Endovascular Embolization in Acquired Hemophilia A: A Case Study Highlighting Diagnostic and Therapeutic Strategies

Introduction

Acquired hemophilia A (AHA) is a rare hematologic disorder caused by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII) inhibitors that impair the intrinsic coagulation system. Individuals with AHA present with isolated prolonged activated partial thromboplastin time (aPTT) and unexpected bleeding manifestations, ranging from mild to life-threatening, in the absence of a personal or family history of coagulopathy or anticoagulation/antiplatelet treatment [1,2]. In contrast to congenital hemophilia, which typically manifests as hemarthrosis, AHA is characterized by a greater incidence of subcutaneous, intramuscular, and retroperitoneal hemorrhages that are often very extensive [3,4]. In approximately 50% of patients, there is an identifiable underlying clinical condition, including autoimmune disorders, such as lupus erythematosus and rheumatoid arthritis, as well as solid and hematological malignancies. Other potential triggers include chronic inflammatory bowel diseases, infections, and certain medications, such as penicillin and interferon. Additionally, it can occur during the postpartum period of an otherwise normal pregnancy, underscoring the varied clinical contexts in which AHA can develop [1,2].

AHA is associated with significant mortality, which can reach up to 40% if patients do not receive treatment within the first week, and has an estimated variable according to age incidence ranging from 0.045 in 1 million per year in individuals under 16 years, to 14.7 in 1 million per year in those over 85 years [3–7]. AHA predominantly affects the elderly population, with a median presentation age of 60 to 67 years; however, in the age group of 20 to 40 years, prevalence is higher in female patients, linked to the heightened risk of disease during pregnancy and the postpartum period, whereas in adults over 85 years, it is more frequently observed in male patients [8].

Delays in diagnosis frequently occur due to the rare condition being overlooked by medical professionals who lack familiarity with the disease. The first step for the diagnosis of AHA (FVIII inhibitor) is the mixing study, which helps differentiation between factor deficiencies and factor inhibitors [6]. In this procedure, the patient’s plasma is combined in a 1: 1 ratio with normal pool plasma, which contains 100% activity for each factor. After mixing, 2 measurements of PT and aPTT are conducted: one immediately and another after 2 h of incubation at 37°C. In both assessments, PT and aPTT should normalize despite factor deficiencies; however, in the presence of inhibitors, aPTT will be prolonged in the subsequent measurement (Figure 1) [9]. The next step involves the Bethesda assay, which is an essential diagnostic method used for the detection and quantification of FVIII inhibitors, particularly in cases of AHA.

The Bethesda assay measures the reduction in FVIII activity levels by mixing serial dilutions of the patient’s plasma with pooled control plasma at 37 °C for 2 h. Results are expressed in Bethesda units (BU), which correspond to the reciprocal dilution of patient plasma yielding 50% FVIII activity. Higher Bethesda unit levels correlate with stronger inhibitor presence, signaling more severe FVIII dysfunction [10–12].

Management of AHA consists of a 2-tiered approach: bleeding control by achieving adequate hemostasis via the use of bypassing agents, such as activated coagulation factor complicated concentrate, activated recombinant FVII, or recombinant porcine FVIII, which are effective in the vast majority of cases, and inhibitor eradication with the use of glucocorticoids, cyclophosphamide, and rituximab. In the case of an identifiable underlying condition, treatment for this condition is imperative to prevent relapses [1].

Endovascular embolization has been rarely performed in the bleeding management of patients with AHA, as it poses a therapeutic challenge due to the elevated risk of bleeding. In the present report, we describe a patient with AHA, unresponsive to pharmacological therapy, who was successfully treated with endovascular embolization. Our aim is to underscore the efficacy of this treatment as a potential alternative therapy strategy for deteriorating individuals who are unresponsive to conventional treatment.

Case Report

An 82-year-old woman with a medical history of rheumatic polymyalgia under corticosteroid treatment, dyslipidemia, and hypertension presented to the Emergency Department with left thigh stiffness and extensive ecchymosis.

Upon arrival, she was afebrile and hemodynamically stable, with the following vital signs: blood pressure 125/80 mm Hg, heart rate 65 beats/min, oxygen saturation 98% (FiO2 21%) respiratory rate 20 breaths/min, and a normal ECG. Physical examination revealed extensive bruising throughout the body, notably a large hematoma on the anterior surface of the left thigh. Palpation revealed induration and tenderness, implying significant intramuscular bleeding. No joint swelling or pain characteristic of hemarthrosis was noted.

Initial laboratory investigations (Table 1) revealed a markedly elevated aPTT of 136 s (reference range 25–35 s) and a hemoglobin level of 12.6 g/dL (reference range 12–16 g/dL). Prothrombin time (PT) and international normalized ratio (INR) values were within the reference range. The patient underwent a chest radiograph, which was normal, and subsequently a duplex ultrasound, which did not reveal thrombosis; however, it showed subcutaneous edema of the left thigh.

The patient was then admitted to the Hematology Department for further investigation, where she started to deteriorate, with a significant decrease in hemoglobin levels, and the edema of the left thigh worsened. In parallel with the diagnostic work-up for isolated aPPT, the patient underwent CT angiography, which revealed the presence of a 20-cm hematoma of the vastus lateralis, vastus medialis, and vastus intermedius muscles of the quadriceps femoris, with active contrast extravasation. A mixing study (Table 2) was suggestive for the presence of coagulation inhibitor. The mixing study showed, first, the correction of aPTT following mixing with normal pooled plasma and, second, the prolongation after 2 h of incubation with normal pooled plasma, indicating the presence of inhibitor.

