The effects of oral contraceptive usage on thrombin generation and activated protein C resistance in Saudi women, with a possible impact of the body mass index

Mohamed, Abdulrahman B. O.; Kelchtermans, Hilde; Konings, Joke; Daal, Jamilla van; Marzouki, Anas Al; Harakeh, Steve; Laat, Bas de

doi:10.1371/journal.pone.0206376

Cited by 11 publications

(12 citation statements)

References 34 publications

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“…Oral contraceptives are well known to induce a significant procoagulant effect. Moreover, several authors showed a hypercoagulable thrombin generation profile after the addition of TM or activated protein C in this population 20,27‐29 . These findings were also observed in our subjects taking OC, with higher ETP and peak values following TM addition 26 .…”

Section: Discussionsupporting

confidence: 85%

Biological variation data and analytical specification goal estimates of the thrombin generation assay with and without thrombomodulin in healthy individuals

Mairesse

Bayart

Desmet

et al. 2020

Int J Lab Hematology

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Background Evaluation of an individual’s thrombin‐generating capacity enables a global assessment of the coagulation cascade and is therefore thought to better reflect the clotting function of blood. However, the lack of standardization still hampers the use in routine clinical practice. Methods Nineteen healthy subjects were sampled once a week for 5 consecutive weeks. Thrombin generation assay (TGA) was performed in duplicate by calibrated automated thrombogram (CAT) on platelet poor plasma with and without thrombomodulin. After exclusion of outliers, a nested analysis of variance (ANOVA) was performed to evaluate the biological variability (BV) results. Analytical variation (CVA), within‐individual variation (CVI), between‐individual variation (CVG), index of individuality (II), and reference change value (RCV) were calculated. Results All parameters taken together, the CVA, CVI, and CVG without TM, ranged from 2.8% to 6.5%, from 4.1% to 13.3% and from 10.4% to 28.4%, respectively. For TG with TM, CVI and CVG were higher and ranged from 5.0% to 18.1% and from 14.9% to 35.3%, respectively. For endogenous thrombin potential (ETP), a CVI of 4.1% and CVG of 10.4% were obtained without addition of thrombomodulin (TM). With addition of TM, both CVI and CVG were higher: 14.0% and 34.8%, respectively. The II was low and the RCV ranged from 17.2% to 50.4%. Conclusion CAT parameters are highly individualized and population‐based reference values could be called into question. The assessment of BV and RCV for thrombin generation assays could optimize interpretation of serial patient results and guide setting of analytical specification goals.

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Section: Discussionsupporting

confidence: 85%

Biological variation data and analytical specification goal estimates of the thrombin generation assay with and without thrombomodulin in healthy individuals

Mairesse

Bayart

Desmet

et al. 2020

Int J Lab Hematology

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“…Numerous studies investigated the ETP‐based APC resistance, especially in the setting of hormonal contraceptive and hormone replacement therapies, reported as being responsible for an acquired APC resistance . Based on these studies, regulatory bodies recommends the assessment of the ETP‐based APC resistance during the development of novel steroid contraceptive agents .…”

Section: Discussionmentioning

confidence: 99%

Proof of concept of a new scale for the harmonization and the standardization of the ETP‐based APC resistance

Morimont

Bouvy²,

Delvigne³

et al. 2020

Journal of Thrombosis and Haemostasis

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Background The evaluation of the activated protein C resistance (APCr) based on the endogenous thrombin potential (ETP) is recommended during the development of steroid contraceptives. Results are usually expressed as “normalized APC sensitivity ratio” (nAPCsr) using a reference plasma that should achieve an ETP ratio of 0.1 in presence of exogenous APC. Because of the interassay variability, achieving exactly an ETP ratio of 0.1 in each run is almost impossible, which significantly affects the theoretical 0‐10 scale of nAPCsr. Objectives To compare the nAPCsr to the nAPCsr10, a newly proposed method to express the degree of APC resistance. Methods Individual plasma samples (n = 854) were analyzed to compare nAPCsr and nAPCsr10. These values were obtained using the validated ETP‐based APCr assay. Results The Spearman correlation between nAPCsr and nAPCsr10 had a coefficient of 0.99. Linear regression showed the following equation y = 0.9315*x + 0.03942 (r2 = .97). When differences (nAPCsr10 – nAPCsr) were plotted against nAPCsr10, the mean difference equaled 0.16% or 4.95%. The correction obtained with the use of the nAPCsr10 showed that the results of the nAPCsr were statistically different (P < .0001). Conclusions This new scale provides a harmonization and normalization of the nAPCsr. Results show a better reproducibility with the nAPCsr10. It avoids the additional variability and the unharmonized scale introduced by the use of a reference plasma. This adapted method for the calculation of the APC resistance could provide the regulatory and scientific bodies with more reproducible and harmonized evaluations.

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“…Table 1 shows the number of healthy donors per subgroup: men (49.6%), women without OCs (women -OCs, 37.6%) and women taking OCs (women + OCs, 12.8%). The mean age of the whole population was 35 ± 12 years (mean ± SD), and the median age was 30 years (IQR, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. The female group taking OCs was statistically younger than the men or women without OCs (P = .029 and P < .00, respectively).…”

Section: Study Population Characteristicsmentioning

confidence: 99%

ST Genesia reference values of 117 healthy donors measured with STG‐BleedScreen, STG‐DrugScreen and STG‐ThromboScreen reagents

Ninivaggi

Laat-Kremers

Carlo

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Introduction The ST Genesia is a benchtop, fully automated thrombin generation (TG) device. It is completely standardized and ensures a uniform heat distribution throughout the measurement. We aimed to determine reference values and to compare TG in men and women with and without the use of oral contraceptives (OCs). Materials and Methods Plasma from 117 healthy donors was measured on the ST Genesia with the available reagent kits: STG‐BleedScreen, STG‐DrugScreen, and STG‐ThromboScreen. All kits include at least two quality controls and a reference plasma to normalize data. STG‐ThromboScreen has a second trigger containing thrombomodulin (TM) to include the effect on the protein C pathway. Means were compared with one‐way analysis of variance and reference ranges were established with 2.5th to 97.5th percentiles on absolute TG parameters. Results Mean age of the donors was 35 years (SD ± 12); 49.6% were men, 37.6% women without OCs, and 12.8% women with OCs. Men and women without OCs had, respectively, a mean peak height of 167 nM and 164 nM with STG‐BleedScreen, 335 nM and 351 nM with STG‐DrugScreen, and 192 nM and 198 nM with STG‐ThromboScreen. Women taking OCs had a mean peak height of 263 nM, 473 nM, and 312nM, respectively ( P < .05 compared to men/women without OCs). TM decreased endogenous thrombin potential by 54% in men, 47% in women without OCs, and only 25% in women with OCs ( P < .05 compared to men/women without OCs). Conclusions TG in men and women without OCs was similar; however, women taking OCs had significantly higher TG values, and the effect of TM was also less pronounced in these women.

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The effects of oral contraceptive usage on thrombin generation and activated protein C resistance in Saudi women, with a possible impact of the body mass index

Cited by 11 publications

References 34 publications

Biological variation data and analytical specification goal estimates of the thrombin generation assay with and without thrombomodulin in healthy individuals

Biological variation data and analytical specification goal estimates of the thrombin generation assay with and without thrombomodulin in healthy individuals

Proof of concept of a new scale for the harmonization and the standardization of the ETP‐based APC resistance

ST Genesia reference values of 117 healthy donors measured with STG‐BleedScreen, STG‐DrugScreen and STG‐ThromboScreen reagents

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