Functional polymorphisms in the LDLR and pharmacokinetics of Factor VIII concentrates.
ABO Blood-Group System
Adolescent
Adult
Aged
Drug Monitoring
Factor VIII
/ administration & dosage
Hemophilia A
/ blood
Hemostatics
/ administration & dosage
Humans
Metabolic Clearance Rate
Middle Aged
Models, Biological
Pharmacogenomic Variants
Polymorphism, Genetic
Receptors, LDL
/ genetics
Young Adult
ABO blood-group
LDL-receptor polymorphism
factor VIII
hemophilia A
pharmacokinetics
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
21
12
2018
accepted:
29
04
2019
pubmed:
6
5
2019
medline:
15
7
2020
entrez:
6
5
2019
Statut:
ppublish
Résumé
Optimization of factor VIII (FVIII) infusion in hemophilia A would benefit from identification of FVIII pharmacokinetics (PK) determinants. The low-density lipoprotein receptor (LDLR) contains an FVIII-binding site and might influence FVIII clearance. Consistently, LDLR polymorphisms have been associated with FVIII levels. To investigate the relationships between individual FVIII PK and functional LDLR polymorphisms. Thirty-three hemophilia A patients (FVIII coagulant activity [FVIII:C] ≤2 IU/dL) without inhibitors underwent 85 FVIII single-dose (21.4-51.8 IU/kg) PKs with different FVIII concentrates. Twenty patients underwent repeated PKs (2-6). C measured up to 72 hours was analyzed by two-compartment model. Parameters were evaluated in relation to F8 mutations, ABO blood-group and LDLR genotypes. F8 mutation types were not associated with PK parameters. ABO and LDLR c.1773C/T polymorphism were associated with Alpha, Alpha HL, CLD2, K1-2, and K2-1 parameters, suggesting an influence on the FVIII initial distribution phase. Regression analysis showed an independent association of both ABO and LDLR c.1773C/T with PK parameters (Alpha, β-coefficient -0.311 vs 0.348; CLD2, β-coefficient -0.335 vs 0.318), giving rise to an additive effect in subjects stratified by combined phenotypes. Differently, the LDLR c.81C/T was associated with FVIII clearance and volume of distribution at steady state, which could be related to distinct effects of polymorphisms, potentially linked to LDLR intracellular distribution and FVIII binding behavior. With the limitation of different FVIII concentrates and low number of patients, our data show plausible associations of LDLR polymorphisms with FVIII PK parameters, thus supporting their investigation as candidate functional determinants of FVIII PK.
Sections du résumé
BACKGROUND
Optimization of factor VIII (FVIII) infusion in hemophilia A would benefit from identification of FVIII pharmacokinetics (PK) determinants. The low-density lipoprotein receptor (LDLR) contains an FVIII-binding site and might influence FVIII clearance. Consistently, LDLR polymorphisms have been associated with FVIII levels.
OBJECTIVE
To investigate the relationships between individual FVIII PK and functional LDLR polymorphisms.
PATIENTS/METHODS
Thirty-three hemophilia A patients (FVIII coagulant activity [FVIII:C] ≤2 IU/dL) without inhibitors underwent 85 FVIII single-dose (21.4-51.8 IU/kg) PKs with different FVIII concentrates. Twenty patients underwent repeated PKs (2-6).
FVIII
C measured up to 72 hours was analyzed by two-compartment model. Parameters were evaluated in relation to F8 mutations, ABO blood-group and LDLR genotypes.
RESULTS
F8 mutation types were not associated with PK parameters. ABO and LDLR c.1773C/T polymorphism were associated with Alpha, Alpha HL, CLD2, K1-2, and K2-1 parameters, suggesting an influence on the FVIII initial distribution phase. Regression analysis showed an independent association of both ABO and LDLR c.1773C/T with PK parameters (Alpha, β-coefficient -0.311 vs 0.348; CLD2, β-coefficient -0.335 vs 0.318), giving rise to an additive effect in subjects stratified by combined phenotypes. Differently, the LDLR c.81C/T was associated with FVIII clearance and volume of distribution at steady state, which could be related to distinct effects of polymorphisms, potentially linked to LDLR intracellular distribution and FVIII binding behavior.
CONCLUSIONS
With the limitation of different FVIII concentrates and low number of patients, our data show plausible associations of LDLR polymorphisms with FVIII PK parameters, thus supporting their investigation as candidate functional determinants of FVIII PK.
Identifiants
pubmed: 31055871
doi: 10.1111/jth.14473
pii: S1538-7836(22)14295-9
doi:
Substances chimiques
ABO Blood-Group System
0
Hemostatics
0
LDLR protein, human
0
Receptors, LDL
0
F8 protein, human
839MOZ74GK
Factor VIII
9001-27-8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1288-1296Informations de copyright
© 2019 International Society on Thrombosis and Haemostasis.