Acquired Haemophilia: Unusual presentation of IgG4-related disease

in Max Super Speciality Hospital, Patparganj

Jan 16 , 2023

A 67-year-old diabetic male with coronary artery disease on dual antiplatelets presented with left submandibular swelling. He had been unwell for the past many months with progressive renal failure, one episode of gastrointestinal bleeding and a pathological fracture of the right hip for which cemented hemiarthroplasty was done. Biopsies taken during upper gastrointestinal endoscopy and during arthroplasty showed reactive tissue at both sites. A renal biopsy was also advised but not done. Whole body PET-CT showed FDG avid thickening of the gastro-oesophagal junction, with luminal narrowing, along with multiple FDG avid lymph nodes raising suspicion of lymphoma. A left submandibular lymph node biopsy was done. Forty-eight hours after the biopsy, he developed profuse bleeding from the biopsy site. No bleeder was identified on surgical re-exploration.

A haematology consultation was obtained. Work-up for bleeding revealed anaemia (Hb - 7g/dl) with normal platelet count and normal PT but markedly prolonged APTT of 84 seconds (Control - 27 seconds). On mixing studies with normal plasma, there was no correction of APTT, a sign of factor inhibitor. A Factor VIII level was done which was less than 0.4 %. There was no prior history of any prolonged or unusual bleeding and no family history of bleeding disorder. Bethesda assay revealed the presence of inhibitors to factor VIII clinching the diagnosis as Acquired Haemophilia (AH). He was started on an oral steroid for factor inhibitor with rapid improvement in bleeding symptoms and coagulation parameters over the next 48 hours. ANA was negative, but the direct Coombs test was also strongly positive.

The patient's lymph node biopsy showed the presence of reactive follicles with >50 IgG4 plasma cells per high-power field. Serum IgG4 levels were elevated. An IL-6 level was done to rule out Multicentric Castleman's Disease, which was normal, and serum protein electrophoresis showed polyclonal hypergammaglobulinaemia.

A final diagnosis of IgG4-related disease (IgG4-RD) with AH was made, and the patient was prescribed a weekly course of rituximab 375mg/m2. Steroids were gradually tapered. The patient had complete normalisations of haemoglobin and APTT and improvement in renal function over the next few months.

IgG4-RD is a relatively recently described chronic immune-mediated disease, characterised by the expansion of polyclonal IgG4-positive plasma cells, resulting in multisystemic fibro-inflammatory lesions. Common sites include the lacrimal gland, pancreas and bile duct. Haematological manifestations include eosinophilia, lymphadenopathy and polyclonal hypergammaglobulinemia. Close differentials are lymphoma, Multicentric Castleman's disease and plasma cell disorders. AH is a severe bleeding disorder due to autoantibodies to factor VIII, usually in the setting of auto-immune disorders like rheumatoid arthritis and SLE. The association between AH and IgG4 disease is extremely rare. It is possibly related to the production of antibodies by the plasma cells. Interestingly this patient also had Coombs positive AIHA. Biopsy of affected tissue with ancillary blood investigations is required to differentiate between these entities. Steroids and rituximab are the mainstay of treatment, to which the patient showed a favourable response.