Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications

Abstract

Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.

Fig. 1. A model of COVID-19 microangiopathy pathogenesis.

On the basis of emerging literature on the coagulation disorders and blood vessel pathology in patients with coronavirus disease 19 (COVID-19)^{,,,–,,,–,–,,,}, we hypothesize a unique thrombotic microangiopathy (TMA) syndrome that is non-identical to other TMAs but shares key features with complement-mediated TMA conditions that involve infection-induced, organ transplant-related, autoimmune-mediated or inherited disorders of the complement system^,,,. The SARS-CoV-2 virus probably enters alveolar pneumocytes through the respiratory tract and can also infect adjacent endothelial cells that supply the lungs and other organs that express angiotensin-converting enzyme 2 (ACE2) receptor, the receptor for this pathogen. As would be expected, this invasion triggers a rapid innate immune response by neutrophils and macrophages, activated in large part by type I interferons. If this process is inefficient, or if the adaptive immune response is delayed (owing in part to SARS-CoV-2 being a new infectious agent for which immunological memory has not been established), substantial damage might occur in capillaries or other small vessels surrounding the alveolar spaces, activating a pro-coagulant state. With further persistence of virus, complement-initiated damage to vessels intensifies, and inflammatory cells induce a wider and stronger burst of cytokines, including IL-6, which supports a bidirectional promotion of the immune–coagulation axis. This process might or might not develop into a viral sepsis with full-blown cytokine storm and pneumonia, but often does. A life-threatening coagulopathy is not rare in this COVID-19-associated thrombotic syndrome^,,–,, characterized by microthrombi in small vessels and/or rapidly progressive thromboses in both large and small vessels in multiple organs. MASP, mannan-binding lectin serine protease; MBL; mannose-binding lectin; TF, tissue factor.