Faculty Collaboration Database

Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations. J Thromb Haemost 2015 Jun;13(6):1036-42

Date

03/18/2015

Pubmed ID

25780857

Pubmed Central ID

PMC4512234

DOI

10.1111/jth.12902

Scopus ID

2-s2.0-84930181499 (requires institutional sign-in at Scopus site)   17 Citations

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 List

Boylan B, Rice AS, De Staercke C, Eyster ME, Yaish HM, Knoll CM, Bean CJ, Miller CH, Hemophilia Inhibitor Research Study Investigators

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Biomarkers
Blood Coagulation
Blood Coagulation Tests
Case-Control Studies
Child
DNA Mutational Analysis
Factor VIII
Genetic Predisposition to Disease
Hemophilia A
Hemorrhage
Heterozygote
Homozygote
Humans
Male
Mutation
Phenotype
Predictive Value of Tests
Protein Binding
United States
Young Adult
von Willebrand Factor