Critically ill children treated with heparin during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), are at high risk of developing severe capillary leak syndromes (CLS) and excessive bleeding (EB). These events are attributed to multifactorial causes, including inflammatory cytokines and the anti-coagulant activity of heparin. Very little is known, however, about the role that heparin-binding angiotenic growth factors (HBGFs), acting in synergy with heparin-like drugs, play in this process. A nonsurgical intervention that can effectively control postoperative vascular leakage and bleeding is needed. This proposal is based on our novel observation that Fibroblast Growth Factor-2 (FGF-2), a heparin binding angiogenic growth factor, plays a critical role precipitating lethal bleeding disorders in mice treated with heparin-like drugs. In addition, we found that Angiopoietin-1 (Ang-1), an anti-permeability-anti-inflammatory angiogenic growth factor, can prevent lethal bleeding complications in mice without normalizing their anticoagulant status. Based on these findings, we hypothesize that FGF-2 and other HBGFs, tip the balance to precipitate CLS and EB by inducing changes in vascular tone and permeability in combination with heparin-like drugs. Furthermore, we propose that blocking the permeability signaling pathways induced by heparin + FGF-2 will prevent these complications. Finally, we hypothesize that FGF-2 and other HBGFs will become reliable biomarkers to identify children at high risk of developing CLS and EB.
Three aims will be explored.
In aim 1, will test the hypothesis that heparin, in synergy with FGF-2, induce vascular leakage and bleeding complications by affecting the vascular activity of Angiotensin II (Ang II), VEGF-A, and nitric oxide (NO).
In aim 2 we will identify the basic mechanisms through with Ang-1 prevents the development of severe bleeding complications induced by heparin + FGF-2, and test the hypothesis that blocking the Rho-A, Src, Tek (Tie-2) and other signaling - inflammatory pathways will prevent lethal bleeding complications in mice.
In aim 3, we will follow the clinical outcome of children treated with ECMO and CPB, and define the clinical value of FGF-2 and other HBGFs as biomarkers to identify children at risk of developing severe CLS and EB. These experiments will generate new knowledge and treatments to prevent CLS and EB in children treated with ECMO and CPB, and establish the new notion that blocking the early capillary permeability changes induced by heparin + FGF-2 will prevent CLS and EB in these patients without normalizing their anti-coagulant status.
Critically ill children treated with heparin during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), are at high risk of developing vascular leakage and bleeding complications. Our studies will explore how angiogenic heparin binding growth factors released into the circulation of mice and children interact with heparin-like drugs to cause bleeding complications, and generate new biomarkers and treatments to improve the clinical outcome of these patients.
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