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Am J Physiol Lung Cell Mol Physiol 274: L914-L921, 1998;
1040-0605/98 $5.00
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Vol. 274, Issue 6, L914-L921, June 1998

Effect of a novel covalent antithrombin-heparin complex on thrombin generation on fetal distal lung epithelium

A. K. C. Chan1,2, Leslie Berry3, Lesley Mitchell3, Bryan Baranowski3, Hugh O'Brodovich1,2,4, and Maureen Andrew1,3

1 The Medical Research Council Group in Developmental Lung Biology and 2 Respiratory Research Division, The Hospital for Sick Children, and 4 Department of Paediatrics, University of Toronto, Toronto, Ontario M5G 1X8; and 3 Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Respiratory distress syndrome is characterized by fibrin deposition in the lung. Fibrin adversely affects surfactant function and stimulates proliferation of fibroblasts. There is evidence that these properties may be important to the development of bronchopulmonary dysplasia. Despite successful initial treatment of neonatal respiratory distress syndrome with surfactant, the incidence of bronchopulmonary dysplasia has not decreased. In previous studies, it has been demonstrated that rat fetal distal lung epithelium (FDLE) possesses both procoagulant and anticoagulant properties. In this report, we have demonstrated (using factor VII-deficient plasma) that tissue factor is expressed on the FDLE surface and promotes thrombin generation. To regulate thrombin within this procoagulant environment, we have developed a novel anticoagulant, antithrombin-heparin covalent complex (ATH) that can be retained within the lung after intrapulmonary instillation. We have demonstrated that ATH was superior to antithrombin plus standard heparin in suppressing thrombin generation (P < 0.001) and prothrombin consumption (P < 0.01) in recalcified defibrinated plasma on the surface of FDLE. Further studies with ATH in vivo need to be performed.

tissue factor; respiratory distress syndrome; bronchopulmonary dysplasia; anticoagulant


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L. R. Berry, P. Klement, M. Andrew, and A. K. C. Chan
Effect of Covalent Serpin-Heparinoid Complexes on Plasma Thrombin Generation on Fetal Distal Lung Epithelium
Am. J. Respir. Cell Mol. Biol., February 1, 2003; 28(2): 150 - 158.
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L. Berry, A. Stafford, J. Fredenburgh, H. O'Brodovich, L. Mitchell, J. Weitz, M. Andrew, and A. K. C. Chan
Investigation of the Anticoagulant Mechanisms of a Covalent Antithrombin-Heparin Complex
J. Biol. Chem., December 25, 1998; 273(52): 34730 - 34736.
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