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Four cases of acquired hemophilia A following immunization with mRNA BNT162b2 SARS-CoV-2 vaccine

      Highlights

      • Immunomodulatory effects of SARS-CoV-2 vaccination are still poorly understood.
      • Four cases of Acquired hemophilia A (AHA) observed after mRNA BNT162b2 vaccination
      • Unusually high AHA incidence in eight months in our province (total poulation 526,349)
      • AHA as a possible complication of SARS-CoV-2 immunization, but more data needed

      Abstract

      Acquired hemophilia A (AHA) is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation Factor VIII. Immunomodulatory effects of SARS-CoV-2 vaccination are still poorly understood, with reports of immune-mediated conditions developing after immunization. In the province of Reggio Emilia, Northern Italy, we observed four cases of AHA following SARS-CoV-2 immunization with mRNA BNT162b2 vaccine (produced by Pfizer-BioNTech) during the first eight months from the beginning of SARS-CoV-2 vaccination campaign. During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine. The total population of Reggio Emilia province is 526,349. The unusual observation of four cases of AHA in our province could be of interest and could sensitize healthcare personnel toward a possible complication of SARS-Cov-2 immunization. Nonetheless, vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and to stop the pandemic.

      Keywords

      1. Introduction

      Acquired hemophilia A (AHA) is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation Factor VIII. Estimates of its incidence vary, with roughly 1.4 cases every one million people per year [
      • Collins P.W.
      • Hirsch S.
      • Baglin T.P.
      • Dolan G.
      • Hanley J.
      • Makris M.
      • Keeling D.M.
      • Liesner R.
      • Brown S.A.
      • Hay C.R.
      UK Haemophilia Centre Doctors' Organisation
      Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.
      ]. AHA is mainly associated with malignancy, autoimmune diseases, the postpartum period or some medications; nonetheless, almost half of the cases remain idiopathic [
      • Collins P.W.
      • Hirsch S.
      • Baglin T.P.
      • Dolan G.
      • Hanley J.
      • Makris M.
      • Keeling D.M.
      • Liesner R.
      • Brown S.A.
      • Hay C.R.
      UK Haemophilia Centre Doctors' Organisation
      Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.
      ]. Sporadic AHA cases have been reported in association with infectious diseases or vaccinations [
      • Pirrotta M.T.
      • Bernardeschi P.
      • Fiorentini G.
      A case of acquired haemophilia following H1N1 vaccination.
      ].
      Up to August 2021, more than 200 million cases of COVID-19 have been confirmed worldwide, with more than 4 billion doses of vaccines administered totally (World Health Organization, https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports). SARS-CoV-2 infection has been associated with severe impairment of the immune system, and inflammatory and autoimmune manifestations have been described during the clinical course of COVID-19 [
      • Ramos-Casals M.
      • Brito-Zerón P.
      • Mariette X.
      Systemic and organ-specific immune-related manifestations of COVID-19.
      ]. Immunomodulatory effects of SARS-CoV-2 vaccination are still poorly understood, with reports of immune-mediated conditions developing after immunization [
      • Greinacher A.
      • Thiele T.
      • Warkentin T.E.
      • Weisser K.
      • Kyrle P.A.
      • Eichinger S.
      Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.
      ]. Since the beginning of COVID-19 pandemic, rare cases of AHA have been reported in association with SARS-CoV-2 infection [
      • Franchini M.
      • Glingani C.
      • De Donno G.
      • Casari S.
      • Caruso B.
      • Terenziani I.
      • Perotti C.
      • Del Fante C.
      • Sartori F.
      • Pagani M.
      The first case of acquired hemophilia a associated with SARS-CoV-2 infection.
      ] and vaccination [
      • Radwi M.
      • Farsi S.
      A case report of acquired hemophilia following COVID-19 vaccine.
      ,
      • Farley S.
      • Ousley R.
      • Van Wagoner N.
      • Bril F.
      Autoimmunity after coronavirus disease 2019 (COVID-19) vaccine: a case of acquired hemophilia a.
      ]. In the province of Reggio Emilia, Northern Italy, we observed four cases of AHA following SARS-CoV-2 immunization with BNT162b2 mRNA vaccine (produced by Pfizer-BioNTech) during the first eight months since the beginning of the vaccination campaign (Table 1).
      Table 1Four acquired hemophilia A cases observed following immunization with BNT162b2.
      Case 1Case 2Case 3Case 4
      Sex, ageMale, 86 y-oFemale, 73 y-oMale, 67 y-oMale, 77 y-o
      Clinical presentationSpontaneous disseminated hematomas with severe anemia. APTT ratio 1.91; FVIII:C: 0.06 IU/mL; anti-FVIII: 2.1 Bethesda Units/mLTongue, jaw and right knee hematomas. APTT ratio 2.1; FVIII:C: 0.05 IU/mL; anti-FVIII: 0.8 Bethesda Units/mL.Hematoma of the tongue extending in the cervical region. APTT ratio 2.55; FVIII:C: 0.06 IU/mL; anti-FVIII 2.5 Bethesda Units/mL.Hematuria. APTT ratio 3.61; FVIII:C: 0.02 IU/mL; anti-FVIII 6.9 Bethesda Units/mL.
      Time from last dose of vaccine14 days26 days49 days52 days
      ComorbiditiesRheumatic polymyalgia (remission)Rheumatoid arthritis, Sjogren syndrome (remission)UnremarkableBladder cancer
      Clinical courseHematomas resolved after steroid therapy.

