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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Curr Opin Hematol. 2020 Sep;27(5):341–352. doi: 10.1097/MOH.0000000000000605

The Interaction between the Complement System and Hemostatic Factors

Selin Oncul 1, Vahid Afshar-Kharghan 2
PMCID: PMC7773221  NIHMSID: NIHMS1651337  PMID: 32701617

Abstract

Purpose of review

To discuss the crosstalk between the complement system and hemostatic factors (coagulation cascade, platelet, endothelium, and Von Willebrand Factor), and the consequences of this interaction under physiologic and pathologic conditions.

Recent findings

The complement and coagulation systems are comprised of serine proteases and are genetically related. In addition to the common ancestral genes, the complement system and hemostasis interact directly, through protein-protein interactions, and indirectly, on the surface of platelets and endothelial cells. The close interaction between the complement system and hemostatic factors is manifested both in physiologic and pathologic conditions, such as in the inflammatory response to thrombosis, thrombosis at the inflamed area, and thrombotic complications of complement disorders.

Summary

The interaction between the complement system and hemostasis is vital for homeostasis and the protective response of the host to tissue injury, but also results in the pathogenesis of several thrombotic and inflammatory disorders.

Keywords: hemostasis, thrombosis, coagulation, the complement system, platelet

INTRODUCTION

Two main facts support the presence of interactions between the complement system and hemostatic factors. One is that complement-related disorders are associated with thrombotic complications, such as arterial and venous thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) and microthrombi in atypical hemolytic uremic syndrome (aHUS) (1). Second, the complement and coagulation pathways are functionally and evolutionary related and probably derived from the same ancestral proteins (2).

The complement and coagulation systems have a similar organization as cascades of serine proteases. This old evolutionary organization can be seen in the cascade controlling dorsoventral polarity in Drosophila and hemolymph of horseshoe crab (2).

Coagulation Cascade.

Hemostasis is a highly regulated stepwise process that ensures the coagulation of blood following the injury of blood vessels to prevent excessive bleeding (3). While blood flow is maintained in the blood vessels with an intact endothelium, blood clots form at the site of injury (4). Hemostasis involves platelets, coagulation factors and cofactors, endothelial cells, cytokines, fibrinolytic proteins, and regulatory proteins (5).

The mechanism of hemostasis may be classified into three major events: primary hemostasis, secondary hemostasis, and fibrinolysis. Primary hemostasis is provided by platelets at the site of vessel wall injury and involves adhesion, activation, and aggregation of platelets (6, 7). Secondary hemostasis is achieved by activation of the coagulation system and formation of the fibrin clot. Fibrinolysis limits the deposition of fibrin fibers during thrombosis and removes the blood clot in an organized fashion. In humans, the coagulation cascade and fibrinolysis have reached enormous complexity with multiple proteins involved and several regulatory steps (8, 9).

In the initiation phase of coagulation, vessel wall injury and expression of Tissue Factor (TF) on damaged vessel walls result in the formation of the Tenase (comprises TF and activated factor VII) and Prothrombinase (activated factor V and activated factor X) complexes, and generation of a small amount of thrombin (10). In the amplification phase, thrombin activates platelets, and platelets provide additional activation surface for assembly of coagulation proteins culminating in the formation of the tenase (activated factor VIII and IX) and prothrombinase (activated factor V and activated factor X) complexes. In the propagation phase, prothrombinase on platelets generates additional thrombin that forms fibrin clots in the area of vessel wall damage. Fibrin fibrils are subsequently cross-linked by factor XIIIa. As we will explain later, the complement system interacts with each component of hemostasis, including platelet, endothelial cells, and coagulation factors.

The complement system.

The complement system is an essential part of the innate immune system providing immune surveillance, protection against infections, particularly those caused by encapsulated gram-negative microorganisms, and disposal of damaged/necrotic/apoptotic cells and immune complexes (11). The complement system consists of more than 30 proteins, primarily synthesized by hepatocytes, which exist in circulation and on the cell surface (12, 13). Epithelial cells (including cancer cells), endothelial cells, and many immune cells (lymphocytes, neutrophils, and antigen-presenting cells) also secrete complement proteins (14–18). In addition to its role in the immune system, complement proteins mediate cell-cell interactions in several physiologic processes, such as hematopoiesis, organogenesis, and reproduction (19).

