An association of Vicenza and Normandy variants von Willebrand disease (VWD)

KELLER L; WOODS AI; KEMPFER AC; FARÍAS CE; SÁNCHEZ-LUCEROS A; GROSSO S; LAZZARI MA

Suiza

Congreso; XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007

International Society of Thrombosis and Haemostasis

Introduction: VWD Vicenza is characterized by mild to moderate bleeding tendency, low von Willebrand factor (VWF), factor VIII and presence of ultralarge multimers in plasma, Substitutions M740I (exon 17) and R1205H (exon 27) of VWF gene were reported in this disorder. VWD Normandy (2N) is the result of mutations causing VWF with a defective binding capacity to FVIII. Mutations in exons 18-21, 24 and 25 in VWD 2N were published. We report the association of R924Q (exon 21) and R1205H (exon 27) substitutions in one patient with low VWF, mildly reduced VWF:FVIIIB/VWF:Ag and bleeding tendency. Methods: Patient: woman (18 years) with hematomas and an episode of post-traumatic hemorrhage in her lip at the age of 9 years with replacement therapy (ISTH bleeding score=4). FVIII=14U/dL; VWF:RCo<10U/dL; VWF:Ag=9U/dL; ultralarge multimers: 52% (vn=5-15%)VWF:FVIIIB/VWF:Ag=0,4 (vn>0.8). Her mother (40 years) showed epistaxis, menorrhagia, easy bruising and hemorrhages after abortion (ISTH bleeding score=4). FVIII=40U/dL; VWF:RCo=66U/dL; VWF:Ag=75U/dL; VWF:FVIIIB/VWF:Ag=1; with no ultralarge  multimers. Her father's data: not available. Exons 17-24 and 27 of VWF gene were amplified and analyzed by CSGE and sequenced (ABI Prism 310, Perkin-Elmer).Patient: woman (18 years) with hematomas and an episode of post-traumatic hemorrhage in her lip at the age of 9 years with replacement therapy (ISTH bleeding score=4). FVIII=14U/dL; VWF:RCo<10U/dL; VWF:Ag=9U/dL; ultralarge multimers: 52% (vn=5-15%)VWF:FVIIIB/VWF:Ag=0,4 (vn>0.8). Her mother (40 years) showed epistaxis, menorrhagia, easy bruising and hemorrhages after abortion (ISTH bleeding score=4). FVIII=40U/dL; VWF:RCo=66U/dL; VWF:Ag=75U/dL; VWF:FVIIIB/VWF:Ag=1; with no ultralarge  multimers. Her father's data: not available. Exons 17-24 and 27 of VWF gene were amplified and analyzed by CSGE and sequenced (ABI Prism 310, Perkin-Elmer). Results: Patient: heterozygous for R924Q and R1205H. Mother: heterozygous for R924Q. No other mutations were detected by CSGE screening or in the DNA sequencing studies.Patient: heterozygous for R924Q and R1205H. Mother: heterozygous for R924Q. No other mutations were detected by CSGE screening or in the DNA sequencing studies. Conclusions: The presence of reduced VWF:Ag and VWF:RCo, ultralarge VWF multimers in plasma and the R1205H supported the diagnosis of Vicenza variant of VWD. The low VWF:FVIIIB/VWF:Ag only seems to be in association with R924Q, compatible with type VWD 2N, though in her mother only FVIII level was mildly affected. Up to now, this is the first report of association of Vicenza and VWD 2N in a woman with bleeding tendency, low FVIII, VWF, VWF:FVIIIB/VWF:Ag, and the presence of ultralarge VWF multimers with R924Q and R1205H substitutions in VWF gene.The presence of reduced VWF:Ag and VWF:RCo, ultralarge VWF multimers in plasma and the R1205H supported the diagnosis of Vicenza variant of VWD. The low VWF:FVIIIB/VWF:Ag only seems to be in association with R924Q, compatible with type VWD 2N, though in her mother only FVIII level was mildly affected. Up to now, this is the first report of association of Vicenza and VWD 2N in a woman with bleeding tendency, low FVIII, VWF, VWF:FVIIIB/VWF:Ag, and the presence of ultralarge VWF multimers with R924Q and R1205H substitutions in VWF gene.