About the Condition

Description/definition:

Acquired hemophilia A (AHA) is a rare disorder, resulting in spontaneous bleeding in individuals with no history of bleeding disorders. It is caused by spontaneous inhibition of clotting factor VIII (FVIII) by autoantibodies, and is associated with an underlying medical condition (especially other other autoimmune conditions) in about 50% of cases. It has a mortality rate of up to 40%.

AHA has an incidence of about 1.5 cases per million persons per year and presents most commonly in the elderly at a median age of 75–80 years.

Classification of AHA

Primary or idiopathic (not associated with an identifiable underlying medical condition) – about 50% of cases

Secondary (associated with an underlying medical condition):

  • Autoimmune diseases, including:
    • Systemic lupus erythematosus (SLE)
    • Rheumatoid arthritis
  • Solid or hematological disorders, including:
    • Chronic lymphocytic leukemia (CLL)
    • Multiple myeloma
    • Waldenstrom’s macroglobulinemia
    • Non-Hodgkin lymphoma
  • Pregnancy:
    • A rare cause
    • Typically occurs 1-4 months postpartum.
  • Drugs
  • Dermatological disorders, including:
    • Psoriasis
    • Pemphigus

Pathophysiology:

Acquired hemophilia A is an autoimmune disease caused by spontaneous production of neutralizing IgG autoantibodies directed towards functional epitopes of FVIII and caused by genetically and environmentally mediated breakdown of immune tolerance.

Diagnosis:

Consider diagnosis of acquired hemophilia A in a patient with:

  • Recent onset of unexpected bleeding (often spontaneous) in the absence of family or personal history of bleeding:
    • Bleeding manifestations of patients with acquired inhibitors are generally more severe than those of patients with congenital hemophilia with or without inhibitors.
    • Frequency of bleeding sites:
      • Subcutaneous >80%
      • Gastrointestinal > 20%
      • Muscle bleeding >40%
      • Genitorurinary, retroperitoneal and other < 10%
  • Unexplained prolongation of the aPTT
  • Failure of prolonged aPTT to correct with normal plasma (mixing study):
    • FVIII inhibitors are time- and temperature-dependent and mixing studies with normal plasma may demonstrate inhibition on incubation for 2 hours that is not present immediately after mixing.

Diagnosis is confirmed by:

  • Demonstration of low FVIII activity in factor assay – because of the second-order kinetics of the anti-FVIII antibodies, FVIII levels are not predictive of bleeding risk and patients can have clinically significant bleeding despite only modestly reduced FVIII activity level.
  • Bethesda assay, used to:
    • Confirm presence of inhibitor.
    • Quantitate inhibitor titer.

Note: Lupus anticoagulant should be ruled out – acquired inhibitors may coexist with lupus anticoagulant, which may be causing artefactually prolonged clotting times.

Treatment:

General principles of management:

  • Treat active bleeding:
    • If indicated, bleeding should be treated without delay.
    • 30% of patients do not require hemostatic treatment, especially those with subcutaneous bleeds.
  • Eradication of inhibitor
  • Treatment of underlying condition – in some cases, the treatment of such conditions can lead to the disappearance of the inhibitors and modify the prognosis.
  • Avoid invasive procedures if possible, and minimize venipuncture.

Treatment of active bleeding:

  • First line, either of the following:
    • Recombinant human FVIIa:
      • 90 mcg/kg IV boluses every 2-3 hours until hemostasis is achieved.
      • Doses > 90 mcg/kg not recommended except as rescue therapy due to increased risk of thrombosis.
      • FDA approved for treatment of bleeding episodes and perioperative management in adults with acquired hemophilia A.
      • Risk of arterial and venous thrombotic events.
      • For more dosing information see FDA DailyMed.
    • aPCC (FEIBA):
      • Contains nonactivated factors II, IX, and X, and activated factor VII (factor VIIa) and small quantities of proteins C and S.
      • 50-100 units/kg IV boluses every 8-12 hours to maximum of 200 units/kg/day
      • Risk of thromboembolic events.
      • For more dosing information see FDA DailyMed.
    • If first bypassing agent fails, consider switching treatment to the other bypassing agent.
    • There are no effective laboratory measures to monitor under- or overdosing of bypassing agents.
  • Second line:
    • FVIII concentrate – should be reserved for patients with measurable factor VIII plasma levels and low inhibitor titers.
    • Porcine FVIII:
      • In patients with acquired hemophilia A, inhibitor titer to porcine factor VIII is typically about 5%-10% of the human titer.
      • Patients may develop inhibitors against porcine FVIII following administration.
    • FVIII replacement with plasmapheresis and immunoadsorption:
      • Immunoadsorption is achieved by filtering patient’s plasma through sepharose column with bound recombinant protein A or polyclonal antibodies against human immune globulin.
      • Treatment with human FVIII is usually less effective than bypassing agents unless combined with immunoadsorption.
  • Other treatment considerations:
    • Tranexamic acid:
      • Should be considered for most bleeds.
      • Most effective for bleeding involving mucocutaneous surfaces.
      • Use with caution if given concurrently with activated clotting factor concentrates.
      • Contraindicated in patients with urinary tract bleeding.

Eradication of inhibitor:

  • Patients should start immunosuppression as soon as the diagnosis is made.
  • Immunosuppression should be initiated with prednisone 1 mg/kg/day with or without cyclophosphamide 1-2 mg/kg/d.
  • May consider rituximab 375 mg/m2 IV/week for 4 weeks if standard immunosuppression contraindicated.
  • IVIG is not recommended for inhibitor eradication.

Treatment of underlying conditions (if applicable)

Prognosis:

Severity of bleeding at presentation not predictive of severity of future bleeding and fatal bleeding may still occur until inhibitors are eradicated.

Multicenter study in 2012 of 501 patients with diagnosis of acquired hemophilia A:

  • Median age was 73.9 years.
  • 52% of cases were idiopathic.
  • 474 presented with bleeding.
  • Hemostatic therapy initiated in 71% of patients.
  • 73% of 477 patients receiving immunosuppression achieved complete remission.
  • 28% died within median time of 75 days after diagnosis of AHA, typically from bleeding or sepsis.