Platelets, tiny cells in our blood, play a critical role in stopping bleeding by forming clots. While this is a crucial function, platelets can sometimes become overactive or “hyperreactive,” which can lead to the formation of clots inside blood vessels—a process known as atherothrombosis. This can cause serious cardiovascular events like heart attacks or strokes. However, identifying people who have hyperreactive platelets and are at higher risk for such events has been a challenge. That’s where a new tool called the Platelet Reactivity Expression Score (PRESS) comes in.

What is the PRESS Tool?

PRESS is a tool developed by researchers at New York University Grossman School of Medicine to help identify individuals with hyperreactive platelets. It combines two types of information: how strongly a person’s platelets clump together (known as platelet aggregation) when exposed to a specific substance, and data from RNA sequencing, which provides insights into the genetic activity within the platelets.

To create PRESS, the researchers measured how platelets responded to epinephrine, a hormone that can trigger platelets to aggregate. They focused on patients with peripheral artery disease (PAD), a condition where blood vessels in the legs are narrowed, reducing blood flow. This condition can increase the risk of cardiovascular events.

Defining a gene signature of platelet hyperreactivity: Platelet Reactivity Expression Score (PRESS)

A, B To generate a platelet hyperreactivity gene signature, platelets were collected from PACE-PAD patients before lower extremity revascularization (LER, n = 129). Platelet RNA-seq and stratification of patients by hyperreactive platelet responses (aggregation responses > 60% versus = 40% to 0.4 µM epinephrine, n = 84). Violin plots showing platelet aggregation distribution, median represented by the bold dashed line and IQR by dashed lines. P < 0.001 as determined by a 2-sided Mann-Whitney U-test. C, D Overlap of transcripts differentially expressed (using both DESeq2 Wald test and the Wilcoxon rank-sum test after adjustment for age, sex, and race/ethnicity) between patients with hyperreactive or not hyperreactive platelets (n = 796), and transcripts significantly correlated with platelet aggregation responses to 0.4 µM epinephrine (n = 2035). Overlapping genes, n = 451 (PRESS gene set), 174 transcripts positively and 277 transcripts negatively associated with platelet hyperreactivity. E Boxplot showing the platelet hyperreactivity signature score in 10-fold cross-validation training comparing hyperreactive platelet and not hyperreactive platelet patient groups. The line across the box indicates the median, with the whiskers extending to ±1.5 × IQR following z-score normalization. Each outlier outside the whiskers are represented by individual marks. n = 84. F Receiver operating characteristic (ROC) curve of the mean 10-fold cross-validation training of the hyperreactive platelet signature, the shaded areas represent 95% CIs plotted for sensitivity at given in-sample specificities. Source data are provided as a Source Data file. Panel A created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.

Why is Hyperreactivity Important?

In the study, the researchers found that PAD patients whose platelets showed a hyperreactive response—meaning they clumped together more than 60% of the time when exposed to epinephrine—had a much higher chance of experiencing a cardiovascular event within 30 days compared to those without hyperreactive platelets. Specifically, 37.2% of those with hyperreactive platelets experienced a cardiovascular event, compared to only 15.3% of those without this response. This indicates that hyperreactive platelets can be a strong predictor of cardiovascular risk.

How Effective is PRESS?

The PRESS tool was tested in different groups of people, including both PAD patients and healthy individuals. It performed well in identifying those with hyperreactive platelets. In PAD patients, PRESS had an area under the curve (AUC) score of 0.81, which indicates strong accuracy. In healthy participants, it had an AUC score of 0.77, which is also considered reliable. This means that PRESS could potentially be used in a clinical setting to identify individuals at higher risk for cardiovascular events due to hyperreactive platelets.

Why Does This Matter?

Identifying people with hyperreactive platelets is important because it opens the door to personalized medicine. If doctors know that a patient has hyperreactive platelets, they can tailor treatments to reduce the risk of cardiovascular events. For example, patients might receive specific antithrombotic therapies—medications that reduce the formation of blood clots—based on their PRESS score.

What’s Next?

While the results are promising, the researchers acknowledge that further studies in larger groups of patients are needed to confirm the effectiveness of PRESS. If these studies are successful, PRESS could become a valuable tool in managing cardiovascular risk, particularly for patients with conditions like PAD.

The development of the Platelet Reactivity Expression Score represents a significant step forward in cardiovascular care. By helping to identify individuals with hyperreactive platelets, PRESS has the potential to improve the way we prevent and treat cardiovascular diseases, ultimately saving lives.

Availability – Code is available on https://github.com/ruggleslab/press