ABSTRACT
In this chapter we review the mechanisms of platelet thrombus formation on injured and exposed
vascular subendothelium. The chapter reviews the biology of von Willebrand factor (vWF)
multimer binding to a primary vWF receptor on platelet membranes. This vWF receptor is the
GP Iba component of the GP Iba=Ibb IX V complex, often referred to as ‘‘GP Ib’’ and abbreviated ‘‘GP Iba’’ in the manuscript. Within the Weibel-Palade bodies of human endothelial cells and the a-granules of megakaryocytes and platelets, vWF monomers of molecular mass 280,000Da form disulfide bonds and polymerize into vWF multimers. The largest vWF
multimers may contain more than 40 subunits, with a molecular mass in excess of 20 million
Da. These large and biologically active vWF multimers are released from the endothelial cells
both forward into the bloodstream and backward into the subendothelium. The large subendo-
thelial vWF multimers mediate the adhesion of platelets from the blood at sites of vascular
damage. Each platelet contains approximately 25,000 copies of the GP Iba=Ibb IX V complex. Under arterial flowing conditions, the normal adhesion of platelets from whole blood onto
exposed subendothelial vascular surfaces after endothelial cell injury depends on large vWF
multimers immobilized with collagen in the subendothelium. Platelets adhere, tether, and roll
on exposed subendothelium through the reversible binding of platelet GP Iba components to regions within the Al domain of the vWF monomeric subunits that comprise the large vWF
multimers. Fluid shear stress in rapidly flowing arterial blood may enhance this adhesive interaction
by altering the conformation of the vWF-binding site in the GP Iba molecules. Large vWF multimers composed of these monomers are entangled with collagen in the subendothelium.
Interactions between activated GP IIb=IIIa receptors and subendothelial large vWF multimers strengthen the initial platelet GP Iba vWF bonds responsible for platelet tethering and rolling on an exposed subendothelial surface. The platelets are arrested on the exposed subendothelium to
complete the adhesion process. The subsequent aggregation of platelets from flowing blood onto
