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Published on: May 23, 2025
Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension
Nobuhiro Yaoita1, Ryutaro Shirakawa1, Yoshihiro Fukumoto1
1From 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.).
Insights
Platelets in chronic thromboembolic pulmonary hypertension (CTEPH) are highly activated and show increased responsiveness to thrombin. This study provides direct evidence of platelet hyperactivation in CTEPH, distinct from pulmonary arterial hypertension (PAH).
Area of Science:
- Hematology
- Cardiovascular Research
- Pulmonary Hypertension Research
Background:
- Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe condition caused by pulmonary artery obstruction.
- The prothrombotic state in CTEPH, particularly concerning platelet activation, remains incompletely understood.
- Distinguishing CTEPH from pulmonary arterial hypertension (PAH) is crucial for appropriate diagnosis and treatment.
Purpose of the Study:
- To investigate platelet activation status and responsiveness in patients with CTEPH.
- To compare platelet activation markers and thrombin responsiveness between CTEPH, PAH, and non-hypertensive individuals.
- To determine if CTEPH is associated with a prothrombotic platelet phenotype.
Main Methods:
- Platelet activation markers, including GTP-bound small GTPases (Rap1, RhoA, RalA, Rac1, Ras) and surface expression of P-selectin and activated GPIIb/IIIa, were measured.
- Ex vivo platelet responsiveness to thrombin stimulation was evaluated in patients with CTEPH (n=25), PAH (n=19), and without pulmonary hypertension (non-PH, n=15).
- Conventional markers like D-dimer and fibrin degradation products were also assessed.
Main Results:
- Patients with CTEPH exhibited significantly higher levels of P-selectin positive platelets compared to non-PH individuals (P<0.01).
- Activated GPIIb/IIIa-positive platelets were also significantly elevated in CTEPH patients versus non-PH (P=0.01).
- GTP-bound RalA was significantly higher in CTEPH patients compared to non-PH (P=0.048), and GTP-bound RhoA was elevated in PAH patients compared to non-PH (P=0.04). Platelets from CTEPH patients showed hyperresponsiveness to thrombin stimulation.
Conclusions:
- The study provides the first direct evidence of heightened platelet activation in CTEPH.
- Platelets from CTEPH patients demonstrate hyperresponsiveness to thrombin stimulation, suggesting a prothrombotic tendency.
- These findings highlight the role of platelet activation in the pathophysiology of CTEPH.
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.
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