Disease relevance of VWF

• However, the interaction of GPIb and von Willebrand factor (VWF) in a widely used experimental model in thrombosis research, that of the pig, has not been clearly elucidated [1].
• Intermediate levels of vWF, as in heterozygous von Willebrand's disease (vWD), support platelet deposition to extents not significantly different from normal conditions [2].
• Through this mechanism von Willebrand factor may contribute to arterial thrombosis and atherogenesis [3].
• In addition, neutralization of vWF activity in normal pigs by a monoclonal antibody prevents the induction of occlusive thrombosis by the stenosis and pinch-injury procedure [4].
• We studied the role of von Willebrand factor in coronary thrombosis in normal, heterozygous, and homozygous von Willebrand's disease pigs by producing coronary stenosis with a Goldblatt clamp positioned around the left anterior descending coronary artery [5].

High impact information on VWF

• We concluded that: the plasmatic compartment is only minimally replenished by the vWF from platelets and megakaryocytes; and the platelet vWF alone only partially corrects the abnormal tests of the hemostatic mechanism in severe vWd [6].
• Transfused vWF corrected the bleeding time at a level of 10 U/dl, which is lower than that required for a von Willebrand pig [6].
• After engraftment the circulating leukocytes were of the male karyotype, and the platelets were strongly positive for von Willebrand factor (vWF) by indirect immunofluorescence [6].
• von Willebrand factor (vWF) is essential for the induction of occlusive thrombosis in stenosed and injured pig arteries and for normal hemostasis [7].
• Our animal model demonstrated that vWF in the plasma compartment is essential for the development of arterial thrombosis and that it also contributes to the maintenance of bleeding time and hemostasis [7].

Chemical compound and disease context of VWF

• A similar inhibition in thrombus formation due to vWF deficiency was observed in both heparinized and native blood; however, thrombus formation was significantly more reduced (p less than 0.05) in the presence of heparin, presumably due to the lack of stability of the accumulated platelets in the absence of fibrin formation [2].
• von Willebrand disease (vWD), one of the most common bleeding disorders in humans, is manifested as a quantitative or qualitative defect in von Willebrand factor (vWF), an adhesive glycoprotein (GP) with critical hemostatic functions [8].
• Intimal hyperplasia (IH) in carotid arteries was prominent in C57BL/6J mice, absent in RIIIS/J mice, and moderate in RIIIS/J treated with DDAVP (intima-media ratio, 71% +/- 18%, 0, and 32% +/- 12%, respectively; P <.01). vWF deposition occurred in all hyperplastic intima subjacent to intact endothelium [9].
• These findings suggest that exposure to low levels of carbon monoxide may increase the incidence of myocardial infarction and that the absence of von Willebrand factor may be protective [10].
• 1. The antithrombotic effect of aurintricarboxylic acid (ATA) which inhibits binding of von Willebrand factor (vWF) to platelet glycoprotein lb (GPlb) receptor was evaluated in photochemically-induced thrombosis models in the femoral artery of rats and guinea-pigs [11].

Biological context of VWF

• O-linked glycosylation and functional incompatibility of porcine von Willebrand factor for human platelet GPIb receptors [12].
• Native porcine vWF A1-domains had enhanced human platelet activation potential when compared with human recombinant vWF A1 [12].
• The deduced amino acid sequence corresponds to residues 473-891 of the human mature vWF subunit and is 79% homologous with the human protein [13].
• Platelet aggregation to VWF in the presence of either ristocetin or botrocetin was tested [1].
• Therefore, on collagen type I, both the activation of blood coagulation proteins and the presence of vWF contribute significantly to the platelet-platelet interactions necessary for thrombus formation [2].

Anatomical context of VWF

• METHODS: Recombinant human or porcine vWF A1-domains were transiently over-expressed in COS-7 cells as FLAG-tagged fusion protein, linked to plasma membranes via GPI anchors [12].
• Regrowing endothelial cells appeared to contain granular VWF from days 12 to 21, but this was not readily evident at later time points [14].
• von Willebrand factor (VWF) is a well-characterized multimeric glycoprotein present in platelets and plasma and synthesized by vascular endothelial cells and megakaryocytes [14].
• VWF antigen is not present in porcine arterial endothelium (except for the pulmonary artery) but is readily detected in porcine venous endothelial cells [14].
• The results suggest that balloon injury is associated with deposition and medial absorption of plasma or platelet VWF in this porcine model over a time period that precedes and overlaps vascular smooth muscle proliferation and endothelial recoverage [14].

Associations of VWF with chemical compounds

• Significant differences are found in two discontinuous segments thought to be involved in the binding of vWF to platelet glycoprotein Ib [13].
• Porcine vWF lacks four contiguous residues in the first segment and has two positively charged arginine residues in the second [13].
• A well-demarcated homogeneous layer of VWF was observed on the luminal surface from 30 minutes to day 7, but there was a progressive shift of positive staining from the lumen to the outer media from days 1 to 7 [14].
• Variations in the method of inhibiting coagulation (none, heparin, citrate, hirudin, and EDTA) and of perfusing blood (in vitro v ex vivo) were compared by determining the influence of wall shear rate and vWF on the deposition of 111In-labeled platelets on subendothelium [15].
• Porcine factor VIII:C prepared by affinity interaction with von Willebrand factor and heterologous antibodies: sodium dodecyl sulfate polyacrylamide gel analysis [16].

Regulatory relationships of VWF

• P-selectin mRNA is expressed at a later phase of megakaryocyte maturation than mRNAs for von Willebrand factor and glycoprotein Ib-alpha [17].

Other interactions of VWF

• PAEC11 displayed endothelial cell characteristics since it endocytosed acetylated low density lipoproteins, produced von Willebrand factor, and expressed E-selectin [18].
• Antithrombotic effect of a recombinant von Willebrand factor, VCL, on nitrogen laser-induced thrombus formation in guinea pig mesenteric arteries [19].
• Immunohistochemistry for relaxin, cytokeratin, vimentin, and von Willebrand factor was performed on uteroplacental tissue at Day 30 of gestation [20].
• Finally, tempol attenuated sepsis-induced endothelial (von Willebrand factor) and hemostatic dysfunction (thrombin-antithrombin complexes, plasminogen activator inhibitor-type 1) [21].
• For this study, we examined healing cutaneous wounds in Yorkshire pigs with antibodies to fibronectin, laminin, von Willebrand factor VIII, and keratin [22].

Analytical, diagnostic and therapeutic context of VWF

• We speculate that alterations in glycosylation of vWF and other adhesion proteins associated with the targeting of the alpha1,3-Gal-epitope in mutant swine may have salutatory effects on the primate platelet activation observed in these xenografts [12].
• We have examined the localization of VWF in porcine vessel walls during neointima formation after bilateral carotid balloon-angioplasty [14].
• VWF was detected at the site of injury in localized, adherent platelet aggregates at 10 minutes after angioplasty that were not present at later time points [14].
• DESIGN AND METHODS: Standard aggregometry and perfusion studies with circulating blood were applied to isolated platelets or to blood reconstituted with isolated platelets, VWF and red blood cells from the different species [1].
• Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras [7].

References