Pseudo-von Willebrand's Disease

Weiss, Harvey J.; Meyer, Dominique; Rabinowitz, Rosanne; Piétu, Geneviève; Girma, Jean‐Pierre; Vicic, William J.; Rogers, John

doi:10.1056/nejm198202113060603

Cited by 205 publications

(28 citation statements)

References 34 publications

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“…Variant forms ofvWd with enhanced RIPA have been described which show similar characteristics to those of our four patients, including the increased aggregation ofPRP to low-dose ristocetin, the altered multimeric structure of plasma vWf, and the occurrence of thrombocytopenia (1)(2)(3)(4)(5)(20)(21)(22)(23). Type Ilb vWd is described as a plasma abnormality, since the patients' plasma vWf binds to normal platelets at lower ristocetin concentrations than does normal vWf (1).…”

Section: Discussionsupporting

confidence: 78%

“…In pseudo-vWd or platelet-type vWd, the plasma vWf defect is secondary to a platelet abnormality that results in the adsorption of the largest multimeric forms of plasma vWf to platelets independent of ristocetin. Since the plasmas of these patients lack the largest multimers, platelet aggregation ensues only when normal vWfin the form ofcryoprecipitate or purified protein (possessing the largest multimers) is infused in vivo or added in vitro to their platelet-rich plasma (PRP) or when these multimeric forms are released in vivo after I-desamino-8-D-arginine vasopressin (DDAVP) infusion (2,(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

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Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

Grainick¹,

Williams²,

McKeown³

et al. 1985

J. Clin. Invest.

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We have investigated and characterized the abnormalities in four unrelated patients with von Willebrand's disease (vWd) who have (a) enhanced ristocetin-induced platelet aggregation (RIPA) at low ristocetin concentrations, (b) absence of the largest plasma von Willebrand factor (vWf) multimers, and (c) thrombocytopenia. The platelet-rich plasma of these patients aggregates spontaneously without the addition of any agonists. When isolated normal platelets are resuspended in patient plasma spontaneous aggregation occurs; however, the patients' plasmas did not induce platelet aggregation of normal washed formalinized platelets. When the patients' platelets are suspended in normal plasma, spontaneous aggregation is not observed. The spontaneous platelet aggregation (SPA) is associated with dense granule secretion as measured by ATP release and alpha granule release as measured by fl-thromboglobulin and platelet factor 4 release.The SPA is totally inhibited by 5 mM EDTA, prostaglandin I2, and dibutryl cyclic AMP, while it is only partially inhibited by 1 mM EDTA, acetylsalicylic acid, or apyrase. A monoclonal antibody directed against glycoprotein Ib (GPIb) and/or a monoclonal antibody against the glycoprotein IIb/IIIa (GPIIb/ IIIa) complex totally inhibits the SPA.The vWf was isolated from the plasma of one of these patients. The purified vWf induced platelet aggregation of normal platelets resuspended in either normal or severe vWd plasma, but the vWf did not induce platelet aggregation of normal platelets resuspended in afibrinognemic plasma. Sialic acid and galactose quantification ofthe patient's vWf revealed approximately a 50% reduction compared with normal vWf. These studies indicate that a form of vWd exists, which is characterized by SPA that is induced by the abnormal plasma vWf. The SPA is dependent on the presence of plasma fibrinogen, and the availability of the GPIb and the GPIIb/IIIa complex. In this variant form of vWd the abnormal vWf causes enhanced RIPA, SPA, and thrombocytopenia.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

Grainick¹,

Williams²,

McKeown³

et al. 1985

J. Clin. Invest.

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“…13). The latter is associated with platelet-type pseudo-von-Willebrand disease (14,15) and may be responsible for the enhanced interaction with plasma vWF typical of this congenital bleeding disorder (16). We found that beads coated with the 45-kDa GP Ib␣ domain behave like platelets in the interaction with immobilized vWF under flow conditions.…”

mentioning

confidence: 75%

“…This paradox may be resolved by considering that prolongation of the effective lifetime of the GP Ib␣-vWF bond caused by the G233V substitution may alter the association-dissociation equilibrium that normally permits soluble vWF and platelets to coexist in blood. Indeed, both clinical and experimental evidence suggest that circulating plasma vWF binds with enhanced affinity to platelets in patients with platelet-type pseudo-von-Willebrand disease (14)(15)(16). Thus, it is conceivable that the mutant receptor on circulating platelets, because of its heightened ligand-binding capacity, becomes blocked by plasma vWF and is consequently unable to interact with vascular surfaces when required for initiating hemostasis at sites of tissue injury (33).…”

Section: Discussionmentioning

confidence: 99%

Adhesive properties of the isolated amino-terminal domain of platelet glycoprotein Ibα in a flow field

