Genetics of type 2B von Willebrand Disease: “True 2B,” “tricky 2B,” or “Not 2B.” What Are the Modifiers of the Phenotype?

Othman, Maha; Favaloro, Emmanuel J.

doi:10.1055/s-0028-1103363

Cited by 30 publications

(16 citation statements)

References 62 publications

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“…Most of them are associated with a shortage of large VWF multimers (type 2B VWD) but some have a full complement of large VWF multimers. 22,23,32 For the purpose of the study, and to emphasize the difference from and similarity to classic type 2B, these latter patients are identified as cases of atypical type 2B VWD.…”

Section: Discussionmentioning

confidence: 99%

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

Casonato¹,

Gallinaro²,

Cattini³

et al. 2010

Haematologica

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BackgroundType 2B von Willebrand factor (VWF) is characterized by gain of function mutations in the A1 domain inducing a greater affinity for platelet GPIb, possibly associated with the disappearance of large VWF multimers and thrombocytopenia. Design and MethodsVWF survival was explored using 1-desamino-8-D-arginine vasopressin (DDAVP) in 18 patients with type 2B von Willebrand disease (VWD) and compared with their platelet count and large VWF multimer representation. ResultsA similarly significant shorter VWF survival, expressed as T1/2elimination (T1/2el), was observed in patients lacking large VWF multimers (type 2B) and in those with a normal multimer pattern (atypical type 2B) (4.47±0.41 h and 4.87±0.9 h, respectively, vs. normal 15.53±2.17 h) due mainly to a greater VWF clearance. The half-life of large VWF multimers, explored by VWF collagen binding (VWF:CB) activity, was likewise reduced. The similarly reduced VWF half-life was also confirmed by the increase in the VWF propeptide ratio (a useful tool for exploring VWF survival) which was found to be the same in type 2B and atypical type 2B patients. The post-DDAVP drop in platelet count occurred in all patients lacking large multimers but not in those with a normal multimer pattern. A correlation was always found between pre-and/or post-DDAVP thrombocytopenia and the lack of large VWF multimers in type 2B VWD while these were unrelated to the reduced VWF half-life. ConclusionsIn addition to demonstrating that a shorter VWF survival contributes to the type 2B and atypical type 2B VWD phenotype, our findings suggest that VWF clearance and proteolysis are independent phenomena. representation or thrombocytopenia. Haematologica 2010(8);95:1366-1372. doi:10.3324/haematol.2009 This is an open-access paper.

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Section: Discussionmentioning

confidence: 99%

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

Casonato¹,

Gallinaro²,

Cattini³

et al. 2010

Haematologica

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“…PT-VWD clinically and phenotypically mimics type 2B VWD. Although PT-VWD and 2B VWD can be distinguished by special phenotypic evaluation [13] or by a genetic approach (analysis of the GPIBA and/or VWF genes [14]), the fact remains that the GPIBA receptor is able to moderate the phenotypic expression of VWF and this can lead to a condition that is difficult for many to distinguish from VWD caused by a mutation in the VWF gene.…”

Section: Molecular Analysis Of the Vwf Gene Is Not Required For Diagnmentioning

confidence: 99%

“…Such diagnostic ÔclarityÕ is likely to be more elusive than currently appreciated. A recent evaluation of the VWD database [22] and literature has highlighted several genetic classification discrepancies (Table 1 and [14,23]). Thus, several mutations have been ascribed to different VWD types by different researchers, different amino acid substitutions within the same location can also lead to discrepancies in VWD typing, and adjacent or close-proximity mutations will also be ascribed to different VWD types.…”

Section: Does Genetic Testing Firm Up the Diagnosis Of A Particular Tmentioning

confidence: 99%

Genetic testing for von Willebrand disease: the case against

Favaloro

2010

Journal of Thrombosis and Haemostasis

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“…Inherited platelet disorders: a clinical approach to diagnosis & management menorrhagia and excessive bleeding after tooth extraction, tonsillectomy and other surgical procedures; however, severe bleeding symptoms have also been reported [25,27]. Although the platelet count may be normal, thrombocytopenia can be observed, which may become more severe under conditions of stress, pregnancy and infection due to the increased release of endogenous VWF under these conditions.…”

Section: Reviewmentioning

confidence: 97%

Inherited platelet disorders: a clinical approach to diagnosis and management

Cox

Price

Kahr

2011

Expert Review of Hematology

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Inherited platelet disorders encompass a heterogeneous group of bleeding disorders where a variety of molecular defects can affect platelet number, function or both. The defects involve deficiencies or dysfunction of platelet receptors, signaling pathways, cytoskeletal proteins, granule contents and abnormalities in procoagulant activity. These disorders can be difficult to distinguish clinically as they present with the common symptom of mucocutaneous bleeding. Inherited thrombocytopenia needs to be considered in all patients suspected of having primary immune thrombocytopenia, where platelets may also have functional defects. After a careful history and physical examination, initial investigations include a complete blood count with a peripheral smear, followed by appropriate specific investigations that often require specialized referral centers. This article is a summary of the current data on clinical presentation, pathogenesis, diagnosis and management of inherited platelet disorders.

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Genetics of type 2B von Willebrand Disease: “True 2B,” “tricky 2B,” or “Not 2B.” What Are the Modifiers of the Phenotype?

Cited by 30 publications

References 62 publications

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

Genetic testing for von Willebrand disease: the case against

Inherited platelet disorders: a clinical approach to diagnosis and management

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