[75] showed significant correlation of FVIII
half-life with pre-infusion VWF antigen levels during SCH727965 treatment of haemophilia A patients with recombinant FVIII; (iii) DDAVP-induced VWF increase altered high-purity FVIII kinetics in haemophilia A patients [76] and (iv) Eikenboom et al. [77] evaluated the FVIII/VWF ratios in different types of VWD showing that the ratio increased when VWF synthesis was reduced, but remained 1 when VWF clearance was increased. It has to be emphasized that FVIII half-life significantly correlated with the VWF level over a wide concentration range between 1 U mL−1 and 3 U mL−1 VWF:Ag, i.e. there was sufficient stabilization of FVIII throughout the entire range to prevent proteolytic FVIII cleavage. The molar ratio of VWF monomers and FVIII at the physiological VWF:FVIII ratio of 1:1 unit is theoretically 50:1 and has been experimentally determined as 20:1, probably due to the globular ‘ball-of-yarn’-structure of circulating VWF presenting only a fraction of FVIII binding sites on its surface. The huge excess of FVIII-binding sites theoretically allows stabilization of ABT-263 supplier up to 20-times FVIII relative to VWF, i.e. up to 20 U FVIII:Ag by 1 U VWF:Ag before saturation of VWF. Following the thesis that (i) FVIII passively follows VWF clearance, (ii) a constant clearing rate of VWF is assumed and (iii) bearing in mind the multimeric structure of VWF, it becomes immediately
apparent that the number of FVIII molecules cleared over time strongly depends on the FVIII loading of VWF, i.e. the actual VWF:Ag/FVIII:Ag ratio. Higher loading of circulating VWF multimers increases the number of cleared FVIII molecules per VWF clearing event. This is essentially what was observed during the pharmacokinetic
study by Kessler et al. [62]: almost physiological FVIII half-life for the concentrate exhibiting a 1:1 VWF:RCo/FVIII:C-ratio and a prolonged FVIII half-life for the concentrate with a roughly 2.3:1 VWF:RCo/FVIII:C-ratio. However, the most exciting consequence of VWF-dependent FVIII clearance is the fact that this mechanism intrinsically constitutes a self-regulating mechanism of the physiological VWF/FVIII ratio in plasma. At situations of high VWF/FVIII ratios 3-mercaptopyruvate sulfurtransferase (i.e. low FVIII plasma concentrations), FVIII clearance is lower, whereas at low VWF/FVIII ratios (i.e. high FVIII plasma concentrations) FVIII clearance increases. At the physiological situation of a 1:1-ratio, VWF-dependent FVIII clearance and synthesis of FVIII and VWF are in equilibrium [Fig. 11 (C. Kannicht, Unpublished data)]. Kannicht et al. are in the process of setting up a mathematical model considering intrinsic FVIII synthesis, known VWF-clearance rates and possible clearance of free FVIII to simulate FVIII clearance in VWD patients dependent on pre-infusion VWF levels and administered VWF/FVIII ratios. There has been much work on inhibitors in haemophilia, but not in VWD.
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