Influence of ABO Locus on PFA-100 Collagen-ADP Closure Time Is Not Totally Dependent on the Von Willebrand Factor. Results of a GWAS on GAIT-2 Project Phenotypes.

Núria Pujol-Moix,Dolors Llobet,Anders Hamsten,Angel Martinez-Perez,Noèlia Vilalta,José Soria,Joan Souto,Maria Sabater-Lleal

doi:10.3390/ijms20133221

Abstract

(1) Background: In a previous study, we found that two phenotypes related to platelet reactivity, measured with the PFA-100 system, were highly heritable. The aim of the present study was to identify genetic determinants that influence the variability of these phenotypes: closure time of collagen-ADP (Col-ADP) and of collagen-epinephrine (Col-Epi). (2) Methods: As part of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia (2) Project, 935 individuals from 35 large Spanish families were studied. A genome-wide association study (GWAS) with ≈ 10 M single nucleotide polymorphisms (SNPs) was carried out with Col-ADP and Col-Epi phenotypes. (3) Results: The study yielded significant genetic signals that mapped to the ABO locus. After adjusting both phenotypes for the ABO genotype, these signals disappeared. After adjusting for von Willebrand factor (VWF) or for coagulation factor VIII (FVIII), the significant signals disappeared totally for Col-Epi phenotype but only partially for Col-ADP phenotype. (4) Conclusion: Our results suggest that the ABO locus exerts the main genetic influence on PFA-100 phenotypes. However, while the effect of the ABO locus on Col-Epi phenotype is mediated through VWF and/or FVIII, the effect of the ABO locus on Col-ADP phenotype is partly produced through VWF and/or FVIII, and partly through other mechanisms.

Highlights

Platelet reactivity can be measured using a wide variety of laboratory functional tests
Unlike von Willebrand factor (VWF), which has an important role in primary hemostasis, factor VIII (FVIII) is fundamental for coagulation
The mechanism by which the FVIII influences the PFA-100 closure times (CTs) could be partially explained by its close relationship with the VWF

Summary

Introduction

Platelet reactivity can be measured using a wide variety of laboratory functional tests. Such tests are classified into two main types [1]: (1) tests based on platelet aggregation activated by agonists, in platelet-rich plasma or in whole blood; (2) tests based on platelet adhesion under shear stress. Among the second group of tests, the PFA-100 system (Siemens Healthcare Diagnostics, Marburg, Germany) measures platelet function by simulating in vitro a vessel wall under shear stress. The membrane has a hole through which the anticoagulated blood passes; the closure times (CTs) of this hole are inversely proportional to the functional capacity of platelets. Long CTs gave reliable measurements of hemostatic deficiencies due to low levels of von Willebrand factor (VWF) or platelet functional defects [2,4]. Some authors have suggested that factor VIII (FVIII) has no impact on the PFA-100 CTs [2,5], while others have found the contrary [14]

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