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Thromb Haemost 1997; 77(03): 568-576
DOI: 10.1055/s-0038-1656007
Platelets
Schattauer GmbH Stuttgart

Surface-Secreted von Willebrand Factor Mediates Aggregation of ADP-Activated Platelets at Moderate Shear Stress: Facilitated by GPIb but Controlled by GPIIb-IIIa

M M Frojmovic
1   The Departments of Physiology and Medicine, McGill University Medical Clinic, Montreal General Hospital, Montreal, Canada
,
A Kasirer-Friede
1   The Departments of Physiology and Medicine, McGill University Medical Clinic, Montreal General Hospital, Montreal, Canada
,
H L Goldsmith
1   The Departments of Physiology and Medicine, McGill University Medical Clinic, Montreal General Hospital, Montreal, Canada
2   The Departments of Physiology and Medicine, McGill University Medical Clinic, Montreal General Hospital, Montreal, Canada
,
E A Brown
1   The Departments of Physiology and Medicine, McGill University Medical Clinic, Montreal General Hospital, Montreal, Canada
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Publikationsverlauf

Received 21. November 1995

Accepted after resubmission 04. November 1996

Publikationsdatum:
11. Juli 2018 (online)

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Summary

We previously showed that ADP activation of washed human platelets in plasma-free suspensions supports aggregation at moderate shear stress (0.4-1.6 Nm-2) in Poiseuille flow. Although most activated platelets expressed maximal fibrinogen-occupied GPIIb-IIIa receptors, aggregation appeared to be independent of bound fibrinogen, but blocked by the hexapeptide GRGDSP. Here, we tested the hypothesis that von Willebrand factor (vWF) secreted and expressed on activated platelets mediates aggregation at moderate shear rates from 300 to 1000 s_1 corresponding to shear stresses from 0.3 to 1.1 Nm-2. Relatively unactivated platelets (<15% expressing prebound fibrinogen) were prepared from acidified citrated platelet rich plasma (cPRP) by single centrifugation with 50 nM stable prostacyclin derivative ZK 36374 and resuspended in Tyrodes-albumin at 5 X 104 cells ε_1. Flow cytometric measurements with monoclonal antibody (mAb) 2.2.9 reporting on surface-bound vWF, and with mAb S12 reporting on a-granule secreted P-selectin, showed that 65% and 80%, respectively, of all platelets were maximally activated with respect to maximal secretion and surface expression of these proteins. “Resting” washed platelets exhibited both surface-bound vWF and significant P-selectin secretion. We showed that mAbs 6D1 and NMC4, respectively blocking the adhesive domains on the GPIb receptor recognizing vWF, and on the vWF molecule recognizing the GPIb receptor, partially inhibited ADP-induced aggregation under shear in Couette flow, the degree of inhibition increasing with increasing shear stress. In contrast, mAb 10E5, blocking the vWF binding domain on GPIIb-IIIa, essentially blocked all aggregation at the shear rates tested. We conclude that vWF, expressed on ADP-activated platelets, is at least the predominant cross-bridging molecule mediating aggregation at moderate shear stress. There is an absolute requirement for free activated GPIIb-IIIa receptors, postulated to interact with platelet-secreted, surface bound vWF. The GPIb-vWF cross-bridging reaction plays a facilitative role becoming increasingly important with increasing shear stress. Since aurin tricarboxylic acid, which blocks the GPIb binding domain on vWF, was also found to completely block aggregation in Poiseuille flow, we conclude that it too affects the GPIIb-IIIa interaction.

 

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