title: Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension.
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.
  
  
  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.affiliation: 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.).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yaoita
authors.affiliation: 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.).
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Shirakawa
authors.affiliation: 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.).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: 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.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sugimura
authors.affiliation: 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.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: 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.).
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.affiliation: 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.).
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nochioka
authors.affiliation: 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.).
authors.forename: Masanobu
authors.initials: M
authors.lastname: Miura
authors.affiliation: 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.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tatebe
authors.affiliation: 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.).
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Aoki
authors.affiliation: 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.).
authors.forename: Saori
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: 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.).
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: 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.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kimura
authors.affiliation: 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.).
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.affiliation: 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.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Horiuchi
mesh_terms: D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011655:Pulmonary Embolism / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D012044:Regression Analysis; D013917:Thrombin / Q000494:pharmacology; D020725:ral GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005337:Fibrin; D013917:Thrombin; D020725:ral GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: GTP-binding proteins; blood platelets; chronic thromboembolic pulmonary hypertension; pulmonary hypertension