Platelets are circulating cell fragments known to clump up and form blood clots that stop bleeding in injured vessels. Cardiologists have long known that platelets can become "hyperreactive" to cause abnormal clotting that blocks arteries and contributes to heart attack, stroke, and poor blood flow (peripheral artery disease) in the legs of millions of Americans.

Despite this major contribution to cardiovascular risk, routine measurement of whether each patient's platelets clump (aggregate) too much has been infeasible to date. This is because results delivered by the method typically used to determine platelet activity, called platelet aggregometry, vary too much from lab to lab.

To address this challenge, a new study led by researchers at NYU Grossman School of Medicine has precisely identified a group of patients with platelet hyperreactivity and then surveyed them to reveal 451 genes, the activity of which differed significantly in those with hyperreactive platelets versus those without. Publishing in Nature Communications, the research team then used bioinformatics to assign a weight to each genetic difference and generate each patient's Platelet Reactivity ExpresSion Score (PRESS).

"Our results demonstrate that our new platelet-centric scoring system can, for the first time and across populations, circumvent aggregometry to reliably predict platelet hyperreactivity and the related risk of cardiovascular events," said corresponding study author Jeffrey Berger, MD, director of the Center for the Prevention of Cardiovascular Disease 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 may otherwise remain unknown.

"Physicians currently prescribe aspirin, a medication that counters platelet activity, to patients based on available risk factors, including high cholesterol or high blood pressure, which are not directly related to platelet function," added Berger. "PRESS promises to help physicians confine anti-platelet treatment to the people most likely to benefit: those with platelet hyperreactivity."

Aspirin is known to protect against abnormal clotting by acting on platelets, but in doing so, it increases the risk of bleeding, according to the study authors. The field needs a reliable way to identify patients for whom protection against heart attack outweighs bleeding risk.

Platelet score

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

Experience on Berger's team and in other labs working with platelets led to a switch to an aggregometry method that instead exposes platelets to a very small dose (4 μM or microMolar) of epinephrine known to weakly encourage aggregation. The field settled on 60% aggregation in a platelet sample at 0.4 μM of epinephrine as the threshold over which platelets would be designated as hyperreactive. While this method is not new, the current study provides new evidence that patients meeting this hyperreactivity definition are at much greater risk for cardiovascular events.

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