Acquired hemophilia A (AHA) is associated with acquired autoantibodies against coagulation factors; they neutralize the factors and thus shorten the half-life of cogulation factor VIII (FVIII) in plasma. AHA is very rare in adolescents and young adults (AYAs), but is potentially life-threatening. Uncontrolled bleeding may occur in patients with no relevant family or personal medical history [1,2]. A delayed AHA diagnosis may cause fatal bleeding and accompany severe complications. Once the AHA is diagnosed, the control of abnormal bleeding and elimination of FVIII antibodies as soon as possible [8,10]. A high index of suspicion and specialized coagulation tests are required for rapid diagnosis . We report on an AYA patient with unusual clinical manifestations who was diagnosed with AHA to discuss our diagnostic procedure and management, and her prognosis. This case study was approved by the Institutional Review Board of our hospital (KHNMC 2022-01-007).
A 19-year-old woman was transferred to our emergency department with a major bleeding disorder. She reported multiple bruises on, and painful swelling of, the right lower leg about 1 month in duration; and recent lower abdominal pain with gross hematuria. She had no history of trauma or any bleeding disorder. Six years before, when operated on to correct spinal scoliosis, none of the platelet count, prothrombin time (PT), or activated partial thromboplastin time (aPTT) were abnormal; the operation was not associated with massive bleeding or any other complication. She had no familial history of bleeding disorder and autoimmune disorder. The initial vital signs were blood pressure 94/57 mmHg, heart rate 74/min, respiratory rate 20/min, and body temperature 37.2°C. Physical examination revealed bruises and a hematoma on the right calf and a right-ankle swelling (Fig. 1). Neurological examination revealed no weakness nor numbness, but a slight limitation in the right leg range of motion. The swelling made it difficult to walk.
The initial laboratory findings revealed anemia [hemo-globin 8.7 g/dL (normal 12.0-16.0 g/dL); hematocrit 26.7% (normal 36.0-48.0%)], but normal white blood cell and platelet counts. The aPTT was prolonged to 113.7 s (normal 26.7-36.6 s) and the FVIII activity was below 1% (normal 60-140%); but the factor IX activity was normal [80.4%, (normal 60-140%)]. Mixing tests revealed that the aPTT was not corrected. Later, the FVIII antibody level was assayed at 22.4 Bethesda units (BU). Given the absence of any history of bleeding and the laboratory abnormalities, she was diagnosed with AHA. There was no autoantibody associated with any autoimmune disease; no laboratory data indicated such a disease.
Initial magnetic resonance imaging (performed at another hospital) revealed perifascial hemorrhagic fluid in the left lower leg, diffuse subcutaneous edema in the anterior lower leg, and decreased perfusion with a heterogeneous signal change in the subfascial region of the peroneus longus muscle suggesting muscle infarction or rhabdomyolysis (Fig. 2). Given the persistent hematuria, ultrasonography of the kidney and bladder were performed. A hyperechoic mass was observed, but was presumed to be a blood clot.
Initially, she was treated with bypassing agents [re-combinant activated coagulation factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC)] to control the bleeding because neutralizing FVIII antibodies were detected. Firstly, she was injected with rFVIIa (4.8 kIU/kg) every 6 h for 4 days to control the acute bleeding. After stabilization, aPCC was adminis-tered for 10 days. An oral steroid (prednisolone) was used to eliminate the FVIII antibodies. Over the first 3 weeks, the steroid dose was 1 mg/kg/day; FVIII antibodies became undetectable and the FVIII level rose to 11.8%. Thereafter, the steroid dose was reduced over 4 weeks. At the end of the steroid treatment, FVIII antibody was not detected; the FVIII activity was 23.5%. Also, the gross hematuria, bruising and swelling of both legs became normalized. She was discharged after about 1 month. In outpatient clinic, the FVIII level increased with the absence of FVIII antibody, and then normalized (>100%) (Fig. 3).
