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ORIGINAL RESEARCH article

Front. Cardiovasc. Med.
Sec. Thrombosis and Haemostasis
Volume 11 - 2024 | doi: 10.3389/fcvm.2024.1490601

Thrombomodulin is a Stronger Indicator of Combined Oral Contraceptives-induced Activated Protein C Pathway Resistance in the Thrombin Generation Test than Activated Protein C

Provisionally accepted
Marisa Ninivaggi Marisa Ninivaggi Lily Sokolova Lily Sokolova Demy Donkervoort Demy Donkervoort Bas De Laat Bas De Laat Romy De Laat-Kremers Romy De Laat-Kremers *
  • Synapse BV, Maastricht, Netherlands

The final, formatted version of the article will be published soon.

    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% (1289 vs 768 nM•min) in women without COC and an ETP reduction of 24% (1704 vs 1287 nM•min) in women with COC. The addition of 1.5 nM APC causes an ETP reduction of 41% (1289 vs 759 nM•min) in women without COC and an ETP reduction of 23% (1704 vs 1316 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.

    Keywords: Thrombin, activated protein C, Thrombomodulin, coagulation, Combined oral contraceptives

    Received: 03 Sep 2024; Accepted: 13 Nov 2024.

    Copyright: © 2024 Ninivaggi, Sokolova, Donkervoort, De Laat and De Laat-Kremers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Romy De Laat-Kremers, Synapse BV, Maastricht, Netherlands

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.