Complement-mediated Diseases Research Articles

The Role of the Complement System in Autoimmune Diseases and Therapeutic Targeting

The complement system, a critical component of the innate immune system, plays a dual role in immune defense and pathogenesis, particularly in autoimmune diseases. Comprising over 30 proteins, the complement system facilitates pathogen clearance, inflammation, and immune modulation. However, its dysregulation can lead to uncontrolled activation and contribute to the development and progression of various autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), antiphospholipid syndrome (APS), and vasculitis. In these diseases, excessive complement activation triggers inflammation, immune cell recruitment, and tissue damage, exacerbating the autoimmune response. This review provides an in-depth analysis of the complement system’s role in autoimmune diseases, exploring how its three activation pathways—classical, lectin, and alternative—contribute to disease pathogenesis. It also discusses key complement proteins such as C3, C5, and the membrane attack complex (MAC) in promoting inflammatory responses in these conditions. Moreover, the review highlights recent advances in therapeutic strategies targeting the complement system, including the development of C5 inhibitors like eculizumab and C3 inhibitors, which show promise in treating complement-mediated autoimmune diseases. These therapies aim to reduce inflammation and tissue destruction, offering new approaches for managing autoimmune disorders. Understanding complement dysregulation is crucial for the development of more effective treatments in the future. Keywords: Complement system, Autoimmune diseases, Complement activation, Inflammation, Therapeutic targeting

What is proven in the treatment of complement-mediated kidney diseases?

Complement-mediated kidney diseases encompass acomplex group of diseases that are primarily caused by dysregulation of the complement system. The complement system is acrucial component of the innate immune system consisting of soluble and membrane-bound proteins. The complement system is essential for the defence against pathogens and homeostasis but its uncontrolled activation can lead to an exaggerated cellular response to immunogenic, inflammatory and metabolic stimuli. For example, glomerular deposition of immune complexes can activate the complement system and contribute to the progression of kidney diseases. The most well-known complement-mediated kidney diseases are atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, which falls under the group of membranoproliferative glomerulonephritis (MPGN). Diagnosing these diseases requires detailed investigations with respect to triggering factors, including genetic analyses and the measurement of specific complement factors. New therapeutic approaches with drugs targeting complement system activation are now offering promising treatment options. These medications fundamentally differ from other immunosuppressive drugs and specifically target the pathological processes within the complement system. This article provides an overview of the mechanisms of complement regulation, the pathophysiological foundations of complement-mediated kidney diseases and the latest diagnostic and therapeutic advances. The goal is to provide adeeper understanding of these complex conditions and to emphasize the importance of an interdisciplinary approach in treatment and research.

Acquired and genetic determinants of disease phenotype and therapeutic strategies in C3 glomerulopathy and immunoglobulin-associated MPGN.

C3 glomerulopathy (C3G), a prototype of complement mediated disease, is characterized by significant heterogeneity, not only in terms of clinical, histological and biological presentation but also of prognosis, and response to existing therapies. Recent advancements in understanding the factors responsible for alternative pathway dysregulation in the disease have highlighted its even more complex nature. Here, we propose a reexamination of the diversity of C3G presentations in light of the drivers of complement activation. Autoantibodies targeting complement proteins, genetic abnormalities in complement genes and monoclonal immunoglobulins are now well-known to drive disease occurrence. This review discusses how these drivers contribute to the heterogeneity in disease phenotype and outcomes, providing insights into tailored diagnostic and therapeutic approaches. In recent years, a broad spectrum of complement inhibitory therapies has emerged, soon to be available in clinical practice. The recognition of specific clinical, biological, and histological patterns associated with different forms of C3G is crucial for personalized management, particularly treatment strategies.

C3 glomerulopathy: a kidney disease mediated by alternative pathway deregulation.

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal complement. Consequently, all effector loops of the complement are active and can lead to pathologies, such as C3a- and C5a-mediated inflammation, C3b opsonization, surface C3b-mediated AP C3 convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage. The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in the plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes and chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either due to decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components and regulators or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here, we summarize both the causes of C3G and the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that effectice treatment for C3G will become availabe in the near future.

Childhood onset C3 glomerulopathy: recurrence after kidney transplantation-a case series.

