Cardiovascular and genetic determinants of platelet ADP- and epinephrine-induced hyperreactivity – Results from the Gutenberg Health Study

Introduction Platelets contribute to the development of cardiovascular diseases with arterial or venous origin. This study aimed to compare platelet ADP and epinephrine hyperaggregability to other platelet function tests and to determine the predictive value of clinical factors and common genetic variants.

Method Normal- vs. high-responsive platelets to 0.5 µM of ADP and epinephrine in the light transmission aggregometry (LTA) were discriminated by the intersection of two distributions in a Gaussian mixture model from 903 population-based Gutenberg Health Study participants. Utilizing robust Poisson regression analysis, prevalence ratios (PR) were estimated between four platelet hyperaggregability comparison groups and 1) additional platelet parameters assessed by LTA, flow cytometry, platelet function analyzer, and calibrated automated thrombinography, 2) clinical characteristics, and 3) platelet-related common genetic variants.

Results Platelet hyperaggregability in response to ADP and/or epinephrine was associated with maximum aggregation for all tested agonists and tissue factor exposure in vivo after adjustment for age, sex, platelet count and platelet function-interfering medications (PR>1, all group comparisons). Increased platelet aggregation induced by ADP and epinephrine was strongly related to atrial fibrillation (PR>1, all group comparisons), whereas dyslipidemia was associated with ADP high-responsive platelets and venous thromboembolism with epinephrine high-responsive platelets in the LTA (p<0.05). Common variants in GPVI (rs1613662, rs1671152) demonstrated predictive impact on platelet ADP hyperaggregability and rs3737224 (PEAR1) and rs11575845 (MPIG6B) on platelet epinephrine hyperaggregability (p<0.05).

Conclusion This study identifies common and specific cardiovascular and genetic determinants of platelet ADP and epinephrine hyperresponsiveness independent of established confounders. Evaluation of platelet ADP/epinephrine hyperaggregability may provide 1) diagnostic value for platelet hyperactivity in atrial fibrillation, dyslipidemia, and VTE and 2) benefits for personalized antiplatelet treatment.

Conflict of Interest

One author has received research funding outside the present study from Boehringer Ingelheim, Sanofi-Aventis, Bayer HealthCare, Daiichi Sankyo Europe, and Novartis, and honoraria for lectures or consulting from Boehringer Ingelheim, Bayer HealthCare, Evonik, AstraZeneca and Sanofi-Aventis.

Publication History

Article published online:
26 February 2024