Will Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis?
Authors: Courtney M. Campbell, Rami Kahwash
Journal: Circulation (2020)

HomeCirculationVol. 141, No. 22Will Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBWill Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis? Courtney M. Campbell and Rami Kahwash Courtney M. CampbellCourtney M. Campbell Courtney M. Campbell, MD, PhD, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Suite 200, 473 W 12th Ave, Columbus, OH 43210. Email E-mail Address: [email protected] Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. and Rami KahwashRami Kahwash Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. Originally published9 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047419Circulation. 2020;141:1739–1741Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 9, 2020: Ahead of Print SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus responsible for the current pandemic, resulting in an escalating number of cases and fatalities worldwide. Despite a high infection rate of coronavirus disease 2019 (COVID-19), only an estimated 15% of patients require hospitalization, with 5% requiring intensive care. Nearly half (49%) of patients requiring intensive care died. How and why patients succumb to SARS-CoV-2 infection is not well understood. A poignant New York Times article described the sudden decompensation and death of a young physician after she had documented viral clearance and was preparing to go home.Several early publications from the Wuhan region of China focused on describing clinical characteristics of hospitalized patients with severe COVID-19 illness. These initial observational studies demonstrate in severe cases evidence of coagulation dysfunction through elevated D-dimer, elevated lactate dehydrogenase, elevated total bilirubin, and decreased platelets with slight or no changes in partial thromboplastin time or activated partial thromboplastin time. In patients with severe or fatal COVD-19, there is also evidence of end-organ damage with acute kidney injury and primarily mildly elevated troponin. In the study by Shi et al,1 a significantly higher percentage of patients with cardiac injury (average troponin I 0.19 µg/L) died compared with those patients without cardiac injury (51.2% versus 4.5%, respectively).The mechanism of cardiac injury for COVID-19 is uncertain. No series of cardiac imaging data, such as echocardiography or cardiac magnetic resonance imaging, has been published for patients with COVID-19. Theories include direct viral damage via the angiotensin-converting enzyme 2 receptor, myocarditis, systemic inflammatory response with cytokine storm, destabilized coronary plaques, and aggravated hypoxia. In case reports of COVID-19–related myocarditis, patients had minimal pulmonary involvement and significant cardiac involvement and recovered from COVID-19. Cardiac biomarkers in the myocarditis cases were much higher than the average values of cardiac injury in patients with COVID-19 reported in the observational studies. Whether myocarditis as a COVID-19 mechanism applies broadly is uncertain. Excessive cytokine release has also been observed in patients with COVID-19. High cytokines were also found in patients with SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus), but subsequent studies demonstrated that corticosteroids did not improve mortality and delayed viral clearance. Tocilizumab, an interleukin-6 inhibitor, is being studied as a potential treatment option. However, elevated cytokines in this context could be a biomarker of critical illness with COVID-19 rather than the pathogenic mediator.In a joint webinar between the Chinese Cardiology Association and the American College of Cardiology on March 28, 2020, the Chinese cardiologists described diffuse microvascular thrombi in multiple organs on autopsy review of COVID-19 nonsurvivors. Given this diffuse thrombosis, Chinese physicians recommended treatment of patients with COVID-19 with systemic anticoagulation, but no trials or publications have evaluated this approach. Similar findings of diffuse multiorgan microvascular thrombosis without viral infiltrates were seen in an autopsy case report for a patient who died of SARS.2Thrombotic microangiopathy (TMA) can occur in many different clinical scenarios, including pathogenic complement activation. The complement system is a mediator of the innate immune response that promotes inflammation, defends against bacterial infections, and often neutralizes infectious viruses. In brief, the complement cascade can be activated via the classical pathway, triggered by antibody-antigen complexes; the alternative pathway, stimulated by specific surface antigens; and the lectin pathway, initiated by binding mannose residues on the pathogen surface. These pathways converge on the common pathway. The common pathway includes production of C3a and C5a inflammatory mediators and C3b-initiated pathogen opsonization and ends in formation of the C5b-9 membrane attack complex, which lyses target cells, resulting in cell death (Figure [A]). Two murine studies directly investigated complement activation in coronavirus infections and asked whether activation of the system would be protective or pathogenic. In a murine model lacking C3 and thus unable to activate the common complement pathway, SARS-CoV infection severity was decreased, with less respiratory dysfunction and lower cytokine levels despite equal viral loads (Figure [C]).2 The authors suggest that a significant portion of SARS-mediated disease is likely immune mediated. In a murine model of MERS-CoV infection, increased concentrations of C5a and C5b-9 