Current Understanding of Inherited Modifiers of FVIII Pharmacokinetic Variation

Abstract

The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including VWF gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.

Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice

“…The greatest difference was found in rFVIII expressed in human embryonic kidney (HEK) cells, whereas the use of baby hamster kidney (BHK) and Chinese hamster ovary (CHO) cells also resulted in such a difference [58]. The half-life of VWF is dependent on its ABO(H) group glycans, where the O-type glycanbearing VWF variants have significantly shorter plasma half-life, associated with FVIII level as noted above [11].…”

“…This FVIII fraction is subjected to fast clearance with the half-life of ~2 h [10] that engages ~24% of the infused FVIII upon its binding to endogenous VWF and gradual dissociation from it. The fraction of FVIII bound to VWF is cleared via VWF clearance mechanisms with the plasma half-life of ~20 h. With contributions of both pathways, the overall FVIII plasma half-life is ~12 h [11]. Plasma levels of FVIII and VWF strongly correlate with an estimate that each 1% change in VWF level results in a respective change of FVIII level by ~0.5% [11,12].…”

“…The fraction of FVIII bound to VWF is cleared via VWF clearance mechanisms with the plasma half-life of ~20 h. With contributions of both pathways, the overall FVIII plasma half-life is ~12 h [11]. Plasma levels of FVIII and VWF strongly correlate with an estimate that each 1% change in VWF level results in a respective change of FVIII level by ~0.5% [11,12]. Individual VWF levels are highly variable (in the range of 50-200%) [13].…”

“…Recently, Swystun and Lillicrap described particular variants of LDLR, ASGPR, CLEC4M, TC2N, and ABO(H) affecting the plasma half-lives of FVIII and VWF in support of development of personalized treatment plans for patients with hemophilia A [11]. It should also be noted that elevated FVIII levels are associated with increased risk of thrombosis [78].…”