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In 2017 in the Journal of the American College of Cardiology, Dr. Diacovo and colleagues outlined their novel and groundbreaking process analyzing responses to single agents and combinations of platelet agonists and antagonists, and their findings of the efficacy and optimal usage of cangrelor on P2Y12 receptor function in neonatal and pediatric CHD patients.1
Using a novel mouse model created by the Diacovo lab while at Columbia University, and microfluidic devices by colleagues at the University of Pennsylvania capable of assessing clotting using 20-times less blood than in standard testing platforms (a significant advancement and desirous approach, particularly in neonates where blood draw amounts are limited for safety concerns), the researchers were able to not only show efficacy of the entire testing platform for determining platelet reactivity in these subject, but they were also able to show the in vivo efficacy of cangrelor setting the stage for the first trial in neonatal cardiac patients.
“A major success of our work during the first three years was our ability to go from our basic science studies to preclinical and then rapidly translate it into a phase 1 clinical trial that we are in the process of finishing,” says Dr. Diacovo.
The types of studies Dr. Diacovo and colleagues are engaged in are providing the framework and foundation for a new paradigm of treatment determination to combat the scourge of arterial thromboembolic disease. By providing sound, evidence-based guidance and real-time analysis of platelet function in individuals, the most appropriate course of pharmacologic therapy to mitigate clot formation risk may be predicted.
“A large part of our research agenda from the outset has been to test these novel drugs in animal models in order to make better predictions of how these pharmaceutical agents will actually work before introducing them into a child. Just looking at laboratory values has little bearing on actual function. This functionality is a crucial part of the equation we must work to understand,” says Dr. Diacovo.
The existing methodologies and dearth of evidence to support treatments to combat arterial thromboembolic disease have relied mainly on extrapolation.
While Dr. Diacovo and colleagues are still working to finish their first phase 1 trial, planning currently is underway for a second trial that will examine specific Xa inhibitory agents like apixaban. Dr. Diacovo’s team is working to finish various ex vivo studies using their microfluidic devices and mouse modeling technologies to assess the differences between adults and neonates.
“Our preliminary work shows a vast difference between the two age groups, which you may understand intuitively, but because no one has been able to do these studies in the past we lack basic, concrete knowledge of how these agents work in the very young. Knowing what the true pharmacokinetics or pharmacodynamics are of these drugs in our neonatal patients, again, is the crux of our entire research endeavor,” says Dr. Diacovo.
1. Kaza EA, Egalka MC, Zhou H, Chen J, Evans D, Prats J, Li R, Diamond SL, Vincent JA, Bacha A, Diacovo TG. P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease. J Am Coll Cardiol. 2017; 2(4): 465-476.
Neonatal and Pediatric Platelet Function and Pharmacology. NIH Project Number: 7R01HD081281-04. Principal Investigator: Thomas G. Diacovo, MD.