Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension

Nobuhiro Yaoita, Ryutaro Shirakawa, Yoshihiro Fukumoto, Koichiro Sugimura, Satoshi Miyata, Yutaka Miura, Kotaro Nochioka, Masanobu Miura, Shunsuke Tatebe, Tatsuo Aoki, Saori Yamamoto, Kimio Satoh, Tomohiro Kimura, Hiroaki Shimokawa, Hisanori Horiuchi

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2486-2494
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number11
DOIs
Publication statusPublished - 2014 Nov 1

Keywords

  • Blood platelets
  • Chronic thromboembolic pulmonary hypertension
  • GTP-binding proteins
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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