The study results indicate that mPAP values have a significant positive correlation with serum tPAI-1 and uric acid levels in all enrolled patients. Among patients with mPAP values less than 25 mmHg PAP, a significant positive correlation is observed with serum tPAI-1 and TM levels. The uric acid levels revealed a lower degree of association than the tPAI-1 levels, which was found to be an independent marker in the group with lower mPAP values.
The severity of PAH in patients is indicated by the mPAP levels evaluated by RHC, which is an invasive examination. Therefore, less-invasive and reliable biomarkers that reflect the disease status accurately are desired. Serum uric acid is a traditional biomarker that reflects endothelial function and is a potential risk factor for arteriosclerotic change [15, 16]. In the present study, uric acid levels revealed a significant positive correlation with mPAP values in all enrolled patients. This result is supported by the findings in some previous studies on atherosclerosis. However, in the group with mPAP values less than 25 mmHg, uric acid levels did not show a significant association with mPAP.
According to the diagnostic criteria for PAH, an mPAP level of 25 mmHg is the cut-off value. Many clinicians focus on the preclinical stage of PAH predominantly, and the patients with mPAP levels less than 25 mmHg should be on intensive, careful follow-up because the response to treatment changes dramatically according to the state of the disease [1–4]. Hence, we focused our investigations in this group. The results indicate that unlike serum uric acid levels, tPAI-1 levels alone are an independent characteristic marker in the group with lower mPAP levels. Additionally, the mPAP levels reveal a significant positive association with serum tPAI-1 and TM but not uric acid levels, which means that these markers could be potential predictors of severity in patients with PAH in their early stages.
tPAI-1 is an inhibitor of plasminogen, which regulates the systemic fibrinolytic system, and the levels indicate microvascular injury due to various conditions, including diabetes mellitus . It complements the activities of protein anticoagulants and endothelial-derived platelet inhibitors, such as proteins C, S, anti-thrombin III, and nitric oxide . It is an endogenous defense mechanism for the prevention of atherosclerotic change, and there are some reports that the tPAI-1 levels are positively and independently associated with the degree of IMT [6, 7].
In contrast, TM is a factor that regulates the anticoagulation system by capturing thrombin and activating protein C. Once damage to endothelial cells occurs, TM expressed on endothelial cells is cleaved from the membrane, and the product is detectable in a soluble form in circulating peripheral blood. This indicates that TM can be a marker of endothelial cell damage [18–20]. The mechanism in advanced PAH is speculated to involve an increased release of tPAI-1 and TM from smooth muscle and endothelial cells caused by pulmonary vascular damage. This could result in elevated serum tPAI-1 and TM levels, as indicated in the present study. Ogawa et al. suggested that thrombin modulates pulmonary circulation through activation of the Akt pathway in smooth muscle cells among patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) . It also meant that TM levels could be altered due to endothelial dysfunction in the pulmonary artery. However, the concentration of circulating serum TM in peripheral blood would be saturated and the rest would be recruited by the kidney. In fact, there were no significant differences in the concentration of TM between the groups with mPAP levels less than or more than 25 mmHg.
We have demonstrated that mPAP levels have a significant positive correlation with serum tPAI-1 and TM but not uric acid values, which means that these markers could be potential predictors of severity in patients with PAH, especially in their early stages with mPAP levels less than 25 mmHg.
This study has few limitations. First, this study was retrospective in nature with its inherent defects; therefore, a prospective study is needed in the future to confirm the results. Second, the population size is small, and the patients were from heterogeneous backgrounds. A larger sample size that includes a larger cohort of severe cases would allow a more reliable statistical evaluation.