Ninivaggi Marisa, Sokolova Lily, Donkervoort Demy, de Laat Bas, de Laat-Kremers Romy
Department of Functional Coagulation, Synapse Research Institute, Maastricht, Netherlands.
Department of Data Analysis and Artificial Intelligence, Synapse Research Institute, Maastricht, Netherlands.
Front Cardiovasc Med. 2024 Nov 29;11:1490601. doi: 10.3389/fcvm.2024.1490601. eCollection 2024.
The mechanism by which combined oral contraceptives (COCs) lead to hypercoagulation is not fully understood, although activated protein C (APC) pathway resistance has been implicated. APC and thrombomodulin (TM) tend to be considered as interchangeable reagents, even though their biological action in coagulation is different. However, it remains unclear which reagent is better suited for the detection of APC pathway resistance. We compared the effectiveness of TM and APC in TG to detect COC-induced APC pathway resistance using thrombin generation (TG).
TG was measured on ST Genesia in 48 healthy women, of whom 24 used COCs. TG was triggered with STG-ThromboScreen (with and without TM), spiked with a low and high concentration of TM or APC (2 or 15 nM TM, or 1.5 or 5.5 nM APC), aimed to achieve 50% and 90% ETP inhibition, respectively.
TG was higher in women using COCs. TM and APC inhibit TG in all women, although their inhibitory effect is more pronounced in women without COC compared to women with COC. The addition of 2 nM TM causes an ETP reduction of 40% (1,289 vs. 768 nM•min) in women without COC and an ETP reduction of 24% (1,704 vs. 1,287 nM•min) in women with COC. The addition of 1.5 nM APC causes an ETP reduction of 41% (1,289 vs. 759 nM•min) in women without COC and an ETP reduction of 23% (1,704 vs. 1,316 nM•min) in women with COC. The difference in effect between women with and without COC is largest when 15 nM TM, aimed at 90% ETP inhibition, is used. 15 nM TM leads to the smallest overlap in ETP inhibition between women with and without COC (27% overlap), compared to 2 nM TM (41% overlap), and 1.5 nM APC (38% overlap) and 5.5 nM APC (41% overlap).
Although TM and APC are often used interchangeably to assess the sensitivity of the APC system in TG, our findings suggest that TM is a better discriminator to detect COC-use induced APC pathway resistance. In addition, we found that the ETP is a better TG test readout for APC pathway resistance testing than the peak height.
尽管已发现活化蛋白C（APC）途径抵抗与复方口服避孕药（COC）导致的高凝状态有关，但其具体机制尚未完全明确。尽管APC和血栓调节蛋白（TM）在凝血过程中的生物学作用不同，但它们往往被视为可互换的试剂。然而，目前尚不清楚哪种试剂更适合用于检测APC途径抵抗。我们使用凝血酶生成试验（TG）比较了TM和APC在检测COC诱导的APC途径抵抗方面的有效性。
对48名健康女性进行了TG检测，其中24名使用COC。使用STG-ThromboScreen（添加和不添加TM）触发TG，并分别添加低浓度和高浓度的TM或APC（2或15 nM TM，或1.5或5.5 nM APC），旨在分别实现50%和90%的内源性凝血酶原时间（ETP）抑制。
使用COC的女性TG水平较高。TM和APC均可抑制所有女性的TG，但与使用COC的女性相比，它们对未使用COC的女性的抑制作用更为明显。添加2 nM TM可使未使用COC的女性的ETP降低40%（1289 vs. 768 nM•min），使用COC的女性的ETP降低24%（1704 vs. 1287 nM•min）。添加1.5 nM APC可使未使用COC的女性的ETP降低41%（1289 vs. 759 nM•min），使用COC的女性的ETP降低23%（1704 vs. 1316 nM•min）。当使用旨在实现90% ETP抑制的15 nM TM时，使用和未使用COC的女性之间的效应差异最大。与2 nM TM（41%重叠）、1.5 nM APC（38%重叠）和5.5 nM APC（41%重叠）相比，15 nM TM导致使用和未使用COC的女性在ETP抑制方面的重叠最小（27%重叠）。
尽管TM和APC经常被互换使用以评估TG中APC系统的敏感性，但我们的研究结果表明，TM在检测COC使用引起的APC途径抵抗方面是更好的鉴别指标。此外，我们发现对于APC途径抵抗检测，ETP是比峰高更好的TG检测读数。
