The first case of acquired hemophilia <scp>A</scp> associated with <scp>SARS‐CoV</scp>‐2 infection
Authors: Massimo Franchini, Claudia Glingani, Giuseppe De Donno, Salvatore Casari, Beatrice Caruso, Isabella Terenziani, Cesare Perotti, Claudia Del Fante, Filippo Sartori, Mauro Pagani
Journal: American Journal of Hematology (2020)

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by circulating autoantibodies directed against clotting factor VIII (FVIII).1, 2 It involves more frequently elderly people with no previous personal or family history of bleeding. Approximately half of patients with AHA do not have underlying or predisposing disorders (idiopathic cases), with the remaining cases being associated with a wide array of conditions or diseases (ie, post-partum, autoimmune and dermatologic disorders, malignancies, infections and drugs).3 In more than 80% of cases AHA is characterized by hemorrhage into the skin, muscles, soft tissues and mucous membranes (eg, epistaxis, gastrointestinal and urological bleeds, retroperitoneal hematomas).3 We present here the case of a 66-year-old man, who in November 2011 presented to the emergency room of the Mantua city hospital with spontaneous severe cutaneous and muscle bleeding. He had no history of bleeding. Blood tests revealed normocytic anemia (hemoglobin 9 g/dL) with normal white cell and platelet count and a prolonged activated partial-thromboplastin time (aPTT) (ratio 2.97, normal range 0.82-1.18) with normal prothrombin time. A mixing study resulted in failure of aPTT correction, suggesting the presence of an inhibitor that was successively identified as directed against FVIII (FVIII activity <1%, inhibitor titer 25 Bethesda units [BU]). The diagnosis of idiopathic AHA was made. The patient was successfully treated with intravenous recombinant activated factor VII (90 μg/kg every 3 hours until bleeding stopped) and oral prednisone and cyclophosphamide (1 mg/kg/day for 4 weeks, then gradually tapered) with a complete remission (CR) achieved on day +21. Following a 9-year period of well-being with normal coagulation checks performed every 6 months, the patient was re-admitted to the Mantua city Hospital on March 2020 because of fever (38.7°C), cough, asthenia and difficulty breathing for 3 days. The diagnosis of Coronavirus Disease 2019 (COVID-19) was confirmed by RT-PCR in nasal swab. A chest CT scan showed a bilateral interstitial pneumonia. Due to the concomitant presence of an extensive hematoma in the trunk, an aPTT was performed and resulted prolonged (ratio 2.87). The diagnosis of AHA was again formulated (FVIII <1%, inhibitor titer 19 BU) and the patient was treated with the same anti-hemorrhagic and immunosuppressive treatment, reaching CR on day +20. In addition, the patient received anti-viral drugs (lopinavir-ritonavir 400 mg/twice daily) and non-invasive mechanical ventilation with oxygen as treatment for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, leading to the resolution of the disease on day +14. In this case, the first reported in literature, the re-appearance of AHA was triggered by acute SARS-Cov-2 infection. This finding is particularly interesting considering the close interaction between SARS-Cov-2 and the hemostatic system.4 The AHA cases associated with other viral infections, including hepatitis B and C viruses, have also been described.3 The recent association between immune thrombocytopenic purpura and COVID-19 further strengthens the virus-induced immune dysregulation,5 which could have played a key role in the pathogenesis of AHA. We therefore recommend a daily coagulation monitoring (APTT) in patients admitted with acute COVID-19 infection and the inhibitor search (through a mixing test) in those cases with otherwise unexplained onset or worsening of the hemorrhagic picture and/or aPTT prolongation. The authors declare no competing financial interests. M.F., F.S. and M.P. designed and performed research; I.T., C.G. and B.C. analyzed data; M.F., C.D.F., C.P., G.D.D. and S.C. wrote the paper together; and all authors approved the final manuscript.