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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1302.)
© 2003 American Heart Association, Inc.

Thrombosis

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

Hans Ulrichts; Karen Vanhoorelbeke; Sandra Cauwenberghs; Stephan Vauterin; Hartmut Kroll; Sentot Santoso; Hans Deckmyn

From the Laboratory for Thrombosis Research, IRC, KULeuven Campus Kortrijk, Belgium and Institute for Clinical Immunology and Transfusion Medicine (H.K., S.S.), Justus Liebig University, Giessen, Germany.

Correspondence to Dr Hans Deckmyn, Laboratory for Thrombosis Research, IRC, KULeuven Campus Kortrijk, E. Sabbelaan 53, 8500 Kortrijk, Belgium. E-mail Hans.Deckmyn{at}kulak.ac.be

Objective— Glycoprotein (GP) Ib is the functionally dominant subunit of the platelet GPIb-IX-V receptor complex. The N-terminal domain of the GPIb chain contains binding sites for -thrombin and von Willebrand factor (VWF). The human platelet alloantigen (HPA)-2 polymorphism of the GPIb gene is associated with a C/T transition at nucleotide 1018, resulting in a Thr/Met dimorphism at residue 145 of GPIb. 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 expressed in CHO cells were used.

Methods and Results— Of 74 moAbs directed against human GPIb, 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 -thrombin to the recombinant alloform fragments or of antibodies directed against the -thrombin binding anionic sulfated tyrosine sequence (AA269-282).

Conclusions— Whereas the Thr145Met dimorphism does not affect -thrombin binding, it does influence the conformation of the N-terminal flanking region and first leucine-rich repeat of GPIb and by this has an effect on VWF binding.

Key Words: glycoprotein Ib • Willebrand • HPA-2 polymorphism • thrombin

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