Page 51 - 2020_07-Haematologica-web

Diagnosis and treatment of acquired hemophilia A
in 75% of cases; <40% in 100% of cases), and the presence of autoantibodies, detected by the Bethesda assay or by enzyme-linked immunosorbent assay (ELISA).10 If the pro- thrombin time (PT) is prolonged, it must be attributed to other reasons, e.g., anticoagulant treatment. The bleeding pattern in AHA is characteristic of the disease, with subcu- taneous bleeds being most common (observed in 80% of
patients), followed by muscle, gastrointestinal, genitouri- nary, and retroperitoneal bleeds (in 45%, 21%, 9% and 9% of patients, respectively).2 Joint bleeds, the hallmark of con- genital hemophilia, are much less common in AHA.2,8 In some cases, patients with AHA have not yet started to bleed at the time of diagnosis.2 In these patients, a pro- longed APTT may be the only sign of AHA.
Table 2. Summary of recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Recommendation
Diagnosis
• We recommend that the diagnosis of AHA should be considered whenever an acute or recent onset of bleeding is accompanied by an unexplained prolonged APTT.
• We recommend that an unexplained APTT prolongation prior to surgery should be investigated and not ignored.
• We recommend confirming a diagnosis of AHA by testing FVIII activity and inhibitor concentration using the Bethesda assay and/or an anti-FVIII ELISA.
• We recommend testing for anti-porcine inhibitors using a modified Bethesda assay, if treatment with rpFVIII is an option.
Hemostatic treatment
• We recommend that hemostatic treatment be initiated in patients with AHA and clinically relevant bleeding irrespective of inhibitor titer and residual FVIII activity.
Grade according to Guyatt et al.16
1B
1C 1B
1B
1B
• We recommend the use of rFVIIa, APCC or rpFVIII instead of human FVIII concentrates or desmopressin for the treatment of clinically 1B relevant bleeding in patients with AHA.
• We recommend that alternative treatment strategies from among the first-line agents be used if appropriate initial treatment fails. 1C
• For initial treatment with rFVIIa, we recommend bolus injection of 90 μg/kg every 2−3 h until hemostasis is achieved. 1B
• For initial treatment with APCC, we recommend bolus injections of between 50−100 U/kg every 8−12 h, up to a maximum of 200 U/kg/day. 1B
• For initial treatment with rpFVIII, we recommend the approved dose of 200 U/kg, followed by further doses to maintain trough levels >50%. 1B
• We recommend close monitoring of FVIII activity during therapy with rpFVIII. 1B
• We suggest the use of recombinant or plasma-derived human FVIII concentrates only if bypassing agents or rpFVIII are unavailable
or ineffective and the inhibitor titer is low. We recommend against the use of desmopressin. 1B •We recommend the prophylactic use of bypassing agents or rpFVIII to cover minor or major invasive procedures. 1B
Inhibitor eradication
• We recommend IST in all patients with AHA. However, particular caution should be exercised in frail patients. 1B
• We suggest using prognostic markers (FVIII activity, inhibitor titer, if available) to individualize IST. 2B
• We suggest that patients with FVIII ≥1 IU/dL and inhibitor titer ≤20 BU at baseline receive first-line treatment with corticosteroids 2B alone for 3−4 weeks.
• We suggest combining corticosteroids with rituximab or a cytotoxic agent for first-line therapy in patients with FVIII <1 IU/dL or
inhibitor titer >20 BU. 2B
• We suggest extending observation in patients who do not achieve remission with first-line IST but have continued improvement
of FVIII activity and inhibitor titer. 2B
• We suggest second-line therapy with rituximab or a cytotoxic agent, whichever was not used during first-line therapy. 1B
• For corticosteroid therapy, we suggest prednisolone or prednisone at a dose of 1 mg/kg/day PO for a maximum of 4−6 weeks
(followed by a tapered withdrawal). 2B
• We suggest rituximab at a dose of 375 mg/m2 weekly for a maximum of 4 cycles. 2B
• As cytotoxic therapy, we suggest cyclophosphamide at a dose of 1.5−2 mg/kg/day PO for a maximum of 6 weeks, or MMF at a dose
of 1 g/day for 1 week, followed by 2 g/day. 2B
• We do not recommend the use of high-dose human FVIII for immune tolerance induction in AHA. 2C
• We do not recommend the use of high-dose intravenous immunoglobulins for inhibitor eradication in patients with AHA. 1B
• We recommend follow-up after complete remission, using FVIII:C monitoring monthly during the first 6 months, every 2−3 months up 1B to 12 months, and every 6 months during the second year and beyond, if possible.
• In women with pregnancy-associated AHA, we suggest the same approach for IST as in other patients, but with a more careful 2C consideration regarding the use of cytotoxic agents.
• We recommend thromboprophylaxis according to ASH guidelines if FVIII:C has returned to normal levels. If indicated, therapy 1C with anti-platelet drugs or oral anticoagulants should be initiated after normal FVIII:C levels have been achieved.
AHA: acquired hemophilia A; APTT: activated partial thromboplastin time; FVIII: factor VIII; ELISA: enzyme-linked immunosorbent assay; rpFVIII: recombinant porcine FVIII; rFVIIa: recombinant activated factor VII; APCC: activated prothrombin complex concentrate; IST: immunosuppressive therapy; BU: Bethesda unit; PO: orally; MMF: mycophenolate mofetil; IVIG: intravenous immunoglobulins; FVIII:C: factor VIII activity; ASH: American Society of Hematology.
haematologica | 2020; 105(7)
1793