Thrombotic microangiopathy in a patient with COVID-19
Authors: Kenar D. Jhaveri, Lea R. Meir, Bessy Suyin Flores Chang, Rushang Parikh, Rimda Wanchoo, Maria Louise Barilla-LaBarca, Vanesa Bijol, Negin Hajizadeh
Journal: Kidney International (2020)

We describe a patient with coronavirus disease 2019 (COVID-19) and clinically significant kidney biopsy-proven thrombotic microangiopathy. A 69-year-old Caucasian female with a 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 assay or serologic testing at our center. A chest X-ray showed bilateral diffuse patchy opacities.Table 1Chronological treatment and laboratory dataTreatment givenDay 1Day 7Day 16Day 17Day 18Day 19Day 20Day 21Hydroxychloroquine/low-molecular-weight heparinAnakinra & tocilizumabConvalescent plasmaIntubationDialysis startedKidney biopsyEculizumabHemoglobin (11.5–15.5 g/dl)1311.512.911.88.08.38.66.9Platelets (150–400 K/ul)203142851497372127Serum creatinine, mg/dl0.720.750.572.062.494.07On dialysisOn dialysisFibrinogen (350–510 mg/dl)62159128117166D-dimer (<229 ng/ml DDU)411606814,56812,1935927ADAMTS 13 activity level (>66.8%)43.2Alkaline phosphatase (40–120 U/l)137118292296194212204294AST (10–40 U/l)704463316404254173148ALT (10–45 U/l)38302797146239230165LDH (50–242 U/l)45910733518513051834707C-reactive protein (0–0.40 mg/dl)10.352.466.8518.5420.7313.618.02Hep- PF 4 AB result (0.0–0.9 U/ml)<0.6Hep- PF 4 AB interpretationNegativeSchistocytes in smearPresentPresentHaptoglobin (34–200 mg/dl)<20<20ADAMTS 13, disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Hep, heparin; LDH, lactate dehydrogenase; PF, endogenous protein platelet factor 4.Medication dosages: anakinra 100 mg q6 × 8 doses; tocilizumab 400 mg i.v. × 2 doses; eculizumab 900 mg i.v.—1 dose was able to be given (patient expired). Open table in a new tab ADAMTS 13, disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Hep, heparin; LDH, lactate dehydrogenase; PF, endogenous protein platelet factor 4. Medication dosages: anakinra 100 mg q6 × 8 doses; tocilizumab 400 mg i.v. × 2 doses; eculizumab 900 mg i.v.—1 dose was able to be given (patient expired). 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 are given in Table 1). On day 12, the patient's labs demonstrated down-trending platelets, hemoglobin, and worsening kidney function. There was concern for microangiopathic hemolytic anemia. Due to worsening hypoxemia, the 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 hemolysis (presence of schistocytes, undetectable haptoglobin levels, high lactate dehydrogenase level). Urinalysis showed hematuria, large blood, 30–40 red blood cells/high-power field, and 1.4 g 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). Although beta 2 glycoprotein-1 IgM levels were elevated, other laboratory and clinical features of antiphospholipid antibody were absent (Table 2). The disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) level was not low. Complement 3 and 4 were in the 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 did not have any other systemic findings of macro thrombi. Subsequent detailed complement testing revealed a low factor H complement antigen, and 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 900 mg on day 21. Unfortunately, the patient expired on day 23 in the setting of worsening shock.Table 2Antiphospholipid panel and complement panelComprehensive complement testing with results and reference rangesSerum complement total—56U/ml (30–75)Serum complement C3—105 mg/dl (75–175)Serum complement C4—26 mg/dl (14–40)Serum factor B complement antigen—28 mg/dl (15.2–42.3)Serum factor H complement antigen—22 mg/dl (23.6–43.1)Plasma C4d complement—2.3 mcg/ml (<9.9)Plasma CBb complement—4.4 mcg/ml (<1.7)Plasma SC5b-9 complement—875 ng/ml (<251)Antiphospholipid antibody testing with results and reference rangesAnticardiolipin IgG—13.6 GPL (0–12.5)Anticardiolipin IgM—12.5 MPL (0–12.5)Anticardiolipin IgA—6.7 APL (0–12.5)Beta 2 glycoprotein—1 IgG—<5 SGU (<20)Beta 2 glycoprotein—1 IgM—68.6 SMU (<20)Beta 2 glycoprotein—1 IgA—8 SAU (<20)APL, A phospholipids units; GPL, G phospholipids units; MPL, M phospholipids units; SAU, standard IgA aB2G2P1 unit; SGU, standard IgG aB2GPI unit; SMU, standard IgM aB2GPI unit. Open table in a new tab APL, A phospholipids units; GPL, G phospholipids units; MPL, M phospholipids units; SAU, standard IgA aB2G2P1 unit; SGU, standard IgG aB2GPI unit; SMU, standard IgM aB2GPI unit. Coagulopathy associated with SARS-CoV-2 has been widely reported.1Chng W.J. Lai H.C. Earnest A. Kuperan P. Haematological parameters in severe acute respiratory syndrome.Clin Lab Haematol. 2005; 27: 15-20Crossref PubMed Scopus (29) Google Scholar,2Fan B.E. Chong V.C.L. Chan S.S.W. et al.Hematologic parameters in patients with COVID-19 infection.Am J Hematol. 2020; 95: E131-E134Crossref PubMed Scopus (495) Google Scholar The profound hypoxia, inflammation, and disseminated intravascular coagulation have all been implicated as potential causes.2Fan B.E. Chong V.C.L. Chan S.S.W. et al.Hematologic parameters in patients with COVID-19 infection.Am J Hematol. 2020; 95: E131-E134Crossref PubMed Scopus (495) Google Scholar There has also been a report of coagulopathy secondary to development of antiphospholipid antibodies.3Zhang Y. Xiao M. Zhang S. et al.Coagulopathy and antiphospholipid antibodies in patients with Covid-19.N Engl J Med. 2020; 382: e38Crossref PubMed Scopus (1627) Google Scholar Our patient had no evidence of disseminated intravascular coagulation. Although we cannot completely rule out antiphospholipid 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 antiphospholipid 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.4McNally T. Purdy G. Mackie I.J. et al.The use of an anti-beta 2-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis.Br J Haematol. 