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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 7; pp. 1302 - 1307
• Main Authors: Ulrichts, Hans, Vanhoorelbeke, Karen, Cauwenberghs, Sandra, Vauterin, Stephan, Kroll, Hartmut, Santoso, Sentot, Deckmyn, Hans
• Format: Journal Article
• Language: English
• Published: American Heart Association, Inc 01.07.2003
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000079510.23517.43

OBJECTIVE—Glycoprotein (GP) Ibα is the functionally dominant subunit of the platelet GPIb-IX-V receptor complex. The N-terminal domain of the GPIbα chain contains binding sites for α-thrombin and von Willebrand factor (VWF). The human platelet alloantigen (HPA)-2 polymorphism of the GPIbα gene is associated with a C/T transition at nucleotide 1018, resulting in a Thr/Met dimorphism at residue 145 of GPIbα. To study the structural and functional effects of this dimorphism, N-terminal fragments (AA1-289) of the HPA-2a and HPA-2b alloform of GPIbα expressed in CHO cells were used. METHODS AND RESULTS—Of 74 moAbs directed against human GPIbα, 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 α-thrombin to the recombinant alloform fragments or of antibodies directed against the α-thrombin binding anionic sulfated tyrosine sequence (AA269-282). CONCLUSIONS—Whereas the Thr145Met dimorphism does not affect α-thrombin binding, it does influence the conformation of the N-terminal flanking region and first leucine-rich repeat of GPIbα and by this has an effect on VWF binding.