Introduction: Although widely used for the treatment of VWD, optimal doses of VWF/FVIII concentrates for surgical procedures in patients with VWD need to be determined. Two prospective, multicenter studies were undertaken to evaluate the efficacy and safety in surgery of a VWF/FVIII concentrate marketed in the United States (US; Humate-P®) and the European Union (EU; Haemate-P®) in patients with VWD (Lethagen et al. JTH, 2007). Initially, all patients had pharmacokinetic (PK) studies to guide individual dosing for surgery.

Results: In the US study, 41 subjects received 60 IU/kg VWF: RCo, and in the EU study 28 subjects received approximately 80 IU/kg VWF: RCo. At specified time points before and after infusion, median levels, half-life, mean change from baseline and in-vivo recovery (IVR) values were determined for VWF: RCo and FVIII: C. Collagen binding capacity (VWF: CB) was correlated with VWF: RCo; and VWF multimer analyses were also performed. In the US and EU studies, median baseline VWF: RCo levels were 13 (range[r] 6–124) and 8.1 (r 5–58) IU/dL; the highest median post-infusion values were 163 (r 84–330) and 147 (r 53–387) IU/dL. Mean change from baseline in the US study was > 100 IU/dL immediately after the infusion, decreasing to about 10 IU/dL at 48 hours post-infusion. The median terminal half-life of VWF:RCo in the US study was 11.7 (r 3.5–74.9) hours. These results are consistent with early and rapid distribution phase, followed by a much slower terminal elimination phase. The median incremental in vivo recovery (IVR) for VWF: RCo in the US and EU studies was 2.4 and 1.9 IU/dL/IU/kg respectively. In the US and EU studies, median baseline levels of FVIII: C were 39 (r 0.5 to 96) and 33 (r 2–106) IU/dL. Mean change of FVIII: C from baseline in the US study was about 60 IU/dL post-infusion, levels decreasing to slightly above 20 IU/dL at 48 hours post-infusion. Median incremental IVRs for FVIII: C in the US and EU studies were 2.7 and 2.8 IU/dL/IU/kg. Median baseline levels of VWF: CB were 13.0 (r 1.5–101) and 10.4 (r 1.0–84) IU/dL. For the US study, the highest median post-infusion VWF: CB value was 131.5 (r 60–204) IU/dL 15 minutes post-infusion. For the EU study, the highest median VWF: CB value was 147 (r 21–330) IU/dL 30 minutes post-infusion. At 48 hours, levels decreased to near baseline (median: 26.5 [r 10–136] IU/dL in the US study, and 13 [r 2–112] IU/dL in the EU study). Conclusions: VWF: CB values correlated well with VWF: RCo values. Analyses showed that high molecular weight VWF multimers were detectable up to 24 hours post-infusions in all subjects with absent multimers at baseline. The PK data suggest a possibility of slight accumulation of FVIII: C, presumably due to a dynamic stabilization of exogenously injected and endogenously released FVIII. The slow terminal elimination phase of VWF: RCo, compared to shorter distribution phase, suggests a minimal risk of VWF: RCo accumulation, easily managed by adjusting the dosing interval. For surgical coverage, an individual patient’s PK results safely guided initial dosing, with subsequent doses based on their clinical and laboratory responses.

Author notes

Disclosure: Employment: Garrett Bergman and Sigurd Knaub are employees of CSL Behring. Carl Friedman is a consultant for CSL Behring. Membership Information: Jorge Di Paola, Advisory Board CSL Behring.