Hans Deckmyn

Von Willebrand Factor But Not α-Thrombin Binding to Platelet Glycoprotein Ibα Is Influenced by the HPA-2 Polymorphism

Objective—Glycoprotein (GP) Ib&agr; is the functionally dominant subunit of the platelet GPIb-IX-V receptor complex. The N-terminal domain of the GPIb&agr; chain contains binding sites for &agr;-thrombin and von Willebrand factor (VWF). The human platelet alloantigen (HPA)-2 polymorphism of the GPIb&agr; gene is associated with a C/T transition at nucleotide 1018, resulting in a Thr/Met dimorphism at residue 145 of GPIb&agr;. To study the structural and functional effects of this dimorphism, N-terminal fragments (AA1-289) of the HPA-2a and HPA-2b alloform of GPIb&agr; expressed in CHO cells were used. Methods and Results—Of 74 moAbs directed against human GPIb&agr;, 2 antibodies with epitope between AA1-59 could differentiate between both alloforms. In addition, VWF bound with a higher affinity to the recombinant HPA-2a fragment or to homozygous HPA-2a platelets. In contrast, no difference was found in the binding of &agr;-thrombin to the recombinant alloform fragments or of antibodies directed against the &agr;-thrombin binding anionic sulfated tyrosine sequence (AA269-282). Conclusions—Whereas the Thr145Met dimorphism does not affect &agr;-thrombin binding, it does influence the conformation of the N-terminal flanking region and first leucine-rich repeat of GPIb&agr; and by this has an effect on VWF binding.