Platelet Hyperreactivity Score May Improve CVD Risk Detection

A novel score of platelet reactivity expression appears promising for detecting hyperreactivity in patients at increased risk for cardiovascular events, potentially allowing clinicians to better identify who might be vulnerable to future atherothrombotic events and thus benefit from personalized antiplatelet therapy, new data suggest.

The score, known as PRESS, was developed by a team led by Jeffrey S. Berger, MD (NYU Langone Health, New York, NY), and improves on existing measures for detecting hyperreactivity, namely platelet aggregometry. More than 30 years ago researchers first demonstrated, in a cohort from the Framingham Heart Study, that high levels of reactivity are predictive of cardiovascular events, but measuring platelet aggregation routinely is cumbersome.

“I think this is a game changer,” Berger told TCTMD. “For the first time, we have identified a circulating genetic signature of platelet hyperreactivity.”

The PRESS score was derived from a population of patients with PAD, then validated in healthy participants with no CVD diagnoses. The study was published this week in Nature Communications.

“What we demonstrated across different populations [is that] we can pretty soundly discriminate somebody who has or does not have platelet hyperreactivity. Taking that one step further, if they have this high platelet hyperreactivity based on their genetic signature, we found that they're at higher risk for having a cardiovascular event,” Berger added.

Score Performs Well

For the study, Berger and colleagues enrolled 300 PAD patients (mean age 70 years, 33% female) scheduled for a lower-extremity revascularization by surgery, endovascular therapy, or a hybrid procedure between March 2014 and November 2017. More than 50% had known CAD, 53% had diabetes, and 78% had chronic limb-threatening ischemia. Prior to the procedure, the researchers identified those with platelet hyperreactivity via aggregometry and epinephrine exposure.

To develop the PRESS score, the investigators sifted through hundreds of genes, comparing those whose activity was different in patients with versus without hyperreactive platelets. Using bioinformatics, a weight was assigned to each genetic difference that was found and an individualized PRESS score was generated for each participant.

For the first time, we have identified a circulating genetic signature of platelet hyperreactivity. Jeffrey Berger

PRESS identified a hyperreactive phenotype in those with PAD (AUC 0.81; 95% CI 0.68-0.94). In multivariable adjustment, PAD patients who had a PRESS score above the median were at higher risk of a future cardiovascular event (adjusted HR 1.90; 95% CI 1.07-3.36).

At 30 days, the rate of major adverse cardiovascular and limb events (a composite measure of death, MI, stroke, and lower extremity amputations) was higher in patients with preprocedural platelet hyperreactivity as measured by PRESS than in those without (HR 2.76; P = 0.001).

Clinically, PAD patients with a hyperreactive platelet phenotype did not differ by age, sex, or race/ethnicity. However, they were more likely to have diabetes and to present with gangrene. In multivariable adjustment, gangrene was the only clinical factor independently associated with increased risk of platelet hyperreactivity (adjusted OR 2.98; 95% CI 1.40-6.34).

In the second phase of the study, PRESS also performed well in an independent cohort of healthy participants with no known CAD at identifying those who had the phenotype (AUC 0.77; 95% CI 0.75-0.79).

More Work Needed

For now, Berger said, the ability to generate the PRESS score is not at a level where it can be easily done via a finger stick or other point-of-care testing, but that may be possible with further adaptation of the score.

“I envision that one day just as a person goes to their doctor to get their blood pressure checked and their cholesterol checked, there will be an assessment of their platelet activity done right there,” he said. “If their platelets are deemed hyperreactive, [their physician] would be able to decide on the appropriate course of action in terms of antiplatelet therapy.”

Behnood Bikdeli, MD (Brigham and Women’s Hospital, Boston, MA), who commented on the findings for TCTMD, agreed that cardiologists need to do better in terms of risk profiling and identifying those at greatest risk of adverse events after interventions.

“What they investigated is biologically plausible and makes sense,” he noted. “That said, I believe there may be further steps needed before we can implement this in practice. These include intra-individual assessment of these platelet hyperreactivity markers over time to see if they are persistent or not and assessing age-sex-race interactions, which will likely need a larger multicenter study, and along the same lines, external validation of these thought-provoking findings.”