A potentially life-threatening association of autoimmune blistering disease we bloody well need to be aware of: Acquired hemophilia A
By Warren R. Heymann, MD
Oct. 29, 2018
I have been treating patients with autoimmune bullous disorders for nearly four decades. The diseases’ vagaries and associations always astound me. I have never encountered (nor have been aware of) acquired hemophilia A (AHA) in the context autoimmune bullous diseases (ABD), until I read the article by Wernham et al. The authors detailed the case of a 48 year-old woman with confirmed pemphigus foliaceus who developed an acute drop in hemoglobin due to AHA. She ultimately improved with the administration of blood products and inhibitor bypassing agents. (1)
After reading the article, I had many questions: Precisely, what is AHA? How rare is it? How does it differ from congenital hemophilia? What are other associations? How is it diagnosed and treated?
According to Filipczak et al: “Acquired hemophilia A (AHA) is potentially life‐threatening bleeding disorder caused by autoimmune‐mediated impairment of coagulation factor VIII function, resulting in severe hemorrhagic diathesis. The incidence rate is 1.34–1.48/million per year. In over half of cases, no underlying diseases are found (idiopathic form). The secondary form occurs in neoplastic and lymphoproliferative diseases, as well as in drug reactions and among puerperal women. In 35–40% of cases, AHA accompanies autoimmune diseases, including bullous dermatoses.”
AHA differs from congenital hemophilia A (CHA) in that both adult sexes are affected in AHA, rather than boys for CHA. Spontaneous hemarthroses are the major complications of CHA. AHA may present with life-threatening hemorrhage of mucous membranes, in soft tissue (muscle, skin) and mucous membranes. (2)
The original report of an ABD with AHA, to the best of my knowledge, was a case of pemphigus vulgaris, reported in 1956. (I could not get the article itself to confirm this). (3) Subsequent associations have included the Senear-Usher syndrome (4), bullous pemphigoid (5), epidermolysis bullosa acquisita (6), and linear IgA bullous dermatosis (7). Other dermatoses that have associated with AHA include erythema multiforme, psoriasis, exfoliative dermatitis, and erythema annulare centrifugum. (5)
The mortality rate of AHA ranges from 7.9 to 22%, mandating early diagnosis and therapy. The diagnosis of AHA is rendered on the basis of clinical symptoms and laboratory findings such as elongation of the activated partial thromboplastin time (APTT), a decrease of factor VIII activity, and existence of factor VIII inhibitors. Factor VIII inhibitors are usually composed of the IgG4 subclass, but are rarely IgM or IgA. (7)
Mechanistically, the presumption is that patients have cross-reacting antibodies between the particular ABD antigen and factor VIII, an increased propensity to develop a second autoreactive antibody after developing the first one, or (from my perspective the least likely option) mere coincidence. (5)
Treatment of AHA focuses on replenishing factor VIII, by using products such as activated prothrombin complex concentrate (7), or plasma fractions with factor VIII inhibiting bypass activity (5), in concert with immunosuppression. Prednisone, cyclophosphamide, azathioprine, vincristine or mycophenolate mofetil may be utilized. (2) Increasingly, rituximab is being administered effectively for both AHA and ABD. (8) Patients should be monitored for recurrences for two years with periodical assessment of APTT and factor VIII activity. (2)
Louis Pasteur said: “chance favors the prepared mind.” You are now prepared to recognize and manage the rare occurrence of AHA in patients with ABD. I hope you never get the chance.
Point to remember: An acute onset of bleeding (in skin, muscle, or soft tissue) in patients with autoimmune bullous diseases, accompanied by a rapid drop in hemoglobin, is indicative of acquired hemophilia A.
1. Wernham AG, et al. Pemphigus foliaceus and acquired haemophilia: A rare but important association with life-threatening consequences. Clin Exp Dermatol 2018; 43; 825-8.
2. Filipczak A, et al. Coexistence of pemphigus foliaceous and acquired hemophilia A: A case report. J Dermatol 2015; 42: 638-41.
3. Klingmuller G, et al. Pemphigus vulgaris with inhibitor hemophilia. Hautarzt 1956; 7: 200-6.
4. Reimer G, et al. Senear-Usher syndrome: Acquired hemophilia caused by the occurrence of a factor VIII inhibitor. Hautarzt 1982; 33: 645-8.
5. Aljasser M, et al. Bullous pemphigoid associated with acquired hemophilia A: A rare association of autoimmune disease. J Cutan Med Surg 2014; 18: 123-6.
6. Yan T-M, et al. Coexistence of acquired hemophilia A and epidermolysis bullosa acquisita: Two case reports and published work review. J Dermatol 2017; 44: 76-9.
7. Arakaki O, et al. Case of linear immunoglobulin A bullous dermatosis associated with acquired hemophilia. J Dermatol 2008; 35: 437-46.
8. Chiba T, et al. Acquired haemophilia treated successfully with rituximab in a patient with pemphigus vulgaris. Haemophilia 2013; 19: e 98-9.
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