Acquired Hemophilia Guidelines

Updated: Mar 28, 2022
  • Author: Sara J Grethlein, MD, MBA, FACP; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Guidelines

Guideline Recommendations

The United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) has published guidelines on the diagnosis and treatment of acquired clotting factor inhibitors—principally, factor VIII (FVIII) inhibitors (acquired hemophilia A). [17] An international group has published guidelines specifically on acquired hemophilia A. [2]

Diagnosis

Both the UKHCDO and the international guidelines recommend considering the diagnosis of acquired hemophilia A when acute or recent onset of bleeding is accompanied by an unexplained prolonged activated partial thromboplastin time (aPTT). [2, 17] The international group also recommends the following [2] :

  • Confirm the diagnosis of acquired hemophilia A by testing FVIII activity and inhibitor concentration using the Bethesda assay and/or an anti-FVIII enzyme-linked immunosorbent assay (ELISA).
  • Test for anti-porcine inhibitors, using a modified Bethesda assay, if treatment with recombinant porcine factor VIII (rpFVIII) is an option.

The UKHCDO recommends considering acquired inhibitors to clotting factors other than FVIII if acute or recent onset of bleeding is accompanied by unexplained prolonged screening tests—prothrombin time (PT), aPTT, or thrombin time (TT)—that fail to correct with normal plasma. [17]

Treatment

The guidelines provide recommendations and suggestions on treatment of clinically relevant bleeding and on immunosuppression to eliminate the inhibitor. The UKHDCO notes that asymptomatic patients with acquired clotting factor inhibitors (other than to FVIII) may not require treatment, because some inhibitors are transient and others do not cause clinical bleeding, despite producing significant laboratory abnormalities. The UKHDCO also recommends that patients with acquired clotting factor inhibitors be treated jointly with hemophilia centers experienced in the management of inhibitors. [17]

Hemostasis

International recommendations on hemostatic treatment in acquired hemophilia A are as follows [2] :

  • Initiate hemostatic treatment in patients with clinically relevant bleeding irrespective of inhibitor titer and residual FVIII activity.
  • For treatment of clinically relevant bleeding, use recombinant activated factor VII (rFVIIa), an activated prothrombin complex concentrate (APCC) such as factor eight inhibitor bypassing activity (FEIBA), or rpFVIII rather than human FVIII concentrates or desmopressin.
  • If initial treatment fails, use alternatives from among the first-line agents.

Dosing recommendations for initial hemostatic treatment are as follows:

  • rFVIIa: Bolus injection of 90 μg/kg every 2-3 h until hemostasis is achieved
  • APCC: Bolus injections of 50-100 U/kg every 8-12 h, up to a maximum of 200 U/kg/day
  • rpFVIII: 200 U/kg, then further doses to maintain trough levels > 50%

Additional hemostasis recommendations are as follows:

  • Monitor FVIII activity during therapy with rpFVIII.
  • Use recombinant or plasma-derived human FVIII concentrates only if bypassing agents or rpFVIII are unavailable or ineffective and the inhibitor titer is low; do not use desmopressin.
  • For minor or major invasive procedures, provide prophylaxis with bypassing agents or rpFVIII.

UKHCDO recommendations for hemostatic treatment are as follows [17] :

  • If indicated, treat bleeding without delay, using rFVIIa or FEIBA (note that the UKHCDO guidelines do not address use of rpFVIII, which had not yet been approved at that time)
  • Not all bleeds need hemostatic treatment, and many subcutaneous bleeds can be managed conservatively.
  • If the initial bypassing agent is ineffective, the other should be tried at an early stage.
  • Do not use rFVIIa at doses higher than 90 μg/kg except as rescue therapy, because of the increased risk of thrombosis.
  • FVIII replacement combined with plasmapheresis and immunoadsorption can be considered for severe bleeding or if first-line therapy is unsuccessful.
  • Tranexamic acid should be considered for all bleeds, especially those involving mucosal surfaces.
  • Once in remission, patients should be assessed for the risk of venous thrombosis and given prophylaxis if indicated.

Immunosuppressive therapy

Both guidelines recommend immunosuppression to eradicate the inhibitor, starting as soon as the diagnosis of acquired hemophilia has been made, although the UKHCDO notes that hemostatic control should be the priority in the acute setting, and the international group advises exercising particular caution in frail patients. [2, 17]

The international guidelines include the following suggestions on immunosuppressive therapy [2] :

  • Individualize immunusuppressive therapy, using prognostic markers (FVIII activity, inhibitor titer, if available).
  • In patients with baseline FVIII ≥1 IU/dL and inhibitor titer ≤20 Bethesda units (BU), use corticosteroids alone for 3-4  wk as first-line treatment.
  • In patients with FVIII < 1 IU/dL or inhibitor titer > 20 BU, use corticosteroids combined with rituximab or a cytotoxic agent (cyclophosphamide or mycophenolate mofetil).
  • Extend observation in patients who do not achieve remission with first-line immunosuppressive therapy but have continued improvement in FVIII activity and inhibitor titer.
  • For second-line therapy, use rituximab or a cytotoxic agent, whichever was not used in first-line therapy.

Dosing suggestions are as follows [2] :

  • Corticosteroids: Prednisolone or prednisone, 1 mg/kg/day PO for a maximum of 4-6 wk, followed by tapered withdrawal
  • Rituximab: 375 mg/m 3 weekly for a maximum of four cycles
  • Cyclophosphamide: 1.5-2 mg/kg/day PO for a maximum of 6 wk
  • Mycophenolate mofetil: 1 g/day for 1 wk, then 2 g/day

Additional recommendations are as follows [2] :

  • Do not use high-dose human FVIII for immune tolerance induction.
  • Do not use high-dose intravenous immunoglobulins (IVIG) for inhibitor eradication.
  • In women with pregnancy-associated acquired hemophilia A, consider using the same approach to immunosuppression; however, cytotoxic agents should not be used in women who are pregnant or breastfeeding.
  • After complete remission, provide follow-up: Monitor FVIII:C monthly for the first 6 months, every 2-3 months for the remainder of the first year, then every 6 months during the second year and beyond, if possible.
  • If FVIII:C has returned to normal levels, provide thromboprophylaxis according to American Society of Hematology guidelines, starting therapy with antiplatelet drugs or oral anticoagulants if indicated.

UKHCDO recommendations for immunosuppressive therapy include the following [17] :

  • Initiate immunosuppression with prednisolone 1 mg/kg/d, either alone or combined with cyclophosphamide 1–2 mg/d orally.
  • Avoid cyclophosphamide and other alkylating agents, if possible, in women of reproductive age.
  • Consider rituximab as first-line therapy if standard immunosuppression is contraindicated, but it may have limited efficacy if used as a single agent.
  • Consider second-line therapies if the patient shows no response within 3–5 weeks. The most common second-line treatment is rituximab combined with other agents; alternative options are calcineurin inhibitors, multiple immunosuppressive agents, and immune tolerance protocols.
  • IVIG is not recommended as treatment for inhibitor eradication.
  • Follow up patients at least monthly for the first 6 months, because relapse is common.
  • In patients with a past history of acquired hemophilia, measure coagulation indices, or preferably a FVIII level, before any invasive procedures.
  • When the FVIII level is normal, assess the patient for the risk of venous thrombosis and provide thromboprophylaxis if appropriate.