From the Department of Pathology and Laboratory Medicine (P.T.), Department of Medicine/Hematology-Oncology (P.W., J.P.S.), University of Wisconsin School of Medicine and Public Health, Madison; Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand (P.T.); Blood Research Institute, Blood Center of Wisconsin, Milwaukee (P.E., A.E.M.); and School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia (P.E.).
Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):266-274. doi: 10.1161/ATVBAHA.117.309919. Epub 2017 Nov 2.
Combined oral contraceptives induce a reversible hypercoagulable state with an enhanced risk of venous thromboembolism, but the underlying mechanism(s) remain unclear. Subjects on combined oral contraceptives also demonstrate a characteristic resistance to APC (activated protein C) in the thrombin generation assay. Here, we report the potential role of plasma factor IXa (FIXa) as a mechanism for hormone-induced systemic hypercoagulability.
A novel assay was used to determine FIXa activity in plasma samples from volunteer blood donors. Plasma from 36 premenopausal females on hormonal contraception and 35 not on hormonal contraception, 35 postmenopausal females, and 10 males were analyzed for FIXa activity, total PS (protein S), total tissue factor pathway inhibitor (TFPI), and TFPI-α antigen. Premenopausal females on hormonal contraception demonstrated significantly increased FIXa activity and decreased TFPI-α compared with the other groups. Remarkably, FIXa values were not normally distributed in the hormonal contraception group, but skewed toward the high end. Plasma FIXa activity inversely correlated with both TFPI-α and total PS antigen. Ex vivo determination of TF-dependent FIX activation in FV-deficient plasma demonstrated that inhibitory anti-TFPI antibodies enhanced FIXa generation by 2- to 3-fold, whereas addition of 75 nmol/L PS reduced FIXa generation by ≈2-fold. Further, increasing FIXa concentration enhanced APC resistance during TF-triggered plasma thrombin generation.
Elevation of plasma FIXa activity in association with reductions in TFPI-α and PS is a potential mechanism for systemic hypercoagulability and resistance to APC in premenopausal females on hormonal contraception.
口服避孕药会导致一种可逆转的高凝状态，增加静脉血栓栓塞的风险，但潜在机制尚不清楚。服用口服避孕药的患者在凝血酶生成试验中也表现出 APC（活化蛋白 C）的特征性抵抗。在这里，我们报告了血浆因子 IXa（FIXa）作为激素诱导全身高凝状态的潜在机制。
使用一种新的测定法来确定来自志愿者献血者血浆样本中的 FIXa 活性。分析了 36 名处于激素避孕的绝经前女性、35 名未接受激素避孕的绝经前女性、35 名绝经后女性和 10 名男性的血浆 FIXa 活性、总 PS（蛋白 S）、总组织因子途径抑制剂（TFPI）和 TFPI-α 抗原。与其他组相比，处于激素避孕的绝经前女性表现出明显增加的 FIXa 活性和降低的 TFPI-α。值得注意的是，激素避孕组的 FIXa 值不是正态分布，而是偏向高值。血浆 FIXa 活性与 TFPI-α 和总 PS 抗原呈负相关。在 FV 缺乏的血浆中进行的 TF 依赖性 FIX 激活的体外测定表明，抑制性抗 TFPI 抗体将 FIXa 的生成增强了 2-3 倍，而添加 75nmol/L PS 将 FIXa 的生成减少了约 2 倍。此外，增加 FIXa 浓度可增强 APC 抵抗 TF 触发的血浆凝血酶生成。
在接受激素避孕的绝经前女性中，血浆 FIXa 活性升高，同时 TFPI-α 和 PS 减少，这可能是全身高凝状态和 APC 抵抗的潜在机制。
