Bullous pemphigoid associated with acquired hemophilia A: A case report

Abstract

BACKGROUND

Acquired hemophilia A (AHA) is a rare and potentially severe bleeding disorder caused by circulating autoantibodies against factor VIII (FVIII). In approximately 50% of the patients, the condition is associated with autoimmune diseases, cancers, medication use, pregnancy, and the post-partum period. Bullous pemphigoid (BP) is a chronic autoimmune subepidermal blistering disease associated with tissue-bound and circulating autoantibodies against BP antigens 180 (BP180) and 230 (BP230). AHA-associated BP has a high mortality rate; hence, the understanding of this disease must improve.

CASE SUMMARY

A 69-year-old man presented with erythema, blisters, blood blisters, and crusts accompanied by severe pruritus for more than 20 days, and ecchymosis and swelling on his left upper arm for 3 days. Pathological examination revealed a subepidermal blister that contained eosinophils. Laboratory tests showed that the BP180 autoantibody levels had increased, isolated activated partial thromboplastin time was notably prolonged (115.6 s), and coagulation FVIII activity was extremely low (< 1.0%). Furthermore, the FVIII inhibitor titer had greatly increased (59.2 Bethesda units). Therefore, the patient was diagnosed as having BP associated with AHA, prescribed 0.05% topical halometasone cream, and transferred to a higher-level hospital for effective treatment; however, he died after 2 days.

CONCLUSION

AHA associated BP is rare, dangerous, and has a high mortality rate. Therefore, its timely diagnosis and effective treatment are necessary.

Key Words: Bullous pemphigoid; Acquired hemophilia A; Acquired hemophilia A; Factor VIII; Case report

Core Tip: Bullous pemphigoid associated with acquired hemophilia A is a rare disorder with unknown etiology and a high mortality rate. Because it develops in patients without a known bleeding disorder, clinicians should be aware of it and ensure its timely diagnosis and appropriate and effective treatment.

INTRODUCTION

Acquired hemophilia A (AHA) is an acquired bleeding disorder in which coagulation factor VIII (FVIII) activity is reduced owing to the presence of autoantibodies against FVIII in patients with non-hereditary hemophilia[1]. Its etiology in approximately 50% of patients remains unclear. Further, approximately half of the patients with AHA have autoimmune diseases, malignant tumors, and allergic reactions to drugs (penicillin and its derivatives). AHA is predominantly a disease of the elderly (mean patient age: 75.70 years)[2]; however, it has been reported in younger patients in Asian countries (mean age: 58.10 years)[3]. The disease incidence ratio is similar between the sexes. Bullous pemphigoid (BP) is a chronic autoimmune subepidermal blistering disease, associated with tissue-bound and circulating autoantibodies directed against BP antigen 180 (BP180) and BP antigen 230 (BP230)[4]. Here, we report a case of a patient with BP for more than 20 days and complicated by AHA after 17 days, characterized by skin involvement such as blisters, blood blisters, and ecchymosis.

CASE PRESENTATION

Chief complaints

A 69-year-old man presented with erythema, blisters, blood blisters, and scabs accompanied by severe pruritus for more than 20 days, and ecchymosis and swelling on his left upper arm for 3 days.

History of present illness

The patient presented with oral blisters and erosion as the first manifestations, which gradually extended to both forearms and the trunk. He complained of a poor appetite; however, there were no signs of gastrointestinal bleeding, such as hematemesis, melena, hemoptysis, and hematuria.

History of past illness

His history of past illness included a 6-year history of hypertension with a maximum blood pressure of 180/100 mmHg and high left lower limb amputation that he had undergone more than 10 years before the current disease presentation. His medications included nifedipine oral tablets 10 mg thrice daily. He was not on any new medication. The patient denied a history of diabetes, coronary heart disease, hepatitis, tuberculosis, and any infectious diseases as well as any close contact with infected people. He also denied any food or drug allergy. His vaccination history was unknown.

Personal and family history

He denied a previous bleeding tendency when disclosing his personal and family history.

Physical examination

A physical examination revealed blisters and blood blisters on the neck, limbs, and trunk; some of the blisters were shriveled and crusted. We also noted ecchymosis on both upper limbs accompanied by severe swelling of the left hand and forearm as well as erosion of the oral mucosa, which was covered with exudates (Figure 1). The BP disease area index severity score was 65, which was defined as severe BP.

Figure 1 Clinical feature. Ecchymosis, blisters and blood blisters on the extremities. A: Ecchymosis and blood blisters on the swollen right upper extremity. B: Blisters and blood blisters on the left wrist. C: Bean-sized blood blisters on the right forearm. D: Ecchymosis on the left upper extremity.

Laboratory examinations

Target antigen-specific serological confirmatory testing by enzyme-linked immune-sorbent assay (ELISA) showed normal desmoglein 1 autoantibodies (6.9 U/mL, normal range: 0–20 U/mL), normal desmoglein 3 autoantibodies (8.21 U/mL, normal range: 0–20 U/mL), and increasing BP180 autoantibodies (25.7 U/mL, normal range: 0–9 U/mL). Blood routine showed normocytic anemia (red blood cell count: 2.12 × 10¹²/L, normal range: 4.30–5.80 × 10¹²/L; hemoglobin level: 74 g/L, normal range: 130–175 g/L), mean corpuscular volume of 92.7 fL (normal range: 82–100 fL), and a normal platelet count (209 × 10⁹/L, normal range: 125–350/L). The patient’s coagulation profile showed severe prolongation of the activated partial thromboplastin time (115.6 s, normal range: 27–45 s) and normal prothrombin time 11.5 s, normal range: 11–15 s, fibrinogen level 3.14 g/L, normal range: 2–4 g/L, and D-dimer level 1.53 μg/mL, normal range: 0–0.5 μg/mL. The coagulation factor test showed that FVIII activity had decreased to 1.0% (normal range: 50%–150%) and the activity of factors Ⅸ, XI, and XII had increased to 63% (normal range: 50%–120%), 71.2% (normal range: 50%–120%), and 45.8% (normal range: 50%–120%), respectively. The FVIII inhibitor titer was 59.2 Bethesda units (normal range: < 0.6). The activity of von Willebrand factor antigen was 209.0% (normal range: 50%–160%).

