Total Plasma Protein S Is a Prothrombotic Marker in People Living With HIV.
Total Plasma Protein S Is a Prothrombotic Marker in People Living With HIV.
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DOI：
10.1097/qai.0000000000002994
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发表时间：
2022-08-01
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HIV-1感染与多种促凝血剂变化和血栓形成风险增加相关。这种风险的可能机制包括循环单核细胞、细胞外囊泡和病毒颗粒上促凝血组织因子（TF）的表达增强和/或获得性蛋白S（PS）缺乏，PS是抗凝蛋白C（PC）的关键辅因子。PS缺乏症发生在高达76%的HIV-1（PLWH）感染者中。由于体外血浆凝血酶生成增加是死亡率的强预测因子，我们研究了PS和血浆TF是否与血浆凝血酶生成相关。我们分析了来自9名健康对照、17名首次诊断的PLWH（初治）和13名接受抗逆转录病毒治疗（ART）的PLWH的血浆样本。测定血浆凝血酶生成、总PS和游离PS、PC、C4 BP-β和TF活性。我们确定，标准血浆凝血酶生成试验是不敏感的PS，由于缺乏PC的激活，并开发了一个修改的PS敏感的测定。在58%的未经治疗的PLWH样本和38%的ART治疗的PLWH样本中，总血浆PS降低，并且与改良试验中凝血酶生成增加相关。相反，在我们的患者人群中，血浆TF没有增加，这表明它不会显著促进离体血浆凝血酶的产生。这些数据表明，减少总血浆PS有助于与HIV-1感染相关的血栓形成的风险，可以作为一个促血栓形成的生物标志物。此外，我们改进的凝血酶生成试验提供了一个更敏感的工具，以评估获得性PS缺乏PLWH的功能后果。
HIV-1 infection is associated with multiple procoagulant changes and increased thrombotic risk. Possible mechanisms for this risk include heigthened expression of procoagulant tissue factor (TF) on circulating monocytes, extracellular vesicles, and viral particles and/or acquired deficiency of protein S (PS), a critical cofactor for the anticoagulant protein C (PC). PS deficiency occurs in up to 76% of people living with HIV-1 (PLWH). As increased ex vivo plasma thrombin generation is a strong predictor of mortality, we investigated whether PS and plasma TF are associated with plasma thrombin generation. We analyzed plasma samples from 9 healthy controls, 17 PLWH on first diagnosis (naïve), and 13 PLWH on antiretroviral therapy (ART). Plasma thrombin generation, total and free PS, PC, C4BP-β, and TF activity were measured. We determined that the standard plasma thrombin generation assay is insensitive to PS, due to a lack of PC activation, and developed a modified PS-sensitive assay. Total plasma PS was reduced in 58% of the naïve and 38% of the ART-treated PLWH samples, and correlated with increased thrombin generation in the modified assay. Conversely, plasma TF was not increased in our patient population, suggesting that it does not significantly contribute to ex vivo plasma thrombin generation. These data suggest that reduced total plasma PS contributes to the thrombotic risk associated with HIV-1 infection and can serve as a prothrombotic biomarker. In addition, our refined thrombin generation assay offers a more sensitive tool to assess the functional consequences of acquired PS deficiency in PLWH.