Is the COVID‐19 thrombotic catastrophe complement‐connected?

Abstract

In December 2019, the world was introduced to a new betacoronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for its propensity to cause rapidly progressive lung damage, resulting in high death rates. As fast as the virus spread, it became evident that the novel coronavirus causes a multisystem disease (COVID-19) that may involve multiple organs and has a high risk of thrombosis associated with striking elevations in pro-inflammatory cytokines, D-dimer, and fibrinogen, but without disseminated intravascular coagulation. Postmortem studies have confirmed the high incidence of venous thromboembolism, but also notably revealed diffuse microvascular thrombi with endothelial swelling, consistent with a thrombotic microangiopathy, and inter-alveolar endothelial deposits of complement activation fragments. The clinicopathologic presentation of COVID-19 thus parallels that of other thrombotic diseases, such as atypical hemolytic uremic syndrome (aHUS), that are caused by dysregulation of the complement system. This raises the specter that many of the thrombotic complications arising from SARS-CoV-2 infections may be triggered and/or exacerbated by excess complement activation. This is of major potential clinical relevance, as currently available anti-complement therapies that are highly effective in protecting against thrombosis in aHUS, could be efficacious in COVID-19. In this review, we provide mounting evidence for complement participating in the pathophysiology underlying the thrombotic diathesis associated with pathogenic coronaviruses, including SARS-CoV-2. Based on current knowledge of complement, coagulation and the virus, we suggest lines of study to identify novel therapeutic targets and the rationale for clinical trials with currently available anticomplement agents for COVID-19.

COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management

“…Venous thromboembolism (VTE) very commonly complicates the clinical course of inpatients with COVID-19, despite thromboprophylaxis; the risk appears highest among critically ill inpatients monitored in the intensive care unit (ICU). 15 The incidence of VTE in COVID-19 patients has been reported to occur in ∼10-35%, with autopsies indicating that it may reach nearly 60% 12,16 ; with pulmonary embolism being the most common thrombotic complication. 17 A recent large meta-analysis of 44 studies reporting on acute complications and mortality in 14,866 hospitalized COVID-19 patients indicated that VTE occurred in 15%; however, the authors admit to very low-quality evidence due to high heterogeneity and risk of bias (Table 1).…”

“…Due to the involvement of complement and neutrophils, in addition to platelets and other coagulation and endothelial factors, in the pathogenesis of virus-induced immuno-inflammatory coagulopathy and thrombotic microangiopathy, there is a suggestion that early intervention with anticomplement agents and NET inhibition may be important to limit cell/tissue damage and its attendant thrombosis; however, this remains to be tested. 10,12,13…”

“…12 It has been proposed that SARS-CoV-2 may also trigger complement activation through its recognition by the host as a foreign pathogen, by acting as a cofactor to enhance lectin pathway activation, and by invading and injuring ACE2 receptor-expressing host cells, with all these actions promoting a thromboinflammatory response, which in turn, recircles to further amplify complement activation and clotting. 12 Hence the suggestion that early intervention for COVID -19 with anticomplement agents may be important to limit cell/ tissue damage, which remains to be tested (see discussion below). As mentioned, in addition to complement, neutrophils yielding high tissue factor (TF) expression and releasing NETs carrying active TF, also contribute to the maladaptive immune response that leads to hyper-inflammatory reaction and thrombotic microangiopathy; hence, the recommendation for strategies against SARS-CoV-2 that exploit complement and/or NET inhibition.…”

Impairment in selenocysteine synthesis as a candidate mechanism of inducible coagulopathy in COVID-19 patients

“…Dysregulated immune response, via establishment of a pro-inflammatory feedback loop, presumably exerts damage to the lung parenchyma [30] and triggers a peculiar hemophagocytic lymphohistiocytosis [31] , which has been extensively demonstrated in severe COVID 19 patients. Endothelial injury, mediated by direct SARS-CoV-2 infection of endothelial cells [32] (in which selenium-dependent GPX1 may play a crucial part by enhancing SARS-CoV-2 virulence [8] ) and the generalized excessive pro-inflammatory state, has been robustly implicated in COVID-19 coagulopathy [33] , via multiple mechanisms including platelet activation [34] , fibrinolysis shutdown [35] , [36] , massive von Willebrand factor release [37] , increased thrombin production [4] , disproportionate complement activation leading to thrombogenesis [38] and Neutrophil Extracellular Traps (NETs) formation [39] . Therefore, impairment in selenocysteine synthesis may contribute to COVID-19 coagulopathy via the dysregulated immune response pathway.…”

The immune response to SARS-CoV-2. Focus on severe COVID-19 pathogenesis

“…This is clinically present as ARDS or AKI [39]. Both diseases, when fully presented are difficult to control even in the ICU settings [40][41][42][43]. Therefore, many strategies focused on prevention of complement activation are proposed as important aspects of COVID-19 treatment.…”