Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53201-2178, USA.
J Thromb Haemost. 2012 Jul;10(7):1417-24. doi: 10.1111/j.1538-7836.2012.04746.x.
von Willebrand factor (VWF) binds to subendothelial collagen at sites of vascular injury. Laboratory testing for von Willebrand disease (VWD), however, does not always include collagen binding assays (VWF:CB) and standard VWF:CB assays use type I and/or type III collagen rather than type VI collagen.
We report here on several mutations that exclusively alter binding to type VI collagen.
PATIENTS/METHODS: Healthy controls and index cases from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen. VWF gene sequencing was performed for all subjects.
Two healthy controls and one type 1 VWD subject were heterozygous for an A1 domain sequence variation, R1399H, and displayed a selective decreased binding to type VI collagen but not types I and III. Expression of recombinant 1399H VWF resulted in absent binding to type VI collagen. Two other VWF A1 domain mutations, S1387I and Q1402P, displayed diminished binding to type VI collagen. An 11 amino acid deletion in the A1 domain also abrogated binding to type VI collagen.
VWF:CB may be useful in diagnosis of VWD, as a decreased VWF:CB/VWF:Ag ratio may reflect specific loss of collagen binding ability. Mutations that exclusively affect type VI collagen binding may be associated with bleeding, yet missed by current VWF testing.
血管性血友病因子（VWF）与血管损伤部位的内皮下胶原结合。然而，针对血管性血友病（VWD）的实验室检测并不总是包括胶原结合检测（VWF：CB），且标准的 VWF：CB 检测使用的是 I 型和/或 III 型胶原，而非 VI 型胶原。
我们在此报告了几种仅改变与 VI 型胶原结合的突变。
患者/方法：对 Zimmerman 计划中 VWD 的分子和临床生物学的健康对照者和索引病例进行了 VWF 抗原（VWF：Ag）、VWF 瑞斯托霉素辅因子活性和 I、III 和 VI 型胶原的 VWF：CB 分析。对所有受试者进行了 VWF 基因测序。
两名健康对照者和一名 1 型 VWD 患者为 A1 结构域序列变异 R1399H 的杂合子，表现为选择性地降低了与 VI 型胶原的结合，但与 I 型和 III 型胶原的结合不受影响。重组 1399H VWF 的表达导致其与 VI 型胶原结合缺失。另外两种 VWF A1 结构域突变 S1387I 和 Q1402P 显示出与 VI 型胶原结合能力降低。A1 结构域中的 11 个氨基酸缺失也会破坏与 VI 型胶原的结合。
VWF：CB 可能有助于 VWD 的诊断，因为 VWF：CB/VWF：Ag 比值降低可能反映了胶原结合能力的特异性丧失。仅影响 VI 型胶原结合的突变可能与出血有关，但目前的 VWF 检测可能会遗漏这些突变。
