Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations

for the Hemophilia inhibitor research study investigators

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. Objectives: To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. Patients/Methods: Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. Results: Four cases had VWF:Ag < 3 IU dL-1 and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL-1 and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. Conclusions: These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy.

Original languageEnglish (US)
Pages (from-to)1036-1042
Number of pages7
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Hemophilia A
von Willebrand Factor
Genotype
Phenotype
Mutation
von Willebrand Diseases
Factor VIII
Type 3 Von Willebrand's Disease
Type 1 von Willebrand Disease
Type 2 von Willebrand Disease
Hemorrhage
Diagnostic Errors

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

@article{8c0b0d20796c419ab8939b9226ab5c1c,
title = "Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations",
abstract = "Background: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. Objectives: To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. Patients/Methods: Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. Results: Four cases had VWF:Ag < 3 IU dL-1 and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL-1 and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. Conclusions: These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy.",
author = "{for the Hemophilia inhibitor research study investigators} and B. Boylan and Rice, {A. S.} and {De Staercke}, C. and Eyster, {M. E.} and Yaish, {H. M.} and Knoll, {C. M.} and Bean, {C. J.} and Miller, {C. H.} and Abshire, {Thomas C.} and Amy Dunn and Kempton, {Christine L.} and Bockenstedt, {Paula L.} and Brettler, {Doreen B.} and {Di Paola}, {Jorge A.} and Gita Massey and Barrett, {John C.} and Neff, {Anne T.} and Shapiro, {Amy D.} and Michael Tarantino and Wicklund, {Brian M.} and Manco-Johnson, {Marilyn J.} and Escobar, {Miguel A.} and Gill, {Joan C.} and Cindy Leissinger",
year = "2015",
month = "6",
day = "1",
doi = "10.1111/jth.12902",
language = "English (US)",
volume = "13",
pages = "1036--1042",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "6",

}

Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations. / for the Hemophilia inhibitor research study investigators.

In: Journal of Thrombosis and Haemostasis, Vol. 13, No. 6, 01.06.2015, p. 1036-1042.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations

AU - for the Hemophilia inhibitor research study investigators

AU - Boylan, B.

AU - Rice, A. S.

AU - De Staercke, C.

AU - Eyster, M. E.

AU - Yaish, H. M.

AU - Knoll, C. M.

AU - Bean, C. J.

AU - Miller, C. H.

AU - Abshire, Thomas C.

AU - Dunn, Amy

AU - Kempton, Christine L.

AU - Bockenstedt, Paula L.

AU - Brettler, Doreen B.

AU - Di Paola, Jorge A.

AU - Massey, Gita

AU - Barrett, John C.

AU - Neff, Anne T.

AU - Shapiro, Amy D.

AU - Tarantino, Michael

AU - Wicklund, Brian M.

AU - Manco-Johnson, Marilyn J.

AU - Escobar, Miguel A.

AU - Gill, Joan C.

AU - Leissinger, Cindy

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Background: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. Objectives: To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. Patients/Methods: Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. Results: Four cases had VWF:Ag < 3 IU dL-1 and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL-1 and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. Conclusions: These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy.

AB - Background: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. Objectives: To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. Patients/Methods: Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. Results: Four cases had VWF:Ag < 3 IU dL-1 and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL-1 and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. Conclusions: These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy.

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U2 - 10.1111/jth.12902

DO - 10.1111/jth.12902

M3 - Article

C2 - 25780857

AN - SCOPUS:84930181499

VL - 13

SP - 1036

EP - 1042

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 6

ER -