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Journal Presentation

By

Dr. Tasfina Haque

FCPS part II trainee, Dept. of haematology

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International recommendations on the diagnosis and treatment of acquired hemophilia A �

Vol. 105 No. 7 (2020): July, 2020 https://doi.org/10.3324/haematol.2019.230771

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Case scenario..

A 68-year-old man presented with multiple spontaneous haematomas (gluteal, neck, and lower limbs), in the absence of personal or family history of bleeding or clotting disorders.

His past medical history included type 2 diabetes mellitus, prostatic hypertrophy, psoriasis. He was not taking any anticoagulant medication.

​

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  • On admission, laboratory investigations revealed
  • haemoglobin 8.2 g/L
  • platelet count (1,68,000 /L)
  • WBC : within normal range

​

  • Coagulation tests showed
  • PT and INR: normal
  • aPTT: 54.8 seconds. APTT was not modified after mixing test
  • lupus anticoagulant (LAC) : negative,
  • FVIII:C was 16%,
  • FVIII inhibitor: 2.3 BU/ml,
  • . Factor IX, factor X, factor XI, factor XII, and von Willebrand Factor were normal
  • , bleeding time : 7 minutes and 30 seconds.

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THIS PATIENT WAS DIAGNOSED AS A CASE OF ACQUIRED HAEMOPHILIA A

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International recommendations on the diagnosis and treatment of acquired hemophilia A �

Vol. 105 No. 7 (2020): July, 2020 https://doi.org/10.3324/haematol.2019.230771

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Introduction�

  • Acquired hemophilia A (AHA), a rare autoimmune bleeding disorder1, 2 characterized by the development of auto-antibodies against endogenous factor VIII (FVIII) causing spontaneous, mild to life-threatening bleeds in individuals with no personal or family history of bleeding.
  • Approximately 10% of patients do not present with bleeding.

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  • Two peaks in AHA incidence are typically observed; one associated with pregnancy, and another with older age (>60 years old). Approximately half of patients with AHA have concomitant disorders, most often other autoimmune disorders or malignancy.

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methods

  • Recommendations for diagnosis and management were formulated according to Guyatt et al.,16 as detailed in Online Supplementary Table S1. We used GRADE 1 for recommendations (“we recommend”) whenever a clear impact on patients’ safety or benefit would outweigh risks and burden. More specifically, GRADE 1B was used when the statement was supported by data from at least one observational or interventional study, and when the recommendation seemed to apply to most patients in most circumstances without reservation; GRADE 1C was used for recommendations that lacked support from such evidence, but still appeared to be important for patients’ safety or benefit. GRADE 2 (“we suggest”) was used for weaker suggestions (2B for those with support from registries or studies, and 2C without) that may change when new data become available. Table 2 lists our main recommendations in the order in which they are discussed.

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methods

First, each author independently reviewed the 2009 international AHA recommendations,1 identifying areas in which an update was required based on their personal experience and knowledge of current literature. Feedback was consolidated in a single document, and the latest available published evidence was assessed to ascertain the extent to which each proposed statement was justified, with particular emphasis on the results of the AHA registries summarized in Table 1. A PubMed literature search was conducted to identify additional relevant publications published since 2009. The search strategy and a PRISMA diagram are provided in the Online Supplementary Material.

           

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DIAGNOSIS of AHA

The diagnosis is often delayed because of a lack of recognition of

this rare disorder by physicians who are not familiar with the disease.

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Clinical Signs and Symptoms:

The bleeding pattern in AHA is characteristic of the disease.

Patients usually present with subcutaneous bleeds (observed in 80% of patients), followed by muscle, gastrointestinal, genitourinary, and retroperitoneal bleeds.

Joint bleeds, the hallmark of congenital hemophilia, are much less common in AHA.

In some cases, patients with AHA have not yet started to bleed at the time of diagnosis.

In these patients, a prolonged APTT may be the only indication of AHA.

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  • The bleeding phenotype of AHA is variable, ranging from life-threatening bleeds to mild or no bleeding.

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Diagnosis…

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  • Typically, patients with AHA present without a previous personal or family history of bleeding. There maybe history of concomitant autoimmune or malignant diseases.

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Laboratory Investigations�

  • isolated prolonged activated partial thromboplastin time (APTT),
  • reduced FVIII activity (FVIII:C) (<1% in 50% of cases; <5% in 75% of cases; <40% in 100% of cases),
  • the presence of autoantibodies, detected by the Bethesda assay or by enzyme-linked immunosorbent assay (ELISA).

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Figure 1.Diagnostic pathway for acquired hemophilia A. The activated partial thromboplastin time (APTT) mixing study will not be needed in an environment in which factor VIII (FVIII) activity is immediately available. Note that the presence of lupus anticoagulant does not exclude acquired hemophilia A. See the ‘Diagnosis’ section for more details. FVIII:C: factor VIII activity; AHA: acquired hemophilia A; ELISA: enzyme-linked immunosorbent assay; rpFVIII: recombinant porcine factor VIII.

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Recommendations for diagnosis:

  • diagnosis of AHA should be considered whenever an acute or recent onset of bleeding is accompanied by an unexplained prolonged APTT.
  • unexplained APTT prolongation prior to surgery should be investigated and not ignored.
  • Confirming a diagnosis of AHA by testing FVIII activity and inhibitor concentration using the Bethesda assay and/or an anti factor VIII ELISA.

