Studies on the prolonged bleeding time in von Willebrand's disease

Smiley, R. K.; Tittley, P.; Rock, Gail

doi:10.1016/0049-3848(89)90196-5

Cited by 23 publications

(12 citation statements)

References 24 publications

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“…This pig had no detectable platelet vWF by immunofluorescence and plasma vWF ristocetin cofactor activity of 10-20%. In humans, platelet vWF is also an important determinant of bleeding time (27,(30)(31)(32). In dogs that do not express platelet vWF, the bleeding time appears to be largely determined by plasma vWF (26).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in humans and pigs demonstrate that bleeding time prolongation is associated with decreased platelet vWF, independent of changes in plasma vWF (5,(27)(28)(29)(30). Interestingly, for porcine vWD and human type III vWD, infusion of plasma and platelet vWF is required to normalize the bleeding time, whereas infusion of plasma vWF alone is insufficient (5,(31)(32)(33)(34). In contrast, infusion of F.VIII-deficient canine cryoprecipitate largely corrects the bleeding time in canine vWD (26).…”

Section: Introductionmentioning

confidence: 99%

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Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

Nichols

Samama

Bellinger

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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von Willebrand factor (vWF) is essential for the induction of occlusive thrombosis in stenosed and injured pig arteries and for normal hemostasis. To separate the relative contribution of plasma and platelet vWF to arterial thrombosis, we produced chimeric normal and von Willebrand disease pigs by crossed bone marrow transplantation; von Willebrand disease (vWD) pigs were engrafted with normal pig bone marrow and normal pigs were engrafted with vWD bone marrow. Thrombosis developed in the chimeric normal pigs that showed normal levels of plasma vWF and an absence of platelet vWF; but no thrombosis occurred in the chimeric vWD pigs that demonstrated normal platelet vWF and an absence of plasma vWF. The ear bleeding times of the chimeric pigs were partially corrected by endogenous plasma vWF but not by platelet vWF. 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

Nichols

Samama

Bellinger

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies have clearly demonstrated that bleeding time may correct poorly in VWD patients, even following treatment with VWF concentrate (Mannucci et al , 1987; Smiley et al , 1989). Similarly, in vitro perfusion studies showed that the collagen‐adherence of VWD‐deficient platelets resuspended in normal plasma remained significantly lower than that of normal platelets.…”

Section: Clinical Significance Of Platelet Vwfmentioning

confidence: 99%

Platelet von Willebrand factor – structure, function and biological importance

et al. 2010

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Summary Besides circulating in normal plasma, von Willebrand factor (VWF) is also stored at relatively high concentration within the α‐granules of platelets. This pool of platelet VWF exists distinct from plasma VWF, and is enriched in haemostatically‐active high molecular weight multimers. Interestingly, the glycosylation profile of platelet VWF differs significantly from that of plasma VWF. Total sialic acid and galactose expression are reduced twofold on platelet VWF, and ABO blood group carbohydrate determinants are not present on the N‐linked glycans of platelet VWF. Consequently, in view of the critical role played by VWF glycans in modulating its activity, it is not surprising that the functional properties of platelet VWF differ markedly compared to those of plasma VWF. Nevertheless, animal model studies suggest that both plasma and platelet VWF play important roles in securing primary haemostasis. In addition, platelet VWF antigen and activity levels vary markedly between patients with different types of von Willebrand disease (VWD). Future studies to define the biochemical mechanisms responsible for these differences between plasma and platelet VWF are thus not only of basic scientific interest, but also of direct translational importance.

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“… 2 Interestingly, in porcine and human type 3 (the most severe form) von Willebrand disease (VWD), replacement of both plasma and platelet VWF is required to normalize the bleeding time, whereas plasma VWF alone is insufficient (Bowie et al 1986; Castillo et al 1991; Mannucci et al 1987; Nichols et al 1995; Smiley et al 1989). …”

mentioning

confidence: 99%

Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

Nichols

Dillow²,

Franck³

et al. 2009

ILAR Journal

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Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders.

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Studies on the prolonged bleeding time in von Willebrand's disease

Cited by 23 publications

References 24 publications

Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

Platelet von Willebrand factor – structure, function and biological importance

Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

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