Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A

Abstract

In haemophilia A patients factor VIII (FVIII) recovery and half-life can vary substantially. There are parameters known to modulate FVIII pharmacokinetics (PK), but they explain only about 34% of the variability. The aim of this study was to identify new parameters that influence FVIII PK and thus to expand the current knowledge. FVIII PK were determined in 42 haemophilia A patients (37 severe, 5 moderate) without inhibitor. Patients' characteristics and laboratory parameters were evaluated for an association with FVIII PK. We analysed plasma levels of low-density lipoprotein receptor-related protein 1 (LRP1) and protein C (PC) activity, which had been hypothesized to influence FVIII activity. Furthermore, four variations in intron 6 of the LRP1 gene, which had been shown to influence LRP1, were investigated. FVIII half-life differed widely from 6.2 to 20.7 h, with a median of 10.0 h. Patients with blood group O had shorter FVIII half-life compared to patients with non-O blood group (median FVIII half-life 9.0 h vs. 10.4 h, P = 0.018). Age was significantly associated with FVIII half-life (r = 0.32, P = 0.035). Besides age, also VWF antigen (r = 0.52, P < 0.001) and blood group (r = -0.37, P = 0.015) was associated with FVIII half-life. No correlation was found with FVIII- or LRP1-genotype, LRP1 or PC concentrations. Our data showed large differences in FVIII PK between individual patients and revealed age, blood group and VWF levels as important determining factors for FVIII half-life. FVIII genotype or levels of LRP1 or PC had no influence on FVIII PK.

Efficacy and safety of prophylaxis with BAY 81‐8973 in Chinese patients with severe haemophilia A enrolled in the LEOPOLD II trial

“…In general, PK data for Asian patients were within the range of values seen for non‐Asian patients. This finding is as expected because ethnic differences in the PK parameters of BAY 81‐8973 are unlikely, given that clearance of endogenous human FVIII is not mediated by drug‐metabolizing enzymes having a genetic polymorphism …”

Can you grow out of von Willebrand disease?

“…Despite the rise in secretion, the VWFpp:Ag ratio falls with age indicating an increase in half‐life as well . This is consistent with the reported increase in FVIII half‐life with age because FVIII survival is largely determined by VWF . The reduction in clearance is unexplained but once more is significantly more marked in the non‐O group.…”

FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors

“…Plasma samples from a cohort of 42 patients with hemophilia A (recently described by Kepa et al 2 ) were screened for FVIII-binding IgG antibodies. Antibodies were analyzed by using fully validated semiquantitative, directbinding enzyme-linked immunosorbent assays (ELISAs) as described in Whelan et al 6 Details of the validation procedure as well as details of the cutoff determination and the sensitivity of the ELISAs are provided in Whelan et al 6 and Hofbauer et al 7 Initially, all samples were screened in a 1:20 dilution for FVIII-binding IgG antibodies.…”

“…It is generally accepted that the von Willebrand factor (VWF) level significantly influences pharmacokinetic (PK) parameters such as FVIII half-life. [2][3][4][5] Different VWF levels only partially explain the variability in FVIII half-life, which leaves the question of which other parameters are accountable. This study was conducted to evaluate the effect of non-neutralizing, FVIII-specific immunoglobulin G (IgG) antibodies on FVIII half-life.…”