C3 Glomerulopathy (C3G) is a complement-mediated disease, with predominant C3 deposits, where pathogenic genetic variants in complement system components and circulating autoantibodies result in loss of control of the alternative pathway, have been described. A high incidence of disease recurrence including graft failure has been reported after kidney transplantation (KTx). Currently treatment modalities for preventing and treating post KTx C3G recurrence (plasma exchange, rituximab and eculizumab) in adults have yielded inconsistent results. Data on post KTx C3G recurrence in childhood-onset C3G is still unknown. A comprehensive case study of patients diagnosed with C3G as children or adolescents, who underwent KTx between the years 2015-2023. Data collected included complement workup, treatment modalities, and outcomes. 19 patients with C3G were identified during the study period. Five patients developed ESRD and received a kidney transplant. C3G recurrence was diagnosed post KTx in 100% of patients. Graft function improved in 3 of these patients (two with anti-factor H antibodies) after eculizumab treatment, one patient reached graft failure 9 months after transplantation despite eculizumab, recieved a second successful transplantation with pre-emptive eculizumab treatment and one patient showed histologic signs of disease recurrence without clinical signs. C3G recurrence after KTx in patients diagnosed as children or adolescents may be higher than previously described. Treatment with eculizumab is beneficial in some patients. New treatments are needed for improving post-transplant outcome in patients with C3G.

Challenges and Results of ClinGen Gene-Disease Clinical Validity Curation for Complement-Mediated Kidney Disease

Challenges and Results of ClinGen Gene-Disease Clinical Validity Curation for Complement-Mediated Kidney Disease

A Real-World Study on the Clinical Characteristics and Treatments of Complement-Mediated Kidney Diseases in China

A Real-World Study on the Clinical Characteristics and Treatments of Complement-Mediated Kidney Diseases in China

HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases.

Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation. In this study, we investigated the effect of HIF stabilizer desidustat in complement-mediated diseases. Oral administration of desidustat (15 mg/kg) was effective to reduce the kidney injury in mice that was induced by either lipopolysaccharide (LPS), doxorubicin or bovine serum albumin (BSA)-overload. Complement activation-induced membrane attack complex (MAC) formation and factor B activity were also reduced by desidustat treatment. In addition, desidustat was effective against membranous nephropathy caused by cationic BSA and retinal degeneration induced by sodium iodate in mice. C3-deposition, proteinuria, malondialdehyde, and interleukin-1ß were decreased and superoxide dismutase was increased by desidustat treatment in cBSA-induced membranous nephropathy. Desidustat specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway. This effect appears to be mediated by inhibition of factor B. These data demonstrate the potential therapeutic value of HIF stabilization by desidustat in treatment of complement-mediated diseases.

Therapeutic targeting of factor D and MASP3 in complement-mediated diseases: Lessons learned from mouse studies.

The alternative pathway (AP) plays a major role in many complement-mediated human diseases. Factor D (FD), a rate-limiting enzyme in AP complement activation, is an attractive therapeutic target. Unlike other complement proteins, FD is synthesized primarily in adipose tissue, and its levels in human blood are relatively low. However, because of FD's high turnover rate, therapeutic targeting with monoclonal antibodies and chemical inhibitors has been challenging. The recent discovery that FD activity is regulated by mannose-binding lectin-associated serine protease 3 (MASP3), through conversion of a zymogen to mature FD, has sparked interest in MASP3 inhibition as a new way to block FD function and AP complement activity. Here, we review studies of mouse models of FD and MASP3 inhibition. We additionally discuss the lessons learned from these studies and their implications for therapeutic targeting of human FD and MASP3.

#1222 Crovalimab: patient preferences and ongoing phase III COMMUTE trials in acute haemolytic uraemic syndrome (aHUS)

