lethal E. coli sepsis, supplementation with C1-INH significantly reduced plasma levels of FXII, prekallikrein, and C4b/c, suggesting substantial inhibition of activation of the contact system and the classical complement pathway, respectively [129]. In patients with septic shock, C1-INH is effective in improving survival, hypotension, and renal injury [130, 131]. In addition, C1-INH binds directly to Gram-negative endotoxins, particularly to S. typhimurium LPS [132]. Binding is mediated by lipid A, the component of LPS that is primarily responsible for the pathophysiology of endotoxin shock [133]. Binding of C1-INH prevents LPS from interacting with the LPS receptor complex on the surface of macrophages, thereby inhibiting TNF-α production [132].

Complement occupies a strategic position in the first line of defense in innate immunity and exhibits an extensive network of interactions with various inflammatory mediators (Fig. 4) [48, 134]. For example, the complement anaphylatoxins C3a and C5a promote inflammatory activation of vascular cells [78], are generated immediately after the activation of the innate immune response, and contribute to the regulation of the cytokine responses [48]. Several interactions between anaphylatoxins and the cytokine networks have been postulated [48]. C3a and C5a also induce the release of pro-inflammatory and pro-coagulant cytokines such as TNF-α and interleukin-6 from monocytes and endothelial cells, as well as the expression of TF and adhesion molecules [77, 135, 136], and the recruitment and activation of leukocytes, endothelial cells, and platelets [3, 75]. In turn, TNF-α effectively enhances TF expression on monocytes and IL-6 increases platelet production and thrombosis [48]. Inflammatory cytokines also decrease the levels of several anticoagulants, including TM, endothelial cell PC receptor, and PS [48, 137].

Fig. 4.

Indirect procoagulant properties of complement. C3a and C5a induce monocytes and endothelial cells to release pro-inflammatory and pro-coagulant cytokines such as interleukin-6, TNF-α, and adhesion molecules. Inflammatory cytokines increase the recruitment and activation of leukocytes, endothelial cells, platelets, and TF, whereas decreasing the levels of several anticoagulants, including TM, endothelial cell PC receptor, and PS. C5b-9 directly triggers NETosis, which in turn induces the release of the pro-inflammatory cytokine IL-17 from neutrophils. Complement factors C3 and factor B (FB), as components of NETs, convey a variety of properties that link the coagulation and complement system. Activated eosinophils, basophils, and monocytes also release NETs, which trap and kill bacteria and invading pathogens, and provide a scaffold for platelets and erythrocytes aggregation, ultimately leading to thrombosis and thromboinflammation.

Fig. 4.

Indirect procoagulant properties of complement. C3a and C5a induce monocytes and endothelial cells to release pro-inflammatory and pro-coagulant cytokines such as interleukin-6, TNF-α, and adhesion molecules. Inflammatory cytokines increase the recruitment and activation of leukocytes, endothelial cells, platelets, and TF, whereas decreasing the levels of several anticoagulants, including TM, endothelial cell PC receptor, and PS. C5b-9 directly triggers NETosis, which in turn induces the release of the pro-inflammatory cytokine IL-17 from neutrophils. Complement factors C3 and factor B (FB), as components of NETs, convey a variety of properties that link the coagulation and complement system. Activated eosinophils, basophils, and monocytes also release NETs, which trap and kill bacteria and invading pathogens, and provide a scaffold for platelets and erythrocytes aggregation, ultimately leading to thrombosis and thromboinflammation.

Close modal

Neutrophils are early and key players in thrombotic inflammation, and stimulated neutrophils are also important fulcrums for local complement-coagulation regulation [53]. Activated neutrophils release NETs, a process known as NETosis [53]. NETs are net-like structures that are secreted during a specialized cell death process in which cells remain intact and retain certain biological functions [53, 138, 139]. Activated eosinophils, basophils, and monocytes also release NETs [53]. NETs trap and kill bacteria and invading pathogens and provide a scaffold for platelets and erythrocytes aggregation, which leads to thrombosis and thromboinflammation [53, 140, 141]. Interestingly, mice lacking C3 or C3aR are less prone to form NETs [53, 54], which emphasizes the link to complement [53]. Complement factors C3 and factor B as components of NETs [27, 53, 54] convey a variety of properties that link the coagulation and complement system [53]. C5b-9 also directly triggers NETosis, which in turn induces the release of the pro-inflammatory cytokine IL-17 from neutrophils [44, 53].

The treatment of sepsis-associated coagulopathy has been a challenge in the field of critical care medicine. Inhibition of the abnormal activation of the complement system and reduction of sepsis-induced inflammatory response and excessive activation of the coagulation system may become a new strategy for the treatment of sepsis-associated coagulation dysfunction or thromboinflammation. For instance, C5a inhibitor IFX-1 (vilobelimab) and C3 inhibitor compstatin are designed for the treatment of septic shock, while C1-INH infusion increases survival rates for patients with sepsis [45]. Moreover, there is a successful case report about the use of C5a inhibitor eculizumab in sepsis-induced multiorgan failure or sepsis-induced DIC patients [142, 143]. In addition, whether other parts of the complement activation chain, such as complement C4 and MAC, could be new therapeutic targets also requires further investigation.

On the other hand, to prevent unnecessary damage to healthy host cells, the body has tightly regulated mechanisms to limit these prothrombotic and proinflammatory properties of the assembled components of the complement terminal pathway. These mechanisms can be summarized as follows: vitronectin binds to C5b-7, preventing it from binding to the surface of the outer membrane [53, 144]. Clusterin interacts with C7, C8, and C9, weakening the ability of the C5b-9 complex to integrate into the membrane [53, 145]. Polyphosphate binds to C6, destabilizing C5b and C6 and preventing C5b-8 and C5b-9 complexes from integrating into the membrane [53, 146]. Glycosylphosphatidylinositol-linked CD59 binds to C8 and C9 at the cell surface, preventing C9 polymerization [53, 147]. In summary, MAC-triggered thrombo-inflammatory effects are coordinately suppressed through the above shared regulatory pathways, and these complement-negative regulatory mechanisms provide additional potential candidate targets for regulating sepsis-associated thromboinflammation.

The authors declare that they have no conflict of interest.

This work was supported by grants from the National Natural Science Foundation of China (82104269, 81872880), the Science and Technology Commission of Shanghai Municipality (21140905300), and Shanghai “Rising Stars of Medical Talents” Youth Development Program-Youth Medical Talents: Clinical Pharmacist Program (SHWSRS [2021]_099).

W.-Z.B. conceptualized the study; W.X. and T.Y. drafted the manuscript; W.X., T.Y., B.-S.H., and G.-G.M. performed the literature collection and collation; and W.-Z.B. and W.-H.B. reviewed and revised the manuscript. All authors have approved the final vision of this manuscript.

Additional Information

Xin Wei and Ye Tu contributed equally to this work.

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