1995; 91: 471Crossref PubMed Scopus (126) Google Scholar Ideally, a confirmation of autoantibodies is needed at 12 weeks, which was not possible to do 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.5Gaillard F. Ismael S. Sannier A. et al.Tubuloreticular inclusions in COVID-19–related collapsing glomerulopathy.Kidney Int. 2020; 98: 241Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,6Su H. Yang M. Wan C. et al.Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.Kidney Int. 2020; 98: 219-227Abstract Full Text Full Text PDF PubMed Scopus (1292) Google Scholar To our knowledge, there have been no published cases of SARS-CoV-2–associated systemic thrombotic microangiopathy. We report the first case of thrombotic microangiopathy 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.7Caprioli J. Noris M. Brioschi S. et al.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.Blood. 2006; 108: 1267-1279Crossref PubMed Scopus (614) Google Scholar Acute kidney injury is not uncommon in patients with COVID-19.8Hirsch J.S. Ng J.H. Ross D.W. et al.Acute kidney injury in patients hospitalized with COVID-19.Kidney Int. 2020; 98: 209-218Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar Causes of acute kidney injury can range from pre-renal azotemia, to acute tubular injury, to collapsing glomerulopathy.5Gaillard F. Ismael S. Sannier A. et al.Tubuloreticular inclusions in COVID-19–related collapsing glomerulopathy.Kidney Int. 2020; 98: 241Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,6Su H. Yang M. Wan C. et al.Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.Kidney Int. 2020; 98: 219-227Abstract Full Text Full Text PDF PubMed Scopus (1292) Google Scholar,9Mohamed M.M.B. Lukitsch I. Torres-Ortiz A.E. et al.Acute kidney injury associated with coronavirus disease 2019 in urban New Orleans.Kidney360. 2020; 1https://doi.org/10.34067/KID.0002652020Crossref Scopus (190) Google Scholar 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 acute kidney injury. Earlier diagnosis could perhaps lead to prompt treatment with plasma exchange or complement pathway inhibitors. KDJ serves as a consultant for Astex Pharmaceuticals and Natera. All the other authors declared no competing interests. The authors acknowledge 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. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in ChinaKidney InternationalVol. 98Issue 1PreviewAlthough the respiratory and immune systems are the major targets of Coronavirus Disease 2019 (COVID-19), acute kidney injury and proteinuria have also been observed. Currently, detailed pathologic examination of kidney damage in critically ill patients with COVID-19 has been lacking. To help define this we analyzed kidney abnormalities in 26 autopsies of patients with COVID-19 by light microscopy, ultrastructural observation and immunostaining. Patients were on average 69 years (19 male and 7 female) with respiratory failure associated with multiple organ dysfunction syndrome as the cause of death. Full-Text PDF Open AccessAcute kidney injury in patients hospitalized with COVID-19Kidney InternationalVol. 98Issue 1PreviewThe rate of acute kidney injury (AKI) associated with patients hospitalized with Covid-19, and associated outcomes are not well understood. This study describes the presentation, risk factors and outcomes of AKI in patients hospitalized with Covid-19. We reviewed the health records for all patients hospitalized with Covid-19 between March 1, and April 5, 2020, at 13 academic and community hospitals in metropolitan New York. Patients younger than 18 years of age, with end stage kidney disease or with a kidney transplant were excluded. Full-Text PDF Tubuloreticular inclusions in COVID-19–related collapsing glomerulopathyKidney InternationalVol. 98Issue 1PreviewA 79-year-old man of African ancestry, with a history of hemorrhagic stroke, monoclonal gammopathy of unknown significance, and stage 3 chronic kidney disease due to hypertension, was admitted to Bichat Hospital on day 1 after the first symptom of coronavirus disease 2019 (COVID-19) (fever). Severe acute respiratory syndrome coronavirus 2 polymerase chain reaction was positive on nasal swab. At admission, urinary dipstick was normal and plasma creatinine was 224 μmol/l. On day 4 plasma albumin was at 29 g/l and proteinuria was 11.4 g per gram of urinary creatinine (80% of albumin). Full-Text PDF Thrombotic microangiopathy: COVID-19 or hydroxychloroquine?Kidney InternationalVol. 98Issue 6PreviewI read with great interest the letter to the editor by Jhaveri et al. reporting the first published case report of thrombotic microangiopathy in a patient with coronavirus disease 2019 (COVID-19).1 Although there was a clear temporal relationship between the presentation with COVID-19 and development of thrombotic microangiopathy, I wonder whether the authors considered the possibility of a drug-induced thrombotic microangiopathy, in particular hydroxychloroquine, which was introduced on day 1 of admission. Full-Text PDF The authors replyKidney InternationalVol. 98Issue 6PreviewWe thank Hasbal for the concern expressed1 regarding hydroxychloroquine (HCQ) as the cause of the thrombotic microangiopathy (TMA) in our published case titled "Thrombotic Microangiopathy in a Patient With COVID-19."2 An immune-mediated thrombotic microangiopathy usually requires ongoing exposure to the drug. In our case, the patient mentioned was on HCQ for a duration of 5 days. The initial 2 doses were prior to admission, and the drug was continued during the initial 3 days of hospitalization. Full-Text PDF