Complement activation occurs via three pathways: classical, mannose-binding lectin (MBL), and alternative pathways (20, 21) (Figure 1). Although each complement pathway is activated by a different initiating factor, the later stages of pathways converge. After complement activation, pro-inflammatory mediators such as anaphylatoxins are released, the surface of the pathogen is opsonized, and the pathogen is lysed by the membrane attack complex (MAC) (22).

Figure 1.

Figure 1.

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The complement system activation pathways and the regulatory proteins.

An antigen-antibody complex initiates the classical pathway (Figure 1). C1 complex (C1q, C1r, and C1s) binds to the Fc region of complement-fixing antibodies on the surface of the pathogens. C1r and C1s are then activated to cleave C4 (into C4a and C4b) and C2 (into C2a and C2b). Subsequently, C4b and C2a generate C4bC2a (C3 convertase) on pathogenic surfaces cleaving C3 into the anaphylatoxin C3a and the opsonin C3b. C3b binds to hydroxyl groups of carbohydrates and proteins on the surface of the pathogens by covalent bonds. Furthermore, C3b participates in the generation of C4bC2aC3b, also known as C5 convertase, that cleaves C5 into the anaphylatoxin C5a and the opsonin C5b. C5b, together with C6 and C7, binds to the lipid membranes to form the C5b-7 complex (23). Membrane-bound C5b-7 complex recruits C8 and exposes the C9-binding site in C8 (24). Incorporation of C9 molecules to C5b-8 builds C5b-9, also termed as MAC, which ultimately causes lysis by perforating the membrane of the pathogens (25).

Activation of the lectin and the alternative pathways do not require the presence of an antibody (Figure 1). The lectin pathway is activated by binding of pattern recognition receptors (PRRs) such as membrane binding lectins (MBLs) and ficolins to pathogen-associated molecular patterns (PAMPs) on the pathogen surface culminating in the formation of a complex between MBLs and MBL-associated serine proteases (MASPs) (26, 27). MASP-1 is the most abundant MASP in the serum, and it is involved with the cleavage of C2 of the complement system (28, 29). MASP-2, on the other hand, can cleave both C2 and C4 to form C4bC2a, the C3 convertase complex. MASP-3 competes with MASP-2 to bind to MBL and has a role in suppressing the activation of the complement system (30). MASP-3 is an important intermediator between alternative and lectin complement pathways via activating pro-factor D (31). Activated factor D participates in the alternative complement pathway (32). C3 is cleaved by C4bC2a, and C3b engages in the generation of C4bC2aC3b, also known as C5 convertase. The rest of the process is similar to the classical pathway (33).

The alternative complement pathway is in a default activation mode, but the complement regulatory proteins continuously suppress its activity (Figure 1). C3 undergoes spontaneous low-level hydrolysis and generates a small amount of C3b in the plasma that can adhere to the surface protein and carbohydrate moieties of nearby cell membranes (or even artificial membranes such as dialysis membrane and intravenous catheters) (34). If the surface-bound C3b is not rapidly inactivated, it can bind to Factor B and recruits Factor D to cleave Factor B into Ba and Bb (35). C3bBb is the C3 convertase of the alternative pathway that is further stabilized by Properdin (Factor P) and cleaves C3 to C3a and C3b (36). Since C3b can be deposited on all cell membranes, host cells are protected by the rigorous defense, provided by the negative complement regulatory proteins in plasma, such as Factor H, Factor I, C4b binding protein (C4BP) as well as on the cell surface, such as decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP or CD46), membrane inhibitor of reactive lysis (MIRL, CD59), and thrombomodulin (TM or CD141) (37–41).

A crucial step in the negative regulation of complement pathways is the degradation of C3b to inactive C3b (iC3b). Factor H is a plasma protein that negatively regulates the alternative complement pathway, in both fluid phase and on cell surfaces, by acting as a cofactor for Factor I-mediated cleavage of C3b to iC3b (42). Half of all the mutations associated with the aHUS involve gene encoding Factor H (43). C4BP inhibits classical, lectin, and alternative pathways by acting as a cofactor for Factor I-mediated cleavage of C3b and C4b (44). CD55 and CD59 are cell-surface proteins that are linked to the cell membrane by glycosylphosphatidylinositol (GPI) anchors and are deficient in PNH (45). CD55 dissociates C3 convertase and C5 convertase complexes, and CD59 dissociates C5b-9 on the cell surface (46, 47). MCP has the cofactor activity for cleavage of C3b and C4b by Factor I in the classical and the alternative pathways, respectively (48). Figure 1 shows the complement activation pathways and complement regulatory proteins in each pathway.

