von Willebrand factor.

Abstract

A perspective on von Willebrand factor (vWF) 1 within a series on cell adhesion in vascular biology offers the opportunity to review the current understanding of platelet function in hemostasis and thrombosis. Platelets contribute to maintaining the normal circulation of blood through the preservation of vascular integrity and the control of hemorrhage after injury. Thus, the formation of platelet thrombi is a needed defense mechanism, but may precipitate diseases such as myocardial infarction in the setting of atherosclerosis (1, 2). Acute thrombotic arterial occlusion is the leading cause of morbidity and mortality in industrial societies, underscoring the relevance of studies aimed at unraveling how platelets respond to vascular injury. Particularly important in this regard is vWF, along with the subendothelial matrix components and membrane receptors that interact with it, owing to a key role in supporting unique aspects of platelet function. Indeed, vWF-dependent adhesion mechanisms can be viewed as the evolutionary adaptation to the need of establishing firm contact between a circulating element and the vessel wall meeting any mechanical challenge created by blood flow conditions. Platelet function: A paradigm of adhesion mechanisms for circulating vascular cellsPlatelets survey the inner lining of the vessel wall without interacting with it under normal circumstances, but respond rapidly to alterations of endothelial cells by attaching firmly to the site of lesion, where exposure of subendothelial structures may have occurred. A first layer of platelets adheres to the reactive surface, subsequently growing by accrual of additional platelets through homotypic aggregation. Both processes depend on the binding of membrane receptors to immobilized or soluble ligands, and are modulated by stimulus-coupled biochemical and cytoskeletal responses. Platelet thrombus formation is the paradigm of adhesion for circulating vascular cells, that can interact efficiently with the vessel wall only by withstanding opposing forces created by blood flow. In fact, the tendency of cells to move with the layer of fluid adjacent to the reactive surface creates unique biomechanical requirements for the formation of adhesive bonds. In a vessel, the velocity of blood near the wall is lower than towards the center, a difference resulting in a shearing effect between contiguous layers of fluid moving at different speed. Thus, "shear" is the consequence of the relative parallel motion of fluid planes during flow; it is greatest near the wall and decreases progressively towards the center of the vessel (3). The local shear rate is expressed in cm/s per cm, or the equivalent inverse second (s Ϫ 1 ). Fluid shear stress is force per unit area, the underlying cause of the shearing motion of blood. Shear rate is directly proportional to shear stress and inversely proportional to fluid viscosity. Assuming for blood a viscosity of 4 centipoise, the numerical value of shear stress (in dyn/cm 2 ) corresponds to shear rate divided by 40.The ro...

Interaction of von Willebrand Factor Domain A1 with Platelet Glycoprotein Ibα-(1–289)

“…Platelet adhesion mediated by VWF is rapid and efficient, and the evaluation of the process by video microscopy suggests the rate constants for the binding of A1 to GPIb␣ could be correspondingly fast (19,21,40). However, these studies do not provide direct information about intrinsic dissociation constants or reaction rates, and the results are compatible with other models.…”

“…Subsequently, integrin-ligand interactions can mediate stable platelet adhesion. The high efficiency of platelet tethering has suggested that the kinetics of VWF-GPIb binding must be fast and that rapid tethering facilitates the formation of much tighter integrin-dependent bonds that require more time to form (19,21). To date, however, direct measurements of the kinetics of VWF A1-GPIb␣ binding have not been reported.…”

Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity

“…The platelet-adhesive blood coagulation protein, von Willebrand factor (VWF), is synthesized mainly in vascular endothelial cells (7)(8)(9)(10). VWF is released into plasma as ''unusually large'' multimeric forms (UL-VWFM), highly active in interactions with platelets and collagen (11,12).…”

Binding of platelet glycoprotein Ibα to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13

“…Besides facilitating the cleavage of vWF by ADAMTS13, fluid shear stress also promotes vWF binding to platelets (19). Binding sites on vWF for platelet GPIb and collagen are in domains A1 and A3, respectively, flanking the ADAMTS13 cleavage site in domain A2.…”