intracellular trafficking. All mutants except for skipping exon 33 showed reduced eion and secretion and most colocalized with the endoplasmic reticulum. In-frame skipping of exons 33-34 was the only mutant that was able to multimerize and retain functional platelet, collagen, and Factor VIII (FVIII) binding without co-eion of wildtype Differential intracellular trafficking of von Willebrand Differential intracellular trafficking of von Willebrand factor (vWF) and vWF propeptide in porcine endothelial cells lacking Weibel-Palade bodies and in human endothelial cells
Intracellular trafficking of factor VIII to von Willebrand factor storage granules J. Clin. Invest. , 101 ( 1998 ) , pp. 613 - 624 CrossRef View Record in Scopus Google Scholar Intracellular Trafficking of Factor VIII to von Willebrand In plasma, von Willebrand factor (vWf) associates with Factor VIII (FVIII); however, the site at which these proteins first interact has not been defined. Administration of 1-desamino-8-D-arginine vasopressin (DDAVP) causes a rapid, concomitant elevation in plasma levels of both vWf and FVIII, suggesting the existence of a DDAVP-releasable storage pool for both proteins. Intracellular cotrafficking of factor VIII and von Weibel-Palade bodies (WPBs) are the endothelial storage organelles that are formed upon von Willebrand factor (VWF) eion. Apart from VWF, WPBs contain a variety of hemostatic and inflammatory proteins. Some of these are thought to be targeted to WPBs by directly interacting with VWF in the secretory pathway. Previous studies have demonstrated that coeion of factor VIII (FVIII)
von Willebrand Factor (VWF) is a large, multimeric adhesive glycoprotein that is involved in the formation of a platelet plug after vascular injury. 1 In addition, VWF functions as a molecular chaperone for factor VIII (FVIII) in the circulation, preventing its proteolytic degradation and premature clearance. 2 Mutations and deletions in the gene encoding VWF are associated with an autosomally inherited Intracellular trafficking of factor VIII to von Willebrand Nine patients (10 infusions) with a confirmed diagnosis of type 3 VWD were infused with von Willebrand factor (human), a preparation of von Willebrand factor (VWF) with a very low factor VIII content. Mutations in the D1 domain of von Willebrand factor secretions of von Willebrand factor. Our results support that the mutations in the D1 domain lead to defective multimerization, intracellular trafficking, and secretion of von Willebrand factor and result in bleeding of patients. Keywords:von Willebrand disease, VWF propeptide, VWF gene mutation, VWF multimerization, ER retention Findings
Findings Von Willebrand factor propeptide (VWFpp), composed of D1 and D2 domains, is necessary for the multimerization, intracellular trafficking, and secretion of the factor . Few mutations in the D1 domain of VWFpp have been reported, and the pathogenic nature of Storage of Factor VIII Variants with Impaired von Rosenberg JB , Greengard JS , Montgomery RR ( 2000 ) Genetic induction of a releasable pool of factor VIII in human endothelial cells . Arterioscler Thromb Vasc Biol 20 :2689 - 2695 . 11. Rosenberg JB , Foster PA , Kaufman RJ , Vokac EA , Moussalli , et al. ( 1998 ) Intracellular trafficking of factor VIII to von Willebrand factor storage Storage of Factor VIII Variants with Impaired von Rosenberg JB, Foster PA, Kaufman RJ, Vokac EA, Moussalli , et al. (1998) Intracellular trafficking of factor VIII to von Willebrand factor storage granules. J
The clinical association of factor VIII (FVIII) deficiency with both hemophilia A and von Willebrand disease (VWF) has been recognized for more than 50 years.1-3 However, the mechanism by which regulated secretion of both proteins occurs, remains controversial.1 Since FVIII is deficient in both hemophilia A and severe von Willebrand disease (VWD), it was not surprising to find that the reason von Willebrand factor storage and multimerization:2 von Willebrand factor storage and multimerization:2 independent intracellular processes. by S L Haberichter, S A Fahs, R R Montgomery. Blood. Read more Intracellular Trafficking of Factor VIII to von Willebrand Intracellular Trafficking of Factor VIII to von Willebrand Factor Storage Granules. von Willebrand Factor-dependent Storage of Factor VIII. 613. J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 0021-9738/98/02/0613/12 $2.00 Volume 101, Number 3, February 1998, 613624 jci.