COVID-19, microangiopathy, hemostatic activation, and complement Wen-Chao Song, Garret A. FitzGerald J Clin Invest. 2020. https://doi.org/10.1172/JCI140183. Viewpoint The COVID-19 pandemic caused by the SARS–CoV-2 virus has swept the globe with devastating societal consequences and has placed tremendous stress on health care systems. Although severe respiratory disease is a dominant feature, strokes, venous thrombosis, renal failure, cardiomyopathy, and coronary and systemic vasculitis have complicated the clinical phenotype (1–5). Indeed, besides typical features of acute respiratory distress syndrome (ARDS), patients with COVID-19 exhibit a thrombotic necrotizing injury of the lung capillaries (6). This clinical pattern, together with a low blood platelet count (thrombocytopenia) and elevated plasma fibrin degradation products (D-dimers) (7, 8), is highly suggestive of complement activation. Complement and its dysregulation in human disease The complement system is part of the innate immune system and can be activated via three separate pathways: the Ab-dependent classical pathway, the mannose-binding lectin (MBL) pathway, and the alternative pathway (Figure 1 and ref. 9). Activated complement can produce direct effector functions by target opsonization with cleaved complement component 3 (C3) and C4 fragments, promotion of inflammation with C3a and C5a, and direct cell lysis with the assembly of the membrane attack complex (MAC) C5b-9 (Figure 1 and ref. 9). Complement activation also primes adaptive immune responses. For example, the adjuvant effect of C3 activation in eliciting a robust Ab response is well established (9). Our understanding of inappropriate complement activation in human […] Find the latest version: https://jci.me/140183/pdf The Journal of Clinical Investigation VIEWPOINT COVID-19, microangiopathy, hemostatic activation, and complement Wen-Chao Song1,2 and Garret A. FitzGerald1,2,3 1Department of Systems Pharmacology and Translational Therapeutics, 2Institute for Translational Medicine and Therapeutics, and 3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. The COVID-19 pandemic caused by the Our understanding of inappropriate COVID-19. Pathogen infection is a com- SARS–CoV-2 virus has swept the globe with complement activation in human disease mon external trigger of increased comple- devastating societal consequences and has derives mainly from genetic mutations ment activation. Although complement, placed tremendous stress on health care of complement proteins — either loss-of- like other innate immune system compo- systems. Although severe respiratory dis- function mutations in regulatory proteins nents, helps to control initial bacterial or ease is a dominant feature, strokes, venous that protect host tissues under homeostatic viral infections, there is a risk of comple- thrombosis, renal failure, cardiomyopathy, conditions or gain-of-function mutations ment becoming detrimental in later stages and coronary and systemic vasculitis have resulting in resistance to regulatory pro- of the infection because of overactivation complicated the clinical phenotype (1–5). tein surveillance (10). Paroxysmal noctur- directly induced by the pathogen, or sec- Indeed, besides typical features of acute nal hemoglobinuria (PNH), for example, ondarily via damaged host tissues. Run- respiratory distress syndrome (ARDS), is caused by deficiency of 2 complement away complement activation may over- patients with COVID-19 exhibit a throm- regulatory proteins on affected blood cells, whelm host cell regulatory mechanisms, botic necrotizing injury of the lung capillar- decay-accelerating factor (DAF, also known particularly in individuals with genetic ies (6). This clinical pattern, together with a as CD55) and CD59, and is characterized by predispositions to subclinical complement low blood platelet count (thrombocytope- complement-mediated hemolysis and mul- regulation insufficiency. nia) and elevated plasma fibrin degradation tiorgan thrombosis (11). The thrombotic The clinical phenotypes of COVID-19 products (D-dimers) (7, 8), is highly sugges- microangiopathy (TMA) of the atypical likely reflect direct effects of virus-me- tive of complement activation. hemolytic uremia syndrome (aHUS) leads diated physical damage to tissue integ- to thrombocytopenia, hemolytic anemia, rity as well as maladaptive host immune Complement and its and renal failure (12). However, thrombotic responses. For example, endothelial cells dysregulation in human events in aHUS are not confined to the kid- express high levels of angiotensin-con- disease ney; 3% to 10% of patients have cardiac verting enzyme 2 (ACE2), the receptor for The complement system is part of the complications due to coronary