Direct Thrombin Inhibitors Fail to Reverse the Negative Effects of Heparin on Lung Growth and Function after Murine Left Pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth. The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. While DTIs are increasingly used for systemic anticoagulation clinically, CDH patients may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model was also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin.