van Meegeren M E R, Mancini T L, Schoormans S C M, van Haren B J T, van Duren C, Diekstra A, Laros-van Gorkom B A P, Brons P P T, Simons A, Hoefsloot L, van Heerde W L
Hemophilia Treatment Center, Radboud University Medical Center, Nijmegen, The Netherlands.
Unit Thrombosis Hemostasis, Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Haemophilia. 2015 Sep;21(5):e375-83. doi: 10.1111/hae.12733. Epub 2015 Jul 24.
Von Willebrand disease (VWD) type 2N is characterized by a defective binding of factor VIII (FVIII) to von Willebrand factor (VWF) resulting in diminished plasma FVIII levels and a clinical phenotype mimicking mild haemophilia A. Several mutations in the FVIII binding site of VWF have been reported.
This study aims to examine the effect of genotype on clinical phenotype in a cohort of VWD 2N patients.
Patients with at least one genetically confirmed 2N mutation were selected retrospectively from a cohort of patients with suspected VWD. Clinical and laboratory phenotypes including bleeding scores (BS) were obtained and analysed.
Forty-two VWD 2N patients with a mean age of 44 years were included. Eleven patients were homozygous or compound heterozygous (genetically confirmed group) and 31 patients were heterozygously affected (carriers group). Statistically significant differences between genetically confirmed VWD 2N patients and carriers were found in FVIII activity, VWF antigen levels, VWF-FVIII binding capacity, FVIII/VWF antigen ratio (all P<0.001), VWF-ristocetin activity (p=0.001) and VWF collagen binding (P = 0.002). Median BS was 6 in genetically confirmed VWD 2N patients compared with 3 in carriers (P = 0.047). Haemarthrosis, muscle haematomas and postpartum haemorrhage were only reported in genetically confirmed 2N patients.
Phenotypic analysis showed that all laboratory parameters are lower in genetically confirmed VWD 2N patients compared with heterozygous 2N carriers. The clinical phenotype in genetically confirmed VWD 2N patients is comparable to mild haemophilia A patients and more severe than heterozygous 2N carriers.
2N型血管性血友病（VWD）的特征是凝血因子VIII（FVIII）与血管性血友病因子（VWF）结合存在缺陷，导致血浆FVIII水平降低，临床表型类似轻度A型血友病。已报道VWF的FVIII结合位点存在多种突变。
本研究旨在探讨一组2N型VWD患者的基因型对临床表型的影响。
从疑似VWD患者队列中回顾性选择至少有一个经基因确认的2N突变的患者。获取并分析包括出血评分（BS）在内的临床和实验室表型。
纳入42例平均年龄44岁的2N型VWD患者。11例为纯合子或复合杂合子（基因确认组），31例为杂合子受累（携带者组）。基因确认的2N型VWD患者与携带者在FVIII活性、VWF抗原水平、VWF-FVIII结合能力、FVIII/VWF抗原比值（均P<0.001）、VWF-瑞斯托霉素活性（p=0.001）和VWF胶原结合（P = 0.002）方面存在统计学显著差异。基因确认的2N型VWD患者的中位BS为6，而携带者为3（P = 0.047）。仅在基因确认的2N型患者中报告了关节积血、肌肉血肿和产后出血。
表型分析表明，与杂合子2N携带者相比，基因确认的2N型VWD患者的所有实验室参数均较低。基因确认的2N型VWD患者的临床表型与轻度A型血友病患者相当，且比杂合子2N携带者更严重。
