Blood platelet score detects previously unmeasured risk of heart attack and stroke

Platelets are circulating cell fragments that clump together and form blood clots that stop bleeding in damaged vessels. Cardiologists have long known that platelets can become “overreactive” and cause abnormal clotting that blocks arteries and contributes to heart attacks, strokes and poor blood flow (peripheral artery disease) in the legs of millions of Americans.

Despite this major contribution to cardiovascular risk, it has not been possible until now to systematically measure whether each patient’s platelets clump (aggregate) excessively. Indeed, the results obtained by the method generally used to determine platelet activity, called platelet aggregometry, vary too much from one laboratory to another.

To address this challenge, a new study by researchers at NYU Grossman School of Medicine precisely identified a group of patients with platelet hyperreactivity, then interrogated them to reveal 451 genes whose activity differed significantly in patients with hyperreactive platelets compared to those without. Nature CommunicationsThe research team then used bioinformatics to assign a weight to each genetic difference and generate each patient’s expression of platelet reactivity (PRESS) score.

“Our results demonstrate that our novel platelet-centric scoring system can, for the first time and in all populations, bypass aggregometry to reliably predict platelet hyperreactivity and the associated risk of cardiovascular events,” said the study’s corresponding author, Jeffrey Berger, MD, director of the Center for Cardiovascular Disease Prevention at NYU Grossman School of Medicine.

The researchers found that their new score can detect platelet hyperreactivity, both in patients at imminent risk of heart attack and in healthy patients whose future risk might otherwise remain unknown.

“Physicians currently prescribe aspirin, a drug that counters platelet activity, to patients based on available risk factors, such as high cholesterol or high blood pressure, which are not directly related to platelet function,” Berger added. “PRESS promises to help physicians limit antiplatelet therapy to those most likely to benefit: those with platelet hyperreactivity.”

By acting on platelets, aspirin is known to protect against abnormal clotting, but in doing so it increases the risk of bleeding, the study authors said. Research needs to find a reliable way to identify patients for whom the protection against heart attacks outweighs the risk of bleeding.

Platelet score

Progress toward the design of PRESS began with a shift in aggregometry methods that expose each patient’s platelets to high doses of proteins known to strongly promote aggregation. Platelets that fail to aggregate under these extreme conditions are termed dysfunctional, but these tests were not designed to directly assess hyperreactivity.

Experience in Berger’s group and in other platelet labs led to a shift to an aggregometry method that exposes platelets to a very low dose (4 μM or micromolar) of epinephrine, which is known to weakly promote aggregation. The field has adopted a threshold of 60% aggregation in a platelet sample at 0.4 μM epinephrine, beyond which platelets would be classified as hyperreactive. Although this method is not new, the current study provides new evidence that patients meeting this definition of hyperreactivity are at much higher risk of cardiovascular events.

Specifically, the team used the newer but still laborious method of aggregometry to track the impact of platelet activity on MACLE (major adverse cardiovascular and limb events), a composite measure of death, heart attack, stroke, and lower-limb amputations in patients participating in the Platelet Activity and Cardiovascular Events in PAD (PACE-PAD) clinical trial. MACLE was measured in this high-risk group of patients after undergoing lower-extremity revascularization (LER), a group of procedures that open up clogged arteries.

In 254 PACE-PAD patients whose platelet aggregation was measured with 0.4 μM epinephrine, 17.5% had hyperreactive platelets, and patients with hyperreactivity had more than double the incidence of heart attack, stroke, or acute limb ischemia or major amputation within 30 days of LER than those without hyperreactivity.

The team has unique expertise in aggregometry and their goal was to create a generalizable measure of risk that could one day be easily performed in physician offices. To make global implementation possible, the researchers designed PRESS based on a genetic signature and independent of blood sampling techniques and other variables that affect aggregometry.

To create the PRESS score, the researchers collected platelet genetic material from 129 PACE-PAD patients before their LER procedure and designed the score based on genetic differences observed with hyperreactivity. The researchers confirmed the accuracy of the score by comparing it to platelet aggregation tests.

To further validate the PRESS score, the team studied the relationship between the score and cardiovascular risk in several other patient groups. Among them was the Heart Attack Research Program, which enrolled women undergoing coronary angiography. In this group, the PRESS score was higher in people who had had a heart attack than in those with stable coronary artery disease. Among patients with lower-extremity atherosclerosis followed for an average of 18 months, patients with a PRESS score above the average score were 90% more likely to have a major cardiovascular event than those with a score below the average score.

“In current practice, antiplatelet therapy is not routinely recommended for prevention of a first heart attack or stroke, but a platelet-based test would help identify patients at greatest risk and those who would benefit most from antiplatelet therapy to prevent a cardiovascular event,” said study author Tessa Barrett, PhD, assistant professor in the departments of medicine and pathology at NYU Langone. “Our score has the potential to further personalize cardiovascular disease risk prevention.”

In addition to Berger and Barrett, the study authors from the Department of Medicine at NYU Grossman School of Medicine were Macintosh Cornwell, Yuhe Xia, Matthew Muller, Nathaniel Smilowitz, Jonathan Newman, Florencia Schlamp, Caron Rockman, Kelly Ruggles and Judith Hochman, MD, associate director of the Leon H Charney Division of Cardiology. Another study author was Deepak Voora, MD, of the Duke Center for Applied Genomics & Precision Medicine.