Liver and renal functions; results of infectious disease screening and the anti-neutrophil cytoplasmic antibody assay; and levels of anti-nuclear antibody 20 and male tumor markers were not abnormal.

Imaging examinations

A biopsy sample was obtained from the edge of an active lesion. The sample was obtained such that some adjacent healthy skin was included in it so that the level of the blister could be accurately identified. The tissue section was fixed in 10% neutral formalin, paraffin-embedded, sectioned, and stained with hematoxylin and eosin. Histopathologic testing indicated a subepidermal blister containing eosinophils and infiltration of eosinophils around small vessels in the dermis (Figure 2). Direct immunofluorescence (DIF) revealed linear typical deposition of complement C3 along the dermo-epidermal junction (Figure 3).

Figure 2 Hematoxylin and eosin staining. Subepidermal blister (red arrow), which contains eosinophils (yellow arrow) and infiltration of eosinophils around small vessels in the dermis. A: Hematoxylin and eosin (HE) × 10; B: HE × 40; C: HE × 100.

Figure 3 Direct immunofluorescence. Linear typical deposition of complement C3 along the dermo-epidermal junction.

FINAL DIAGNOSIS

Based on the clinical presentation, pathological findings, and laboratory examination results, a diagnosis of BP associated with AHA was made.

TREATMENT

Symptomatic treatment such as anti-infection treatment and hemostasis was administered and topical 0.05% halometasone cream was prescribed.

OUTCOME AND FOLLOW-UP

Once the diagnosis of BP associated with AHA was made, the patient was immediately transferred to the provincial hospital for further treatment. However, he died 2 days later.

DISCUSSION

AHA is a rare hemorrhagic disease caused by the production of FVIII autoantibodies and a serious reduction of FVIII activity. Its incidence is estimated to be 1.0–2.0 cases per million population per year[5]. If not treated in a timely manner, it causes severe bleeding, endangering the affected patients' lives. The clinical manifestations of AHA vary greatly. However, 90% of patients present with severe bleeding[6], and the associated mortality rate ranges between 9% and 33% depending on the series of events in the first 2 months after diagnosis[7]. The etiology of the disease remains unknown. According to a previous study[8], 50% of the cases are related to the underlying diseases or conditions, including autoimmune diseases such as systemic lupus erythematosus[9], rheumatoid arthritis[10], autoimmune hemolytic anemia[11], and BP[12-15]; perinatal period in female patients[16]; malignant tumors such as urothelial carcinomas; and reactions to drugs[17] such as penicillin, chloramphenicol, and anti-TNF-α antibodies (e.g., adalimumab)[18].

BP is diagnosed based on the typical clinical presentation, compatible histologic features, and, most importantly, positive DIF microscopy studies. Further support for the diagnosis of BP requires the detection of specific circulating IgG autoantibodies (anti-BP180, anti-BP230) via either indirect immunofluorescence microscopy or ELISA[4,19]. Our patient was diagnosed based on his clinical features, histopathological examination results, DIF microscopy results, and results of target antigen-specific serological confirmatory tests by ELISA.

Control of acute bleeding and prevention of injuries that may provoke bleeding are top priorities in patients with AHA. Comparative clinical studies to support treatment recommendations for AHA do not exist. Based on recent registry findings and the clinical experience in treating patients with AHA, Tiede et al[6] suggested treatment with bypassing agents, including recombinant activated factor VII, activated prothrombin complex concentrate, and recombinant porcine FVIII in bleeding patients. Autoantibody eradication can be achieved with immunosuppressive therapy, including corticosteroids, cyclophosphamide and rituximab, or combinations thereof. FVIII activity at presentation, inhibitor titer, and autoantibody isotype are prognostic markers for remission and survival. Binet et al[12] reported a case of successful management of AHA associated with BP using methylprednisolone at decreasing dose levels and four courses of rituximab. Rituximab is commonly used to treat BP[20]. Rituximab is a monoclonal antibody against CD20, a transmembrane protein expressed by B cells. It is known that B-cells secrete IgE; thus, B-cells may be a co-pathway for BP and AHA. Fakprapai et al[14] described the case of a 68-year-old Thai woman who was diagnosed with and treated for BP for 11 months and whose condition was complicated by AHA for 3 days. This woman was treated with systemic corticosteroids and cyclophosphamide combined with bypassing agents for bleeding control. The therapy resulted in significant clinical improvement, and subsequently, negative antibody levels.

In our case, the patient was only prescribed topical halometasone cream without systematic corticosteroids or other immunosuppressive therapy before the diagnosis of BP associated with AHA. He was immediately transferred to the superior hospital after the explicit diagnosis. The treatment in the superior hospital remains unknown, and the patient died after 2 days.

CONCLUSION

Owing to life-threatening bleeding in severe AHA cases, early diagnosis and effective treatment are necessary for BP associated with AHA.