Abstract Background and Aims aHUS is a rare, life-threatening, complement-mediated disease characterised by thrombotic microangiopathies (TMAs). Existing C5 inhibitor (C5i) therapies, such as eculizumab (ecu) and ravulizumab (ravu), are effective for aHUS management but can be burdensome in both adults and children, typically requiring regular intravenous (IV) infusions every 2 weeks (Q2W, ecu) or every 8 weeks (ravu). Crovalimab (crova), a novel C5i with low-volume, subcutaneous (SC) administration every 4 weeks (Q4W), allows for convenient self-administration outside of a healthcare setting. Crova is currently being evaluated in two ongoing global, Phase III, single-arm trials in aHUS: COMMUTE-a (NCT04861259) and COMMUTE-p (NCT04958265). The efficacy and safety of crova have also been evaluated in patients (pts) with paroxysmal nocturnal haemoglobinuria (PNH), another complement-mediated rare blood disorder, in the global, randomised, Phase III COMMODORE 1 (NCT04432584) and COMMODORE 2 (NCT04434092) trials (Röth EHA 2023; #S181, Scheinberg EHA 2023; #S183). Here, we report pt preference data from COMMODORE 1 and 2. Method COMMODORE 1 and 2 enrolled C5i-experienced and C5i-naive pts with PNH, respectively. Pts were randomised 1:1 in COMMODORE 1 and 2:1 in COMMODORE 2 to receive crova (weight-based tiered dosing regimen consisting of loading doses followed by SC Q4W maintenance) or ecu (900 mg IV Q2W) over a 24-week primary treatment period. After completing 24 weeks of treatment, all pts received crova if continuing the trial. Treatment preference was assessed in adult pts using the validated Patient Preference Questionnaire (PPQ) after 17 weeks of crova treatment in C5i-experienced pts randomised to crova in COMMODORE 1 and in pts initially randomised to ecu who switched to crova at Week 25 in both COMMODORE 1 and 2. COMMUTE-a is enrolling pts with aHUS aged ≥12 years and weighing ≥40 kg (N ≈ 80), while COMMUTE-p is enrolling pts with aHUS aged ≥28 days to <18 years and weighing ≥5 kg (N ≈ 45). Both studies are enrolling 3 cohorts (Fig. 1): (1) Naive: pts not previously treated with a C5i (n ≈ 40 in COMMUTE-a; n ≈ 20 in COMMUTE-p), (2) Switch: pts switching from ecu or ravu (n≈40 in COMMUTE-a; n ≥ 20 in COMMUTE-p), (3) C5 polymorphism cohort in COMMUTE-a: pts with known C5 polymorphisms (n ≤ 5); pretreated cohort in COMMUTE-p: pts previously treated with and discontinued ecu or ravu (n ≤ 10). In both COMMUTE studies, pts will receive weight-based tiered crova dosing consisting of loading doses (IV and SC) followed by SC Q4W maintenance (or Q2W if <20 kg) from Week 5 onward. The primary efficacy objective of both studies is to assess the proportion of C5i-naive pts with complete TMA response from baseline to Week 25. Secondary efficacy endpoints include change from baseline in dialysis requirement status and estimated glomerular filtration rate. Safety, pharmacokinetics, immunogenicity, biomarkers, and pt-reported fatigue will also be assessed. Treatment preference will be assessed using the PPQ in pts ≥12 years old and in caregivers of children <12 years old. Results 89 pts were randomised in COMMODORE 1 (crova: n = 45; ecu: n = 44) and 204 in COMMODORE 2 (crova: n = 135; ecu: n = 69). Of pts randomised to crova in COMMODORE 1, 33 (85%) of 39 pts assessed at Week 17 preferred crova over ecu. Of pts randomised to ecu who switched to crova after the primary treatment period, 27 (96%) of 28 pts who answered the questionnaire in COMMODORE 1 and 32 (84%) of 38 in COMMODORE 2 preferred crova (Fig. 2). The top reasons selected for crova preference over ecu were that the treatment required fewer hospital visits, was easier to administer, took less time to administer, and provided better quality of life (Kulasekararaj ASH 2023; #5628). COMMUTE-a and COMMUTE-p are currently open for recruitment in 17 and 14 countries, respectively. Conclusion Crova was preferred to ecu by most C5i-naive and switch pts with PNH in COMMODORE 1 and 2, largely due to faster, easier administration. Crova, with SC Q4W (or Q2W in pts <20 kg with aHUS) self-administration, can potentially reduce treatment burden vs currently approved C5 is in aHUS. The COMMUTE-a and COMMUTE-p trials evaluating crova in aHUS are currently enrolling.

Targeted complement inhibition using bispecific antibodies that bind local antigens and endogenous complement regulators.

Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for their capacity to inhibit complement activation and cell lysis in an antigen-targeted manner. We observed that the bsAbs inhibited classical, lectin, and alternative pathway complement activation in which sufficient endogenous serum FH and C4BP could be recruited to achieve local inhibition. Importantly, the bsAbs effectively protected antigen-positive liposomes, erythrocytes, and human leukocytes from complement-mediated lysis. In conclusion, localized complement inhibition by bsAbs capable of recruiting endogenous human complement regulators (such as FH or C4BP) to cell surfaces potentially provides a novel therapeutic approach for the targeted treatment of complement-mediated diseases.

Crovalimab: First Approval.

Crovalimab (®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.

Design and Biological Evaluation of the Long-Acting C5-Inhibited Ornithodoros moubata Complement Inhibitor (OmCI) Modified with Fatty Acid.

Disorder of complement response is a significant pathogenic factor causing some autoimmune and inflammation diseases. The Ornithodoros moubata Complement Inhibitor (OmCI), a small 17 kDa natural protein, was initially extracted from soft tick salivary glands. The protein was found binding to complement C5 specifically, inhibiting the activation of the complement pathway, which is a successful therapeutic basis of complement-mediated diseases. However, a short half-life due to rapid renal clearance is a common limitation of small proteins for clinical application. In this study, we extended the half-life of OmCI by modifying it with fatty acid, which was a method used to improve the pharmacokinetics of native peptides and proteins. Five OmCI mutants were initially designed, and single-site cysteine mutation was introduced to each of them. After purification, four OmCI mutants were obtained that showed similar in vitro biological activities. Three mutants of them were subsequently coupled with different fatty acids by nucleophilic substitution. In total, 15 modified derivatives were screened and tested for anticomplement activity in vitro. The results showed that coupling with fatty acid would not significantly affect their complement-inhibitory activity (CH50 and AH50). OmCIT90C-CM02 and OmCIT90C-CM05 were validated as the applicable OmCI bioconjugates for further pharmacokinetic assessments, and both showed improved plasma half-life in mice compared with unmodified OmCI (15.86, 17.96 vs 2.57 h). In summary, our data demonstrated that OmCI conjugated with fatty acid could be developed as the potential long-acting C5 complement inhibitor in the clinic.

Diagnostic Challenges and Emerging Pathogeneses of Selected Glomerulopathies.

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).

The complement cascade in renal pathology

The complement cascade comprises avariety of soluble and cell surface proteins and is an important component of the innate immune system. When the cascade is triggered by any of the three activation pathways, the complement system rapidly produces large amounts of protein fragments that are potent mediators of inflammatory, vasoactive, and metabolic responses. All activation pathways lead to the terminal complement cascade with the formation of the membrane attack complex, which lyses cells by forming membrane pores. Although the complement system is essential for pathogen defense and homeostasis, excessive or uncontrolled activation can lead to tissue damage. Recent research shows that the complement system is activated in almost all kidney diseases, even those not traditionally considered immune-mediated. In directly complement-mediated kidney diseases, complement factors or regulators are defective, afunctional or inactivated by antibodies. In many other renal diseases, the complement system is activated secondarily as aresult of renal damage and is therefore involved in the pathogenesis of the disease, but is not the trigger. The detection of complement deposits is also used to diagnose kidney disease. This review describes the structure of the complement system and the effects of its dysregulation as acause and modulator of renal disease.

Iptacopan: First Approval.

Iptacopan (FABHALTA®) is an oral complement Factor B inhibitor developed by Novartis Pharmaceuticals for the treatment of complement-mediated diseases. Acting upstream of complement 5 in the alternative pathway, iptacopan inhibits both terminal complement-mediated intravascular haemolysis and complement 3-mediated extravascular haemolysis. On 5 December 2023, iptacopan received approval in the USA for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH). This article summarizes the milestones in the development of iptacopan leading to this first approval for PNH.

