Use of APCC in an elderly AHA patient requiring invasive procedures

History, presentation and investigations
An 81-year-old female presented to a private hospital with painful right upper arm swelling and bruising in August 2023. There was no history of trauma or contusion other than a minor sprain 2 weeks prior to presentation. There was also no family history of bleeding tendency. The patient had multiple comorbidities: hypertension, hyperlipidaemia, type 2 diabetes (T2D), overweight (body weight, 60 kg; BMI, 25 kg/m²), osteoarthritis of both knees, and vitamin B12 deficiency.

Blood tests at the private hospital revealed a haemoglobin (Hb) level of 6.3 g/dL, and a very prolonged activated thromboplastin time (aPTT) of 102 seconds (reference range: 23–30 seconds).¹ The patient was given packed cell transfusion and referred to our hospital for further workup, where she was initially assessed within the orthopaedic ward. The sensation and circulation in her right upper arm were intact, although the range of movement was reduced due to pain. Blood tests showed a Hb level of 8.1 g/dL and a normal platelet count. Her aPTT was markedly prolonged at 67 seconds, while her prothrombin time and fibrinogen levels were normal.

A CT scan of the right arm showed a large haematoma at flexor compartment measuring 13.6 x 6.6 x 4.7 cm with no arterial extravasation. The same scan yielded an incidental finding of a 2.5 cm mass in the right breast. Further workup showed a factor VIII (FVIII) level <1 percent (reference range: 50–200 percent) and a normal factor IX level, and mixing study confirmed presence of an aPTTbased inhibitor.¹ Bethesda assay reported a FVIII inhibitor (ie, neutralizing autoantibodies against FVIII) level of 115.8 BU/mL (reference range: 0–1 BU/mL).¹ The patient was diagnosed with acquired haemophilia A (AHA) about 1 week after initial presentation.

Treatment and response
The patient was given 3,000 units of activated prothrombin complex concentrate (APCC) immediately after diagnosis; this was administered once every 12 hours (ie, 100 U/kg/ day).^2,3 At the same time, she was started on prednisolone 1 mg/kg/day (initially equivalent dose as intravenous hydrocortisone, later switched back to oral prednisolone after stabilization) to eradicate FVIII inhibitor.³ Because of her very high antibody level and T2D, the patient was also given rituximab at 375 mg/m² weekly intravenously for four doses to reduce the antibody level more quickly and potentially avoid prolonged exposure to high-dose steroids.³

During her hospital stay, the patient received 3 units of packed cells transfusion along with prophylactic amoxicillin/clavulanic acid to prevent haematoma-related infection. After several days of steroid treatment, the patient’s glycaemic control began to deteriorate, necessitating uptitration of oral antidiabetic medications and insulin. This prompted early introduction of mycophenolate mofetil as a steroid-sparing agent, allowing prednisolone to be tapered more rapidly.

The patient responded well to treatment with APCC and immunosuppressing agents, showing gradual improvement in aPTT. APCC was stopped after 3 weeks of administration. Six weeks after initial presentation, her aPTT was near normal at 36 seconds and FVIII level rebounded to 12 percent, while Bethesda assay showed a FVIII inhibitor level of 1.4 BU/mL.

The patient underwent a biopsy of the right breast mass in September 2023 – 5 weeks post-presentation and 1 week after finishing first-line treatment with APCC. To avoid bleeding complications, the patient was given an additional prophylactic dose of 3,000 units of APCC before the procedure.² The biopsy procedure was uneventful and confirmed carcinoma of the breast.

Her aPTT normalized in October 2023 – 2 months after her initial presentation. The patient underwent a simple mastectomy with sentinel lymph node biopsy in the same month. The operation was uneventful, with no bleeding complications or any subsequent thrombotic events.

The patient continues to undergo regular check-ups every 2–3 months. Her prednisolone was gradually tapered. She was last seen in August 2024, and her aPTT remained normal. The plan is to wean the patient off all AHA medications gradually if she remains stable.

Discussion
AHA is a potentially life-threatening bleeding disorder requiring prompt and correct diagnosis to ensure favourable outcomes, which is challenging due to the rarity of this disease.^3,4 Unusually prolonged aPTT in a patient who presents with bleeding should raise suspicion of AHA. Subsequent testing by mixing study to identify an autoantibody, and a reduced FVIII level will confirm AHA diagnosis. Bethesda assay helps to quantify the FVIII inhibitor level.³

Once AHA is established, the first treatment step is to reinstate haemostasis with a bypassing agent to prevent further bleeding.³ Neutralizing autoantibodies against FVIII can be eliminated through immunosuppression with steroids and/or other agents used in management of autoimmune diseases.³

Two bypassing agents included in international recommendations on diagnosis and treatment of AHA are available in Hong Kong: APCC and recombinant factor Vlla (rFVIIa).³ Although use of APCC in treatment of haemorrhagic episodes in patients with haemophilia A has been established since mid-1970s, head-to-head comparative trials of the two agents in treatment of AHA are not available.^3,5

Propensity score–matched analysis of European Acquired Haemophilia Registry (EACH2; n=501; median age, 73.9 years; male, 53 percent) data indicated indistinguishable efficacy of APCC compared with rFVIIa, with >90 percent bleed control rates when used as first-line treatment.^3,6 While both agents are recommended as first-line treatment for clinically relevant bleeding in patients with AHA, APCC’s less frequent dosing schedule (every 8–12 hours vs every 2–3 hours for rFVIIa) makes its use more convenient in a busy public hospital setting.³

In a retrospective Spanish study of 30 AHA patients (median age, 70 years; male, 66.7 percent) with a total of 67 bleeding events between August 2012 and February 2021, which were treated with APCC or rFVIIa, APCC stopped bleeding in 96 percent of all APCC-managed events.⁴ APCC’s efficacy was 94.1 percent when used as a first-line agent. When used as a secondline agent after first-line treatment failure with rFVIIa (n=9), APCC achieved bleeding cessation in all nine patients (ie, 100 percent efficacy). The efficacy outcome after APCC therapy was not influenced by baseline conditions, such as inhibitor or FVIII level, aPTT, age, bleeding location or severity.⁴

According to animal studies, adverse events associated with APCC are mainly the result of hypercoagulation.² Thrombotic events were reported in 4.8 percent of patients in the EACH2 registry, while the second-largest study on use of APCC in treatment of AHA, FAIR (n=56; median age, 69.9 years), reported no such events.^3,7 International recommendations advise that if antiplatelet drugs or oral anticoagulants are indicated, they should be initiated after normal FVIII levels are achieved.³

In summary, the present case illustrates successful use of APCC in managing initial spontaneous bleeding and preventing bleeding episodes for 10 months since treatment discontinuation in an elderly AHA patient with multiple comorbidities, who had to undergo a minor and eventually a major invasive procedure.

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