Massachusetts Chapter of the American College of Surgeons

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Heparin inhibits lung endothelial cell proliferation and pulmonary functional outcomes
Lumeng J Yu, Victoria Ko, Savas T Tsikis, Jordan D Secor, Scott C Fligor, Amy Pan, Duy T Dao, Lorenzo Anez-Bustillos, Bennet S Cho, and Mark Puder
Dept. of Surgery, Vascular Biology Program, Boston Children’s Hospital, Boston, MA

Background: Neonates with congenital diaphragmatic hernia suffer from pulmonary hypoplasia. The most critical patients may require extracorporeal membrane oxygenation with systemic anticoagulation. Many more will require central venous access and lower doses of anticoagulation to maintain line patency. Previously, we demonstrated that high-dose heparin inhibited murine compensatory lung growth (CLG). We investigate the functional effects of low and high dose heparin in this model.
Methods: Lung endothelial cell proliferation was assessed in the presence of heparin. Plasma anti-factor Xa activity was measured in C57BL/6 mice that received three doses of saline (control), low- (250U/kg), or high-dose (500U/kg) heparin. A separate cohort of mice were assessed by treadmill exercise tolerance testing (TETT) at baseline, underwent pneumonectomy two days later, then received control or low- or high-dose heparin for eight days post-operatively followed by repeat TETT.
Results: Heparin induced dose-dependent decreases in lung endothelial cell proliferation. In mice, high-dose heparin increased anti-factor Xa activity to therapeutic levels while low-dose heparin did not. Baseline exercise tolerance was similar. On post-operative day eight, mice receiving either low or high dose heparin ran for significantly shorter distance and time compared to those who had received saline.
Conclusion: While heparin impairs lung endothelial cell proliferation in a dose-dependent manner, even non-therapeutic low doses of heparin impaired exercise tolerance in a murine CLG model. As such, the anticoagulation strategy for neonates with pulmonary hypoplastic diseases requires reevaluation.


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