Higher recovery of factor VIII (FVIII) with intermediate FVIII/von Willebrand factor concentrate than with recombinant FVIII in a haemophilia A patient with an inhibitor

The first line of therapy for acute bleeding in patients with low-responding factor VIII (FVIII) inhibitors is FVIII concentrates (1). Most inhibitors, recognizing the FVIII light chain, inhibit von Willebrand factor (VWF) and phospholipid binding to FVIII (2,3), and appears to be less active in vitro against plasmaderived FVIII concentrates containing VWF (pdFVIII/VWF) than VWF-free FVIII concentrates (4–7). These findings suggest that pdFVIII/VWF might be therapeutically more effective than recombinant FVIII (rFVIII) in patients with FVIII inhibitors. However, no clinical studies supporting this concept have been reported. In the present study, we have compared the recovery of FVIII activity (FVIII:C) after treatment with pdFVIII/VWF and rFVIII for massive intramuscular bleeding that occurred during regular infusion of FVIII for immune tolerance induction (ITI) therapy in a young male haemophilia A patient with an inhibitor. Immune tolerance induction therapy was commenced in our patient at the age of 9 years (18 October 1999) with the administration of 100 U kg of rFVIII (Recombinate; Baxter Healthcare Corp., Westlake Village, CA, USA) daily for 3 weeks, followed by infusions three to four times a week. Inhibitor levels fluctuated for 3 years after ITI therapy were initiated (maximum inhibitor level, 152.0 BU mL) and regular infusions of FVIII were continued. The number of bleeding episodes appeared to decline, and since January 2003, the inhibitor level has been kept constant within a low range from 0.9 to 2.1 BU mL. He was admitted into our hospital with severe pain in his right buttock and walking difficulties on 6 January 2004. He had suffered from painful swelling in his right buttock 2 weeks before admission without improvement in spite of daily infusions of FVIII (100 U kg). A subcutaneous haematoma (7 · 8 cm) was evident on the right buttock, with heat sensation, and impaired flexion and extension of the right hip joint. Computer tomography scanning demonstrated a massive intramuscular haematoma, measuring 10 cm in diameter, in the right gluteus maximus and gluteus medius muscles. On admission, 12 h after infusion of 4000 U (87 IU kg) of rFVIII, the FVIII inhibitor titre was 1.7 BU mL. As the bleeding manifestations had not responded to the infusion of rFVIII, 4000 U of activated prothrombin complex concentrate (Feiba Immuno; Baxter Healthcare Corp.) were administered. Nevertheless, the swelling and pain in the right buttock increased. Subsequently, replacement therapy with the same dose of rFVIII (4000 IU) was administered and continued (Fig. 1). Clinical symptoms gradually improved and the patient was discharged on 30 January. Regular prophylaxis in this patient is now maintained using FVIII/VWF concentrate. The inhibitor titre in this patient remained constant, within the range of 1.5–2.0 BU mL, throughout the present series of investigations. Therefore, it was possible to compare the recovery Correspondence: Midori Shima MD, Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara city, Nara 634-8522, Japan. Tel. : +81 744 29 8881; fax: +81 744 24 9222; e-mail: mshima@naramed-u.ac. jp