THE INTERACTION BETWEEN THE COMPLEMENT SYSTEM AND HEMOSTATIC FACTORS

The complement and coagulation systems are both crucial for the host response to infections and injury. Although the complement and coagulation systems are usually regarded as separate processes, they have been proved to be descendants of common ancestor genes. The horseshoe crab, which is considered as a living fossil since its origin goes back to more than 500 million years, is equipped with an integrated system that functions as both the coagulation and complement systems to defend against infection and blood loss (49). Both systems are mainly constructed by the serine proteases and their regulators (2, 50). Many of the proteins involved in these cascades are related to each other by gene duplications and alternative splicing (51–54).

The complement and coagulation systems are not only structurally and evolutionary related but are also functionally closely connected. Formation of blood clots at the site of tissue injury is associated with activation of an inflammatory response, including innate immunity in the wound to minimize infection.

Interaction between complement and coagulation proteins

Thrombin, although it is not a component of C5 convertase, can cleave C5 at a site (R947) that is close to that of the C5 convertase-cleavage site (R751), and generates C5aT that is structurally and functionally similar to C5a. The other product of the cleavage of C5 by thrombin, C5bT, participates in the downstream complement activation leading to the formation of C5bT-9, which exhibits higher lytic activity than C5b-9. Thrombin can also cleave C5 at the C5 convertase cleavage site (R751) at a much slower rate and generate a low level of C5a and C5b (55, 56). Thus at the coagulation site, thrombin cleaves C5 and produces C5a-like molecules. C5a is an anaphylatoxin and chemoattracts neutrophils and monocytes to the location of thrombosis. Neutrophil elastase released from activated neutrophils generates additional C5a by proteolysis of C5 (57). C5a, in turn, increases expression of TF on monocytes and endothelial cells, further promoting coagulation (58, 59). C5a can also enhance the ability of neutrophils to form neutrophil extracellular traps (NETs) (60–62). Neutrophils and NETs can activate complement pathways and generate additional C5a (63, 64). As a result, neutrophils and NETs provide another link between acute injury, thrombosis, and inflammation.

C5a can also inhibit fibrinolysis by activating plasminogen activator inhibitor-1 (PAI-1) in mast cells and basophils in tissue and blood (65).

Interaction between the complement system and platelets

The complement activation endproducts activate platelets and generate procoagulant platelet microvesicles and activated platelets can activate the complement system in the vicinity of platelets.

Several complement proteins, including C3, C5, C6, C7, C8, and C9 potentiate thrombin-induced platelet secretion and aggregation (66). The anaphylatoxin C3a induces platelet activation and aggregation (67). Also, the treatment of platelets with sublytic concentrations of C5b-9 caused transient membrane depolarization (68), granule secretion (69), generation of procoagulant platelet microparticles (70), and translocation of phosphatidylserine to the outer membrane leaflet (71, 72).

Activated platelets activate the complement system through alternative, classical, and lectin pathways. P-selectin expressed on activated platelets activates the alternative complement pathway (73), and the C1q receptor on activated platelets activates the classical pathway (74). Chondroitin sulfate released from α granules of activated platelets activates the lectin pathway around platelets (75). Activated platelets generate anaphylatoxins and chemoattract neutrophils and monocytes to the site of thrombosis. Deposited C3b and C3b degradation products (iC3b) opsonize platelets and mediate binding of platelets to CR3 (CD11b/CD18 or MAC1) and CR4 (CD11c/CD18) on neutrophils and monocytes (76).

