A recent research project has developed a scoring system aimed at identifying patients with overactive platelets and assessing their risk for future cardiovascular diseases.
Platelets, which are small cell fragments found in the blood, play a crucial role in clotting by sticking together to stop bleeding when blood vessels are injured. Cardiologists have known for some time that certain platelets can become overly reactive, leading to excessive clotting that can block arteries and increase the likelihood of heart attacks, strokes, and circulation issues (such as peripheral artery disease) affecting millions of Americans.
Despite their significant role in cardiovascular problems, checking individual patients for excessive platelet clumping (aggregation) has been challenging so far. Traditional testing methods, known as platelet aggregometry, produce inconsistent results across different laboratories.
To overcome this issue, a study led by researchers from NYU Grossman School of Medicine successfully identified a group of patients with overactive platelets. They conducted a survey that highlighted 451 genes that were notably different in patients with hyperreactive platelets compared to those without. This study, published online on August 20 in Nature Communications, employed bioinformatics to assign a value to each genetic variation and formulated each patient’s Platelet Reactivity ExpresSion Score (PRESS).
“Our findings indicate that this new platelet-focused scoring system can reliably predict platelet hyperreactivity and the associated cardiovascular event risk, independent of aggregometry, for the first time in various populations,” stated Jeffrey Berger, MD, the study’s main author and director of the Center for the Prevention of Cardiovascular Disease at NYU Grossman School of Medicine.
The researchers discovered that their innovative score could identify platelet hyperreactivity in patients at immediate risk of heart attacks as well as in healthy individuals whose future risks may otherwise go unnoticed.
“Currently, doctors prescribe aspirin, a drug that reduces platelet activity, based on risk factors like high cholesterol or high blood pressure, which do not directly relate to platelet function,” Berger explained. “PRESS offers a way to direct anti-platelet treatments to those most likely to benefit, specifically patients with hyperreactive platelets.”
Aspirin can help prevent abnormal clotting but may also increase the risk of bleeding, the study authors indicated. The medical community needs an effective way to identify patients for whom the benefits of heart attack prevention outweigh the potential bleeding risks.
Platelet Score
The development of PRESS marked a shift in the area of research away from traditional aggregometry approaches, which involved exposing patients’ platelets to high levels of proteins that strongly promote aggregation. Platelets that did not clump under these extreme conditions were labeled as dysfunctional, but these tests were not designed to measure hyperreactivity directly.
The team’s experience and insights led to the adoption of a different aggregometry method, which exposed platelets to a much smaller dose (4 μM or microMolar) of epinephrine, known to only mildly stimulate aggregation. The research established a threshold of 60 percent aggregation in platelet samples at 0.4 μM of epinephrine to categorize platelets as hyperreactive. Although this method is not entirely new, the current study provided fresh evidence that patients meeting this criterion face a significantly higher risk of cardiovascular incidents.
Specifically, the group employed this more refined aggregometry method to study the effect of platelet activity on MACLE (major adverse cardiovascular and limb events)—a combined measure of death, heart attack, stroke, and amputations in patients from the Platelet Activity and Cardiovascular Events in PAD (PACE-PAD) clinical trial. MACLE was evaluated in this cohort of high-risk individuals after they underwent lower extremity revascularization (LER) procedures designed to reopen blocked arteries.
Among the 254 PACE-PAD patients whose platelet aggregation was analyzed using 0.4 μM of epinephrine, 17.5% displayed hyperreactive platelets. Those with this hyperreactivity showed more than double the rate of heart attack, stroke, acute limb ischemia, or major amputation within 30 days following LER compared to patients without hyperreactive platelets.
While the research team has specialized expertise in aggregometry, they aimed to develop a universally applicable risk measure that could eventually be easily conducted in doctors’ offices. To facilitate global use, PRESS was created based on a genetic profile, independently of blood collection methods and factors that influence aggregometry outcomes.
To formulate PRESS, the researchers gathered genetic material from the platelets of 129 PACE-PAD patients before their revascularization procedure, shaping the score based on observed genetic variances linked to hyperreactivity. The accuracy of the score was confirmed by comparing it to traditional platelet aggregation tests.
For further validation, the research team investigated the connection between PRESS and cardiovascular risk across various patient groups. This included the Heart Attack Research Program, which involved women undergoing coronary angiography. In this study group, those who had suffered heart attacks had higher PRESS scores compared to those with stable coronary artery disease. Among lower extremity atherosclerosis patients followed for about 18 months, those with PRESS scores above the average were found to be 90% more likely to experience a major cardiovascular event compared to those with scores below the median.
“In current medical practice, anti-platelet treatment is not routinely recommended for preventing first heart attacks or strokes, but platelet-based testing could help identify patients at the highest risk—those who would benefit the most from such therapy to avert cardiovascular incidents,” remarked study author Tessa Barrett, PhD, an assistant professor in the Departments of Medicine and Pathology at NYU Langone. “Our score could enhance the personalization of cardiovascular disease risk prevention strategies.”
Alongside Berger and Barrett, study contributors from the NYU Grossman School of Medicine’s Department of Medicine included 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 author, Deepak Voora, MD, is affiliated with the Duke Center for Applied Genomics & Precision Medicine.
This research was supported by several grants from the National Institutes of Health (NIH) including R01HL114978, R35HL144993, R01HL167917, 5R01HL118049, and K23HL150315. The NYU CTSA grant UL1TR001445 from the National Center for Advancing Translational Sciences (NCATS) also contributed to this study. The NYU Langone Health DART Genomic Technology Core received partial funding from the NYU Cancer Center Support Grant NIH/NCI P30CA016087.
