Nobuhiro Yaoita1, Kimio Satoh1, Taijyu Satoh1, Koichiro Sugimura1, Shunsuke Tatebe1, Saori Yamamoto1, Tatsuo Aoki1, Masanobu Miura1, Satoshi Miyata1, Takeshi Kawamura1, Hisanori Horiuchi1, Yoshihiro Fukumoto1, Hiroaki Shimokawa2. 1. From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (N.Y., K. Satoh, T.S., K. Sugimura, S.T., S.Y., T.A., M.M., S.M., Y.F., H.S.), Clinical Pharmaceutics educational Center, Nihon Pharmaceutical University, Saitama, Japan (T.K.); and Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (H.H.). 2. From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (N.Y., K. Satoh, T.S., K. Sugimura, S.T., S.Y., T.A., M.M., S.M., Y.F., H.S.), Clinical Pharmaceutics educational Center, Nihon Pharmaceutical University, Saitama, Japan (T.K.); and Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (H.H.). shimo@cardio.med.tohoku.ac.jp.
Abstract
OBJECTIVE: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis. It remains to be elucidated whether TAFI is directly involved in the pathogenesis of CTEPH. We examined potential involvement of TAFI in the pathogenesis of CTEPH in humans. APPROACH AND RESULTS: We enrolled 68 consecutive patients undergoing right heart catheterization in our hospital, including those with CTEPH (n=27), those with pulmonary arterial hypertension (n=22), and controls (non-pulmonary hypertension, n=19). Whole blood clot lysis assay showed that the extent of clot remaining after 4 hours was significantly higher in CTEPH compared with pulmonary arterial hypertension or controls (41.9 versus 26.5 and 24.6%, both P<0.01). Moreover, plasma levels of TAFI were significantly higher in CTEPH than in pulmonary arterial hypertension or controls (19.4±4.2 versus 16.1±4.5 or 16.3±3.3 μg/mL, both P<0.05), which remained unchanged even after hemodynamic improvement by percutaneous transluminal pulmonary angioplasty. Furthermore, the extent of clot remaining after 4 hours was significantly improved with CPI-2KR (an inhibitor of activated TAFI) or prostaglandin E1 (an inhibitor of activation of platelets). Importantly, plasma levels of TAFI were significantly correlated with the extent of clot remaining after 4 hours. In addition, the extent of clot remaining after 4 hours was improved with an activated TAFI inhibitor. CONCLUSIONS: These results indicate that plasma levels of TAFI are elevated in patients with CTEPH and are correlated with resistance to clot lysis in those patients.
OBJECTIVE: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis. It remains to be elucidated whether TAFI is directly involved in the pathogenesis of CTEPH. We examined potential involvement of TAFI in the pathogenesis of CTEPH in humans. APPROACH AND RESULTS: We enrolled 68 consecutive patients undergoing right heart catheterization in our hospital, including those with CTEPH (n=27), those with pulmonary arterial hypertension (n=22), and controls (non-pulmonary hypertension, n=19). Whole blood clot lysis assay showed that the extent of clot remaining after 4 hours was significantly higher in CTEPH compared with pulmonary arterial hypertension or controls (41.9 versus 26.5 and 24.6%, both P<0.01). Moreover, plasma levels of TAFI were significantly higher in CTEPH than in pulmonary arterial hypertension or controls (19.4±4.2 versus 16.1±4.5 or 16.3±3.3 μg/mL, both P<0.05), which remained unchanged even after hemodynamic improvement by percutaneous transluminal pulmonary angioplasty. Furthermore, the extent of clot remaining after 4 hours was significantly improved with CPI-2KR (an inhibitor of activated TAFI) or prostaglandin E1 (an inhibitor of activation of platelets). Importantly, plasma levels of TAFI were significantly correlated with the extent of clot remaining after 4 hours. In addition, the extent of clot remaining after 4 hours was improved with an activated TAFI inhibitor. CONCLUSIONS: These results indicate that plasma levels of TAFI are elevated in patients with CTEPH and are correlated with resistance to clot lysis in those patients.
Authors: Evan L Brittain; Thennapan Thennapan; Bradley A Maron; Stephen Y Chan; Eric D Austin; Edda Spiekerkoetter; Harm J Bogaard; Christophe Guignabert; Roxane Paulin; Roberto F Machado; Paul B Yu Journal: Am J Respir Crit Care Med Date: 2018-07-01 Impact factor: 21.405
Authors: Muhammad Shahzeb Khan; Emaan Amin; Muhammad Mustafa Memon; Naser Yamani; Tariq Jamal Siddiqi; Safi U Khan; Mohammad Hassan Murad; Farouk Mookadam; Vincent M Figueredo; Rami Doukky; Raymond L Benza; Richard A Krasuski Journal: Int J Cardiol Date: 2019-02-23 Impact factor: 4.164