were found in sera and lung tissues.4 Blocking C5a with a murine antibody alleviated lung and spleen damage, with decreased cytokine response and viral replication (Figure [D]).Download figureDownload PowerPointFigure. Coronavirus and complement.A, Simplified diagram of the common complement pathway. Eculizumab inhibits C5, preventing breakdown into C5a and C5b, which is an integral component of the membrane attack complex (MAC). B, In humans, overactivation of the complement pathway can lead to thrombotic microangiopathy, resulting in renal and cardiac dysfunction. In atypical hemolytic-uremic syndrome (aHUS), early treatment with eculizumab reverses organ dysfunction. C, On the basis of the mouse model of SARS-CoV (severe acute respiratory syndrome coronavirus)infection described by Gralinski et al,2 lack of the C3 protein results in improved lung function, less cytokine release, and no change in viral load compared with mice with an intact complement system. D, On the basis of the mouse model of MERS-CoV (Middle East respiratory syndrome coronavirus) infection described by Jiang et al,3 antibody blockade of C5 results in improved lung function, less cytokine release, and less viral load compared with untreated mice.In humans, excessive complement activation occurs in a number of pathological settings, leading to diffuse TMA and end-organ dysfunction (Figure [B]). Atypical hemolytic-uremic syndrome (aHUS) is a rare disorder of uncontrolled complement activation characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. TMA in aHUS results in renal dysfunction and, in rare cases, cardiac dysfunction.5 Patients often have an underlying genetic predisposition, with variants in the complement cascade. Alternatively, infection, pregnancy, and certain medications and autoimmune disorders can trigger complement-activating autoantibodies. Importantly, aHUS is treatable with a C5 complement inhibitor, eculizumab. If given early, eculizumab therapy can reverse both renal and cardiac dysfunction.5 Before the introduction of eculizumab, the prognosis of aHUS was poor, with 67% of adults dying within 5 years.Transplant-associated TMA is also thought to be initiated by excessive complement activation, trigged by endothelial injury from chemotherapy, radiation, or viral infection. A recent study showed that 78% of patients with transplant-associated TMA had a pathogenic or likely pathogenic variant in TMA and complement-associated genes.6 Importantly, endothelial injury is a hallmark of COVID-19. Like SARS-CoV, COVID-19 acts primarily through the angiotensin-converting enzyme 2 receptor, which is expressed widely in vascular tissues, including alveolar epithelium and cardiac pericytes.Complement inhibition may be a promising treatment for severe COVID-19 by reducing the innate immune-mediated consequences of severe coronavirus infection, and it would pair well with direct antiviral therapy. The published clinical observations of severe COVID-19 are consistent with excessive complement activation: elevated lactate dehydrogenase, D-dimer, and bilirubin; decreased platelets; mild anemia; renal and cardiac injury; and reportedly diffuse TMA. Patients with severe and fatal cases of COVID-19 might have increased susceptibility to TMA through a genetic predisposition to pathogenic complement activation. Complement inhibition was associated with favorable outcomes in SARS-CoV and MERS-CoV murine models and reversed cardiac dysfunction in aHUS-TMA, which mimics the pathological findings seen in COVID-19. Complement inhibition might be a new target in treating COVID-19–related systemic thrombosis. This approach is worthy of further investigation with a randomized, controlled clinical trial to investigate whether complement inhibition could improve the clinical course for COVID-19 patients with severe disease.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circCourtney M. Campbell, MD, PhD, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Suite 200, 473 W 12th Ave, Columbus, OH 43210. Email courtney.campbell@osumc.eduReferences1. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China [published online March 25, 2020].JAMA Cardiol. doi: 10.1001/jamacardio.2020.0950. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524.Google Scholar2. Xiang-Hua Y, Le-Min W, Ai-Bin L, Zhu G, Riquan L, Xu-You Z, Wei-Wei R, Ye-Nan W. Severe acute respiratory syndrome and venous thromboembolism in multiple organs.Am J Respir Crit Care Med. 2010; 182:436–437. doi: 10.1164/ajrccm.182.3.436CrossrefMedlineGoogle Scholar3. Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, Whitmore A, Heise MT, Baric RS. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis.mBio. 2018; 9:e01753-18. doi: 10.1128/mBio.01753-18CrossrefMedlineGoogle Scholar4. Jiang Y, Zhao G, Song N, Li P, Chen Y, Guo Y, Li J, Du L, Jiang S, Guo R, et al. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.Emerg Microbes Infect. 2018; 7:77. doi: 10.1038/s41426-018-0063-8CrossrefMedlineGoogle Scholar5. Campbell CM, Cassol C, Cataland SR, Kahwash R. Atypical haemolytic uraemic syndrome: a case report of a rare cause of reversible cardiomyopathy.Eur Heart J Case Rep. 2020; 4:1–6. doi: 10.1093/ehjcr/ytaa050CrossrefMedlineGoogle Scholar6. Gavriilaki E, Touloumenidou T, Sakellari I, Batsis I, Mallouri D, Psomopoulos F, Tsagiopoulou M, Koutra M, Yannaki E, Papalexandri A, et al. Pretransplant genetic susceptibility: clinical relevance in transplant-associated thrombotic microangiopathy.Thromb Haemost. March 4, 2020; 120:638–646. doi: 10.1055/s-0040-1702225CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. 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