AHA is a rare but life-threatening bleeding disorder with an annual global incidence of 0.2 to 1.5 cases per million , and is caused by the development of neutrali-zing autoantibodies against coagulation factor FVIII in the absence of any previous relevant history . In women aged 20-34 years, AHA is associated with pregnancy or autoimmune diseases, but is more common in older adults, especially those aged 60-70 years; the incidence in men and in women are similar . About 50% of AHA cases are associated with underlying conditions including auto-immune disorders, malignancies, drug reactions, and pre-gnancy, but the other 50% of cases are idiopathic [1,2]. The clinical manifestations range from minimal to life- threatening bleeding that may be subcutaneous (>80%), muscular (>40%), or gastrointestinal (>20%). In contrast with congenital hemophilia A, joint bleeding is rare in AHA . AHA is even rarer in children than adults; the annual incidence in children under the age of 16 years is 0.045 cases per million . The clinical course is similar to that of adults; the disorder may be idiopathic or related to underlying conditions. Few pediatric cases have been reported; the empirical treatment is that used for adults. However, treatment outcomes are better in pediatric patients, who exhibit more rapid and complete eradication of the FVIII inhibitor [7,8].
AHA is confirmed when the FVIII level is low and an FVIII inhibitor is detected [3,8]. In hemophilia, the levels of antibodies to coagulation factors are usually measured employing the Bethesda assay. The autoantibodies of congenital hemophilia A evidence linear type 1 kinetics but those of AHA show non-linear type 2 kinetics . It can be useful to detect the titer of FVIII antibodies in congenital hemophilia for predicting the exact potency of them, whereas in AHA, the potency of FVIII antibodies can be unpredictable. The serum FVIII concentration thus does not reliably predict the extent of FVIII activity or the severity of the disorder [6,15].
An early diagnosis of AHA is important in terms of appropriate treatment initiation. Clinicians must control both the acute bleeding and eradicate the anti-coagulation factor autoantibody. One survey found that bleeding-related complications were not severe, hemostatic treatment is not always required in 25-30% of AHA patients . Whereas, another study showed about 94.6% of AHA patients admitted to the hospital show constant bleeding causing severe anemia and unstable vital sign . For those patients, hemostatic treatment is inevi-table. As patients express FVIII antibodies, treatment must bypass the FVIII coagulation mechanism. The two most commonly used bypass agents are rFVIIa and aPCC [7-9]. Additionally, tranexamic acid may be combined with rFVII to inhibit fibrinolysis and thus enhance hemostasis [4,5].
While hemostatic agents are used to control bleeding, immunosuppressive treatment is also necessary to suppress production of the FVIII antibody. Such therapy should be immediately initiated when AHA is diagnosed. A recent guideline suggested that first-line immuno-suppressive treatment for AHA patients, especially those with severe disease (FVIII <1%) and FVIII inhibitor levels over 20 BU, should feature a corticosteroid with cyclophosphamide or rituximab for up to 6 weeks [5,14]. The usual prednisolone (prednisone) dose is 1 mg/kg daily alone for 4-6 weeks or with addition of cyclophos-phamide 1.5-2 mg/kg/day orally. If cyclophosphamide is contra- indicated or fails to deliver remission, a rituximab-based treatment may be considered. Apart from rituximab, useful immunosuppressive agents are mycophenolate mofetil, azathioprine, vincristine, and cyclosporine [5,10,12]. The FVIII and the FVIII antibody levels should be assayed weekly until they normalize. Many studies have reported relapses in up to 23% of cases . Thus, follow-up should be scheduled at 6 months (to confirm complete remission) and then every 2-3 months for 1 year [5,13]. Although the antibody level was at least 20 BU, we commenced oral steroid treatment, and reserved additional medication until we had data on the antibody level and the bleeding course. The FVIII antibody was eradicated by the oral steroid; the coagulation factor level normalized. The patient has been under outpatient follow-up for 2 years; no recurrence has been noted.
In summary, AHA is very rare in AYAs, but early diagnosis of an acquired bleeding disorder is important. Appropriate treatment prevents a severe and life-threatening disease course by eradicating the condition.
The authors have no conflict of interest to declare.