      At seven month follow-up (steroid tapering): no bleeding events, FVIII:C 0.82 IU/mL, undetactable inhibitor.
      Hematomas reabsorbed after steroid therapy. At five months follow-up FVIII:C 1.63 IU/mL; undetectable inhibitor.Appearence of a hematoma in the upper left arm and drop in hemoglobin. Therapy with rFVIIa and immunosuppressants. Six days after discharge: FVIII:C 1.21 IU/mL, undetectable inhibitor.Improvement of laboratory and clinical parameters (FVIII:C 0.96 IU/mL; undetectable inhibitor) after methylprednisolone, rituximab and rFVIIa. Developed a severe sepsis and died from its respiratory complications.
      APTT: activated partial thromboplastin time (ratio reference interval: 0.8–1.2); Factor VIII:C: factor VIII procoagulant activity (reference interval: 0.5–1.5 IU/mL); rFVIIa: recombinant activated Factor VII.

      2. Case 1

      On April 2, 2021, a 86 year-old man, affected by rheumatic polymyalgia under low dose steroid therapy was admitted to our Hospital for spontaneous disseminated hematomas, with severe anemia (hemoglobin concentration 66 g/L) and increased activated partial thromboplastin time (APTT) ratio (1.91; reference interval: 0.8–1.2), persisting after mixing study. No personal or family history of coagulopathy was recorded. The measured FVIII procoagulant activity (FVIII:C) was 0.06 IU/mL (reference interval: 0.5–1.5 IU/mL) with detectable inhibitor (2.1 Bethesda Units/mL). APTT was measured with Siemens Actin (Siemens Healthineers, Erlangen, Germany) on a Sysmex CS-5100 automated coagulometer (Sysmex corporation, Kobe, Japan). FVIII:C was measured with HemosIL one-stage assay on a ACL TOP 750 (Werfen, Barcelona, Spain). Anti-FVIII activity was measured with a Nijmegen-Bethesda assay. He had been injected with the second dose of BNT162b2 on the 19th of March. He was discharged after treatment with red cell transfusions and methylprednisolone therapy (1 mg/kg/day), with stable hemoglobin concentrations, FVIII:C within the reference range and undetectable inhibitor. At a follow-up visit seven months after discharge, clinical and laboratory remission persisted.

