Castaman G, Eikenboom J C, Bertina R M, Rodeghiero F
Department of Hematology, Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza, Italy.
Thromb Haemost. 1999 Sep;82(3):1065-70.
In a previous epidemiological investigation among schoolchildren of Northern Italy, a conservative 1% prevalence of type 1 von Willebrand disease (VWD) was found. Diagnosis was based on a positive family history and low von Willebrand factor (VWF) ristocetin cofactor activity. To investigate whether the type 1 VWD phenotype as detected by our original methodology cosegregates with one or more specific alleles of the VWF gene, we have performed genotype analysis in affected subjects and their family members. Eleven of the 14 subjects previously identified as having VWD, all with mild personal bleeding symptoms, agreed to participate in the genetic study. Remarkably, the laboratory measurements of the previous investigation were completely confirmed in 10 of the 11 subjects. Clear cosegregation of the VWD type 1 and a specific VWF allele was observed in one family and was likely in the family of two other pro-bands. In three additional propositi and their families a possible association of the phenotype with a VWF allele was found. No association was observed in the remaining five subjects and their families. During 13-year follow-up few additional bleeding episodes were recorded among investigated subjects, most often occurring in the one family manifesting clear cosegregation. The results of this study illustrate that a personal and family bleeding history and persistently low VWF ristocetin cofactor activity, fitting the usual criteria for type 1 VWD, may not cosegregate with genetic markers at the VWF gene locus. Thus the prevalence of VWD defined as a disorder involving the VWF locus might be overestimated in population study. However, phenotypic diagnosis still remains fundamental to identify patients at risk of bleeding. Further research should clarify whether in families with more severe clinical and laboratory phenotype a clear association with markers of VWF is found.
在之前对意大利北部学童进行的一项流行病学调查中，发现1型血管性血友病（VWD）的保守患病率为1%。诊断基于阳性家族史和低血管性血友病因子（VWF）瑞斯托霉素辅因子活性。为了研究我们最初方法检测到的1型VWD表型是否与VWF基因的一个或多个特定等位基因共分离，我们对受影响的受试者及其家庭成员进行了基因分型分析。之前确定患有VWD的14名受试者中有11名，均有轻度个人出血症状，同意参与基因研究。值得注意的是，之前调查的实验室测量结果在11名受试者中的10名中得到了完全证实。在一个家族中观察到1型VWD与一个特定的VWF等位基因明显共分离，另外两个先证者的家族中也可能存在这种情况。在另外三名先证者及其家族中，发现该表型与一个VWF等位基因可能存在关联。在其余五名受试者及其家族中未观察到关联。在13年的随访期间，在被调查的受试者中记录到的额外出血事件很少，最常发生在表现出明显共分离的那个家族中。这项研究的结果表明，符合1型VWD通常标准的个人和家族出血史以及持续较低的VWF瑞斯托霉素辅因子活性，可能与VWF基因位点的遗传标记不共分离。因此，在人群研究中，被定义为涉及VWF位点的疾病的VWD患病率可能被高估了。然而，表型诊断对于识别有出血风险的患者仍然至关重要。进一步的研究应阐明，在临床和实验室表型更严重的家族中，是否能发现与VWF标记物的明确关联。
