Resistance to activated protein C and impaired TFPI activity in women with previous hormone-induced venous thromboembolism

S N Tchaikovski; M C L G D Thomassen; E Stickeler; K Bremme; J Rosing

doi:10.1016/j.thromres.2021.09.018

Resistance to activated protein C and impaired TFPI activity in women with previous hormone-induced venous thromboembolism

Thromb Res. 2021 Nov:207:143-149. doi: 10.1016/j.thromres.2021.09.018. Epub 2021 Sep 29.

Authors

S N Tchaikovski¹, M C L G D Thomassen², E Stickeler³, K Bremme⁴, J Rosing²

Affiliations

¹ University Clinic for Gynaecology and Obstetrics, RWTH Aachen, Germany; University Clinic for Gynaecology and Obstetrics, Otto von Guericke University Magdeburg, Germany. Electronic address: svetlana.tchaikovski@med.ovgu.de.
² Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
³ University Clinic for Gynaecology and Obstetrics, RWTH Aachen, Germany.
⁴ Department of Women's and Children's Health, Division of Obstetrics and Gynaecology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

PMID: 34634502
DOI: 10.1016/j.thromres.2021.09.018

Abstract

Introduction: Hormonal contraception is a well-known risk factor for venous thromboembolism (VTE). APC resistance and impaired functions of protein S and TFPI are thought to play an important role in the pathogenesis of hormone-related VTE. It is unknown, whether women, who develop VTE during hormonal contraception possess a vulnerability in these pathways, making them susceptible to thrombosis.

Materials and methods: Plasma samples were obtained from 57 premenopausal women in average 15.3 years after hormone-associated VTE and from 31 healthy controls. Thrombin generation at high tissue factor (TF) in the absence and in the presence of activated protein C (APC) and at low TF without and with inhibiting anti-protein S- and anti-TFPI-antibodies was measured via calibrated automated thrombography.

Results: Women with previous hormone-related thrombosis had higher thrombin generation at low TF, higher APC resistance, protein S- and TFPI ratios, differences: 219.9 nM IIa.min (95%CI:90.4 to 349.3); 1.88 (95%CI:0.71 to 3.05); 0.13 (95%CI:0.01 to 0.26) and 0.19 (95%CI:0.08 to 0.30), respectively. Thrombin generation at high TF without APC did not differ between the groups. Smoking decreased thrombin generation at low TF by -222.6 nM IIa.min (95%CI: -381.1 to -64.1), the APC sensitivity ratio by -2.20 (95%CI: -3.63 to -0.77) and the TFPI ratio by -0.16 (95%CI: -0.29 to -0.03), but did not influence thrombin generation at high TF.

Discussion: We demonstrated impairment of the protein S/TFPI system and increased APC resistance in women with previous hormone-induced VTE. Smoking decreased thrombin generation at assay conditions, dependent on the function of the TFPI system.

Keywords: APC resistance; Contraceptives; Protein S; Smoking; TFPI; Thrombosis.