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The Children's National Research Institute

Cardiovascular Disorders

Heparin-Binding Growth Factors

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, excessive bleeding and acute kidney injury. These events are attributed to multifactorial causes, including inflammatory cytokines and the anti-coagulant activity of heparin. However, very little is known about how heparin-binding growth factors released into the circulation of critically ill children modulate this process. A nonsurgical intervention that can effectively control post-operative vascular leakage and bleeding is needed. 

This year, a team of investigators from Children’s National Hospital led by Patricio E. Ray, M.D. (Genetic Medicine), Elizabeth Wilson, M.D., Anthony Sochet, M.D. (Division of Cardiac Intensive Care), discovered that the urinary levels of Fibroblast Growth Factor-2 (FGF-2) and Vascular Endothelial Cell Growth Factor-A (VEGF-A), can be used to identify children at high risk of developing severe bleeding complications and vascular leakage after CPB. This work, supported by an R01 grant from the NHLBI provides significant clinical evidence to validate the studies done in Dr. Ray’s laboratory showing that FGF-2 release into the circulation of mice treated with heparin-like drugs precipitates the development of severe bleeding complications. 

Furthermore, additional work done in this lab, found that Angiopoietin-1, an anti-permeability/anti-inflammatory growth factor, prevented lethal bleeding complications in mice treated with FGF-2 and heparin-like drugs, without normalizing their anticoagulant status. These findings were published in the American Journal of Physiology (Heart and Circulation Physiology). Thus, urinary levels of FGF-2 and VEGF-A might become reliable biomarkers to identify critically ill children at high risk of bleeding when subjected to CPB. In addition, a team of investigators led by Jharna Das, Ph.D., and Aswini K. Panigrahi are currently developing new techniques to identify additional vascular permeability factors released into the circulation of children treated with heparin.