microangi- SARS–CoV-2, and viral infection can dis- innate immune system and can be acti- opathy, and patients often develop com- rupt endothelial cell function directly or vated via three separate pathways: the plications involving other organs (12). The evoke an inflammatory or other immune Ab-dependent classical pathway, the most frequent mutations in aHUS are found response (14). These last mechanisms are mannose-binding lectin (MBL) pathway, in the regulatory protein factor H (FH), and critical in the cytokine storm that com- and the alternative pathway (Figure 1 and such mutations lead to MAC-mediated plicates the most severe phenotype of ref. 9). Activated complement can pro- endothelial injury and capillary thrombo- COVID-19 (15). The anaphylatoxins C3a duce direct effector functions by target sis, which are the hallmarks of TMA (13). and C5a are likely major contributors to opsonization with cleaved complement Both PNH and aHUS are caused by inad- cytokine storm syndrome, both directly component 3 (C3) and C4 fragments, equate control of complement activation through their intrinsic proinflammatory promotion of inflammation with C3a and and successfully treated with eculizumab, a activities in leukocyte activation and C5a, and direct cell lysis with the assembly humanized anti-C5 mAb (9). trafficking and indirectly by synergizing of the membrane attack complex (MAC) with other innate immune sensors, such C5b-9 (Figure 1 and ref. 9). Complement Evidence and mechanism of as TLRs, to amplify inflammation (16). activation also primes adaptive immune complement activation in Indeed, in a Chinese cohort of patients with responses. For example, the adjuvant COVID-19 COVID-19, plasma C5a levels reflected the effect of C3 activation in eliciting a robust It is highly plausible that complement acti- severity of the disease (17). Anecdotally, Ab response is well established (9). vation plays a role in the pathogenesis of treating two of these patients with an anti- C5a mAb coincided with resolved fever and increased oxygen saturation (17). Conflict of interest: Conflict of interest WCS owns equity in, receives consultant fees and research grants from, and It is likely that complement is activated is an inventor on patents for anti-complement mAbs (WO2018/165062, WO2018/148486, and US2020/0148754A1) in COVID-19 via multiple pathways, both and gene therapy (WO2017/053732A2), licensed to Kira Pharmaceuticals and Aevitas Therapeutics. GAF is an advi- by SARS–CoV-2 itself and by damaged tis- sor to Calico Laboratories, from which he receives salary and research support. Copyright: © 2020, American Society for Clinical Investigation. sues and dying cells at later stages of the Reference information: J Clin Invest. https://doi.org/10.1172/JCI140183. disease (Figure 1). For example, natural jci.org 1 VIEWPOINT The Journal of Clinical Investigation Figure 1. Potential mechanisms of complement-mediated pathology in COVID-19. SARS–CoV-2 virus may directly activate the complement pathways. Damaged host tissues could also secondarily activate complement via any of the three pathways: the classical pathway, the lectin pathway, or the alter- native pathway. Complement activation generates the anaphylatoxins C3a and C5a and the MAC C5ab-9. The C5a anaphylatoxin can cause neutrophil and monocyte activation, promote the formation of NET and platelet-leukocyte aggregates, and stimulate neutrophil degranulation and the release of tissue factor to trigger the extrinsic coagulation pathway. These C5a effects may contribute to a hypercoagulative state leading to VTEs and disseminated intra- vascular coagulation (DIC). The MAC C5b-9 can cause direct endothelial injury and platelet activation, leading to TMA. Capillary and blood vessel occlusion by TMA and VTEs eventually results in tissue ischemia and oxidant injury, contributing to multiorgan failure in COVID-19. AKI, acute kidney injury; FB, complement factor B; FD, complement factor D; P, properdin. (IgM) Abs that recognize viral antigens or Complement-mediated Eculizumab effectively inhibits C5 neoantigens exposed on damaged host coagulopathy and to block venous thromboembolic events tissues could trigger the classical path- microangiopathy in COVID-19 (VTEs) in PNH and TMA in aHUS (9). way (18). The lectin pathway could also Complement activation may also con- Until recently, the relative contributions activate in response to viral components tribute to hemostatic activation leading of the C5a and C5b-9 pathways to these such as the nuclear protein (N protein), as to coagulopathy and explain microvascu- pathologies remained unknown. Exper- demonstrated in a recent study for SARS- lar injury, pathological features that are iments in a mouse model carrying