Thrombocytopathy and type 2B von Willebrand disease

Ware, Jerry

doi:10.1172/jci73169

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…Do mutations other than V1316M exhibit the same platelet functional inhibition? Finally, Jerry Ware raised the issue of potential implications for anti-thrombotic targeting of VWF/GPIb-IX axis [ 151 ]. Indeed, could type 2B mimetics bind to normal platelets and inhibit αIIbβ3 activation, thereby initiating a new strategy for antithrombotic therapy?…”

Section: Pathologies Of Vwf and Platelet Functionsmentioning

confidence: 99%

Of von Willebrand factor and platelets

Bryckaert

Rosa

Denis

et al. 2014

Cell. Mol. Life Sci.

170

137

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Hemostasis and pathological thrombus formation are dynamic processes that require multiple adhesive receptor-ligand interactions, with blood platelets at the heart of such events. Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury. This review will recapitulate our current knowledge on the subject from the rheological aspect to the spatio-temporal development of thrombus formation. We will also discuss the signaling events generated by VWF/GPIb-IX-V interaction, leading to platelet activation. Additionally, we will review the growing body of evidence gathered from the recent development of pathological mouse models suggesting that VWF binding to GPIb-IX-V is a promising target in arterial and venous pathological thrombosis. Finally, the pathological aspects of VWF and its impact on platelets will be addressed.

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Section: Pathologies Of Vwf and Platelet Functionsmentioning

confidence: 99%

Of von Willebrand factor and platelets

Bryckaert

Rosa

Denis

et al. 2014

Cell. Mol. Life Sci.

170

137

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“…Although most of the mutations found in this vicinity are reported to cause type 2B VWD, only a few have also been reported for type 2A VWD (Penas et al , ). In this line, mutations that affect the p.Cys1272‐Cys1458 disulfide loop (e.g., p.Cys1272Arg and p.Cys1458Tyr) destabilize the A1 domain, resulting in loss of GPIbα‐dependent VWF function, whereas most of the A1 domain mutations induce conformational changes leading to VWF GOF (Cooney & Ginsburg, ; Ware, ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of VWF gene conversions causing von Willebrand disease

Ahmad

Kannan²,

Obser

et al. 2018

Br J Haematol

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Summary We previously reported that von Willebrand Factor gene (VWF) conversions are a relatively frequent cause of von Willebrand disease (VWD), however, their molecular pathomechanisms resulting in variant phenotypes is largely unknown. Here, we characterized VWF conversions harbouring missense and synonymous mutations, through generating a series of mutant constructs followed by transient expression in 293 cells, and qualitative and quantitative analysis of recombinant VWF (rVWF). The characterization of mutant rVWF showed the critical roles of synonymous variants in the pathogenicity of VWF conversions. The gene conversion variants p.Val1229Gly, p.Asn1231Thr, p.Asn1231Ser and p.Ala1464Pro in the absence of synonymous p.Ser1263= and p.Gln1449= showed minimal effect on rVWF synthesis and activity. Interestingly, a construct including the synonymous variants displayed significantly low rVWF expression and activity. The variant p.Pro1266Leu showed gain of rVWF function toward glycoprotein Ibα; surprisingly, this function was significantly abolished in the presence of gene conversion variants p.Val1229Gly‐p.Asn1231Thr. Taken together, our expression studies suggest that synonymous variants in the combination of other gene conversion variants suppress the protein expression, possibly due to defective primary mRNA structure or processing. The variants p.Val1229Gly‐p.Asn1231Thr affected the VWF gain of function caused by variant p.Pro1266Leu, probably due to conformational changes in VWF.

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“…This altered platelet function would of course add to increase the risk of bleeding carried by low VWF with loss of HMW multimers and thrombocytopenia. 20…”

Section: How Type 2b Vwf Influences Plateletsmentioning

confidence: 99%

Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality

Castaman

Federici

2016

Semin Thromb Hemost

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Type 2B von Willebrand disease (VWD2B) is a rare, autosomal-dominant inherited bleeding disorder, characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma and often with variable degree of thrombocytopenia and loss of high-molecular-weight multimers von Willebrand factor (VWF). All these phenomena are caused by a mutant VWF, normally synthesized and assembled by endothelial cells, but with heightened affinity binding to the platelet receptor glycoprotein Ib-α (GpIb-α). When this abnormal VWF is released into the circulation and under specific clinical circumstances, in vivo platelet clumping is observed. Mutations, invariably clustered in exon 28 of the VWF gene encoding for the VWF A1 domain involved in VWF binding to GpIb-α, are responsible for VWD2B phenotype. Clinical and laboratory phenotype appears strongly related to the type of VWF-causative mutations. However, recent evidences suggest that a true platelet defect is also present in this type, with several morphological and functional abnormalities being detected in a subset of VWD2B patients.

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Thrombocytopathy and type 2B von Willebrand disease

Cited by 3 publications

References 12 publications

Of von Willebrand factor and platelets

Of von Willebrand factor and platelets

Characterization of VWF gene conversions causing von Willebrand disease

Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality

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