Submitted December 16, 2005
Accepted May 8, 2006
Activation-independent platelet adhesion and aggregation
under elevated shear stress
Zaverio M Ruggeri*, Jennifer N Orje, Rolf Habermann, Augusto B Federici, and Armin J Reininger
Roon Centre for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA, USA
* Corresponding author; email: ruggeri{at}scripps.edu.
Platelet aggregation, which contributes to arrest
bleeding but also to thrombovascular disorders, is
thought to initiate after signaling-induced activation.
We found that this paradigm does not apply under blood
flow conditions comparable to those existing in stenotic
coronary arteries. Platelets interacting with
immobilized von Willebrand factor (VWF) aggregate
independently of activation when soluble VWF is present
and the shear rate exceeds 10,000 s-1 (shear
stress 400 dyn/cm2). Above this threshold,
active A1 domains become exposed in soluble VWF
multimers and can bind to glycoprotein Ib
promoting additional platelet recruitment. Aggregates
thus formed are unstable until the shear rate approaches
20,000 s-1 (shear stress 800
dyn/cm2). Above this threshold, adherent
platelets at the interface of surface-immobilized and
membrane-bound VWF are stretched into elongated
structures and become the core of aggregates that can
persist on the surface for minutes. When isolated
dimeric A1 domain is used instead of native VWF
multimers, activation-independent platelet aggregation
occurs without requiring shear stress above a threshold
level, but these aggregates never become firmly attached
to the surface and progressively disaggregate as shear
rate exceeds 6,000 s-1. Platelet and VWF
modulation by hydrodynamic force is a mechanism for
activation-independent aggregation that may support
thrombotic arterial occlusion.