      3. Case 2

      On May 29, 2021, a 73 year-old woman with a remote diagnosis of rheumatoid arthritis and Sjogren syndrome was admitted to our Hospital for spontaneous tongue, jaw and right knee hematomas. She had been injected with BNT162b2 on May 3 (2nd dose). She noticed a first haematoma on the tongue 14 days after the first dose and knee and jaw hematomas few days after the second dose. At admission, hemoglobin concentration was 97 g/L, APTT ratio was increased (2.1) and not corrected by a mixing study. FVIII:C was 0.05 IU/mL, with anti-FVIII activity (0.8 Bethesda Units/mL). Methylprednisolone therapy was started (1 mg/kg/die). At discharge, hemoglobin values were stable and FVIII:C was within the reference range, with undetectable anti-FVIII. At a follow-up visit five months after discharge, clinical and laboratory remission persisted.

      4. Case 3

      On August 4, 2021, a 67 year-old man was admitted to the Emergency Room for urgent otolaryngological assessment due to a large hematoma of the tongue, extending in the cervical region. His medical history was unremarkable. He received the second dose of BNT162b2 on June 16. Hemoglobin concentration was 125 g/L, the APTT ratio was 2.55, FVIII:C was 0.06 IU/mL with detectable anti-FVIII activity (2.5 Bethesda Units/mL). Due to appearance of a hematoma in the upper left arm and a concomitant drop in hemoglobin concentrations, recombinant activated clotting Factor VII was administered (90 mg/kg every 6 h during active bleeding) and immunosuppressive therapy with prednisone and cyclophosphamide (both 1 mg/kg per os) was initiated. At discharge, hemoglobin values were stable and FVIII:C was within reference range, with undetectable inhibitor. Three months after discharge, no bleeding events nor alterations in laboratory results were recorded.