Additionally, the assessment of coagulation factors revealed a severe deficiency of FVIII, with activity less than 1%. Bethesda assay revealed FVIII inhibitor of 7.2 BU, confirming the diagnosis of AHA.

Oral immunosuppressive therapy consisting of prednisone (1 mg/kg/day) and cyclophosphamide (1.5 mg/kg/day) was administered immediately following the diagnosis, to eradicate inhibitory autoantibodies. Moreover, recombinant activated human FVII was administered, with an initial bolus dose of 90 μg/kg every 6 h. Transfusion support with packed red blood cells was also provided.

Despite optimal treatment, the patient’s condition continued to deteriorate. She continued to require packed red blood cell transfusions, and as the hemorrhage continued, with a further drop in hemoglobin level to 6.4 g/dL on day 2 of hospitalization; she became hemodynamically unstable. We performed a new CT angiography, which revealed a significant increase in the hematoma.

Given the lack of response to replacement therapy and immunosuppression, in addition to the fact that the patient was hemodynamically unstable and the bispecific antibody emicizumab was not available, we opted for an interventional therapeutic approach, which presented technical challenges, due to the patient’s elevated bleeding risk. A catheterization was performed through the left radial artery, followed by the insertion of a 6F sheath and embolization of a branch of the left superficial femoral artery (Figures 2, 3). The procedure was performed with the administration of recombinant activated human FVII at a dosage of 90 μg/kg intravenous bolus every 2 to 3 h, due to the patient’s susceptibility to periprocedural bleeding, requiring a balanced management approach.

After embolization, the bleeding stopped immediately. The patient’s condition improved significantly over the subsequent days. During the course of treatment, hemoglobin levels improved, aPTT levels progressively normalized, the FVIII activity increased, and the hematoma reduced in size. An investigation into the etiology of AHA was also conducted, consisting of comprehensive autoimmune diseases investigations and screening for malignancies and infectious diseases. She was discharged after 3 weeks, on a tapering dose of corticosteroids, and was scheduled for monthly follow-ups (Table 3). Bethesda assay at 1 and 4 months indicated the absence of inhibitor, with FVIII levels normalizing to 108% by month 3.

Discussion

AHA is a challenging diagnosis due to its rare occurrence; epidemiological data can be underestimated because it remains largely undiagnosed, especially in elderly patients receiving antithrombotic treatment. New onset of bleeding of variable severity with prolonged aPTT, in the absence of previous personal or family history of bleeding, in patients not receiving antiplatelet/anticoagulation therapy, should prompt immediate diagnostic work-up of AHA.

In the realm of pathophysiology, AHA is characterized by the development of autoantibodies, predominantly IgG, targeting coagulation FVIII. These antibodies bind to specific domains of FVIII, particularly the A2, A3, and C2 regions, disrupting its essential functions, leading to the inhibition of FVIII activity. This interference impairs FVIII’s interaction with phospholipids, von Willebrand factor, and factors IXa and X, which are crucial for the propagation of the coagulation cascade. The autoantibodies demonstrate non-linear kinetics (type II kinetics), indicating a complex inactivation process. Furthermore, these antibodies are temperature- and time-dependent and non-complement fixing, contributing to the hemostatic imbalance observed in patients with AHA [13,14]. The Bethesda assay is crucial in quantifying the inhibitor both for the initial diagnosis and for guiding treatment decisions.

Approximately 50% of AHA cases are classified as idiopathic, whereas the remaining cases are associated with identifiable underlying conditions. In our case, we conducted a comprehensive investigation into the etiology of AHA, revealing no pathological findings. Consequently, the most likely cause of the AHA was the rheumatic polymyalgia experienced by the patient.

In most cases, pharmacological treatment is effective; however, some patients, as in our case, can be unresponsive or experience life-threatening bleeding episodes requiring interventional treatment. Angiography and embolization in individuals with acquired and congenital hemophilia present significant technical challenges due to the increased risk of periprocedural bleeding, requiring a multidisciplinary approach in specialized therapeutic centers with collaboration between hemostasis experts and skilled interventionists. There are currently only a few case reports in the literature that describe the use of endovascular embolization in patients with AHA [15–19]. This fact can be attributed to both the rarity of the disease and the lack of specific guidelines for managing invasive procedures in patients with AHA, as individuals with bleeding disorders have typically been excluded from clinical trials, resulting in only consensus statements being available.

When an endovascular approach is inevitable, replacement therapy should be initiated as soon as possible, prior to any invasive procedure or in parallel to the process, and the peak level of the impaired clotting factor should ideally exceed 80% of normal during the periprocedural period [20,21].

Endovascular treatment of bleeding in patients with AHA could be especially advantageous in specific clinical scenarios involving critically ill and rapidly deteriorating patients with AHA, as in our case, taking into consideration technical parameters such as the catheterization site and the interventionist’s skills, as well as the concurrent administration of bypassing agents. The whole procedure should be performed under the consultation of hemostasis experts who can evaluate and perform decision-making in such tough clinical cases. In our case, the patient underwent successful embolization of a left superficial femoral artery branch. The procedure was performed under adequate clotting factor administration and closed monitoring of hemostatic parameters.

Conclusions

This case highlights, on one hand, the importance of a timely, interdisciplinary approach to AHA, using diagnostic assays, bypassing agents, and immunosuppressants and, on other hand, the lifesaving role of endovascular embolization when needed. Early recognition plays a key role in reducing mortality, and a targeted personalized therapeutic approach can significantly improve outcomes, even in elderly patients with significant comorbidities. Given the rare nature of AHA, the continued reporting of such cases is essential for advancing our understanding and management of this complex and life-threatening disorder.