Leveraging Age-Dependent Clotting Mechanism for Hemostatic Material Design
This proposal seeks to develop age-specific hemostatic therapies for addressing life-threatening post-operative bleeding in neonates. Neonates have immature hemostatic systems which can lead to serious outcomes during cardiac surgery with cardiopulmonary bypass. Current practice is to transfuse adult blood products, but this can lead to increased risk of thrombosis. Our research shows structural and functional differences between neonatal and adult fibrin clots, including decreased fiber branching and faster degradation times in neonates. To improve efficacy and safety, novel materials targeting the neonatal clotting cascade are proposed. In vitro, microphysiological system, and in vivo studies will be conducted to characterize a fibrin-triggered hemostatic hydrogel. This approach could provide a safer and more effective way to treat post-operative bleeding in neonates.
Sponsor
American Heart Association
The grant—running from July 1, 2022 to June 30, 2025—is for a total of $300,000.
Principle Investigators
Ashley Brown
Michael Daniele
More Details
The overarching objective of this proposal is to develop age-specific hemostatic therapies for addressing life-threatening post-operative bleeding in neonates. The hemostatic system is immature at birth and matures throughout the first year of life. Neonates (babies <30 days of age) are known to exhibit both qualitative and quantitative differences in many coagulation factors, including hyporeactive platelets, decreased fibrin polymerization rates, and low levels of many pro- and anti-coagulant factors compared to adults. In compromised neonates with a predisposition to bleeding or thrombotic complications, this hemostatic immaturity has dire clinical consequences. For example, neonates with complex congenital heart disease requiring cardiac surgery with cardiopulmonary bypass (CPB) are at high risk for severe bleeding, which results in substantial morbidity and mortality in these patients. Mitigating bleeding is currently addressed through transfusion of adult blood products, including platelets and cryoprecipitate (fibrinogen component). Unfortunately, thrombosis is associated with blood product transfusion. While many coagulation factors are altered in neonates compared to adults, our recent studies show that significant structural and functional differences between neonatal and adult fibrin clots likely contribute to these outcomes. For example, neonatal fibrin clots have minimal fiber branching and are significantly softer than adult clots with faster degradation times. When neonatal and adult fibrinogen are mixed (to mimic transfusion of adult fibrinogen to neonates) the resultant fibrin networks have increased resistance to fibrinolysis compared to neonatal only clots. These data suggest that though adult fibrinogen is effective at inducing clot formation in neonates, age-related mismatches in fibrinogen properties may contribute to increased thrombosis after transfusion of adult fibrinogen to neonates. Developing novel hemostatic materials that specifically target the neonatal clotting cascade represents a promising approach for improving efficacy and safety when treating bleeding in neonates. These studies will first characterize a fibrin-triggered hemostatic hydrogel to augment hemostasis in neonates through a combination of in vitro analyses, microphysiological systems, and in vivo studies.