Nobuhiro Yaoita1, Ryutaro Shirakawa1, Yoshihiro Fukumoto1, Koichiro Sugimura1, Satoshi Miyata1, Yutaka Miura1, Kotaro Nochioka1, Masanobu Miura1, Shunsuke Tatebe1, Tatsuo Aoki1, Saori Yamamoto1, Kimio Satoh1, Tomohiro Kimura1, Hiroaki Shimokawa1, Hisanori Horiuchi2. 1. From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (N.Y., Y.F., K.S., S.M., Y.M., K.N., M.M., S.T., T.A., S.Y., K.S., H.S.); and Department of Molecular and Cellular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan (R.S., T.K., H.H.). 2. From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (N.Y., Y.F., K.S., S.M., Y.M., K.N., M.M., S.T., T.A., S.Y., K.S., H.S.); and Department of Molecular and Cellular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan (R.S., T.K., H.H.). horiuchi@idac.tohoku.ac.jp.
Abstract
OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease that is distinct from pulmonary arterial hypertension (PAH). Although CTEPH is characterized by obstruction of major pulmonary artery because of chronic thrombus, it remains unclear whether CTEPH is associated with prothrombotic condition. APPROACH AND RESULTS: In addition to conventional markers, GTP-bound levels of Rap1, RhoA, RalA, Rac1, and Ras in platelets, which are implicated for platelet activation, were measured in patients without pulmonary hypertension (non-PH, n=15), patients with PAH (n=19), and patients with CTEPH (n=25). Furthermore, the responsiveness to ex vivo thrombin stimulation was also evaluated. The ratios of the P-selectin positive platelets in the non-PH patients, patients with PAH, and patients with CTEPH were 1.40% (median and interquartile range, 0.83-1.82), 2.40% (1.80-3.39), and 2.63% (1.90-8.22), respectively (non-PH versus CTEPH, P<0.01). The activated GPIIb/IIIa-positive platelets were 6.01% (1.34-7.87), 11.39% (5.69-20.86), and 9.74% (7.83-24.01), respectively (non-PH versus CTEPH, P=0.01). GTP-bound RhoA was 1.79% (0.94-2.83), 4.03% (2.01-5.14), and 2.01% (1.22-2.48), respectively (non-PH versus PAH, P=0.04), and GTP-bound RalA was 1.58% (1.08-2.11), 3.02% (2.03-3.54), and 2.64% (1.42-4.28), respectively (non-PH versus PAH, P=0.023; non-PH versus CTEPH, P=0.048). In contrast, Rac1, Rap1, or Ras was not activated in any groups. The platelets of patients with CTEPH exhibited hyperresponsiveness to ex vivo thrombin stimulation compared with those of non-PH patients when evaluated for the surface markers. Either D-dimer or fibrin degradation product level was not increased in patients with CTEPH. CONCLUSIONS: These results provide the first direct evidence that platelets of patients with CTEPH are highly activated and exhibit hyperresponsiveness to thrombin stimulation.
OBJECTIVE:Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease that is distinct from pulmonary arterial hypertension (PAH). Although CTEPH is characterized by obstruction of major pulmonary artery because of chronic thrombus, it remains unclear whether CTEPH is associated with prothrombotic condition. APPROACH AND RESULTS: In addition to conventional markers, GTP-bound levels of Rap1, RhoA, RalA, Rac1, and Ras in platelets, which are implicated for platelet activation, were measured in patients without pulmonary hypertension (non-PH, n=15), patients with PAH (n=19), and patients with CTEPH (n=25). Furthermore, the responsiveness to ex vivo thrombin stimulation was also evaluated. The ratios of the P-selectin positive platelets in the non-PH patients, patients with PAH, and patients with CTEPH were 1.40% (median and interquartile range, 0.83-1.82), 2.40% (1.80-3.39), and 2.63% (1.90-8.22), respectively (non-PH versus CTEPH, P<0.01). The activated GPIIb/IIIa-positive platelets were 6.01% (1.34-7.87), 11.39% (5.69-20.86), and 9.74% (7.83-24.01), respectively (non-PH versus CTEPH, P=0.01). GTP-bound RhoA was 1.79% (0.94-2.83), 4.03% (2.01-5.14), and 2.01% (1.22-2.48), respectively (non-PH versus PAH, P=0.04), and GTP-bound RalA was 1.58% (1.08-2.11), 3.02% (2.03-3.54), and 2.64% (1.42-4.28), respectively (non-PH versus PAH, P=0.023; non-PH versus CTEPH, P=0.048). In contrast, Rac1, Rap1, or Ras was not activated in any groups. The platelets of patients with CTEPH exhibited hyperresponsiveness to ex vivo thrombin stimulation compared with those of non-PH patients when evaluated for the surface markers. Either D-dimer or fibrin degradation product level was not increased in patients with CTEPH. CONCLUSIONS: These results provide the first direct evidence that platelets of patients with CTEPH are highly activated and exhibit hyperresponsiveness to thrombin stimulation.
Authors: Evandro M Neto-Neves; Mary B Brown; Maria V Zaretskaia; Samin Rezania; Adam G Goodwill; Brian P McCarthy; Scott A Persohn; Paul R Territo; Jeffrey A Kline Journal: Am J Pathol Date: 2017-02-07 Impact factor: 4.307
Authors: George A Alba; Deepak Atri; Sriranjani Darbha; Inderjit Singh; Victor F Tapson; Michael I Lewis; Hyung J Chun; Yen-Rei Yu; Bradley A Maron; Sudarshan Rajagopal Journal: Curr Cardiol Rep Date: 2021-08-19 Impact factor: 2.931