Pharmacokinetics of von Willebrand factor and factor VIIIC in patients with severe von Willebrand disease (type 3 VWD): estimation of the rate of factor VIIIC synthesis

Abstract

Nine patients (10 infusions) with a confirmed diagnosis of type 3 VWD were infused with von Willebrand factor (human), a preparation of von Willebrand factor (VWF) with a very low factor VIII content. Each patient was infused with one dose of approximately 50 or 100 iu ristocetin cofactor activity (VWF:RiCoF) per kg body weight. Bleeding times were performed during the 24 h period after infusion. Plasma samples were obtained over the 96 h period after infusion and were analysed for factor VIII coagulant activity (FVIIIC), VWF:RiCoF, von Willebrand factor antigen (VWF:Ag), and multimers. The FVIIIC data were analysed by non-linear least-squares analysis assuming constant FVIIIC 'synthesis' and exponential decay. The VWF data were fitted for exponential decay. The average decay rates for FVIIIC, VWF:RiCoF and VWF:Ag were 0.041, 0.061 and 0.056 respectively. The average calculated 'synthesis' rate for FVIIIC was 6.4 u/dl/h. The synthesis of FVIIIC was slightly faster and the decay slightly slower following the infusion of 100 iu VWF:RiCoF/kg than of 50 iu VWF:RiCoF/kg. Correction of the bleeding time was strongly dose dependent. At 4 h post infusion the median bleeding time was 9 min following a dose of 50 iu VWF:RiCoF/kg versus 3 min with a dose of 100 iu VWF:RiCoF/kg. There was no decrease in the bleeding time until the level of VWF:Ag or VWF:RiCoF reached > 100 u/dl.

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study

“…of the endogenous synthesis of FVIII in VWD after the administration of VWF. 21 The half-life of VWF:RCof, approximately 7 hours, was substantially shorter than the half-life of VWF:Ag, approximately 13 hours, similar to values reported for another FVIII/VWF concentrate. 12 Postinfusion shortening of bleeding time was transient and generally lasted less than 6 hours.…”

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

“…Likewise, plasma clearance (CL) is: CL = Kel × VD and the baseline rate of VWF:Ag release (Vre) is: Vre = B × CL. The VD of VWF could not be calculated from our data, so the VD reported by Menache et al 30 after intravenous VWF administration (40 mL/kg) was considered to obtain an approximate estimate of Q, CL and Vre in our patients. The kinetic parameters were compared with those obtained previously in a group of normal subjects.…”

Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study

“…6,7 The half-life of VWF-bound FVIII is significantly longer than plasma FVIII from patients lacking VWF (type III VWD). 8,9 This FVIII-VWF complex is formed primarily through an interaction between the light chain of FVIII 7,10 and the DЈ and D3 domains of VWF. [11][12][13] FVIII is activated to FVIIIa when it is cleaved by thrombin at A1-A2 and A2-B junctions in the heavy chain and in the N-terminal region of the light chain, 3 whereas cleavage in the light chain releases FVIIIa from VWF.…”