Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: Literature Review

Abstract

Coronavirus disease 2019 (COVID-19) can lead to clinically significant multisystem disorders that also affect the kidney. According to recent data, renal injury in the form of thrombotic microangiopathy (TMA) in native kidneys ranks third in frequency. Our review of global literature revealed 46 cases of TMA in association with COVID-19. Among identified cases, 18 patients presented as thrombotic thrombocytopenic purpura (TTP) and 28 cases presented as atypical hemolytic uremic syndrome (aHUS). Altogether, seven patients with aHUS had previously proven pathogenic or likely pathogenic genetic complement abnormalities. TMA occurred at the time of viremia or even after viral clearance. Infection with COVID-19 resulted in almost no or only mild respiratory symptoms in the majority of patients, while digestive symptoms occurred in almost one-third of patients. Regarding the clinical presentation of COVID-19-associated TMA, the cases showed no major deviations from the known presentation. Patients with TTP were treated with plasma exchange (88.9%) or fresh frozen plasma (11.1%), corticosteroids (88.9%), rituximab (38.9%), and caplacizumab (11.1%). Furthermore, 53.6% of patients with aHUS underwent plasma exchange with or without steroid as initial therapy, and 57.1% of patients received a C5 complement inhibitor. Mortality in the studied cohort was 16.7% for patients with TTP and 10.7% for patients with aHUS. The exact role of COVID-19 in the setting of COVID-19-associated TMA remains unclear. COVID-19 likely represents a second hit of aHUS or TTP that manifests in genetically predisposed individuals. Early identification of the TMA subtype and appropriate prompt and specific treatment could lead to good outcomes comparable to survival and recovery statistics for TMA of all causes.

Pitfalls of Thrombotic Microangiopathies in Children: Two Case Reports and Literature Review

“…The primary mechanisms of TMA in COVID-19 patients are complement-mediated disease and acquired deficiency of ADAMTS13. However, COVID-19 patients may also develop TMA in association with the presence of other bacterial toxins, malignancies, or medications [ 61 ]. Nevertheless, in a vast majority of these cases, abnormalities in the complement system that serve as the initial trigger for TMA may not be identified.…”

COVID‐19 associated thrombotic microangiopathy

“…Eculizumab was also used to treat cases with TMA due to COVID-19 infection, and it was highlighted that both haemoglobin levels and platelet counts increased rapidly, and serum creatinine levels decreased. 10,11,22 In our first case, we administered eculizumab because of prolonged anuria and need for haemodialysis, and persistent haemolysis.…”

Effect of coronaviruses on blood vessel permeability: potential therapeutic targets

“… 85 , 86 In mild to severe COVID-19 patients, profound increases in cytokine production, including IL-1β, IL-6, IL-2R, TNF-α, and IFN-γ (‘cytokine storm’), fibrosis, and microthrombi formation, including thrombotic microangiopathy in patients with severe disease, are usually observed. 70 , 75 , 87 – 89 Thus, besides immune and resident cells overreaction, unbalanced AT1R signaling in endothelium and vascular smooth muscles may contribute to the cytokine storm, fibrosis, and microthrombi formation observed in several patients infected with SARS-CoV-2. 84 , 85 , 88 Microthrombi formation was even considered a marker of COVID-19 severity, and other mechanisms may favor it, including (1) direct injury of endothelial cells by the virus with activation of the coagulation cascade, (2) neutrophil-derived tissue factor (TF)-rich neutrophil extracellular traps (NETs) formation, favoring platelet clot and activation of the extracellular pathway of coagulation, (3) enhanced neutrophil and platelet adhesion to microvessels, leading to hypoxia and upregulation of the TF expression, (4) activation of complement factors, and (5) high numbers of both thrombospondin 1 (THBS-1)+ monocytes and Myl9+ platelets.…”

“… 89 It is characterized by widespread thrombosis in capillaries and arterioles clinically manifested by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. 89 Acute kidney disease may accompany thrombotic microangiopathy in some COVID-19 patients. 97 Activated platelets and NETs play an essential role in full thrombotic microangiopathy development.…”

“… 97 Activated platelets and NETs play an essential role in full thrombotic microangiopathy development. 89 Furthermore, in SARS-CoV-2 infection, thrombotic microangiopathy appears triggered in some individuals by uncontrolled complement activation and genetic background. 89 Additional studies are needed to elucidate how the SARS-CoV-2 virus and thrombotic microangiopathy interact.…”