key: cord-341415-g781zhu6
authors: Jhaveri, Kenar D.; Meir, Lea R.; Flores Chang, Bessy Suyin; Parikh, Rushang; Wanchoo, Rimda; Barilla-LaBarca, Marie Louise; Bijol, Vanesa; Hajizadeh, Negin
title: Thrombotic microangiopathy in a patient with COVID-19
date: 2020-06-07
journal: Kidney Int
DOI: 10.1016/j.kint.2020.05.025
sha: 
doc_id: 341415
cord_uid: g781zhu6

nan

We describe a patient with coronavirus disease 2019 (COVID-19) and clinically significant kidney biopsy proven thrombotic microangiopathy(TMA).

A 69-year-old Caucasian female with past medical history of asthma presented to the emergency department with productive cough, fever, and shortness of breath of 2 weeks duration. In the emergency room, she was afebrile with a respiratory rate of 22 breaths per minute and oxygen saturation of 89% on room air. Initial laboratory tests showed a normal white blood cell count, hemoglobin level and platelet count. Inflammatory lab parameters were elevated (Table 1) . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was confirmed in the patient by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay or serologic testing at our center. A chest x-ray showed bilateral diffuse patchy opacities.

The patient was admitted and treatment with hydroxychloroquine, low molecular weight heparin, and oxygen was initiated. Over the next several days, she received anakinra and tocilizumab(dosages and details in Table 1 ). On day 12, the patient's labs demonstrated downtrending platelets, hemoglobin and worsening kidney function. There was concern for microangiopathic hemolytic anemia. Due to worsening hypoxemia, patient received convalescent plasma treatment as part of an expanded access trial. On day 17, the patient was intubated due to worsening respiratory failure. In addition, the patient developed findings of hemolysis (presence of schistocytes, undetectable haptoglobin levels, high lactate dehydrogenase) Urinalysis showed hematuria, large blood, 30-40 red blood cells/HPF and 1.4grams of protein. The patient's kidney function worsened requiring initiation of continuous renal replacement therapy. On day 20, the patient underwent a kidney biopsy that revealed severe acute thrombotic microangiopathy with cortical necrosis (Figure 1 ). While beta 2 glycoprotein-1 IgM levels were elevated, other laboratory and clinical features of anti-phospholipid antibody were absent( Table 2) . A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) level was not low. Complement 3 and 4 were in normal range. Heparin induced antibody testing was negative. Coagulation parameters were normal. A kidney sonogram was negative for renal vein thrombosis and arterial clots. The patient didn't have any other systemic findings of macro thrombi. Subsequent detailed complement testing revealed a low factor H complement antigen, elevated plasma CBb complement and plasma SC5b-9 complement levels suggesting an activation of the alternative complement pathway ( Table 2) . Genetic testing was not performed. Given clinical instability, plasma exchange was not performed. Instead, the patient was given a single dose of eculizumab at 900mg on day 21. Unfortunately, the patient expired on day 23 in the setting of worsening shock.

Coagulopathy associated with SARS-CoV-2 has been widely reported (1, 2) . The profound hypoxia, inflammation as well as disseminated intravascular coagulation(DIC) have all been implicated as potential causes (2) . There has also been a report of coagulopathy secondary to development of antiphospholipid antibodies (3). Our patient had no evidence of DIC. While we cannot completely rule out anti phospholipid antibody syndrome, it is less likely to have played a role in this case as there was no prior history of autoimmunity and no other current stigmata of evolving connective tissue disease such as lupus or anti phospholipid syndrome in other body systems. Transient elevation of both beta-2 glycoprotein-1 IgG and IgM can be seen in the setting of infections and drug exposures(4). Ideally a confirmation of auto-antibodies is needed at 12 weeks which was not able to be done in this case. Collapsing glomerulopathy associated with SARS-CoV-2 has now been reported from several centers as the first described glomerular pathology in this setting (5, 6) . To our knowledge, there have been no published cases of SARS-CoV-2 associated systemic TMA. We report the first case of TMA associated with SARS-CoV-2 with presence of diffuse cortical necrosis and widespread microthrombi in the kidney biopsy. It is not clear if the virus played a direct pathogenic role or unmasked a latent complement defect( as noted in our complement testing) leading to widespread endothelial damage and micro thrombi (7). AKI is not uncommon in patients with COVID-19 (8) . Causes of AKI can range from pre renal azotemia, acute tubular injury to collapsing glomerulopathy (5, 6, 9) . Physicians treating patients with COVID-19 should keep microangiopathic disease in the differential diagnosis when systemic findings of hemolysis are present along with thrombocytopenia and AKI. Earlier diagnosis could perhaps lead to prompt treatment with plasma exchange or complement pathway inhibitors.

The report acknowledges the Northwell Covid-19 Research consortium.

The Northwell Health Institutional Review Board approved this case as minimal-risk research using data collected for routine clinical practice and waived the requirement for informed consent. 

Haematological parameters in severe acute respiratory syndrome

Hematologic parameters in patients with COVID-19 infection

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

The use of an anti-beta 2-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis

Tubuloreticular inclusions in COVID-19-related collapsing glomerulopathy

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

International Registry of Recurrent and Familial HUS/TTP: Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

Acute Kidney injury in patients hospitalized with COVID

Acute kidney injury associated with coronavirus disease 2019 in Urban New Orleans

Serum Complement total -56U/ml( 30-75) Serum Complement C3 -105mg/dl

Serum Factor B Complement Antigen -28mg/dl( 15.2-42.3) Serum Factor H Complement Antigen-22mg/dl( 23.6-43.1) Plasma C4d Complement -2

Anti-phospholipid antibody testing with results and reference ranges

Anti Cardiolipin IgG-13.6 GPL( 0-12.5)

Anti Cardiolipin IgM-12

Anti Cardiolipin IgA-6.7APL( 0-12.5) Beta2 glycoprotein-1 IgG-<5 SGU( <20 ) Beta 2 glycoprotein-1 IgM -68.6 SMU( <20) Beta 2 glycoprotein -1