key: cord-0953101-dcfi1ik3 authors: Valga, Francisco; Vega- Díaz, Nicanor; Macia, Manuel; Monzón, Tania; Rodriguez-Perez, Jose C title: Targeting complement in severe Coronavirus disease 2019 to address microthrombosis date: 2020-06-12 journal: Clin Kidney J DOI: 10.1093/ckj/sfaa095 sha: 265c3591944e836084d9cc14bc23f1c5f44162ea doc_id: 953101 cord_uid: dcfi1ik3 nan kidney or heart (Table 1) [5] [6] [7] [8] [9] [10] . However, we have not found alterations in haptoglobin or the presence of schistocytes to date. A related virus, SARS-CoV, promotes complement activation, increasing C5a levels and contributing to hyperinflammation [11] . Generally speaking, sepsis or critical injury (e.g. in the context of COVID-19) will activate immune cells that cause endothelial dysfunction, resulting in the activation of two molecular pathways: further inflammation and microthrombosis associated with complement activation and excess thrombin generation [2, 9] . Microthrombi may have different clinical manifestations depending on the most affected organ, such as ARDS in the lung, acute renal failure and haemolytic uraemic syndrome or acute myocardial infarction, among others [2] . While complement protects from infection, dysregulated complement activation could cause TMA and contribute to ARDS as suggested for other coronaviruses [2, 5, 12] . Additionally, in the context of inflammation, non-complement proteases, such as thrombin, a coagulation pathway protein [13] , and proteases from neutrophils and macrophages can generate C5a from C5, independently from the plasma complement system [14] . We agree with Campbell that severe COVID-19 manifestations have commonalities with thrombotic microangiopathies that respond to the C5a complement inhibitor eculizumab [6, 15] . In this regard, anti-complement therapies should be part of clinical trials with well-defined entry criteria for a combined inflammatory-microthrombotic syndrome and integrating the approach within the current therapeutic algorithm for COVID-19 [1] . Indeed, two Phase 2 clinical trials testing eculizumab for DIC, disseminated intravascular coagulation; APS, anti-phospholipid syndrome; RBC, red blood cells; FFP, fresh frozen plasma ; PE, plasma exchange; HUS, haemolytic uraemic syndrome; aHUS, atypical haemolytic uraemic syndrome; TTP, thrombotic thrombocytopenic purpura ; PC, platelet concentrate; AC, antithrombin concentrate; rhTM, recombinant human thrombomodulin. [2] , which includes endothelial dysfunction as the origin of the damage and the two main pathways. The first is the inflammatory pathway that would be related to the activation of monocytes-macrophages triggering the 'cytokine storm' leading to a systemic inflammatory response syndrome that usually occurs in association with ARDS and, ultimately, multi-organ failure. The second is the microthrombotic , closely related to activation of the complement, platelet and coagulation disorders. Also, there are factors that interact with both pathways, for example, the inducible serine protease that activates C5; some cytokines favour the development of disseminated intravascular coagulation and hypoxia favours a prothrombotic state per se by stimulating thrombin. patients with severe COVID-19 are scheduled to start soon or have started in April 2020 (NCT04288713, NCT04346797). Furthermore, the relative contribution of anticoagulation and complement targeting should be defined [16] . It is likely that anticoagulation targets a relatively late event that may be driven by earlier complement activation and endothelial injury [2] . In order to clarify this hypothesis, we have designed a scheme (Figure 1 ). COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal Acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis Pathological findings of COVID-19 associated with acute respiratory distress syndrome Pulmonary pathology of earlyphase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis? 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