Sage Journals: Discover world-class research

Abstract

Hypoxemia is a clinical characteristic of pulmonary embolism (PE). Hypoxemia is associated with variations in serum prostate-specific antigen (PSA) levels. Thus, the present study aimed to determine serum PSA levels in patients with PE, which may be helpful in improving clinical evaluation in screening for prostate diseases in those with PE. Clinical data from 61 consecutive male patients with PE and 113 age-matched healthy male controls were retrospectively analyzed. The pulmonary artery obstruction index (PAOI) was used to evaluate the pulmonary embolic burden. Compared with healthy controls, serum total PSA (tPSA) levels were significantly increased (P = .003), and free PSA (fPSA)/tPSA ratio was significantly decreased in patients with PE (P < .001). There was no significantly difference in serum fPSA levels between patients with PE and healthy controls (P = .253). A significant positive association was observed between serum tPSA levels and PAOI in patients with PE (β = .270, P = .036). Multivariable linear regression analysis revealed that serum tPSA levels were independently associated with PAOI in patients with PE (β = .347, P = .003). Serum tPSA levels were higher in male patients with PE than those in healthy controls, but fPSA was not affected. These findings highlight that PE may elevate serum tPSA levels, and that measures of tPSA should be interpreted with caution in screening for prostate diseases in patients with PE.

Keywords

pulmonary embolism prostate-specific antigen prostate diseases pulmonary artery obstruction index ‌pulmonary embolic burden

Introduction

Prostate-specific antigen (PSA) is a serine protease produced by prostate epithelial cells.¹ In clinical practice, measurement of serum PSA levels plays an important role in screening for prostate diseases. Serum PSA levels have been considered to be a biomarker in screening for prostate disease.^2,3 In males, serum PSA levels have been used as a marker of prostate cancer,⁴ and in other prostate diseases, including prostatitis and benign prostate hyperplasia.^5,6 However, some non-prostate diseases have also been reported to affect serum PSA levels.^7–10 Therefore, it is necessary to explore factors that affect serum PSA levels in non-prostate diseases when screening for prostate diseases, especially among patients with prostate cancer.

It has been suggested that elevated serum PSA levels are associated with ischemic conditions, including coronary artery disease, cardiogenic shock, and prolonged cardiopulmonary resuscitation.^7–9 Notably, hypoxemia increases serum PSA levels during acute exacerbation of chronic obstructive pulmonary disease (COPD).¹⁰ Pulmonary embolism (PE) is caused by partial or complete obstruction of the pulmonary artery¹¹ and, as a pulmonary thromboembolic disease, PE is often involved in hypoxemia.¹² As such, we aimed to investigate serum PSA levels in patients with PE, which may be beneficial for improving the clinical evaluation of prostate diseases screening in individuals with PE.

Methods

Patients and Controls

The medical records of 61 consecutive male patients with PE were reviewed retrospectively from the Affiliated Hospital of Youjiang Medical University for Nationalities, and 113 consecutive, age-matched, healthy males who visited the Affiliated Hospital of Youjiang Medical University for Nationalities for health checkup were included as controls retrospectively. The diagnosis of PE was confirmed in all patients using computed tomography pulmonary angiography (CTPA),¹³ all of whom underwent a thorough evaluation for pulmonary disease. Patients with prostate diseases, coronary heart disease, renal or hepatic disturbances, malignant tumors, or urinary tract infections were excluded. Furthermore, patients with a history of prostate biopsy, urinary tract treatment, and medical or surgical treatment of the prostate were also excluded. This study was approved by the Ethics Committee of the Affiliated Hospital of Youjiang Medical University for Nationalities and conformed to the principles of the Declaration of Helsinki. Requirements for informed consent were waived by the Ethics Committee of the Affiliated Hospital of Youjiang Medical University for Nationalities due to the retrospective design of the study.

Data Collection

Clinical data were extracted from electronic medical records. Clinical and demographic characteristics, disease history, laboratory investigations, and imaging examination results were obtained upon admission. Blood samples were collected for laboratory investigations, which included d-dimer, total PSA (tPSA), free PSA (fPSA), and fPSA/tPSA ratio. Color Doppler ultrasonography was used to evaluate left ventricular ejection fraction (LVEF) and lower-extremity deep venous thrombosis (LEDVT) in patients with PE.

Sample Size and Power

The sample size required for this study was determined using PASS version 21.0.3. The sample size was calculated using the primary variable, tPSA, in patients with PE and controls. It was estimated that 61 patients and 113 controls would be required to achieve 90% power to detect differences.

