M. Alhenc-Gelas, Laboratoire d'Hématologie, HEGP, 20 Rue Leblanc, 75015 Paris, France, Tel.: +33 156093901, Fax: +33 156093393, E-mail:
Thromb Haemost. 2016 Mar;115(3):570-9. doi: 10.1160/TH15-05-0391. Epub 2015 Oct 15.
Inherited protein S deficiency (PSD) is an established risk factor for venous thromboembolism (VTE). However, data are conflicting concerning risk of VTE associated with decreased free PS level (FPS) and information on PROS1 genotype-phenotype relationship is sparse. In a retrospective cohort of 579 patients with inherited type I/III deficiency suspicion, PROS1 genotyping was performed and the effect of genotype on FPS and on VTE risk was investigated. We found 116 (including 65 novel) detrimental mutations (DM) in 222 (type I/III in 194, type II in 28), PS Heerlen in 74, possibly non DM in 38 and no mutation in 245 subjects. Among DMs, type I/IIIDMs only were found in subjects with FPS< 30 %. Prevalence of type I/III DM decreased with increasing FPS level. Risk of VT associated with FPS level and genotype was studied in the 467 subjects with personal or family history of thrombosis. Only type I/IIIDM carriers presented with an increased risk of VTE [1.41 (95 %CI (1.05-1.89)] compared to subjects with no mutation. Among the group of type I/IIIDM heterozygotes and subjects with no mutation, the optimal FPS cut-off point for identifying subjects at increased VTE risk was searched for. We found that only subjects with FPS< 30 % and type I/IIIDM presented with an increased risk [1.48 (95 %CI 1.08-2.04)]. Our findings confirm the value of a cut-off FPS level for identifying subjects at increased VTE risk far below the lower limit of the normal range and suggest a place for PROS1 genotyping in PSD diagnosis strategy.
遗传性蛋白 S 缺乏症 (PSD) 是静脉血栓栓塞症 (VTE) 的既定危险因素。然而，关于与游离蛋白 S 水平降低 (FPS) 相关的 VTE 风险的数据存在冲突，并且关于 PROS1 基因型-表型关系的信息也很稀少。在一项对 579 例疑似遗传性 I/III 型缺陷患者的回顾性队列研究中，进行了 PROS1 基因分型，并研究了基因型对 FPS 和 VTE 风险的影响。我们在 222 例患者中发现了 116 个（包括 65 个新突变）有害突变 (DM)（I/III 型 194 例，II 型 28 例），PS Heerlen 74 例，可能非 DM 38 例，无突变 245 例。在 DM 中，仅在 FPS<30%的患者中发现 I/IIIDM。随着 FPS 水平的升高，I/III 型 DM 的发生率降低。在有个人或家族血栓史的 467 例患者中，研究了 FPS 水平和基因型与 VT 风险的关系。与无突变的患者相比，仅 I/IIIDM 携带者的 VTE 风险增加 [1.41（95%CI（1.05-1.89)]。在 I/IIIDM 杂合子和无突变的患者中，寻找识别 VTE 风险增加的最佳 FPS 截断值。我们发现，只有 FPS<30%且 I/IIIDM 的患者 VTE 风险增加 [1.48（95%CI 1.08-2.04)]。我们的研究结果证实了 FPS 截断值在识别 VTE 风险增加方面的价值，其远低于正常范围的下限，并提示 PROS1 基因分型在 PSD 诊断策略中的地位。
