High Shear Stress Attenuates Agonist-Induced, Glycoprotein IIb/IIIa-Mediated Platelet Aggregation When von Willebrand Factor Binding to Glycoprotein Ib/IX Is Blocked

• Published in: Biochemical and biophysical research communications 1997-04, Vol.233 (3), p.796-800
• Main Authors: Iijima, Kaori, Murata, Mitsuru, Nakamura, Kosei, Kitaguchi, Tetsuya, Handa, Makoto, Watanabe, Kiyoaki, Fujimura, Yoshihiro, Yoshioka, Akira, Ikeda, Yasuo
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - pharmacology; Animals; Antibodies, Monoclonal - pharmacology; Fibrinogen - metabolism; Humans; In Vitro Techniques; Mice; Platelet Aggregation - drug effects; Platelet Aggregation - physiology; Platelet Glycoprotein GPIb-IX Complex - metabolism; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Protein Binding; Stress, Mechanical; von Willebrand Factor - antagonists & inhibitors; von Willebrand Factor - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1997.6554

High shear stress facilitates von Willebrand factor (vWF) binding to platelet glycoprotein (GP) Ib/IX, causing activation of GPIIb/IIIa to induce platelet aggregation. Here we report that activated GPIIb/IIIa, even occupied by ligands, is not sufficient to mediate platelet aggregation under high shear stress conditions when vWF binding to GPIb/IX is blocked. Platelet rich plasma or washed platelet suspension supplemented with purified human fibrinogen at a concentration of 2 mg/mL were treated with an anti-vWF monoclonal antibody NMC-4 which blocks the binding of vWF to GPIb/IX. After addition of 10 μmol/L ADP, aggregation was continuously monitored under various shear stress conditions (0-108 dyne/cm2) using a cone-plate type aggregometer previously described (Ikeda Y et al J Clin Invest 1991; 87:1234). The extent of maximal aggregation of agonist-stimulated platelets in the presence of NMC-4 correlated inversely with the level of shear stress applied, with the virtual absence of aggregation at 108 dyne/cm2. Once aggregated by 10 μmol/L ADP under low shear stress (12 dyne/cm2), platelets could be disaggregated, in part, by the application of high shear stress (108 dyne/cm2), and reaggregated when shear stress was returned to 12 dyne/cm2. Flow cytometric analysis revealed that platelets stimulated with 10 μmol/L ADP at 108 dyne/cm2bound fluorescein isothiocyanate (FITC)-labeled fibrinogen, although aggregation was absent in this experimental condition. These results demonstrate the dual effect of shear stress on platelet functions; a pro-aggregating activity that induces vWF-GPIb/IX interaction leading to platelet activation, and an anti-aggregating force to prevent the growth of platelet thrombi. It is suggested that the efficacy of vWF blockade is greater under high shear than low shear stress conditions, and that a selective inhibition of platelet functions can be possible.