Thromb Haemost 2020; 120(10): 1395-1406
DOI: 10.1055/s-0040-1714214
Coagulation and Fibrinolysis

Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

Iris Garcia-Martínez*
1  Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Nina Borràs*
1  Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Marta Martorell
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Rafael Parra
1  Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Carme Altisent
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Lorena Ramírez
1  Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
,
Maria Teresa Álvarez-Román
3  Thrombosis and Haemostasis Unit, Hospital Universitario La Paz, Madrid, Spain
,
Ramiro Nuñez
4  Hemophilia Unit, Hospital Universitario Virgen del Rocío Sevilla, Sevilla, Spain
,
Juan Eduardo Megias-Vericat
5  Pharmacogenetics Unit of the Pharmaceutical Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain
,
Irene Corrales
1  Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Sofia Alonso
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Francisco Vidal
1  Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2  Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
6  CIBER de Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain
› Author Affiliations
Funding This study was funded by Baxalta US Inc., a Takeda company (grant: H16-32623). This study was also supported by the Spanish Ministry of the Economy and Competitiveness (MINECO, Ministerio de Economía y Competitividad), Instituto de Salud Carlos III (ISCIII) (PI15/01643).

Abstract

The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

Authors' Contributions

F.V., R.P., and M.M. developed the hypothesis, designed the research, and revised the manuscript. R.P., M.M., S.A., C.A., M.T.A-R, R.N., and J.E.M-V. recruited the samples from hemophilic patients included in this study. N.B. selected the SNVs analyzed based on data from the related literature. L.R. performed the molecular analyses. I.G-M. and N.B. identified the SNVs. I.G-M. designed and performed the statistical analyses. I.G-M. and N.B. interpreted the results. I.G-M. and N.B. wrote the manuscript. All authors revised the final version of the manuscript.


* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 24 February 2020

Accepted: 04 June 2020

Publication Date:
29 July 2020 (online)

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York