Modulation of factor VIII pharmacokinetics by genetic components in factor VIII receptors.
Haemophilia
; 29(2): 479-487, 2023 Mar.
Article
em En
| MEDLINE
| ID: mdl-36533781
ABSTRACT
INTRODUCTION:
Gene variation in receptors for circulating factor VIII (FVIII) is candidate to explain the large inter-patient variability of infused FVIII pharmacokinetics (PK) in haemophilia A (HA).AIM:
To compare in an Italian HA cohort (n = 26) the influence on FVIII PK of genetic components in four von Willebrand factor (VWF)/FVIII receptors.METHODS:
Genotypes of low-density lipoprotein receptor (LDLR), asialoglycoprotein receptor minor subunit (ASGR2), family 4 member M (CLEC4M), stabilin2 (STAB2) and ABO blood-group, and VWFAg levels were included as independent variables in linear regression analyses of two-compartment model (TCM) - standard half-life (SHL) FVIII PK parameters.RESULTS:
In the initial FVIII distribution phase, the STAB2 rs4981022 AA, ASGR2 rs2289645 TT and LDLR rs688 TT genotypes may contribute to increase Cmax , and prolong or shorten AlphaHL. In the elimination phase, a shorter BetaHL was associated with the CLEC4M rs868875 GG (beta-coefficient .366, p = .025) and ASGR2 rs2289645 TC (beta-coefficient .456, p = .006) genotypes, which also showed shorter mean residence time (MRT) than TT genotypes (p = .021). The alpha and beta phase effects were independent of ABO and VWFAg levels at baseline. The association of the LDLR rs2228671 genotypes with clearance was independent of ABO (beta-coefficient -.363, p = .035) but not of other receptors or VWFAg, which may point out multiple and competing interactions.CONCLUSIONS:
With the limitation of the small number of HA patients, these observations highlight multiple genetic components acting in distinct phases of FVIII PK and contributing to explain FVIII PK variability. This analysis provides candidates for genotype-based, individual tailoring of FVIII substitutive treatment.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hemostáticos
/
Hemofilia A
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Haemophilia
Assunto da revista:
HEMATOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Itália