Abstract 13401: Resistance of Thrombus to Fibrinolysis in Patients With Chronic Thromboembolic Pulmonary Hypertension -Possible Involvement of Thrombin-Activated Fibrinolysis Inhibitor (TAFI)-
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of pulmonary arteries (PA) due to chronic thrombosis; however, the underlying pathophysiological mechanism(s) of CTEPH remains largely unknown. We hypothesized that thrombus is resistant to fibrinolysis in PA in patients with CTEPH, for which thrombin-activated fibrinolysis inhibitor (TAFI) is involved with a resultant reduced fibrinolysis.
Methods and Results: First, we examined patients with CTEPH (n=27), those with pulmonary arterial hypertension (PAH, n=22) and those with no PH (non-PH, as control, n=22) who underwent right heart catheterization in our institute. We performed the clot lysis assay ex vivo, using whole blood from PA in those patients. After thrombus formation ex vivo, we examined the resistance of thrombus to fibrinolysis using urokinase (10 U/ml) or monteplase (100 ng/ml). The reduction rate of thrombus by monteplase, but not that by urokinase, was significantly reduced in CTEPH compared with PAH or non-PH (58.1 vs. 75.4 /73.5 %, both P<0.01). Next, we examined the clot lysis time, using patient’s plasma in the presence of CaCl2 (1.0 mg/ml), thrombin (2.5U/ml) and monteplase (500 ng/ml). The clot lysis time tended to be prolonged in CTEPH compared with PAH or non-PH (652 vs. 720/894 sec, both P=0.10). Serum levels of TAFI were significantly higher in CTEPH compared with PAH or non-PH (46.3 vs. 38.7/39.1 ug/ml, respectively, both P<0.05). Then, we separated the platelets from the patients and measured the levels of TAFI released from the platelets upon stimulation by thrombin (0.5 U/ml). The levels of TAFI released from the platelets were significantly higher in CTEPH than in PAH or non-PH (2.7 vs. 1.7/1.0 fold, both P<0.05). Finally, in the clot lysis assay with whole blood, the reduction rate of thrombus was significantly improved with a carboxipeptidase R inhibiting peptide, an inhibitor of activated TAFI (1.25 mg/ml) (62.0 vs. 73.4%, P<0.01) or prostaglandin E1 (35.4 ng/ml) (62.2 vs. 70.4%, P<0.01).
Conclusions: These results indicate that TAFI is up-regulated and is substantially involved in the resistance of thrombus to fibrinolysis in CTEPH, suggesting that the endogenous fibrinolysis inhibitor could be a novel therapeutic target in CTEPH.
- © 2013 by American Heart Association, Inc.