In summary, activation of platelets and the complement system are closely linked. Complement activation products activate and degranulate platelets, cause calcium influx, promote platelet microparticle formation, and enhance procoagulant activity. In turn, activated platelets can further activate the complement system and generate more complement activation endproducts. This co-activation cycle has the potential of becoming a pathologic vicious cycle. However, the strong presence of complement regulatory proteins on the platelet surface, including constitutively expressed CD55 and CD59 and GPIIb-IIIa-bound Factor H (77) successfully prevent this vicious cycle under physiologic conditions. Lack of complement regulatory protein, such as CD59 and CD55 in paroxysmal nocturnal hemoglobinuria (PNH) and factor H in atypical hemolytic uremic syndrome (aHUS) can result in thrombotic complications, partly through unchecked platelet activation (78).

The interaction between the complement system and endothelium

Upon stimulation by hypoxia and cytokines (such as TNFα), endothelial cells secrete complement and complement regulatory proteins (79). The endothelial cells also become the target of complement-mediated injury, as is evident in antiphospholipid antibody-induced complement activation and thrombosis (80). Complement dependency of thrombosis and pregnancy loss after injection of β2-GPI antibody in the rodent models of antiphospholipid antibody syndrome (APS) supports a role for the activation of the complement system in the thrombotic complications of APS (81–83). Complement activation is strongly associated with pregnancy loss in patients with systemic lupus erythematosus (SLE) and patients with APS (84).

Endothelial injury is also an essential component of complement-mediated injury in disorders characterized by complement dysregulation, such as PNH and aHUS (85–87).

The standard of care in the treatment of thrombotic complications of complement disorders includes the use of anticoagulants such as heparin, warfarin, or new oral anticoagulants (88, 89), except in patients with the high-risk APS who are triple positive for lupus anticoagulant, anti-cardiolipin antibody, and anti-β2GPI antibody in serologic assays (90). There is some evidence suggesting that the agents targeting the complement system, including eculizumab, a C5 monoclonal antibody inhibitor, can be used in the secondary prevention of venous thrombosis in PNH. However, in our opinion, there is not enough data justifying the use of anti-complement reagents alone and without anticoagulation in PNH patients with a history of venous thrombosis. Anti-complement reagents are important in the treatment and prevention of microthrombi in aHUS and might have a role in the treatment of catastrophic antiphospholipid antibody syndrome (91).

The interaction between the complement system and Von Willebrand Factor (VWF)

Stimulation of endothelial cells or endothelial injury results in the release of Ultralarge VWF multimers (ULVWF). Endothelial cell-anchored ULVWF can bind to complement proteins and activate the alternative complement pathway (92, 93). Under physiologic conditions, ULVWF is rapidly and efficiently cleaved by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) (94, 95). However, inadequate ADAMTS13 function in thrombotic thrombocytopenic purpura (TTP) increases the concentration of ULVWF that results in microvascular thrombosis. Other groups and we have found an increase in complement activation endproducts in TTP, which is at least partially due to the activation of the complement system by ULVWF (96–100). In addition to activating the complement system, ULVWF prevents the negative regulation of the complement system. We have shown that smaller VWF multimers enhance cleavage of C3b, but large and ULVWF multimers have no effect on C3b cleavage and permit a default complement activation (101). The molecular mechanism underlying the difference between the effect of ULVWF, large, and smaller VWF multimers on C3b cleavage is not known. Normal plasma VWF multimers prevent complement activation and steer the complement pathway toward the generation of inactivated C3b (iC3b). ULVWF multimers, present in patients with thrombotic microangiopathy, lack an inhibitory regulatory effect on complement activation, and permit complement activation to proceed (101).

COMMON REGULATORY PROTEINS OF COMPLEMENT AND COAGULATION PATHWAYS

The complement system and hemostasis share common regulatory proteins. The crosstalk between complement and hemostasis occurs at different regulatory steps, as is described below. Figure 2 depicts the regulatory proteins that regulate both the coagulation and complement systems.

Figure 2. Common regulatory proteins of the complement and coagulation systems.

Figure 2.

