B Boylan1, A S Rice1, C De Staercke1, M E Eyster2, H M Yaish3, C M Knoll4, C J Bean1, C H Miller1. 1. Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA. 2. Division of Hematology and Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA. 3. Division of Hematology/Oncology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA. 4. Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.
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.
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.
Authors: B Pezeshkpoor; N Zimmer; N Marquardt; I Nanda; T Haaf; U Budde; J Oldenburg; O El-Maarri Journal: J Thromb Haemost Date: 2013-09 Impact factor: 5.824
Authors: Marco Campos; Ashley Buchanan; Fuli Yu; Maja Barbalic; Yang Xiao; Lloyd E Chambless; Kenneth K Wu; Aaron R Folsom; Eric Boerwinkle; Jing-fei Dong Journal: Blood Date: 2012-01-04 Impact factor: 22.113
Authors: C H Miller; J Benson; D Ellingsen; J Driggers; A Payne; F M Kelly; J M Soucie; W Craig Hooper Journal: Haemophilia Date: 2011-11-21 Impact factor: 4.287
Authors: Madhu Gupta; David Lillicrap; Ann Marie Stain; Kenneth D Friedman; Manuel D Carcao Journal: Pediatr Blood Cancer Date: 2011-03-21 Impact factor: 3.167
Authors: Eva M de Wee; Yvonne V Sanders; Eveline P Mauser-Bunschoten; Johanna G van der Bom; Manon E L Degenaar-Dujardin; Jeroen Eikenboom; Arja de Goede-Bolder; Britta A P Laros-van Gorkom; Karina Meijer; Karly Hamulyák; Marten R Nijziel; Karin Fijnvandraat; Frank W G Leebeek Journal: Thromb Haemost Date: 2012-08-23 Impact factor: 5.249
Authors: J M Soucie; C H Miller; F M Kelly; A B Payne; M Creary; P L Bockenstedt; C L Kempton; M J Manco-Johnson; A T Neff Journal: Haemophilia Date: 2013-11-22 Impact factor: 4.287
Authors: Jill M Johnsen; Shelley N Fletcher; Haley Huston; Sarah Roberge; Beth K Martin; Martin Kircher; Neil C Josephson; Jay Shendure; Sarah Ruuska; Marion A Koerper; Jaime Morales; Glenn F Pierce; Diane J Aschman; Barbara A Konkle Journal: Blood Adv Date: 2017-05-18