Consensus on diagnosis and treatment of complement-mediated kidney diseases

In recent years, the role of complement in various kidney diseases has been gradually elucidated, and drugs targeting complement system have emerged successively, and some of them have been applied in clinical practice. However, there are some problems with complement-targeted therapy. This consensus was initiated by a collaborative group of experts in the diagnosis and treatment of complement-mediated kidney diseases from the medical department of Peking University. Their efforts drew upon domestic and international guidelines/consensuses, as well as the latest literature. The evidence and suggestions on the pathogenesis, diagnosis, complement targeted therapy and vaccine immunization of special pathogenic microorganisms of complement-mediated kidney diseases are briefly described, which aims to provide a reference for the diagnosis and treatment of complement-mediated kidney diseases.

C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement

Complement-mediated diseases can be treated using systemic inhibitors. However, complement components are abundant in circulation, affecting systemic inhibitors' exposure and efficacy. Furthermore, because of complement's essential role in immunity, systemic treatments raise infection risk in patients. To address these challenges, we developed antibody fusion proteins combining the alternative-pathway complement inhibitor factor H (fH1-5) with an anti-C3d monoclonal antibody (C3d-mAb-2fH). Because C3d is deposited at sites of complement activity, this molecule localizes to tissue complement while minimizing circulating complement engagement. These fusion proteins bind to deposited complement in diseased human skin sections and localize to activated complement in a primate skin injury model. We further explored the pharmacology of C3d-mAb-2fH proteins in rodent models with robust tissue complement activation. Doses of C3d-mAb-2fH >1mg/kg achieved >75% tissue complement inhibition in mouse andrat injury models while avoiding circulating complement blockade. Glomerular-specific complement inhibition reduced proteinuria and preserved podocyte foot-process architecture in rat membranous nephropathy, indicating disease-modifying efficacy. These data indicate that targeting local tissue complement results in durable and efficacious complement blockade in skin and kidney while avoiding systemic inhibition, suggesting broad applicability of thisapproach in treating a range of complement-mediated diseases.

Atypical Hemolytic Uremic Syndrome: A Nationwide Colombian Pediatric Series.

Objectives. Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease with genetic predisposition and represents up to 10% of pediatric hemolytic uremic syndrome (HUS) cases. Few studies have evaluated aHUS in Latin American population. We studied a Colombian pediatric cohort to delineate disease presentation and outcomes. Methods. A multicenter cohort of 27 Colombian children with aHUS were included. Patients were grouped by age at onset. Clinical features were compared using analysis of variance (ANOVA) and Fisher exact tests. Renal biopsy was performed on 6 patients who were suspected of having other renal diseases before aHUS diagnosis. Results. Most patients were male (70%). The onset of aHUS occurred frequently before age 4 years (60%) and followed gastroenteritis as the main triggering event (52%). Age groups showed comparable clinical presentation, disease severity, treatment, and outcomes. Pulmonary involvement (67%) was the main extrarenal manifestation, particularly in the 1 to 7 age group (P = .01). Renal biopsies were as follows: 3 had membranoproliferative glomerulonephritis (MPGN) type I, one MPGN type III, one C3-glomerulonephritis, and one rapidly progressive GN. Genetic screening was available in 6 patients and identified 2xCFHR5, 2xMCP, 1xADAMTS13/THBD, and 1xDGKE mutations. A total of 15 relapses were seen, of which 8 (72%) occurred in the 1 to 7 age group. The renal outcome was not significantly different regardless of age group. Conclusion. In our cohort, we observed a relatively high frequency of extrarenal involvement at first presentation represented by pulmonary manifestations. The renal prognosis at initial presentation was worse than in previous reports.

Coagulation and complement crosstalk: molecular mechanisms of complement-mediated diseases

The complement and coagulation systems are ancestrally related mechanisms of serine protease-induced protein activation. Recent studies have shown that the complement system enhances platelet aggregation by activating platelets and vascular endothelial cells. This system is also involved in the expression of tissue factor, which induces the coagulation reaction. Activated platelets and coagulation factors are also known to activate the complement system. In diseases involving the complement system, such as paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, and atypical hemolytic uremic syndrome, excessive activation of this system contributes to complement-mediated thrombosis. The anti-C5 antibody eculizumab has shown a remarkable thromboprophylactic effect in these complement diseases. The recent surge in development of new anti-complement agents has raised expectations for the advancement of treatments and preventive measures for thrombosis associated with complement disorders. This review outlines the crosstalk between these two systems, and describes the mechanisms of several diseases featuring both thrombosis and complement activation.