Direct Thrombin Inhibitors as Alternatives to Heparin to Preserve Lung Growth, Function, and Alveolarization in Congenital Diaphragmatic Hernia
Savas T. Tsikis1,2, Thomas I. Hirsch1,2, Scott C Fligor1,2, Amy Pan1,2, Malachi M. Joiner1,2, Paul D. Mitchell3, Kathleen M. Gura4, Mark Puder1,2
1Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; 2Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; 3Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA; 4Department of Pharmacy and the Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA
Background: Infants with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We now investigate the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban.
Methods: C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin at established dosages to achieve systemic anticoagulation. On postoperative day 8, mice underwent pulmonary function testing (PFT), lung volume measurement, treadmill exercise tolerance testing (TETT), and morphometric analysis.
Results: Heparin administration significantly decreased lung volume, and total lung capacity (TLC) was lowest in heparinized mice. Bivalirudin/argatroban did not significantly alter lung volume or TLC. Heparin decreased TETT as measured by the percent change from baseline in distance run and time spent running. Bivalirudin/argatroban did not significantly affect exercise performance. On morphometric analysis of stained lung sections, heparin, but not bivalirudin/argatroban, decreased alveolarization.
Conclusion: Bivalirudin and argatroban, but not heparin, preserve lung growth, function, and alveolarization in a murine model of CLG. This data supports the use of DTIs for systemic anticoagulation in CDH patients on cardiopulmonary bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted.
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