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Management

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  • The management of AHA has two major goals:
  • achieving hemostasis
  • eradication of inhibitor

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Recommendations for Hemostatic treatment�

  • hemostatic treatment should be initiated in patients with AHA and clinically relevant bleeding irrespective of inhibitor titer and residual FVIII activity
  • rFVIIa, APCC or rpFVIII (recombinant procine FVIII) should be used for the treatment of clinically relevant bleeding in patients with AHA and prophylactically to cover minor or major invasive procedures.

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Immunosuppressive therapy�

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Goals of immunosuppressive therapy and definition of remission

  • The goal of immunosuppressive therapy (IST) is to reduce the risk of bleeding by shortening the time to achieve remission of AHA.
  • The UK surveillance study defined complete remission as:

FVIII normal, inhibitor undetectable, and immunosuppression stopped or reduced to doses used before AHA.

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Recommendations for IST

  • IST should be started in all patients with AHA. However, particular caution should be exercised in frail patients
  • prognostic markers (FVIII activity, inhibitor titer, if available) are tobe used to individualize IST
  • high-dose intravenous immunoglobulins for inhibitor eradication in patients with AHA is not recommended

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Recommendations regarding Immunosuppressive therapy in patients with acquired hemophilia A.

{FVIII; factor VIII activity; BU: Bethseda unit; CTX, cyclophosphamide}

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  • For corticosteroid therapy, it is suggested to start prednisolone or prednisone at a dose of 1 mg/kg/day PO for a maximum of 4−6 weeks (followed by tapered withdrawal)
  • rituximab is suggested to use at a dose of 375 mg/m2 weekly for a maximum of four cycles
  • As cytotoxic therapy, cyclophosphamide is suggested to use 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

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Follow-up�

  • follow-up is recommended after complete remission, using FVIII:C monitoring monthly during the first 6 months, every 2−3 months up to 12 months, and every 6 months during the second year and beyond, if possible

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Pregnancy-associated acquired hemophilia A�

  • In women with pregnancy-associated AHA, the same approach is suggested for IST as in other patients, but with more careful consideration regarding the use of cytotoxic agents

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Here ends the international recommendations mentioned in this journal….�

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Case scenario

A 68-year-old man presented with multiple spontaneous haematomas (gluteal, neck, and lower limbs), in the absence of personal or family history of bleeding or clotting disorders.

His past medical history included type 2 diabetes mellitus, prostatic hypertrophy, psoriasis. He was not taking any anticoagulant medication.

​

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  • On admission, laboratory investigations revealed
  • haemoglobin 8.2 g/L
  • platelet count (1,68,000 /L)
  • WBC : within normal range

​

  • Coagulation tests showed
  • PT and INR: normal
  • aPTT: 54.8 seconds. APTT was not modified after mixing test
  • lupus anticoagulant (LAC) : negative,
  • FVIII:C was 16%,
  • FVIII inhibitor: 2.3 BU/ml,
  • . Factor IX, factor X, factor XI, factor XII, and von Willebrand Factor were normal
  • , bleeding time : 7 minutes and 30 seconds.

​

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Management….

  • The day after the admission, the patient had dyspnoea and haemoglobin levels further decreased (7.0 g/dl),Because of the reduction of haemoglobin levels and the harmful site of bleeding, a 90 g/kg rFVIIa i.v. bolus was administered and repeated after 3 hours with an apparent resolution of bleeding (stable haemoglobin values).
  • Concomitantly, immunosuppressive therapy with prednisone 1 mg/kg/day was started. As spontaneous bruising of the upper limbs occurred and aPTT was still prolonged, cyclophosphamide 1.5 mg/kg/day was added.

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  • Clinical and laboratory features improved in the following two weeks, with a progressive normalization of the aPTT and the eradication of the FVIII inhibitor (undetectable inhibitor, normal FVIII:C). Since inhibitor eradication was obtained, cyclophosphamide was discontinued after 4 weeks and prednisone gradually stopped after 2 months.
  • During a three-year follow-up, no further bleeding occurred.
  • Psoriatic arthritis was diagnosed few months after the withdrawal of immunosuppressive treatment. This underlying immunologic disorder was therefore associated with AHA in this patient.

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Take home messages

  • The diagnosis of Acquired Haemophilia A is often delayed because of a lack of recognition of this rare disorder by physicians who are not familiar with the disease.
  • Approximately 10% of patients do not present with bleeding and, therefore, a prolonged activated partial thromboplastin time should never be ignored especially prior to invasive procedures.

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  • Control of acute bleeding and prevention of injuries that may provoke bleeding are top priorities in patients with AHA.

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  • It is recommended to treat with bypassing agents, including recombinant activated factor VII, activated prothrombin complex concentrate, or recombinant porcine FVIII in bleeding patients. Autoantibody eradication can be achieved with immunosuppressive therapy, including corticosteroids, cyclophosphamide and rituximab, or combinations thereof.
  • The median time to remission is 5 weeks, with considerable interindividual variation and patients should be followed up regularly.

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