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Effect of a novel covalent antithrombin-heparin complex on thrombin generation on fetal distal lung epithelium
A K Chan1, L Berry, L Mitchell
1The Medical Research Council Group in Developmental Lung Biology, Toronto, Ontario M5G 1X8, Canada L8N 3Z5.
Insights
A novel antithrombin-heparin complex (ATH) effectively regulates thrombin generation on lung epithelial cells, offering a potential new treatment for bronchopulmonary dysplasia in infants.
Area of Science:
- Pulmonary Medicine
- Hematology
- Neonatology
Background:
- Respiratory distress syndrome (RDS) involves lung fibrin deposition, impacting surfactant function and fibroblast proliferation, potentially leading to bronchopulmonary dysplasia (BPD).
- Despite surfactant therapy for neonatal RDS, BPD incidence remains high, indicating a need for novel therapeutic strategies.
- Rat fetal distal lung epithelium (FDLE) exhibits both procoagulant and anticoagulant properties.
Purpose of the Study:
- To investigate the role of tissue factor on FDLE in promoting thrombin generation.
- To develop and evaluate a novel anticoagulant, antithrombin-heparin covalent complex (ATH), for intrapulmonary delivery to regulate thrombin in the lung.
- To assess the efficacy of ATH compared to standard antithrombin and heparin in suppressing thrombin generation on FDLE.
Main Methods:
- Tissue factor expression on FDLE was assessed using factor VII-deficient plasma.
- A novel antithrombin-heparin covalent complex (ATH) was developed for intrapulmonary instillation.
- The anticoagulant efficacy of ATH was compared to unfractionated heparin and antithrombin in suppressing thrombin generation and prothrombin consumption on FDLE using recalcified defibrinated plasma.
Main Results:
- Tissue factor expression on FDLE was confirmed to promote thrombin generation.
- ATH demonstrated superior efficacy in suppressing thrombin generation (P < 0.001) and prothrombin consumption (P < 0.01) compared to a combination of antithrombin and standard heparin.
- ATH showed potential for retention within the lung following intrapulmonary administration.
Conclusions:
- ATH is a potent anticoagulant agent effective in regulating thrombin generation on FDLE.
- The findings suggest ATH as a promising therapeutic candidate for managing conditions involving lung fibrin deposition, such as BPD.
- Further in vivo studies are warranted to validate the efficacy and safety of ATH for clinical application.
Abstract:
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.