FVIII Half-life in Patients With Hemophilia Largely Determined by Clearance of VWF

Wide variability of factor VIII (FVIII) clearance often seen across patients with hemophilia is primarily a result of clearance rates of endogenous von Willebrand factor (VWF), found researchers of a new study.

Previous research has suggested that several factors play a role in heterogeneity of FVIII clearance, including plasma VWF:antigen (VWF:Ag) levels at the time of FVIII infusion, ABO(H) blood type, and patient age.

These new findings suggest that variability in recombinant FVIII (rFVIII) half-life in patients, though impacted by all 3 factors, is largely attributed to variability in the clearance of endogenous VWF. The researchers noted that their sample size of 61 adults with the condition was a strength of the study, including more patients than most previous studies. Including just adults also eliminated the potential impact of increased clearance normally found in children, they explained.

Despite all patients receiving the same treatment—Advate—the researcher observed wide variability in half-life, which ranged from 7.7 hours to 20.1 hours, consistent with previous studies. Notably, half-life of treatment was significantly correlated with plasma VWF:Ag levels, with clearance significantly reduced in patients with higher levels of endogenous plasma VWF.

While more infused rFVIII can bind to VWF, mitigating rapid in vivo clearance, data suggest that this does not fully explain the relationship between plasma VWF:Ag levels and FVIII clearance in PWH.

“The positive correlation between VWF:Ag levels and FVIII half-life in PWH could also arise if plasma VWF levels serve as a surrogate measure of the clearance rates of endogenous VWF,” explained the researchers.“Thus, PWH with reduced VWF clearance have increased steady-state plasma VWF:Ag levels. In addition, these subjects have longer FVIII half-lives following the administration of an rFVIII concentrate because the majority is cleared through VWF-dependent clearance pathways. Our data support the hypothesis that heterogeneity in the clearance ofendogenous VWF plays a critical role in the regulation of variability in rFVIII clearance in PWH.”

In multivariate analysis, VWF:Agremained a significant independent indicator of rFVIII clearance. The analysis showed that the effect of age on FVIII clearance was partially independent of VWF.

The group also observed that ABO blood type played a significant role in the clearance of FVIII. Within the group, patients with non-O blood types had significantly longerrFVIII half-lives than patients with O type (median rFVIII half-life, 11.9 vs 11 hours, respectively; P = .035). However, multivariate analysis showed that the effect of ABO blood type was no longer significant, suggesting that the effect of ABO(H) blood type is entirely regulated by its effect on the clearance rates of endogenous VWF.

Reference

Elsheikh E, Lavin M, Heck L, et al. Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor. J Thromb Haemost. Published online January 20, 2023. doi:10.1016/j.jtha.2023.01.013