Treatment for patients with type 3 von Willebrand disease and alloantibodies: a case report

Alloantibodies that bind von Willebrand factor (VWF) and form circulating immune complexes develop in approximately 8–14 per cent of patients with type 3 von Willebrand disease (VWD) who received multiple transfusions, especially in carriers of null mutations [1]. As these antibodies may lead to immune complex-mediated, life-threatening anaphylactic reactions, concentrates containing VWF are generally contraindicated in these patients [2]. We report the case of a patient with type 3 VWD and anti-VWF alloantibodies who was managed with recombinant factor VIII (rFVIII). The patient, a 35year-old female, was previously described on the occasion of her first life-threatening anaphylactic reaction that occurred in May 1993, following the infusion of a FVIII/VWF concentrate (Haemate P; CLS Behring, Marburg, Germany) [3]. On that occasion, she was successfully treated for the first time with rFVIII. From January 1994 to November 2005, the patient was treated with rFVIII (boluses of 5000 U followed by 1500 U h by continuous infusion until the resolution of bleeding) on the occasion of eight haemorrhagic episodes (three episodes of renal colicky pain with macrohaematuria, three episodes of abdominal pain because of haemorrhagic follicular rupture, one episode of menorrhagia and a haematoma of the right arm). Overall, 432 000 IU of rFVIII (144 000 IU of Kogenate and 288 000 IU of Recombinate) were used, the mean number of hours of rFVIII treatment per episode being 36 (range: 12–72) and the mean number of IU of rFVIII infused per episode being 54 000 (range: 23 000–113 000). In all the occasions, treatment was effective in stopping bleeding and no drugsrelated adverse reactions occurred. In December 2005, the patient was retreated for menorrhagia with Recombinate at the usual dosage and a diffuse skin rash appeared after the bolus infusion. Recombinate was immediately stopped, and the cutaneous reaction rapidly regressed. However, it was necessary to restart this rFVIII product (after steroid premedication) because of persistent menorrhagia, but on this occasion, the infusion was uncomplicated (a total of 36 000 IU of Recombinate was administered over 24 h). No blood components were transfused during the bleeding episode. A control of the anti-VWF antigen (VWF:Ag) titre performed in January 2006 showed an increased level (150 U mL) compared with historical controls of the same patient, while the next consecutive blood samples (March and June 2006) documented the progressive decrease of anti-VWF:Ag towards the trough value of 10 U mL. Figure 1 shows the anti-VWF:Ag course. Thus, it can be hypothesized that traces of VWF, responsible for the anamnestic antibody response, were present in the final formulation of Recombinate as a result of the production process, because the VWF gene is co-expressed with the FVIII gene in the cell culture system used for manufacturing this rFVIII [4]. There is limited but favourable experience reported in the literature on the use of rFVIII in type 3 VWD patients with alloantibodies [3]. However, as the half-life of the infused FVIII in the absence of its carrier VWF is very short (1–2 h) in these patients, rFVIII must be administered at very large doses by continuous infusion in order to maintain haemostatic levels of FVIII. Other positive experiences have been reported with the use of the bypassing agent recombinant activated factor VII (rFVIIa) [5]. Correspondence: Massimo Franchini, MD, Servizio di Immunoematologia e Trasfusione – Centro Emofilia, Ospedale Policlinico, Piazzale L.Scuro, 10-37134 Verona, Italy. Tel.: +0039 45 812 3610; fax: +0039 45 812 3612; e-mail: massimo.franchini@azosp.vr.it