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Thrombomodulin (TM), C4b-binding protein (C4BP), and C1-inhibitor (C1-INH) regulate the coagulation and the complement systems. (A) TM regulates the coagulation system by forming a complex with thrombin leading to the generation of APC that further degrades Factors Va and VIIIa. (B) TM-bound thrombin activates TAFI that cleaves C3a and C5a. (C) C4BP acts as a cofactor for protein S in cleaving Factors Va and VIIIa. (D) C4BP inhibits the classical and lectin complement pathways by accelerating the decay of C4b2a, the C3 convertase. C4BP acts as the cofactor for Factor I-mediated cleavage of C4b, and less efficiently of C3b. (E) C1-INH inhibits Factor XIa and the kinin-kallikrein system in the intrinsic coagulation pathway. (F) C1-INH dissociates the C1qrs complex assembled on the antigen-antibody complex in the classical complement pathway. APC: activated protein C; aTAFI: activated thrombin activatable fibrinolysis inhibitor; EPCR: endothelial cell protein C receptor; HMW kininogen: high molecular weight kininogen; PC: protein C; PS: protein S; TAFI: thrombin activatable fibrinolysis inhibitor.

Thrombomodulin (TM).

TM is an important component of the natural anticoagulation mediated by the protein C system (Figure 2A). TM is a surface glycoprotein on endothelial cells that binds to thrombin. The formation of the thrombin−TM complex weakens the procoagulant activity of thrombin that is now able to cleave Protein C and generate activated protein C (APC), which in turn, engages endothelial cell protein C receptor (EPCR) (102). APC, with the cofactor activity of Protein S, degrades activated Factor V and VIII (103). The thrombin-TM complex also activates thrombin activatable fibrinolysis inhibitor (TAFI), also known as carboxypeptidase B2 (CPB2) (Figure 2B). Activated TAFI (TAFIa) removes C-terminal lysine residues from the fibrin in the clot and inhibits fibrinolysis (104). However, TAFIa also has an important role in regulating the complement system and inactivate anaphylatoxins by removing C-terminus arginine from C3a and C5a (105, 106). The importance of TM in the negative regulation of the complement system is demonstrated by the association between mutations in TM and aHUS (107).

C4b binding protein (C4BP).

C4BP is a plasma glycoprotein that binds protein S. C4BP-bound protein S constitutes about 60% of total protein S in plasma (108). C4BP regulates the cofactor activity of protein S in the APC-mediated cleavage of Factor Va. Although C4BP-bound protein S retains the APC-cofactor activity in cleavage of factor VIIIa, it is less efficient as an APC cofactor in cleaving Factor Va (109, 110) (Figure 2C).

C4BP also has a vital role in regulating complement activation (Figure 2D). C4BP is a soluble inhibitor of classical and lectin complement pathways by accelerating the decay of C4b2a, the C3 convertase. C4BP acts as the cofactor for Factor I-mediated inactivation of C4b, and less efficiently of C3b (111–115). The presence of the protein S facilitates the attachment of C4BP to the apoptotic cells preventing excessive activation of the complement system (116, 117).

C1-esterase inhibitor (C1-INH).

C1-INH is a serine protease inhibitor (Serpin) that regulates both the complement system and intrinsic coagulation cascade. C1-INH negatively regulates the intrinsic coagulation cascade by inhibiting plasma Kallikrein, Factor XIIa, factor XIa, and bradykinin (118) (Figure 2E). C1-INH inhibits the classical complement pathways by disrupting the C1qrs complex assembled on the antigen-antibody complex (119, 120) (Figure 2F). C1-INH also inhibits the lectin pathway by inhibiting MASP-1 and MASP-2. Interestingly, antithrombin also inhibits MAPS1 and MASP2, and the inhibitory effect of both antithrombin and C1-INH on the lectin pathway is significantly enhanced in the presence of heparin (121). MASPs are structurally similar to thrombin (122). MASP-1 can cleave fibrinogen, Factor XIII, prothrombin, and TAFI, although with a lower proteolytic activity than thrombin (123–125). Inhibition of MASP-1 hindered coagulation and extend bleeding time both in vitro and in vivo (126, 127).

Deficiency of C1-INH in hereditary angioedema patients may cause an inflammatory response mediated by activation of the complement system and production of vasoactive peptides, including bradykinin that contributes angioedema (128). Despite the inhibitory effect of C1-INH on coagulation, hereditary angioedema is not associated with significant thrombotic complications, and replacement by recombinant C1-INH does not cause bleeding (129).

