Activation-independent platelet adhesion and aggregation under elevated shear stress.
Platelet aggregation, which contributes to bleeding arrest and 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/cm(2)). Above this threshold, active A1 domains become exposed in soluble VWF multimers and can bind to glycoprotein Ibalpha, promoting additional platelet recruitment. Aggregates thus formed are unstable until the shear rate approaches 20 000 s(-1) (shear stress = 800 dyn/cm.(2)). 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 present instead of native VWF multimers, activation-independent platelet aggregation occurs without requiring shear stress above a threshold level, but aggregates never become firmly attached to the surface and progressively disaggregate as shear rate exceeds 6000 s(-1). Platelet and VWF modulation by hydrodynamic force is a mechanism for activation-independent aggregation that may support thrombotic arterial occlusion.
Ruggeri
Zaverio M
ZM
The Scripps Research Institute-MEM 175, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. ruggeri@scripps.edu
Orje
Jennifer N
JN
Habermann
Rolf
R
Federici
Augusto B
AB
Reininger
Armin J
AJ
D001792:Blood Platelets / Q000502:physiology / Q000648:ultrastructure; D018056:Hemorheology; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D046912:Multiprotein Complexes; D015539:Platelet Activation; D010973:Platelet Adhesiveness / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology*; D019038:Platelet Glycoprotein GPIb-IX Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012995:Solubility; D013314:Stress, Mechanical; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism
D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor