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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Boylan
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Rice
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: De Staercke
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Eyster
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Yaish
authors.affiliation: Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Knoll
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Bean
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Miller
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000235:genetics*; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D002648:Child; D004252:DNA Mutational Analysis; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D011485:Protein Binding; D014481:United States; D055815:Young Adult; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014841:von Willebrand Factor; C078147:F8 protein, human; D005169:Factor VIII
keywords: factor VIII; hemophilia A; inherited blood coagulation disorders; von Willebrand disease; von Willebrand factor