THE INTERACTION BETWEEN THE COMPLEMENT SYSTEM AND HEMOSTATIC FACTORS IN VARIOUS DISEASES

Hemolytic uremic syndrome (HUS)

HUS is a rare hemolytic disorder characterized by anemia, thrombocytopenia, thrombotic microangiopathy (TMA), and acute renal failure (130). Approximately 90% of HUS cases are diagnosed in children and are caused by Shiga or Shiga-like toxins produced by Escherichia coli (131). HUS may also develop in association with malignant hypertension, solid organ transplantation, pregnancy, certain bacterial/viral infections (132). HUS caused by complement dysregulation lacks a diarrheal prodrome and is known as atypical HUS (aHUS). In about half of patients with aHUS, mutations in the genes encoding complement proteins can be detected, with a majority of these mutations involving complement regulatory proteins (Factor H, Factor I, MCP) and a small percentage of gain-of-function mutations in complement proteins C3 and Factor B (133–137). About 30% of all detected mutations in aHUS are in the Factor H gene (138–140). About 5–10% of aHUS patients develop antibodies against Factor H that block its complement regulatory activity. There is a correlation between the presence of anti-Factor H antibodies and homozygous deletion of complement factor H related proteins 3 and 1 genes (deletion CFHR3/CFHR1) caused by the non-allelic homologous recombination in chromosome 1q32 (141). The pathogenesis of aHUS is related to an unregulated activation of the alternative complement pathway and endothelial injury in the microvasculature induced by the complement attack. Endothelial damage and activation of platelets play an important role in the development of TMA (142). However, in addition to the excessive activity of the alternative complement pathway, other etiologic factors may contribute to the development of an aHUS phenotype. In a study on 29 patients with aHUS, more than 50% of the patients had reduced ADAMTS13 activity (143). The data suggested that reduced ADAMTS13 activity may contribute to the TMA phenotype in aHUS patients. Partial deficiency of ADAMTS13 alone will not induce a TMA phenotype. Still, it may act together or even synergistically with the primary pathophysiologic triggers, such as an inherited mutation in a complement gene or overproduction and secretion of VWF following endothelial damage, to generate TMA. Consistent with this scenario, 50% of the patients in our aHUS cohort had both excessive complement activation and partially decreased ADAMTS13 activity. It is reasonable to speculate that low ADAMTS13 activity reduces the threshold for a florid TMA phenotype in patients with complement mutations. This relationship may also help to explain the issue of incomplete genetic penetrance in aHUS, as only 50% of individuals with complement mutations present with the disease by the age of 45 (144).

The primary treatment of aHUS consists of supportive care and blocking complement activation. Plasma exchange is useful mainly in a subgroup of patients with an anti-factor H antibody, MCP mutations, or thrombomodulin mutations (145). In addition to eculizumab and Ravulizumab, various anti-complement reagents such as CCX-168 (a small molecule inhibitor of C5a receptor), AMY-101 (a synthetic cyclic peptide inhibitor of C3), and Compstatin (cyclic peptide inhibitor of C3) (146, 147) have been studied in the treatment of aHUS.

PNH

PNH is a rare acquired clonal hematopoietic stem cell (HSC) disorder due to somatic mutations in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene. Since PIGA expression is essential for the biosynthesis of GPI anchors and PIGA mutations causes a decrease in GPI-anchored proteins, including CD55 and CD59 on the cell surface. CD55 and CD59 are negative regulatory proteins of the complement system. CD55 inhibits early steps of complement activation by degrading C3 convertases, C4b2a and C3bBb; meanwhile, CD59 inhibits the formation of C5b-9 by preventing C9 from binding to C5b678 complex (47, 148, 149). PNH is characterized by complement-induced lysis of erythrocytes, intravascular hemolysis, and bone marrow failure (150–155). The prothrombotic state in PNH is multifactorial and is associated with both venous and arterial thrombosis. Intravascular hemolysis results in the release of free hemoglobin into circulation that depletes nitrous oxide and enhances platelet activation (156). Free hemoglobin also inhibits ADAMTS13 function (157, 158). Activation of the complement system in PNH activates platelets and endothelium and results in the release of microparticles from platelets and endothelial cells (159–161). Several coagulation regulatory proteins such as Urokinase-type plasminogen activator receptor (u-PAR) require a GPI anchor for cell surface expression. Decreased fibrinolysis and enhanced coagulation as a result of the reduced function of these coagulation regulatory proteins can also contribute to thrombosis in PNH (162). In addition to eculizumab, Ravulizumab (ALXN1210), a monoclonal antibody with the same mechanism of action as eculizumab but with a longer half-life, has been used in the treatment of PNH (163, 164). Small molecules targeting C3 or C5 have been developed as therapeutic agents for PNH (165, 166).

Thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies

TTP is a microangiopathic hemolytic anemia caused by the systemic microvascular thrombosis involving different organs, including the heart, brain, kidney, and gastrointestinal tract, among others (167). TTP is associated with an inadequate cleavage of anchored ULVWF on endothelial cells or in the circulation due to the functional defect in VWF-cleaving protease, ADAMTS13 (168–172). The VWF-cleaving protease, ADAMTS13, was purified (173, 174) and its encoding gene was identified (95). The majority of TTP patients have reduced ADAMTS13 function due to autoantibodies, and about 5–10% of patients develop TTP due to mutations in the ADAMTS13 gene (hereditary TTP or Schulman-Upshaw syndrome) (175, 176).

Many patients with TTP-like syndrome have normal ADAMTS13 levels (177). There are several reports of patients with reduced ADAMTS13 function who either did not develop TTP or did so later in life (178). These observations raise the possibility of the presence of additional factors besides ADAMTS13 deficiency in the pathophysiology of TTP (178–181). Activation of the complement system in both familial (139) and acquired TTP (99, 180) has been reported, based on the lower concentration of C3, elevated levels of complement activation products (C3a and sC5b-9) (179) and increased complement lysis activity in patients’ sera (99). C3 and C5b-9 are deposited in the kidney tissue of TTP patients (96) and on the endothelial cells exposed to TTP sera (179). The mechanism of activation of the complement system in TTP is not identified; however, two possible origins of complement activation are considered: activation of the complement system on the surface of activated platelets (182) and activation of the complement system by ULVWF (100, 101).

The interaction between the complement system and the VWF in the pathogenesis of TMA has been reproduced in murine models. In an important study, while neither ADAMTS13 deficiency nor heterozygous Factor H mutation resulted in TMA in mice, ADAMTS13 deficient mice that harbored a heterozygote Factor H mutation developed severe TMA (183).

Several other disorders have a TMA phenotype in the spectrum of TTP/aHUS without a severe deficiency in ADAMTS function and without a high incidence of detectable mutations in complement genes, including TMA during pregnancy and after solid organ or bone marrow transplantation, and chemotherapy or cancer-induced TMA. For each of them, several studies are reporting abnormal complement activation or genetic variations in complement genes, but a clear etiologic link between complement disorder and TMA in these disorders has yet to be established. This raises the possibility of a multifactorial etiology that includes a baseline, and probably hereditary, complement dysregulation or reduced ADAMTS13 activity combined with exposure to environmental factors that result in endothelial injury, activation of the coagulation cascade, the release of ULVWF, and platelet activation.

CONCLUSIONS

Complement proteins and hemostatic factors (coagulation proteins, platelets, endothelium, and the VWF/ADAMTS13 axis) directly interact. The surface of endothelial cells, platelets, and VWF multimers provide the platforms for the interaction between hemostatic factors and complement proteins. Furthermore, regulation of complement activity regulates hemostasis, and vice versa, through dual roles of regulatory proteins such as Factor H, VWF, C1-INH, C4BP, and thrombomodulin. Dysregulation of the complement system results in the activation of hemostatic factors and can cause thrombosis. On the other hand, thrombosis or endothelial injury can activate the complement system and results in an inflammatory response and additional tissue injury at the site thrombosis

Key Points.

  • The complement and coagulation systems are genetically and functionally related.

  • Activation of the complement system activates platelets and promotes coagulation.

  • Thrombosis activates the complement system and initiates an inflammatory response.

  • Complement dysregulation causes thrombosis in PNH and aHUS by activating hemostatic factors.

Acknowledgments, Financial support, and sponsorship

This work is supported by the R01CA231141 grant (V. A-K.), 2R01CA177909 grant (V. A-K.), American Society of ‘Hematology’s Bridge Fund (V. A-K.), and 2219-Research Grant as part of the International Postdoctoral Research Scholarship Program of Scientific and Technological Research Council of Turkey (TUBITAK) (S.O.).

Footnotes

Conflicts Of Interest

The authors declare no conflict of interest.

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