AUTHOR=Costanzo Simona , de Laat Bas , Di Castelnuovo Augusto , van der Vorm Lisa , De Curtis Amalia , Cerletti Chiara , Ninivaggi Marisa , Donati Maria Benedetta , Iacoviello Licia , de Laat-Kremers Romy ,  the Moli-sani investigators , Iacoviello Licia , de Gaetano Giovanni , Donati Maria Benedetta , Cerletti Chiara , Bonaccio Marialaura , Bonanni Americo , Costanzo Simona , De Curtis Amalia , Di Castelnuovo Augusto , Gialluisi Alessandro , Gianfagna Francesco , Persichillo Mariarosaria , Di Prospero Teresa , Vermylen Jos , Pegoraro Renzo , Spagnolo Antonio , Assanelli Deodato , Rago Livia , Costanzo Simona , Olivieri Marco , Orlandi Sabatino , Panzera Teresa , Di Castelnuovo Augusto , Bonaccio Marialaura , Costanzo Simona , Esposito Simona , Gialluisi Alessandro , Ghulam Anwal , Gianfagna Francesco , Pepe Antonietta , Ruggiero Emilia , Sharma Sukshma , De Curtis Amalia , Civitillo Concetta , Cretella Alisia , Magnacca Sara , Noro Fabrizia , Persichillo Mariarosaria , Bracone Francesca , De Rita Fiorella , Di Costanzo Giuseppe , Franciosa Sabrina , Morelli Martina , Bonanni Americo , Cardarelli-Campobasso Ospedale A. , Veneziale-Isernia Ospedale F. , Timoteo-Termoli Ospedale San , Rosario-Venafro Ospedale Ss. , Vietri-Larino Ospedale , Caracciolo-Agnone Ospedale San Francesco , di Cura Villa Maria-Campobasso Casa 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 12 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2025.1528871

DOI=10.3389/fcvm.2025.1528871

ISSN=2297-055X

ABSTRACT=BackgroundRecent 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.MethodsTG 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).ResultsIndividuals 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.ConclusionThe 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.