Thrombin-Activatable Fibrinolysis Inhibitor in Chronic Thromboembolic Pulmonary Hypertension.
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.



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.



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.
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.).
Nobuhiro
N
Yaoita
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.).
Kimio
K
Satoh
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.).
Taijyu
T
Satoh
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.).
Koichiro
K
Sugimura
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.).
Shunsuke
S
Tatebe
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.).
Saori
S
Yamamoto
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.).
Tatsuo
T
Aoki
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.).
Masanobu
M
Miura
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.).
Satoshi
S
Miyata
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.).
Takeshi
T
Kawamura
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.).
Hisanori
H
Horiuchi
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.).
Yoshihiro
Y
Fukumoto
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.
Hiroaki
H
Shimokawa
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D006328:Cardiac Catheterization; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005787:Gene Frequency; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011480:Protease Inhibitors / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000201:enzymology; D013997:Time Factors; D015854:Up-Regulation
D015415:Biomarkers; D011480:Protease Inhibitors; C585364:CPB2 protein, human; D025901:Carboxypeptidase B2
angioplasty; fibrinolysis; hemodynamics; plasma; pulmonary hypertension