Department of Biochemistry, CARIM, Maastricht University, Maastricht, the Netherlands.
J Thromb Haemost. 2010 Feb;8(2):294-300. doi: 10.1111/j.1538-7836.2009.03712.x. Epub 2009 Nov 30.
Protein S and tissue factor pathway inhibitor (TFPI) act together in down-regulating coagulation.
To investigate the TFPI/protein S system in hereditary and acquired protein S deficiency.
Plasma antigen levels of protein S and full-length TFPI were determined in heterozygous type I protein S-deficient individuals (n=35), patients on oral anticoagulant treatment (OAT) (n=29), oral contraceptive (OC) users (n=10) and matched controls. Thrombin generation was determined using calibrated automated thrombography.
Full-length TFPI levels were lower in type I protein S-deficient individuals (76.8+/-33.8%) than in age- and sex-matched controls (128.0+/-59.4%, P<0.001). Among protein S-deficient individuals with thrombosis, those on OAT had not only lower total protein S levels (25.7+/-8.2% vs. 54.7+/-8.2%, P<0.001), but also lower full-length TFPI levels (52.6+/-15.0% vs. 75.4+/-22.9%, P=0.009) than those not on OAT. Similarly, OC users had lower protein S (73.8+/-11.5% vs. 87.9+/-10.8%, P=0.005) and full-length TFPI levels (73.7+/-27.7% vs. 106.4+/-29.2%, P=0.007) than non-users. When triggered with tissue factor, plasma from protein S-deficient individuals generated 3-5-fold more thrombin than control plasma. The difference was only partially corrected by normalization of the protein S level, full correction requiring additional normalization of the TFPI level. Protein S-immunodepletion experiments indicated that free protein S and full-length TFPI form a complex in plasma, and the protein S/TFPI interaction was confirmed by surface plasmon resonance analysis.
Full-length TFPI binds to protein S in plasma and is reduced in genetic and acquired protein S deficiency. The concomitant TFPI deficiency substantially contributes to the hypercoagulable state associated with protein S deficiency.
蛋白 S 和组织因子途径抑制物（TFPI）共同作用于凝血的下调。
研究遗传性和获得性蛋白 S 缺乏症中的 TFPI/蛋白 S 系统。
在杂合 I 型蛋白 S 缺乏个体（n=35）、接受口服抗凝治疗（OAT）的患者（n=29）、口服避孕药（OC）使用者（n=10）和匹配的对照组中，测定蛋白 S 抗原水平和全长 TFPI。使用校准的自动血栓形成术测定凝血酶生成。
I 型蛋白 S 缺乏个体的全长 TFPI 水平（76.8+/-33.8%）低于年龄和性别匹配的对照组（128.0+/-59.4%，P<0.001）。在有血栓形成的蛋白 S 缺乏个体中，接受 OAT 的个体不仅总蛋白 S 水平较低（25.7+/-8.2% vs. 54.7+/-8.2%，P<0.001），全长 TFPI 水平也较低（52.6+/-15.0% vs. 75.4+/-22.9%，P=0.009）。同样，OC 使用者的蛋白 S（73.8+/-11.5% vs. 87.9+/-10.8%，P=0.005）和全长 TFPI 水平（73.7+/-27.7% vs. 106.4+/-29.2%，P=0.007）低于非使用者。当用组织因子触发时，蛋白 S 缺乏个体的血浆产生 3-5 倍于对照血浆的凝血酶。这种差异仅部分通过蛋白 S 水平的归一化得到纠正，完全纠正需要额外的 TFPI 水平归一化。蛋白 S 免疫耗竭实验表明，游离蛋白 S 和全长 TFPI 在血浆中形成复合物，并且通过表面等离子体共振分析证实了蛋白 S/TFPI 相互作用。
全长 TFPI 与血浆中的蛋白 S 结合，并在遗传性和获得性蛋白 S 缺乏症中减少。同时的 TFPI 缺乏极大地促成了与蛋白 S 缺乏相关的高凝状态。
