Genetics of Bleeding Disorders in Women

Novelli, Enrico M.; Ragni, Margaret V.

doi:10.1055/s-0028-1103362

Cited by 3 publications

(3 citation statements)

References 70 publications

(97 reference statements)

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“…VWD is known to be the commonest diagnosis in women with bleeding disorders, and women with VWD (including 2B and PT-VWD) suffer a range of symptoms including menorrhagia, epistaxis, mucocutaneous bleeding, traumatic bleeding, dental and oral bleeding (42). Platelet function defects comprise the second most common cause for bleeding in women (43). In summary, unless differential testing is applied, around 15.4% of cases reflecting enhanced RIPA and/or potentially either 2B or PT-VWD will ultimately be identified as PT-VWD.…”

Section: Discussionmentioning

confidence: 99%

Frequency of Platelet type versus Type 2B von Willebrand Disease

Hamilton¹,

Ozelo²,

Leggo³

et al. 2011

Thromb Haemost

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Less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses.

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Section: Discussionmentioning

confidence: 99%

Frequency of Platelet type versus Type 2B von Willebrand Disease

Hamilton¹,

Ozelo²,

Leggo³

et al. 2011

Thromb Haemost

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“…(For a detailed review of genetic causes of bleeding in women, please refer to Novelli and Ragni in this issue of Seminars in Thrombosis and Hemostasis. 53 ) After a standardized exercise protocol, Stakiw and co-workers reported a significant increase in VWF levels together with an increase in HMW VWF, a decrease in the mean platelet count, and also an increase in the ADAMTS13 level in a type 2B VWD group but not for a type 1 VWD group. 9 In pregnancy, VWF levels increase in all women, and type 2B thrombocytopenia is aggravated.…”

Section: Physiologic Factorsmentioning

confidence: 98%

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

Othman¹,

Favaloro²

2008

Semin Thromb Hemost

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Type 2B von Willebrand disease (VWD) is a qualitative type of VWD with a unique feature among VWD types, resulting from an increased binding of von Willebrand factor (VWF) to its platelet receptor glycoprotein 1b-alpha (GP1BA). This heightened responsiveness takes place in vivo without endothelial injury or shear stress induction, typically resulting in loss of the hemostatically most active high-molecular-weight VWF multimers and leading to a bleeding diathesis. This process also typically leads to clearance of platelets and thus usually mild thrombocytopenia. At least this describes the classic representation of type 2B VWD (i.e., the typical picture we have come to know since the description/classification of this disorder in the early 1990s). Over more recent years, several reports have described individual cases, groups of patients, and families diagnosed with type 2B VWD where this picture was not typical in one or more aspects. This review discusses type 2B-like disorders and sheds light on potential phenotypic modifiers that might be responsible for the variation encountered with the classic picture of type 2B VWD as well as the impact on the diagnostic certainty of type 2B VWD.

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“…For example, Bernard-Soulier syndrome (BSS) is apparent in childhood with mucocutaneous bleeding, whereas the MYH9-RDs have a predisposition to kidney failure and hearing loss. 2 Unfortunately, IMTs remain under-recognized, the presence of large platelets often leading to a misdiagnosis of immune thrombocytopenia purpura (ITP) and subsequent inappropriate treatment with steroids or potentially even splenectomy. Many cases of IMT remain without a definitive diagnosis despite complex testing, which has traditionally employed a phenotypic approach.…”

mentioning

confidence: 99%

Inherited Macrothrombocytopenias

Rabbolini

Stevenson

Ward

2014

Semin Thromb Hemost

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Inherited macrothrombocytopenias are a clinically heterogeneous group of disorders, many of which cause moderate-to-severe bleeding tendencies in affected individuals, but which remain under-recognized and are frequently misdiagnosed as immune thrombocytopenia purpura. Diagnostic strategies to date have included a predominant phenotypic approach. The emergence of genetic testing and the implementation of next generation sequencing strategies in the investigation and diagnosis of these disorders have broadened our understanding of their pathogenesis, classification, and presentation. This review describes the increasingly expanding group of recognized inherited macrothrombocytopenias and highlights their pathophysiology and the role of phenotypic and genetic testing in their description and diagnosis.

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Genetics of Bleeding Disorders in Women

Cited by 3 publications

References 70 publications

Frequency of Platelet type versus Type 2B von Willebrand Disease

Frequency of Platelet type versus Type 2B von Willebrand Disease

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

Inherited Macrothrombocytopenias

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