Patient with Moderate Hemophilia A and Development of FVIII Inhibitor in Old Age and Atrial Fibrillation − Interactive Case Study

How would you proceed in each situation in this case? What antithrombotic therapy can be administered to this patient? And what conclusions can we draw from his case for clinical practice? You will find answers to these questions and more in the author's concise video presentation. You can also cast your vote on which of the available options you would choose as the attending physician.

Case Study Author: MUDr. Petr Smejkal, Ph.D.
Department of Clinical Hematology FN Brno, Department of Laboratory Methods, MU Faculty of Medicine Brno

Family History

• In the extended family, 6 living hemophiliacs with FVIII:C levels of 1–4%, none diagnosed with an inhibitor. The deceased brother also had hemophilia without an inhibitor.
• Causal mutation in the FVIII gene Arg1781His (p.Arg1800His).

Personal History

• Male born in 1941, diagnosed with hemophilia A at about 10 years of age, moderate to borderline mild form.
• Treatment on demand, 2004–2013 pdFVIII, once for epistaxis, twice for dental extraction.
• Repeatedly negative FVIII inhibitor.
• Comorbidities:
  • Negative for a-HIV, a-HCV, HBsAg, positive for a-HBsAg and a-HAV
  • Hypertension, benign prostatic hypertrophy
  • Temporary visual impairment in spring 2013
  • Detected stenosis of the right internal carotid artery at 90%, left at 80%

Current Illness

• 2013 surgery for right carotid stenosis with pdFVIII substitution, discharged with ASA.
• Two weeks after discharge, subcutaneous and muscle bleeding, FVIII inhibitor development, high responder, FVIII inhibitor 246 BU/ml, FVIII < 1%.
• Severe muscle bleeds continue about once every two months, treated with aPCC or rFVIIa.
• 10/2013 paroxysm of AF with RVR during anemia post-bleeding, subsequently SR.
• Repeated ITI attempts with immunosuppression, first with corticosteroids, cyclophosphamide, and then rituximab repeatedly.
• Negative inhibitor status and rise in endogenous FVIII levels to the patient's original moderate hemophilia levels was achieved after the second series of rituximab, but the inhibitor recurred, and FVIII levels fell below 1% after three months.
• A total of 14 doses of rituximab 375 mg/m² were administered between 2014 and 2019, three times in a series of 4 weekly infusions, followed by two single infusions when CD20 lymphocytes began to return.
• 8/2017 severe thigh muscle bleed, initiated prophylactic application of aPCC 54 U/kg every other day, later reduced to 37 U/kg three times a week, with only one bleed over two years.
• Since the last dose of rituximab from 7/2019, the inhibitor remained negative, and from 9/2019 FVIII > 1%, with aPCC prophylaxis terminated in October, and FVIII levels rising to 5%.
• 2/2020 Recurrence of inhibitor 0.88 BU/ml and FVIII < 1% with CD20 at 6 cells/µl.
• From 3/2020 prophylaxis/ITI pdFVIII 4500 U (56 U/kg) three times a week.
• 4/2020 FVIII inhibitor rises to 44.55 BU/ml , started prophylactic application of aPCC 49 U/kg three times a week, ex pdFVIII, last dose of aPCC on August 24, 2020.
• Since August 26, 2020 emicizumab 3 mg/kg weekly four times, then 1.5 mg/kg weekly:
  • emicizumab levels after the loading phase 58.1–93.1 µg/ml, inhibitor persists, last measured at 42 BU/ml.

• Patient without bleeding symptoms.
• 12/2020 lower limb swelling, recurrence of atrial fibrillation with their dilatation, diastolic heart failure, adjusted hypertension treatment, added diuretic.

How would you proceed in this case? Vote. 

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Note: F = clotting factor; FVIII:C = factor VIII coagulation activity; r = recombinant; pd = plasma-derived; aPCC = activated prothrombin complex concentrate; ITI = immune tolerance therapy; BU = Bethesda units; ASA = acetylsalicylic acid; DOACs = direct oral anticoagulants; CD20 = marker for B lymphocyte antigen; HIV = human immunodeficiency virus; HAV, HCV = hepatitis A and C viruses