Factor VIII-von Willebrand Factor Binding Defects in Autosomal Recessive von Willebrand Disease Type Normandy and in Mild Hemophilia A

Jacquemin, Marc

doi:10.1159/000214849

Cited by 11 publications

(11 citation statements)

References 26 publications

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“…Despite their distinct roles, FVIII circulates in plasma in a tight complex with VWF. In this complex, FVIII is protected from proteolytic degradation, premature binding to its ligands, and rapid clearance from the circulation (3)(4)(5)(6). The importance of VWF for FVIII biology is exemplified by the idea that defective FVIII binding of VWF is associated with low FVIII plasma levels, resulting in a hemophilia A-like phenotype.…”

Section: Complex Formation Between Coagulation Factor VIII (Fviii) Anmentioning

confidence: 99%

“…The importance of VWF for FVIII biology is exemplified by the idea that defective FVIII binding of VWF is associated with low FVIII plasma levels, resulting in a hemophilia A-like phenotype. This bleeding disorder is referred to as VWF type 2N disease (5,7). Despite this well known clinical phenomenon, detailed molecular insight into how VWF binds FVIII is still lacking.…”

Section: Complex Formation Between Coagulation Factor VIII (Fviii) Anmentioning

confidence: 99%

“…Most of the previously identified VWF type 2N mutations are upstream of the N terminus of VWF (see the ISTH-SSC VWF Database) (5,7). At first sight, one would assume that these residues contribute to FVIII binding as well.…”

Section: Journal Of Biological Chemistry 397mentioning

confidence: 99%

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Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Castro-Núñez

Bloem

Boon-Spijker

et al. 2013

Journal of Biological Chemistry

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Background: von Willebrand factor (VWF) protects factor VIII (FVIII) from rapid clearance and degradation. Results: Mass spectrometric footprinting revealed that FVIII protects Lys-773 and the N-terminal Ser-764 of VWF from chemical modification. VWF(S764A) showed increased and VWF(K773A) showed decreased FVIII binding. Conclusion:The N terminus of VWF is critical for FVIII binding. Significance: This study sheds new light on the mechanism of FVIII-VWF complex assembly.

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Section: Complex Formation Between Coagulation Factor VIII (Fviii) Anmentioning

confidence: 99%

Section: Complex Formation Between Coagulation Factor VIII (Fviii) Anmentioning

confidence: 99%

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Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Castro-Núñez

Bloem

Boon-Spijker

et al. 2013

Journal of Biological Chemistry

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“…Indeed, the majority of VWD-type 2N mutations are located in the region spanning residues 764–1035,54 suggesting that these mutations affect FVIII binding directly by modulation of the FVIII interactive site.…”

Section: The Classical Functions Of Vwf: Fviii Bindingmentioning

confidence: 99%

On the Versatility of Von Willebrand Factor

Lenting¹

2013

Mediterr J Hematol Infect Dis

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Von Willebrand factor (VWF) is a large multimeric protein, the function of which has been demonstrated to be pivotal to the haemostatic system. Indeed, quantitative and/or qualitative abnormalities of VWF are associated with the bleeding disorder Von Willebrand disease (VWD). Moreover, increased plasma concentrations of VWF have been linked to an increased risk for thrombotic complications. In the previous decades, many studies have contributed to our understanding of how VWF is connected to the haemostatic system, particularly with regard to structure-function relationships. Interactive sites for important ligands of VWF (such as factor VIII, collagen, glycoprotein Ibα, integrin αIIbβ3 and protease ADAMTS13) have been identified, and mutagenesis studies have confirmed the physiological relevance of the interactions between VWF and these ligands. However, we have also become aware that VWF has a more versatile character than previously thought, given its potential role in various non-hemostatic processes, like intimal thickening, tumor cell apoptosis and inflammatory processes. In the presence review, a summary of our knowledge on VWF structure-function relationships is provided in the context of the “classical” haemostatic task of VWF and in perspective of pathological processes beyond haemostasis.

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“…Although it has been known that FVIII and VWF associate in plasma and are released together following treatment with desmopressin or 1-deamino-8-D-arginine vasopressin (DDAVP), it was not until recently that human (or murine) microvascular endothelial cells have been demonstrated to synthesize (and store) FVIII. 19–21 Previous studies in our laboratory demonstrated that, if FVIII was synthesized in endothelial cells, it was stored together with VWF in Weibel-Palade bodies. 22,23 It has been assumed that FVIII was synthesized in the liver and probably within the hepatocyte.…”

Section: Gene Therapy Directed At the Local Delivery Of Clotting Factormentioning

confidence: 99%

Alternative Strategies for Gene Therapy of Hemophilia

Montgomery

Shi

2010

Hematology

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Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for “curing” hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome.

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Factor VIII-von Willebrand Factor Binding Defects in Autosomal Recessive von Willebrand Disease Type Normandy and in Mild Hemophilia A

Cited by 11 publications

References 26 publications

Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

On the Versatility of Von Willebrand Factor

Alternative Strategies for Gene Therapy of Hemophilia

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