A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM‐1 VWD)

Tosetto, Alberto; Rodeghiero, Francesco; Castaman, Giancarlo; Goodeve, Anne; Federici, AB; Batlle, J.; Meyer, Dominique; Fressinaud, Édith; Mazurier, Claudine; Goudemand, Jenny; Eikenboom, Jeroen; Schneppenheim, Reinhard; Budde, Ulrich; Ingerslev, Jørgen; Vorlová, Z; Hui‐Kang, David; Holmberg, Lars; Lethagen, Stefan; Pasi, John; Hill, F. G. H.; Peake, I. R.

doi:10.1111/j.1538-7836.2006.01847.x

Cited by 475 publications

(655 citation statements)

References 16 publications

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“…Further study is needed using meticulous identification of symptoms with high predictive values using case-control approach studies such as the current one. In that manner, we can possibly improve bleeding assessment in the future beyond that currently possible [27,28]. Also some complementary laboratory screening probably will always be needed.…”

Section: Discussionmentioning

confidence: 99%

Clinical phenotype in heterozygote and biallelic Bernard‐Soulier syndrome—A case control study

et al. 2014

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Bernard-Soulier syndrome (BSS) is a rare severe autosomal recessive bleeding disorder. To date heterozygous carriers of BSS mutations have not been shown to have bleeding symptoms. We assessed bleeding using a semi-quantitative questionnaire, platelet parameters, PFA-100 closure times, ristocetin response, GP Ib/IX expression and VWF antigen in 14 BSS patients, 30 heterozygote carriers for related mutations and 29 controls. Eight mutations in GP1BA, GP1BB or GP9 were identified including four previously unknown pathogenic mutations. Subjects with BSS reported markedly more mucocutaneous bleeding than controls. Increased bleeding was also observed in heterozygotes. Compared to controls, patients with BSS had lower optical platelet counts (P < 0.001), CD61-platelet counts (P < 0.001) and higher mean platelet volume (17.7 vs. 7.8 fL, P < 0.001) and ristocetin response and closure times were unmeasurable. Heterozygotes had higher MPV (9.7 fL, P < 0.001) and lower platelet counts (P < 0.001) than controls but response to ristocetin and closure times were normal. The VWF was elevated in both BSS and in heterozygotes (P 5 0.005). We conclude that heterozygotes for BSS mutations have lower platelet counts than controls and show a bleeding phenotype albeit much milder than in BSS. Both patients with BSS and heterozygote carriers of pathogenic mutations have raised VWF.

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Section: Discussionmentioning

confidence: 99%

Clinical phenotype in heterozygote and biallelic Bernard‐Soulier syndrome—A case control study

et al. 2014

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“…The bleeding score in 28 family relatives of the propositi of the 5 previously reported and present families, all heterozygous for C2362F mutation was 2 or less (range, À3 to 2; median, À1). In a population of 195 normal controls [10], a female only had a bleeding score of 4 (range, À3 to 4; median, À1). Thus, heterozygotes for C2362F mutation had a bleeding score completely overlapping that of normal controls.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we reassessed bleeding symptoms in all heterozygotes with C2362F of the present and five previously reported families by using a standardized physician-administered questionnaire to estimate the risk of bleeding associated with the mutation [10].…”

Section: Introductionmentioning

confidence: 99%

Autosomal recessive von Willebrand disease associated with compound heterozygosity for a novel nonsense mutation (2908 del C) and the missense mutation C2362F: Definite evidence for the non‐penetrance of the C2362F mutation

Castaman¹,

Bertoncello²,

Bernardi³

et al. 2006

American J Hematol

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A novel null mutation (2908del C in exon 22) of the von Willebrand factor (VWF) gene was identified in compound heterozygosity with the missense mutation G7335T (C2362F) in exon 42 in a propositus from a new family with autosomal recessive von Willebrand disease (VWD). The propositus, referred at age 2 for severe epistaxis and prolonged bleeding after a tongue bite, had factor VIII:C 14-21 IU/dL, VWF Antigen 3-8 IU/dL and Ristocetin Cofactor activity < 3 IU/dL. Multimeric pattern showed the lack of triplet pattern and a faster mobility of central band, while heterozygotes for C2362F showed intermediate mobility compared to normal plasma and plasma from the propositus. In the propositus' family 5 subjects were heterozygotes for the C2362F mutation and 5 were heterozygotes for the cytosine deletion. Bleeding score was assessed with a detailed questionnaire in 28 heterozygotes for C2362F, 23 of whom identified in 5 previously reported families and 5 in the present one, and found to be similar to what is observed in normal controls and heterozygotes for null allele. In conclusion, the mutation C2362F is frequently observed in compound heterozygosity with null alleles in patients with recessive VWD in the Veneto region and cause bleeding only in the compound heterozygous or homozygous state. Am. J. Hematol. 82:376-380, 2007.

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“…The severity of their bleeding diathesis is variable. The bleeding scores of patient VR and of the two sisters, MG and IG, which was calculated using a standardized questionnaire that was developed to investigate patients with type-1 von Willebrand disease [46] were 8, 7, and 13, respectively, (normal values ≤3; unpublished data). The degree of prolongation of their bleeding times was also variable, reflecting the severity of their clinical bleeding scores: 15 and 20 min (results of two measurements in patient VR), 20 min (patient MG) and >30 min (patient IG; normal values <8 min).…”

Section: Bleeding Manifestationsmentioning

confidence: 99%

Molecular defects of the platelet P2 receptors

Cattaneo

2011

Purinergic Signalling

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Human platelets express three types of P2 receptors, which play important roles in platelet function: P2X 1 , P2Y 1 and P2Y 12 . Only patients with either quantitative or qualitative abnormalities of the platelet P2Y 12 receptor have been well-characterized so far. Deficiencies of P2Y 12 are associated with nucleotide deletions in the open-reading frame, frameshifts, and early truncation of the protein, or with a nucleotide substitution in the transduction initiation codon. Congenital dysfunctions of P2Y 12 are associated with molecular defects involving the sixth trans-membrane domain or the adjacent third extracellular loop of the receptor, which identify a region of the protein whose integrity is necessary for normal receptor function. A mutation, predicting a lysine to glutamate (Lys174Glu) substitution was associated with decreased ligand binding to the receptor, suggesting that it is responsible for disruption of the adenosine diphosphate (ADP)-binding site of the receptor. Patients with P2Y 12 defects display a mild-tomoderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and posttraumatic blood loss. Defects of P2Y 12 should be suspected when ADP, even at high concentrations (≥10 μM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis.

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A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM‐1 VWD)

Cited by 475 publications

References 16 publications

Clinical phenotype in heterozygote and biallelic Bernard‐Soulier syndrome—A case control study

Clinical phenotype in heterozygote and biallelic Bernard‐Soulier syndrome—A case control study

Autosomal recessive von Willebrand disease associated with compound heterozygosity for a novel nonsense mutation (2908 del C) and the missense mutation C2362F: Definite evidence for the non‐penetrance of the C2362F mutation

Molecular defects of the platelet P2 receptors

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