Marchese

Saldı́var

Ware

et al. 1999

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

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We have examined the interaction between the amino-terminal domain of platelet glycoprotein (GP) Ib␣ and immobilized von Willebrand Factor (vWF) under f low conditions in the absence of other components of the GP Ib-IX-V complex. Latex beads were coated with a recombinant fragment containing GP Ib␣ residues 1-302, either with normal sequence or with the single G233V substitution that causes enhanced affinity for plasma vWF in platelet-type pseudo-von-Willebrand disease. Beads coated with native fragment adhered to vWF in a manner comparable to platelets, showing surface translocation that ref lected the transient nature of the bonds formed. Thus, the GP Ib␣ extracellular domain is necessary and sufficient for interacting with vWF under high shear stress. Beads coated with the mutated fragment became tethered to vWF in greater number and had lower velocity of translocation than beads coated with the normal counterpart, suggesting that the G233V mutation lowers the rate of bond dissociation. Our findings define an approach for studying the biomechanical properties of the GP Ib␣-vWF bond and suggest that this interaction is tightly regulated to allow rapid binding at sites of vascular injury, while permitting the concurrent presence of receptor and ligand in the circulation.Platelet adhesion to von Willebrand factor (vWF) immobilized at sites of vascular injury initiates thrombus formation in areas of rapid blood flow (1) and represents a critical mechanism in hemostasis and thrombosis. The process is mediated by the glycoprotein (GP) Ib-IX-V complex, in which the aminoterminal domain of the GP Ib␣-chain (2, 3) contains the binding site for the vWF A1 domain (4, 5). This interaction supports platelet tethering to surfaces even at extremely high shear rates but without irreversible attachment. If no other bonds are formed, tethered platelets translocate in the direction of flow, albeit at a markedly lower velocity than freely flowing blood cells (6). On reactive substrates, however, initial contact allows the rapid establishment of additional bonds typically mediated by receptors of the integrin superfamily and results in essentially instantaneous irreversible adhesion, followed by events leading to subsequent thrombus development (1). At present, it is unknown whether any single domain of the GP Ib-IX-V complex can exhibit the vWF binding function of the intact receptor expressed on the platelet surface. Information in this regard could indicate whether linkage to the cytoskeleton (7,8) and͞or interactions between components of the complex (9, 10) contribute to vWF binding.We have addressed these questions by using a recombinant fragment comprising GP Ib␣ residues 1-302 (11). The isolated domain has been shown to undergo tyrosine sulfation and support modulator-dependent vWF binding as the native receptor (12). In the present studies, plastic beads were coated with the fragment, and its activity was tested in a flow field to mimic the function of a surface-expressed cell membrane receptor during vascular in...

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“…These mutations increase the affinity of GPIb␣ for the vWF A1 domain so that binding occurs with a K d of Ϸ600 nM (24), without the need for a cofactor such as ristocetin (31,32). GPIb␣(G233V͞M239V) stimulated the cleavage of substrates A1A2*A3 (without urea) and A1A2A3 (with urea) (Fig.…”

Section: Figmentioning

confidence: 99%

Binding of platelet glycoprotein Ibα to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13

Nishio

Anderson

Zheng

et al. 2004

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

142

135

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von Willebrand factor (vWF) is a multimeric plasma glycoprotein with three tandem A domains. Domains A1 and A3 bind to platelet glycoprotein Ib␣ (GPIb␣) and collagen, respectively. Domain A2 contains the Tyr-1605-Met-1606 bond that is cleaved by the metalloprotease ADAMTS13, and this reaction inhibits platelet thrombus growth. Fluid shear stress increases the rate of cleavage, suggesting that productive interaction with ADAMTS13 requires conformational changes within or near domain A2. The influence of the adjacent A1 and A3 domains was assessed by mutagenesis of a recombinant substrate consisting of domains A1A2A3. Deletion of domain A3 did not affect cleavage by ADAMTS13, whereas deletion of domain A1 increased the rate of cleavage Ϸ10-fold. Similar effects were observed with plasma ADAMTS13 and recombinant ADAMTS13 truncated after the spacer domain. Digestion of A1A2A3 by plasma ADAMTS13 was enhanced to a similar extent by a recombinant mutant fragment of platelet GPIb␣ that binds with high affinity to domain A1 or by heparin. Heparin also increased the digestion of purified plasma vWF. Neither GPIb␣ nor heparin increased the cleavage of substrate A2A3 that lacks domain A1. The results suggest that vWF domain A1 inhibits the cleavage of domain A2, and that inhibition can be relieved by interaction of domain A1 with platelet GPIb␣ or certain glycosaminoglycans. Thus, binding of vWF to its major physiological ligands may promote the feedback inhibition of platelet adhesion by stimulating the cleavage of domain A2 by ADAMTS13 independent of fluid shear stress.

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Pseudo-von Willebrand's Disease

Cited by 205 publications

References 34 publications

Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

Adhesive properties of the isolated amino-terminal domain of platelet glycoprotein Ibα in a flow field

Binding of platelet glycoprotein Ibα to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13

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