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. 2025 Feb 21:12:1528871.
doi: 10.3389/fcvm.2025.1528871. eCollection 2025.

Age- and sex-dependency of thrombin generation parameters in the general Italian population: the Moli-sani study

Simona Costanzo  1 , Bas de Laat  2   3 , Augusto Di Castelnuovo  1 , Lisa van der Vorm  3 , Amalia De Curtis  1 , Chiara Cerletti  1 , Marisa Ninivaggi  3 , Maria Benedetta Donati  1 , Licia Iacoviello  1   4 , Romy de Laat-Kremers  2 ; Moli-sani investigators
Collaborators, Affiliations

Age- and sex-dependency of thrombin generation parameters in the general Italian population: the Moli-sani study

Simona Costanzo et al. Front Cardiovasc Med. .

Abstract

Background: Recent developments have made the thrombin generation (TG) test accessible to the clinical laboratory. Therefore, the clinical interpretation of TG parameters has become of increasing interest, and reference values are required. Age and sex have been shown to affect TG parameters, but no consensus has been reached on the subject. We investigated the effect of age and sex on TG parameters to determine the need for age and sex specific reference values for TG.

Methods: TG was measured in 22,014 individuals of the Moli-sani study, a cross-sectional cohort of the general adult Italian population. TG was measured using Calibrated Automated Thrombinography in platelet poor plasma (PPP) using PPP reagent Low and PPP reagent, in the presence and absence of thrombomodulin (TM).

Results: Individuals were grouped into 6 age categories: 35-44 years of age (n = 5,073), 45-54 (n = 6,448), 55-64 (n = 5,516), 65-74 (n = 3,539), 75-84 (n = 1,261), and 85 years of age and older (n = 106). Men and women were distributed evenly in the age categories. Smoking was more common at younger age, whereas cardiovascular diseases, hypertension, hypercholesterolemia, and diabetes were more common at older age (p < 0.001). Lag time and velocity index increased with age, whereas the endogenous thrombin potential (ETP) and time-to-peak decreased. The inhibitory effect of TM was reduced at higher age (p < 0.001). The TG lag time was shorter in women than men at younger age (6%-7% lower in women), and the ETP was lower in women. The activated protein C (APC) pathway was desensitized in women and older individuals.

Conclusion: The TG profile becomes more "procoagulant" at older age, especially in women. The sensitivity of the APC pathway to TM is reduced with increasing age in men and women. Therefore, age and sex appropriate reference values for TG parameters would be of interest for the ongoing clinical implementation of the TG assay.

Keywords: age; coagulation; sex; thrombin; thrombin generation; thrombomodulin.

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Conflict of interest statement

BdL, LvdV, MN and RdL-K are employees of Synapse Research Institute, part of Diagnostica Stago SAS. BdL is an employee of Diagnostical Stago. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Flow chart for sample selection and analysis.
Figure 2
Figure 2
Thrombin generation parameters measured after stimulation with PPP reagent Low, stratified for age and sex. TG parameters lag time (A), peak height (B), time-to-peak (C), ETP (D) and velocity index (E) according to the different age categories in the Moli-sani cohort. Data are depicted as the median and interquartile range. Data was stratified for sex, showing the data for men in blue and women in pink. Age categories were compared by ANOVA analysis with Bonferroni post hoc testing, with the 35–44 years as reference, separately for men (blue asterisks) and women (pink asterisks). Additionally, the difference between men and women in the same age category is shown as black asterisks. P-values are indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
Figure 3
Figure 3
Thrombin generation parameters measured after stimulation with PPP reagent, stratified for age and sex. TG parameters lag time (A), peak height (B), time-to-peak (C), ETP (D) and velocity index (E) according to the different age categories in the Moli-sani cohort. Data are depicted as the median and interquartile range. Data was stratified for sex, showing the data for men in blue and women in pink. Age categories were compared by ANOVA analysis with Bonferroni post hoc testing, with the 35–44 years as reference, separately for men (blue asterisks) and women (pink asterisks). Additionally, the difference between men and women in the same age category is shown as black asterisks. P-values are indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
Figure 4
Figure 4
Thrombomodulin sensitivity of thrombin generation measured after stimulation with PPP reagent, stratified for age and sex. Normalized inhibition of ETP in men vs. women. Data are depicted as the median and interquartile range. Data was stratified for sex, showing the data for men in blue and women in pink. Age categories were compared by ANOVA analysis with Bonferroni post hoc testing, with the 35–44 years as reference, separately for men (blue asterisks) and women (pink asterisks). Additionally, the difference between men and women in the same age category is shown as black asterisks. P-values are indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
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