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Arteriosclerosis, Thrombosis, and Vascular Biology
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Published Online
on May 29, 2003

Arteriosclerosis, Thrombosis, and Vascular Biology. 2003
Published online before print May 29, 2003, doi: 10.1161/01.ATV.0000079510.23517.43
A more recent version of this article appeared on July 1, 2003
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Submitted on March 26, 2003
Accepted on May 13, 2003

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

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

* To whom correspondence should be addressed. E-mail: Hans.Deckmyn{at}kulak.ac.be.

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

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

Conclusions--Whereas the Thr145Met dimorphism does not affect {alpha}-thrombin binding, it does influence the conformation of the N-terminal flanking region and first leucine-rich repeat of GPIb{alpha} and by this has an effect on VWF binding.
Key words: glycoprotein Ib • Willebrand • HPA-2 polymorphism • thrombin




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