The A/T1381 polymorphism in the Al-domain of von Willebrand factor influences the affinity of von Willebrand factor for platelet glycoprotein Ibα

Many polymorphisms in vonWillebrand factor (VWF) have been reported and their association with VWF plasma levels or cardiovascular diseases has been investigated. The aim of this study was to examine whether the amino acid polymorphismA/T 1381 in the VWF A I-domain would affect VWF binding to platelet GPlb alpha. Sixty-one normal individuals were genotyped at the A/T1381 locus. Twenty-oneA/A1381 homozygotes,30A/TI381 heterozygotes and 10T/T1381 homozygotes were identified. Remarkably, when compared to VWF of A/T1381 and A/A1381 individuals, VWF of individuals carrying the T/T1381 variant showed an increased affinity for its platelet receptor GPlb alpha under static conditions, as reflected by an increased sensitivity to low concentrations of ristocetin or botrocetin. In addition, also the rVWF-T1381 demonstrated a higher affinity for GPIb alpha than rVWF-A1381. Interestingly, this enhanced affinity of the T/T variant over the A/T and A/A variant was, however, too subtle to affect platelet adhesion under physiological flow conditions, which fully corroborates the normal haemostatic phenotype of all individuals. We demonstrate that the VWFA/T1381 polymorphism plays an important role in inter-individual variability of the affinity of VWF for GPlb alpha with T/T variants having a higher affinity than A/A and A/T variants, at least under static conditions in vitro. Further genetic linkage and association studies are necessary to establish whether the A/T 1381 polymorphism could correlate with an increased risk of thrombotic events.