      5. Case 4

      On August 19, 2021, a 77 year-old man with relapsed bladder carcinoma was admitted to the Emergency Room for hematuria. No personal or family history of hemorragic disorders was reported. On June 28, he received the second dose of BNT162b2. Hemoglobin concentration was 66 g/L, APTT was increased (3.61 ratio) and FVIII:C was 0.02 IU/mL with detectable inhibitor (6.9 Bethesda Units/mL). Immunosuppressive therapy with high dose methylprednisolone was initiated without clinical and laboratory resolution. He was then treated with recombinant activated clotting Factor VII for severe anemia (90 mg/kg every 6 h during active bleeding) and the appearance of widespread cutaneous hematomas. Rituximab was added with improvement in laboratory and clinical parameters, leading to undetectable anti-FVIII activity. However, during hospital stay the patient developed sepsis and died from its respiratory complications seven weeks after admission.
      The total population of Reggio Emilia province is 526,349 (Italian National Institute of Statistics, http://dati.istat.it/Index.aspx?QueryId=18560). During the last five years (from January 2016 to December 2020), we observed 0–2 cases per year for a total of 5 cases of AHA (1.9 cases per million people/year), in line with the estimated incidence of the disease. During the first eight months since the beginning of the vaccination campaign against SARS-CoV-2, in our province 235,597 people received at least one dose of BNT162b2. During this time frame, we observed four cases of AHA following the administration of BNT162b2. Two more cases have been diagnosed in patients not vaccinated nor affected by COVID-19. The same mRNA vaccine was reported in association with other immune complications [
      • de Bruijn S.
      • Maes M.B.
      • De Waele L.
      • Vanhoorelbeke K.
      • Gadisseur A.
      First report of a de novo iTTP episode associated with an mRNA-based anti-COVID-19 vaccination.
      ] and in particular with AHA by other authors [
      • Radwi M.
      • Farsi S.
      A case report of acquired hemophilia following COVID-19 vaccine.
      ,
      • Farley S.
      • Ousley R.
      • Van Wagoner N.
      • Bril F.
      Autoimmunity after coronavirus disease 2019 (COVID-19) vaccine: a case of acquired hemophilia a.
      ]. Mucocutaneous bleeding occurred 2–7 weeks after the administration of the second dose. Interestingly, also the other two cases described following injection of BNT162b2 presented after the second dose [
      • Radwi M.
      • Farsi S.
      A case report of acquired hemophilia following COVID-19 vaccine.
      ,
      • Farley S.
      • Ousley R.
      • Van Wagoner N.
      • Bril F.
      Autoimmunity after coronavirus disease 2019 (COVID-19) vaccine: a case of acquired hemophilia a.
      ]: if this could simply be the result of a latency period between the first dose and the occurrence of signs and symptoms or instead the second dose is pathophysiologically relevant is currently unknown. However, one of the cases described by other authors reported mild bruises already after the first dose, even if they aggraveted requiring medical attention only at the second injection [
      • Radwi M.
      • Farsi S.
      A case report of acquired hemophilia following COVID-19 vaccine.
      ]; similarly, our Case 2 reported a first haematoma after the first dose. In three cases, patient history revealed at least one common clinical association of AHA [
      • Collins P.W.
      • Hirsch S.
      • Baglin T.P.
      • Dolan G.
      • Hanley J.
      • Makris M.
      • Keeling D.M.
      • Liesner R.
      • Brown S.A.
      • Hay C.R.
      UK Haemophilia Centre Doctors' Organisation
      Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.
      ]: since co-occurence of autoimmune diseases or immune derangement in the oncological patient are both well-known phenomena, these associations could reflect susceptibility to autoimmunity potentially triggered by vaccination. Case 4 died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy and no relapse has been observed during follow-up, as in the other 2 cases reported [
      • Radwi M.
      • Farsi S.
      A case report of acquired hemophilia following COVID-19 vaccine.
      ,
      • Farley S.
      • Ousley R.
      • Van Wagoner N.
      • Bril F.
      Autoimmunity after coronavirus disease 2019 (COVID-19) vaccine: a case of acquired hemophilia a.
      ]: this could suggest a more favorable prognosis in respect to other nonvaccine-associated cases [
      • Collins P.W.
      • Hirsch S.
      • Baglin T.P.
      • Dolan G.
      • Hanley J.
      • Makris M.
      • Keeling D.M.
      • Liesner R.
      • Brown S.A.
      • Hay C.R.
      UK Haemophilia Centre Doctors' Organisation
      Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.
      ], but longer-term data are definitely needed.
      In conclusion, the overall number of cases observed does not allow to draw any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events [
      • Cittone M.G.
      • Battegay R.
      • Condoluci A.
      • Terzi di Bergamo L.
      • Fernandes E.
      • Galfetti E.
      • Noseda R.
      • Leuppi-Taegtmeyer A.
      • Drexler B.
      • Ceschi A.
      • Tsakiris D.A.
      • Berger C.T.
      • Favre G.
      • Martin T.
      • Korte W.
      • Graf L.
      • Martinez M.
      • Gerber B.
      The statistical risk of diagnosing coincidental acquired hemophilia A following anti-SARS-CoV-2 vaccination.
      ]. Nonetheless, we think the unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize healthcare personnel toward a possible complication of SARS-Cov-2 immunization. Finally, it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and to stop the pandemic [
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • Lockhart S.
      • Perez J.L.
      • Pérez Marc G.
      • Moreira E.D.
      • Zerbini C.
      • Bailey R.
      • Swanson K.A.
      • Roychoudhury S.
      • Koury K.
      • Li P.
      • Kalina W.V.
      • Cooper D.
      • Frenck Jr., R.W.
      • Hammitt Jr., L.L.
      • Türeci Jr., Ö.
      • Nell Jr., H.
      • Schaefer Jr., A.
      • Ünal Jr., S.
      • Tresnan Jr., D.B.
      • Mather Jr., S.
      • Dormitzer Jr., P.R.
      • Şahin Jr., U.
      • Jansen Jr., K.U.
      • Gruber Jr., W.C.
      C4591001 Clinical Trial Group
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ].

      CRediT authorship contribution statement

      All authors made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. All authors participated in drafting the article and revised it critically for important intellectual content. All authors gave final approval of the version to be submitted.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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