Von Willebrand factor platelets

Glycoprotein llb/llla Platelets allbps ICAM-2 Fibrinogen, fibronectin, von Willebrand factor Platelet adhesion and aggregation... 

Von Willebrand factor Platelet-activating factor Adhesion molecules... 

Type 2 von Willebrand disease, diagnosed in 9% to 30% of affected patients, is characterized by a qualitative abnormality of von Willebrand factor. Bleeding manifestations may be more severe than with type 1 disease. Inheritance is most often autosomal dominant, but may be recessive. Type 2 von Willebrand disease may be further subdivided into four variants. Type 2A is the most frequent subtype and is characterized by a reduced von Willebrand factor-platelet interaction and an absence of high- and intermediate-molecular-weight factor multimers. Type 2B is a less common variant in which there is an abnormal von Willebrand factor that has an increased affinity for the platelet glycoprotein Ib receptor. This is associated with thrombocytopenia, which is usually mild. In addition, there are usually no high-molecular-weight forms of von Willebrand factor. Type 2M... 

Multimerin shares many similarities with von Willebrand factor, but, unlike the latter, it is not found in plasma. Within alpha-granules, multimerin is found in an eccentric location, colocalizing with von Willebrand factor. Platelet activation leads to multimerin release with expression of this protein on the activated platelet surface. Increased platelet surface expression of multimerin is a mark of platelet activation, both in vitro and in vivo. The function of multimerin remains to be discovered. 

Coagulation factors are glycoproteins named by roman numbers (the numbers being ascribed at the time of the components definition, not sequence of activation) (Table 1). Besides von Willebrand factor (vWF), the coagulation factors are synthesized in the liver. They have very different half-lifes and different concentrations in the plasma. Several coagulation factors are stored in platelets and endothelial cells and can be released during activation of these cells, which can result in a much higher local concentration of the respective factor (e.g., vWF). 

The von Willebrand factor (vWf) is a heterogeneous multimeric plasma glycoprotein produced by megakaryocytes and endothelial cells which is found in platelets, plasma and the subendothelium. Subendothelial vWf facilitates platelet adhesion, especially under high shear stress, by binding to glycoprotein GPIb-V-IX, a complex of four leucine-rich repeat proteins on platelets. 

Pharmacologic Therapy Treatments used to decrease bleeding time in patients with uremic bleeding include cryoprecipitate, which contains various components important in platelet aggregation and clotting, such as von Willebrand factor and fibrinogen. Cryoprecipitate decreases bleeding time within 1 hour in 50% of patients. However, cost and the risk of infection have limited the use of cryoprecipitate. 

Von Willebrand factor (VWF) is a large multimeric glycoprotein with two main functions in hemostasis to aid the platelet adhesion to injured blood vessel walls and to carry and stabilize factor VIII in plasma. Table 64—4 represents three main vWD phenotypes, their frequency, and genetic transmission.17... 

In the intact blood vessel, ligands involved in adhesion to platelets, such as collagen, fibronectin, and von Willebrand factor, are sequestered in the subendothelium, thus preventing access to platelet adhesive receptors. Table 1 summarizes the functions of platelet membrane integrin receptors. 

CD41/61 representing the GPIIb-IIIa complex, which is a receptor for fibrinogen, von Willebrand factor, fibronectin, and vitronectin. This complex is essential for platelet aggregation. 

Kroll M. H., Harris T. S., Moake J. L Handin R. I Shafer A. I. Von Willebrand factor binding to platelet GP lb initiates signals for platelet activation. J Clin Invest 1991 88, 1568-73. 

Fig. 9.1. A dysfunctional or injured endothelium is at the basis for initiation of and progression to atherosclerosis. Several mechanisms, such as adhesion molecules or liberation of von Willebrand factor (vWf, upper panel), determine a series of phenomena, including platelet activation and aggregation. This participation of platelets involves the implication of molecules like glycoprotein Ilb/IIIa, fibrinogen, and von Willebrand factor. The endothelium also acts as a source of signals that regulate local functions, including VSMCs (lower panel). A list of the most relevant messengers produced by a functional and a dysfunctonal endothelium is presented in the lower panel...

Another type of autoantibody leading to thrombocytopenia that is induced by ti-clopidine is directed against von Willebrand factor metalloproteinase [45 ]. This prevents the normal clearance of large multimers of von Willebrand this can lead to platelet aggregation, and in some cases, to thrombotic thrombocytopenic purpura, commonly referred to as TTP. Many other drugs have been implicated as cases of TTP, but the mechanism is unclear and appears to differ with different drugs [46],... 

Tsai, H.M. et al., Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura, Ann. Intern. Med., 132, 794, 2000. 

Therapeutic irradiation is known to have multiple interactions with the vasculature of the irradiated tissue (12). Radiation has direct cytotoxic effects on the vascular endothelium, likely due to induction of oxidative injury. Radiation-induced injury stimulates inflammation and influx of inflammatory cells in addition to creating aprocoagulant state in the vascular space by the transcriptional induction of tissue factor with the subsequent activation of coagulation factors as well as von Willebrand factor and platelets. Experimental evidence suggests that the mechanism by which radiation initiates these responses is in part through the induction of cell-adhesion molecules including ICAM-1, E-selectin, and P-selectin and in part through local cytokine production and release (13). 

Ionizing radiation induces von Willebrand factor expression (75), and promotes platelet aggregation (76). Radiation enhances platelet adhesion to the extracellular... 

Verheij M, Dewit LG, Bloomgaard MN, et al. Ionizing radiation enhances platelet adhesion to the extracellular matrix of human endothelial cells by an increase in the release of von Willebrand factor. RadiatRes 1994 137 202-207. 

Moake, J. L., Turner, N. A., Stathopoulos, N. A., Nolasco, L., and Heliums, J. D., Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear-stress induced platelet aggregation. J. Clin. Invest. 78,1456-1461... 

Abciximab is a Fab fragment of a murine-human monoclonal antibody that binds to the integrin GPIIb/IIIa receptor on activated platelets and inhibits fibrinogen, von Willebrand factor, and other adhesion molecules from binding to activated platelets, thus preventing their aggregation. See Chapter 34 for additional details. 

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