Use of thromboelastography before the administration of hemostatic agents to safely taper recombinant activated factor VII in acquired hemophilia A: a report of three cases

Case 1

An 82-year-old female was admitted for bullae with bleeding and a nasal hemorrhage. She had no relevant medical history other than a herpes zoster infection 3 years before admission. She was not taking any medication. She had developed bullae with bleeding 2 weeks before admission and saw a dermatologist. Laboratory tests revealed a prolonged activated partial thromboplastin time (APTT), and she visited our clinic. Coagulation tests showed a prolonged APTT (80 sec), reduced factor VIII coagulant activity (FVIII:C) (0.7%), and a high factor VIII (FVIII) inhibitor titer (5.4 Bethesda units [BU]/mL) (Table 1). She was diagnosed with AHA with bullous pemphigoid. Computed tomography (CT) revealed a local alveolar hemorrhage. rFVIIa (90 μg/kg) treatment was started, and the initial dosing interval was 3 hours. Immunosuppressive therapy with 1 mg/kg of prednisolone was also initiated. Before the administration of the first dose of rFVIIa, her clotting time according to rotational thromboelastometry (ROTEM) was extended (70.5 minutes). ROTEM, which was performed at a specialized laboratory, was only used to analyze the patient’s clotting time before the administration of the first dose of rFVIIa. After that, TEG-based analyses were carried out at our laboratory. On the second day of rFVIIa treatment, the subcutaneous bleeding improved, and the rFVIIa dosing interval was gradually increased. Once the dosing interval had reached 6 hours, it was extended based on the patient’s coagulation capacity according to TEG performed immediately before the administration of rFVIIa (Fig. 1A). Thirteen days after the start of rFVIIa treatment, the patient’s R-value was 10 min; i.e., it had almost returned to the reference range (reference range: 4.6-9.1 min). Therefore, the rFVIIa dosing interval was increased from every 6 hours to every 8 hours. At 21 days after the start of the rFVIIa treatment, the patient’s R-value before the administration of rFVIIa was found to be 5.4 min, and hence, rFVIIa was discontinued. The patient did not suffer from any alveolar rebleeding. After the discontinuation of rFVIIa, the patient’s FVIII:C level recovered (87%), and the FVIII inhibitor became undetectable (Fig. 1A). The patient’s ability to perform ADL did not decline, and she was able to return to her daily life quickly. The administration of corticosteroids improved both her AHA and bullous pemphigoid. 1 year after the onset of AHA, the steroid therapy was discontinued. 1 month later, her bullous pemphigoid worsened, but her AHA did not recur. Steroid therapy was resumed, and the recurrent pemphigus was ameliorated. After more than 2.5 years of treatment with maintenance doses of steroid therapy (7.5 mg of prednisolone), the AHA has not relapsed.

Table 1 Characteristics of 3 patients with acquired hemophilia A that underwent TEG-based analysesFig. 1figure 1

Change in the reaction rate time (R) according to thromboelastography (TEG). The levels of factor VIII coagulant activity (FVIII:C) and the R-value according to TEG in three acquired hemophilia A patients (A-C) who were being treated with recombinant activated factor VII (rFVIIa) are shown. The doses of rFVIIa are also represented. The black line and dashed line represent dynamic changes in FVIII:C levels and the R-value, respectively. The x-axis indicates the number of days from the start of rFVIIa treatment until the FVIII:C level rose to > 20%. The day on which rFVIIa treatment was initiated was designated “day 1”. The horizontal dotted line indicates the R-value reference range (4.6-9.1 min) according to TEG. The administration of rFVIIa is indicated by grey boxes. “q3” means that rFVIIa was administered every 3 hours

Case 2

A 56-year-old male with left shoulder joint pain and difficulty walking attended our clinic. He had had hyperuricemia and hyperlipidemia for 10 years and hypertension for 5 years before his visit. He saw an orthopedic surgeon for left shoulder pain. Left shoulder arthrocentesis revealed an intraarticular hemorrhage. 4 days later, he suffered from hip pain, and CT showed a hematoma in his iliopsoas muscle. He visited our clinic so that the reason for his bleeding tendency could be investigated. Laboratory tests showed a normal prothrombin time (PT), a prolonged APTT (68 sec), decreased FVIII:C (1.3%), and an increased FVIII inhibitor concentration (3.2 BU/mL) (Table 1). He was diagnosed with AHA. rFVIIa (90 μg/kg) was administered to control the progression of the pelvic hematoma. At that time, his R-value was prolonged (23.8 min). Immunosuppressive prednisolone therapy was also started. 4 days after the start of the rFVIIa treatment, the left shoulder pain had been ameliorated, and the patient’s R-value had decreased (Fig. 1B). The rFVIIa dosing interval started to be increased. However, after the rFVIIa dosing interval reached 12 hours, TEG-based analysis showed that the patient’s R-value had increased (14.7 min). At that time, his left shoulder pain recurred. Based on the prolonged R-value revealed by TEG, the rFVIIa dosing interval was reduced from every 12 hours to every 6 hours. In addition to the increased R-value, the patient’s FVIII:C level remained low at 1.7%, and cyclophosphamide (100 mg/day) was added as an immunosuppressive therapy. 1 month after the diagnosis, rFVIIa (dosing interval: every 8 hours) was discontinued based on an R-value of 8.2 min being demonstrated by TEG analysis just before the administration of the drug. At that time, his left shoulder pain had improved, and his iliopsoas hematoma had shrunk. The FVIII inhibitor was still detectable (1.9 BU/mL), and 375 mg/m2 of rituximab was administered twice, 1 week apart. After the second infusion of rituximab, the FVIII inhibitor became undetectable. After more than 2.5 years, the AHA has not relapsed.

Case 3

A 58-year-old female, with a history of transient ischemic attacks (TIA) 2 years before her visit, suffered from leg pain and difficulty walking due to an intramuscular hematoma in her lower left leg. She had been taking cilostazol since the TIA. Laboratory tests revealed a normal PT, a prolonged APTT (94 sec), decreased FVIII:C (1.1%), and an increased FVIII inhibitor concentration (5.9 BU/mL) (Table 1). She was diagnosed with AHA and was treated with rFVIIa (90 μg/kg) to reduce the size of the hematoma in her left leg. The administration of 1 mg/kg prednisolone was also started. 7 days after admission, TEG performed just before the administration of rFVIIa revealed that the patient’s R-value was higher than the reference range (12.8 min) (Fig. 1C). At that time, although her leg pain had been relieved, new subcutaneous hemorrhages appeared. Based on the results of TEG, the dosing interval was not extended beyond 4 hours. 11 days after admission, the bleeding symptoms had been ameliorated. The patient’s R-value improved, and the rFVIIa dosing interval was increased to 6 hours. After the R-value reached 8.7 min (dosing interval: every 12 hours), rFVIIa was discontinued. 1 week later, the FVIII inhibitor became undetectable. She was able to return to daily life quickly after being discharged. After more than 1.5 years, the AHA has not relapsed.

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