In a recent study published in Nature Communications, researchers from the United States of America investigated the association between platelet hyperreactivity and the risk of cardiovascular events.

They developed the platelet reactivity expression score (PRESS) to identify individuals with hyperreactive platelets.

They found that patients with peripheral artery disease (PAD) and hyperreactive platelets had a higher incidence of cardiovascular events, and PRESS could effectively identify individuals with hyperreactive platelets and higher cardiovascular risk.

Study: A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk. Image Credit: Jo Panuwat D/Shutterstock.com

Background

Platelets are crucial in atherogenesis and thrombosis, and increased platelet activity is linked to higher long-term mortality and cardiovascular events. Despite advancements in our understanding of platelet biology through transcriptome analyses, routine clinical assessment of platelet aggregation remains challenging.

The Platelet Activity and Cardiovascular Events in PAD (PACE-PAD) study aimed to explore the association between platelet activity and major adverse cardiac or limb events (MACLE) in symptomatic PAD patients undergoing lower extremity revascularization. It also sought to identify a platelet hyperreactivity signature using platelet transcriptomics.

In the present study, researchers developed a score named “PRESS” with the aim of effectively identifying persons with a hyperreactive platelet phenotype and those with an increased cardiovascular risk, potentially offering a tool for personalized cardiovascular risk assessment and management.

About the study

A total of 287 patients scheduled for lower extremity revascularization (LER) from March 2014 to November 2017 were included from various institutions in New York. Procedures included open, endovascular, and hybrid approaches, with a small subset undergoing peripheral angiography without revascularization.

About 54% of the patients had coronary artery disease, 53% had diabetes, and 78% had critical limb ischemia. The patients were followed for 30 days to monitor cardiovascular events using electrocardiograms (ECGs), blood tests, and follow-up calls.

Most participants were White (61%), male (67%), and had an average age of 70 years. Blood samples were collected before procedures for platelet activity measurement and ribonucleic acid (RNA) sequencing. Platelet aggregation was assessed using light transmission aggregometry with various agonists, and platelet hyperreactivity was defined as >60% aggregation to 0.4 µM epinephrine.

PRESS was developed by comparing gene expression between hyperreactive and non-hyperreactive platelet groups using statistical tests (The study used t-tests, Wilcoxon tests, chi-squared tests, Fisher’s exact tests, Cox proportional hazard regressions, Kaplan-Meier curves, log-rank tests, Harrell’s C-statistics) and machine learning models.

PRESS was validated in a separate cohort of healthy individuals and other clinical validation cohorts to demonstrate its ability to identify hyperreactive platelet phenotypes.

The study also explored the gene expression differences between groups. It validated PRESS across multiple conditions, including lower extremity atherosclerosis (n =129), systemic lupus erythematosus (n = 51), coronavirus disease 2019 (COVID-19, n = 8), and acute myocardial infarction (MI, n =19).

Results and discussion

Thirty days after LER, 18.8% of patients were found to have experienced a MACLE, with a higher proportion of these patients (90.7%) presenting with critical limb ischemia compared to those without MACLE (75.5%).

Platelet aggregation was assessed in 254 patients before the procedure, showing that those with MACLE had significantly higher median platelet aggregation in response to 0.4 µM epinephrine.

Notably, 17.5% of patients showed a hyperreactive platelet phenotype, associated with higher rates of diabetes and gangrene and lower rates of antiplatelet therapy.

Further, hyperreactive platelets were found to be linked to a nearly threefold increased risk of MACLE. The addition of platelet hyperreactivity to the Revised Cardiac Risk Index was shown to improve the prediction for MACLE.

The PRESS score revealed 796 differentially expressed transcripts in hyperreactive patients. In the validation cohorts, PRESS was found to distinguish individuals with hyperreactive platelets effectively.

The score yielded an accuracy of 80%, a sensitivity of 71%, and a specificity of 86% in differentiating individuals with platelet hyperreactivity versus those without it. Additionally, PRESS was found to be associated with cardiovascular risk, showing significant differences in major cardiovascular events over a median of 18 months between high and low PRESS groups (p = 0.027).

Overall, the findings highlight the potential of PRESS as a potential diagnostic tool for assessing cardiovascular risk based on platelet reactivity.

However, the study’s limitations include its focus on symptomatic PAD patients on antiplatelet therapy, the need for broader validation, the small derivation cohort, potential circadian variation in platelet activity measurements, and its short follow-up period.

Conclusion

In conclusion, the study suggests that platelet hyperreactivity is linked to 30-day MACLE in PAD patients undergoing LER. Investigating individuals with hyperreactive platelets could potentially lead to targeted antiplatelet therapy to reduce the risk of cardiovascular events.

Additionally, the PRESS score developed in this study could effectively identify patients with hyperreactive platelets and higher cardiovascular risk, offering the potential for personalized diagnostics.

The study warrants further research that validates the PRESS score in larger primary prevention populations to assess its broader applicability.