Age-and Sex-dependency of Thrombin Generation Parameters in the General Italian Population: the Moli-sani Study

Simona Costanzo ¹ Bas De Laat ² Augusto Di Castelnuovo ¹ Lisa Van Der Vorm ³ Amalia De Curtis ¹ Chiara Cerletti ¹ Marisa Ninivaggi ³ Donati Maria Benedetta ¹ Licia Iacoviello ¹ Romy De Laat-Kremers ^2*

• ¹ Research Unit of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy, Pozzilli, Italy
• ² Department of Data Analysis and Artificial Intelligence, Synapse Research Institute, Maastricht, the Netherlands;, Maastricht, Netherlands
• ³ Department of Functional Coagulation, Synapse Research Institute, Maastricht, the Netherlands;, Maastricht, Netherlands

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.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).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.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.