A revised model of platelet aggregation
Suhasini Kulkarni, … , Francois Lanza, Shaun P. Jackson
Suhasini Kulkarni, … , Francois Lanza, Shaun P. Jackson
Published March 15, 2000
Citation Information: J Clin Invest. 2000;105(6):783-791. https://doi.org/10.1172/JCI7569.
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Article

A revised model of platelet aggregation

Abstract

In this study we have examined the mechanism of platelet aggregation under physiological flow conditions using an in vitro flow-based platelet aggregation assay and an in vivo rat thrombosis model. Our studies demonstrate an unexpected complexity to the platelet aggregation process in which platelets in flowing blood continuously tether, translocate, and/or detach from the luminal surface of a growing platelet thrombus at both arterial and venous shear rates. Studies of platelets congenitally deficient in von Willebrand factor (vWf) or integrin αIIbβ3 demonstrated a key role for platelet vWf in mediating platelet tethering and translocation, whereas integrin αIIbβ3 mediated cell arrest. Platelet aggregation under flow appears to be a multistep process involving: (a) exposure of vWf on the surface of immobilized platelets; (b) a reversible phase of platelet aggregation mediated by the binding of GPIbα on the surface of free-flowing platelets to vWf on the surface of immobilized platelets; and (c) an irreversible phase of aggregation dependent on integrin αIIbβ3. Studies of platelet thrombus formation in vivo demonstrate that this multistep adhesion mechanism is indispensable for platelet aggregation in arterioles and also appears to promote platelet aggregate formation in venules. Together, our studies demonstrate an important role for platelet vWf in initiating the platelet aggregation process under flow and challenge the currently accepted view that the vWf-GPIbα interaction is exclusively involved in initiating platelet aggregation at elevated shear rates.

Authors

Suhasini Kulkarni, Sacha M. Dopheide, Cindy L. Yap, Catherine Ravanat, Monique Freund, Pierre Mangin, Kathryn A. Heel, Alison Street, Ian S. Harper, Francois Lanza, Shaun P. Jackson

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Figure 1

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Dynamics of platelet aggregation under flow. Fluorescently labeled human...
Dynamics of platelet aggregation under flow. Fluorescently labeled human platelets in whole blood were perfused over confluent spread platelet monolayers at 150, 600, and 1800 s–1 for 1 minute. (a) The images depict the shear-dependent increase in platelet adhesion after 1 minute of flow. The number of platelets tethering over a 10-second time period is demonstrated in the line graph. Each tethered platelet was examined over a further 10-second time period, and the percentage of (b) platelets translocating and/or detaching and/or (c) forming stationary (immediate stationary or translocating then stationary) contacts was determined. Results represent mean ± SEM (n = 4). (d) Role of GPIbα in mediating platelet–platelet interactions under flow. Before perfusion, blood was incubated for 10 minutes with buffer (control), anti-αIIbβ3 (α-αIIbβ3), anti-GPIbα (α-Ibα), or both α-αIIbβ3 and Ibα antibodies. In other studies GT platelets were perfused over normal platelet monolayers. (e) Fluorescently labeled platelets from a normal donor or a patient with GT were perfused over platelet monolayers prepared from a normal (normal) or a GT donor (normal on GT; GT on GT). The level of platelet tethering in the first 5 seconds of perfusion was determined. These results are representative of 3 experiments and are indicative of the tethering process over the full 1-minute perfusion period.