Department of Reproductive and Developmental Sciences and Public Medicine Sciences, University of Trieste, Trieste, Italy.
Haematologica. 2011 Mar;96(3):417-23. doi: 10.3324/haematol.2010.032631. Epub 2010 Dec 20.
Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.
Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.
Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.
Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.
伯纳德-苏利耶综合征是一种严重的出血性疾病，由于血小板复合物 GPIb/IX/V 的缺陷，该复合物与血管性血友病因子结合。由于该疾病罕见，只有少数病例的报告，因此无法建立基因型与表型之间的相关性。为了确定任何关联，我们描述了迄今为止报告的最大病例系列，该病例系列在同一中心进行了系统评估。
纳入了 13 名患有该疾病的患者和 7 名必然携带者。我们收集了临床方面的信息，并确定了血小板特征，包括数量和大小、膜糖蛋白的表达以及瑞斯托菌素诱导的血小板聚集。通过直接测序 GP1BA、GP1BB 和 GP9 基因来识别突变，并通过分子建模分析显示其效应。
所有患者均有中度血小板减少症伴巨大血小板和出血倾向，个体之间的严重程度不同。与 GPIbα 的表达水平始终低于对照值的 10%一致，血小板聚集不存在或严重减少。在 GP1BA、GP1BB 和 GP9 基因中鉴定出纯合突变；其中 6 种是预期会破坏各自蛋白构象的新改变。除了必然携带者的 GP9 突变导致 GPIb/IX/V 表达减少和聚集缺陷外，所有其他携带者均无明显异常。
无论确定的突变如何，患者的出血倾向与血小板减少症无关，血小板减少症始终为中度，血小板 GPIbα 表达始终严重受损。必然携带者的特征与对照相似，尽管他们的 GPIb/IX/V 表达存在差异。考虑到我们队列的局限性，我们无法确定任何相关性。但是，应该鼓励进一步的研究，以更好地了解这种罕见且被低估的疾病的原因。
