Summary.  von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high‐molecular‐weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.

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We have identified two distinct mechanisms initiating the adhesion of flowing platelets to thrombogenic surfaces. The intergrin alpha IIb beta 3 promotes immediate arrest onto fibrinogen but is fully efficient only at wall shear rates below 600-900 s-1, perhaps because of a relatively slow rate of bond formation or low resistance to tensile stress. In contrast, glycoprotein Ib alpha binding to immobilized von Willebrand factor (vWF) appears to have fast association and dissociation rates as well as high resistance to tensile stress, supporting slow movement of platelets in continuous contact with the surface even at shear rates in excess of 6000 s-1. This eventually allows activated alpha IIb beta 3 to arrest platelets onto vWF under conditions not permissive of direct binding to fibrinogen. The coupling of these different functions may be crucial for thrombogenesis.

We have used confocal videomicroscopy in real time to delineate the adhesive interactions supporting platelet thrombus formation on biologically relevant surfaces. Type I collagen fibrils exposed to flowing blood adsorb von Willebrand factor (vWF), to which platelets become initially tethered with continuous surface translocation mediated by the membrane glycoprotein Ib alpha. This step is essential at high wall shear rates to allow subsequent irreversible adhesion and thrombus growth mediated by the integrins alpha2beta1 and alpha(IIb)beta3. On subendothelial matrix, endogenous vWF and adsorbed plasma vWF synergistically initiate platelet recruitment, and alpha2beta1 remains key along with alpha(IIb)beta3 for normal thrombus development at all but low shear rates. Thus, hemodynamic forces and substrate characteristics define the platelet adhesion pathways leading to thrombogenesis.

Abstract-Platelet adhesion is an essential function in response to vascular injury and is generally viewed as the first step during which single platelets bind through specific membrane receptors to cellular and extracellular matrix constituents of the vessel wall and tissues. This response initiates thrombus formation that arrests hemorrhage and permits wound healing. Pathological conditions that cause vascular alterations and blood flow disturbances may turn this beneficial process into a disease mechanism that results in arterial occlusion, most frequently in atherosclerotic vessels of the heart and brain. Besides their relevant role in hemostasis and thrombosis, platelet adhesive properties are central to a variety of pathophysiological processes that extend from inflammation to immune-mediated host defense and pathogenic mechanisms as well as cancer metastasis. All of these activities depend on the ability of platelets to circulate in blood as sentinels of vascular integrity, adhere where alterations are detected, and signal the abnormality to other platelets and blood cells. In this respect, therefore, platelet adhesion to vascular wall structures, to one another (aggregation), or to other blood cells, represent different aspects of the same fundamental biological process. Detailed studies by many investigators over the past several years have been aimed to dissect the complexity of these functions, and the results obtained now permit an attempt to integrate all the available information into a picture that highlights the balanced diversity and synergy of distinct platelet adhesive interactions. (Circ Res. 2007;100:1673-1685.)Key Words: adhesion molecules Ⅲ platelets Ⅲ vascular biology Ⅲ extracellular matrix Ⅲ collagen P latelets in mammals are anucleated cells that originate from the cytoplasm of bone marrow megakaryocytes 1 and circulate in blood as sentinels of vascular integrity. They show no interaction with the inner surface of normal vessels but adhere promptly where endothelial cells are altered or extracellular matrix substrates are exposed. 2 This is a critical initial step in hemostasis and thrombosis, as well as in inflammatory 3,4 and immunopathogenic responses. 5 The functions of mammalian platelets are conserved throughout evolution and closely reflect those of nucleated thrombocytes in all other vertebrates. 6 -9 After adhering to vascular lesions, platelets can rapidly recruit to the site of injury additional platelets, which are necessary to achieve hemostasis, or different types of leukocytes, which set off host defense responses. Such selective recruitment is orchestrated by activation pathways stimulated by the initial adhesive interactions and by soluble agonists released or generated locally, which lead to the appearance on the platelet membrane of different adhesive molecules capable of attracting distinct circulating cells. Platelet adhesion in a broad sense is the Original received January 2, 2007; revision received March 13, 2007; accepted April 11, 2007 study of the adhesive p...

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To cite this article: Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003; 1: 1335-42.Summary. The adhesive protein von Willebrand factor (VWF) contributes to platelet function by mediating the initiation and progression of thrombus formation at sites of vascular injury. In recent years there has been considerable progress in explaining the biological properties of VWF, including the structural and functional characteristics of specific domains. The mechanism of interaction between the VWF A1 domain and glycoprotein Iba has been elucidated in detail, bringing us closer to understanding how this adhesive bond can oppose the fluid dynamic effects of rapidly flowing blood contributing to platelet adhesion and activation. Moreover, novel findings have been obtained on the link between regulation of VWF multimer size and microvascular thrombosis. This progress in basic research has provided critical information to define with greater precision the role of VWF in vascular biology and pathology, including its possible involvement in the onset of atherosclerosis and its acute thrombotic complications.

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 Ib␣, 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. IntroductionPlatelets aggregate at sites of vascular injury, forming thrombi that contribute to arrest bleeding but also occlude atherosclerotic arteries causing cardiac and cerebrovascular diseases. 1,2 Platelet thrombus formation is thought to occur in successive stages. First, individual platelets adhere to altered vascular surfaces and are activated, after which the integrin ␣IIb␤3 can bind plasma proteins, notably fibrinogen, von Willebrand factor (VWF), and fibronectin; these adhesive substrates immobilized on the membrane surface then recruit additional platelets, resulting in aggregation and thrombus growth. 2 Such events take place in flowing blood that generates shear forces. At shear rates exceeding 1000 s Ϫ1 in the human circulation, initial platelet arrest depends on glycoprotein (GP) Ib␣ binding to immobilized VWF even when extracellular matrices 3 or vascular structures 4 present multiple reactive components. Continued platelet recruitment also becomes dependent on VWF-GP Ib␣ as growing thrombi narrow the lumen where blood flows, locally increasing the shear rate. 5 Current knowledge, therefore, is that rapidly forming but short-lived VWF-GP Ib␣ bonds can keep platelets in contact with a surface or with one another for a limited time, until additional bonds, established mostly through integrin receptors, stabilize adhesion and aggregation. 3,5,6 A feature distinguishing hemostasis from arterial thrombosis is their occurrence in different hemodynamic environments. A 90% lumen reduction in a coronary artery may cause shear rates of 20 000-40 000 s Ϫ1 at or just upstream of the ...