Von Willebrand Factor/Factor VIII Concentrate (Humate-P^®) for Surgical Prophylaxis of Excessive Bleeding in Patients with Von Willebrand Disease (VWD).

Optimal dosing to prevent excessive surgical bleeding in VWD is being investigated in an ongoing prospective, uncontrolled, open-labeled study to establish the safety and efficacy of replacement therapy with a VWF/FVIII concentrate (Humate-P®). This protocol-defined interim analysis describes the results in the first eighteen (18) patients (6 males, 12 females) of a total of 30 planned. Seven patients had Type 1 VWD, 6 had Type 2 (2 with 2A, 3 with 2B, 1 with 2M), and 5 had Type 3. All patients had pre-operative pharmacokinetic assessments to individualize the loading and maintenance doses of VWF/FVIII concentrate utilized for surgery. Fourteen patients had major surgical procedures including neurosurgery, joint replacement, tonsillectomy and complete oral restoration; three had minor procedures; and one had oral surgery. Hemostatic efficacy was assessed by investigators on a four-point scale (excellent, good, moderate/poor, none) immediately after surgery, 24 hours after the last VWF/FVIII concentrate infusion, and 14 days post-op. Good and excellent efficacy were combined into one endpoint of effective hemostasis. Expected estimated blood loss (EBL) was defined prior to the procedure, and actual EBL was recorded post-op. Adverse events were collected throughout the trial until follow-up 4 weeks post-op. Hemostasis was effective in 17/18 patients (94.4%) immediately after surgery; in 17/17 patients (100%) 24 hours after the last VWF/FVIII conc infusion; and in 18/18 (100%) patients 14 days after surgery. Median actual EBL did not exceed expected EBL in any surgery category. Four patients received transfusions (one for pre-existing anemia, three for serious adverse events). Loading doses of VWF/FVIII concentrate ranged from 36 to 135 IU/kg. Maintenance doses were determined by daily monitoring of plasma coagulation factor levels. Median durations of treatment were 2 days for oral surgery, and 4 days for both minor and major surgery. Post-op nausea (n=5) and fever (n=3) were the most commonly reported adverse events. Nausea, headache, and dizziness were considered possibly related to VWF/FVIII concentrate in one patient each; these events were mild in severity and resolved without sequelae. Bleeding-related serious adverse events were reported in three patients: one with GI bleeding post-laparoscopic gastro-jejunal bypass; one with post-craniotomy subdural and intracranial bleeding; and one with post-hysteroscopy/dilatation & curettage hemorrhage followed by hysterectomy. Hemostasis was considered effective in these 3 by the investigators, and in 2 patients by an independent DSMB review; hemostasis was considered ineffective by the DSMB only in the patient with post-hysteroscopy bleeding. No thromboembolic complications or changes in viral titers were observed. This analysis supports VWF/FVIII concentrate safety and efficacy to prevent excessive bleeding during and after a range of surgical procedures in patients with VWD. Enrollment in the trial continues.