Transmembrane Calcium Influx Associated with von Willebrand Factor Binding to GP Ib in the Initiation of Shear-Induced Platelet Aggregation

Yasuo Ikeda; Makoto Handa; Tetsuji Kamata; Koichi Kawano; Yohko Kawai; Kiyoaki Watanabe; Keiko Kawakami; Kiyotaka Sakai; Mayumi Fukuyama; Ichiro Itagaki; Akira Yoshioka; Zaverio M Ruggeri

doi:10.1055/s-0038-1651640

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1993; 69(05): 496-502
DOI: 10.1055/s-0038-1651640

Original Article

Platelets

Schattauer GmbH Stuttgart

Transmembrane Calcium Influx Associated with von Willebrand Factor Binding to GP Ib in the Initiation of Shear-Induced Platelet Aggregation

Yasuo Ikeda

¹The Departments of Hematology and Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

,

Makoto Handa

¹The Departments of Hematology and Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

,

Tetsuji Kamata

¹The Departments of Hematology and Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

,

Koichi Kawano

¹The Departments of Hematology and Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

,

Yohko Kawai

¹The Departments of Hematology and Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

,

Kiyoaki Watanabe

¹The Departments of Hematology and Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

,

Keiko Kawakami

²The Department of Chemical Engineering, Waseda University, Tokyo, Japan

,

Kiyotaka Sakai

²The Department of Chemical Engineering, Waseda University, Tokyo, Japan

,

Mayumi Fukuyama

³The Basic Research Institute, Toray Industries Inc., Kanagawa, Japan

,

Ichiro Itagaki

³The Basic Research Institute, Toray Industries Inc., Kanagawa, Japan

,

Akira Yoshioka

⁴The Department of Pediatrics, Nara Medical School, Nara, Japan

,

Zaverio M Ruggeri

⁵The Roon Research Center for Arteriosclerosis and Thrombosis, Department of Molecular and Experimental Medicine and Committee on Vascular Biology, The Scripps Research Institute, La Jolla, California, USA

› Author Affiliations

Abstract

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Summary

We found that the binding of multimeric vWF to GP Ib under a shear force of 108 dynes/cm² resulted in the transmembrane flux of Ca²⁺ ions with a two-to three-fold increase in their intracellular concentration ([Ca²⁺]_i). The blockage of this event, obtained by inhibiting the vWF-GP Ib interaction, suppressed aggregation. In contrast, the blockage of vWF binding to GP IIb-IIIa, as well as the prevention of activation caused by increased intracellular cAMP levels, inhibited aggregation but had no significant effect on [Ca²⁺]_i increase. A monomeric recombinant fragment of vWF containing the GP Ib-binding domain of the molecule (residues 445-733) prevented all effects mediated by multimeric vWF but, by itself, failed to support the increase in [Ca²⁺]_i and aggregation. These results suggest that the binding of multimeric vWF to GP Ib initiates platelets aggregation induced by high shear stress by mediating a transmembrane flux of Ca²⁺ ions, perhaps through a receptor-dependent calcium channel. The increase in [Ca²⁺]_i may act as an intracellular message and cause the activation of GP IIb-IIIa; the latter receptor then binds vWF and mediates irreversible aggregation.

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References

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