Pulmonary Artery Obstruction Index (PAOI)

In this study, the PAOI was used to assess the pulmonary embolic burden. The PAOI was calculated in patients with PE after CTPA examination. The PAOI is based on the degree of obstruction and location of the thrombus in CTPA results.¹⁴

Statistical Analysis

Continuous data are expressed as median (interquartile range) for non-normally distributed data, whereas categorical data are expressed as frequency (percentage). Differences in continuous variables between the two independent groups were examined using the Mann–Whitney U test. Normal transformation of the dependent variable was performed before univariable and multivariable linear regression analyses. Univariable linear regression analysis was used to assess whether PSA-related parameters were associated with age, body mass index (BMI), histories of smoking, LEDVT, and COPD, and LVEF, PAOI, and d-dimer levels in patients with PE. Multivariable linear regression analysis with enter method was adopted to further identify factors that remained independently associated with tPSA after adjustment for potential confounding factors including age, BMI, history of smoking, history of COPD, and LVEF in patients with PE. Differences with P < .05 were considered to be statically significant. Statistical analyses were performed using SPSS version 25.0.

Results

Features of Patients With PE and Controls

Patient and healthy control characteristics are summarized in Table 1. Results of analysis revealed that serum tPSA levels were significantly elevated in patients with PE compared with healthy controls (P = .003), and that the fPSA/tPSA ratio was significantly reduced in patients with PE compared with healthy controls (P < .001). However, serum fPSA levels were not significantly different between patients with PE and healthy controls (P = .253).

Table 1.

Main Clinical Features in Patients With PE and Healthy Controls.

	Patients With PE	Healthy Controls	P Value
	N = 61	N = 113	P Value
Age (years)	65(53-75)	64(61-66)	.728
BMI (kg/m²)	22.5(20.4-23.8)	21.8(19.8-23.8)	.330
History of smoking (n, %)	35(57.4)	-	-
History of LEDVT (n, %)	23(37.7)	-	-
History of COPD (n, %)	16(26.2)	-	-
LVEF (%)	62(58-70)	-	-
PAOI (%)	8(2-13)	-	-
d-dimer (μg/mL)	2.38(1.12-5.44)	-	-
fPSA (μg/L)	0.25(0.13-0.36)	0.20(0.13-0.33)	.253
tPSA (μg/L)	1.02(0.55-1.74)	0.70(0.40-1.12)	.003
fPSA/tPSA ratio	0.22(0.16-0.31)	0.30(0.23-0.36)	<.001

Abbreviations: BMI, body mass index; LEDVT, lower-extremity deep venous thrombosis; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; PAOI, pulmonary artery obstruction index; tPSA, total prostate-specific antigen; fPSA, free prostate-specific antigen.

Variables Affecting PSA-Related Parameters in Patients With PE

Results of univariable linear regression analysis of PSA-related parameters and clinical variables in patients with PE are summarized in Table 2. Serum tPSA levels were significantly and positively associated with age (β = .469, P < .001), history of COPD (β = .305, P = .017), and PAOI (β = .270, P = .036) in patients with PE. Serum fPSA levels were significantly and positively associated with age (β = .333, P = .009) and history of COPD (β = .267, P = .038) in patients with PE. A significant negative association between fPSA/tPSA ratio and age was observed in patients with PE (β = −.282, P = .028). However, both serum fPSA levels (β = .219, P = .090) and fPSA/tPSA ratio (β = −.125, P = .338) had no significant association with PAOI in patients with PE.

Table 2.

Univariable Linear Regression Analysis Between PSA-Related Parameters and Clinical Variables in Patients With PE.

	tPSA		fPSA		fPSA/tPSA
	β	P Value	β	P Value	β	P Value
Age	.469	<.001	.333	.009	−.282	.028
BMI	.154	.235	.197	.128	.134	.303
History of smoking	−.227	.078	−.192	.137	.048	.716
History of LEDVT	.104	.427	−.017	.895	−.214	.097
History of COPD	.305	.017	.267	.038	−.242	.060
LVEF	.022	.864	.030	.817	.079	.543
PAOI	.270	.036	.219	.090	−.125	.338
d-dimer	.004	.976	.013	.920	−.055	.672

Independent Factors Associated With PSA in Patients With PE

Serum tPSA levels were significantly associated with PAOI in patients with PE in univariable linear regression analysis; as such, after adjusting for potential confounding factors, multivariable linear regression analysis revealed that serum tPSA levels were independently associated with PAOI in patients with PE (β = .347, P = .003), and that increase in serum tPSA levels was also independently associated with history of smoking (β = −.291, P = .017), and history of COPD (β = .339, P = .015) in patients with PE.

Discussion

The present study examined serum PSA levels in males with PE. Results suggested that serum tPSA levels were elevated in patients with PE compared with healthy controls and that serum tPSA levels were independently associated with histories of smoking and COPD in these patients. Importantly, a significant positive association between serum tPSA levels and PAOI was observed in patients with PE after adjusting for underlying confounding factors in multivariable linear regression analysis, indicating that pulmonary embolic burden increases serum tPSA levels in patients diagnosed with PE.

Prostatic ischemia damages epithelial cells of the prostate, resulting in elevated serum PSA levels.¹⁵ It has been widely reported in the literatures that serum PSA levels are associated with ischemic conditions.^7–9 Hypoxemia is more common in patients with PE due to impaired hemodynamics, gas exchange, and mechanical capacity of the lungs.¹² An association between hypoxemia and elevated serum PSA levels has been demonstrated in patients with acute exacerbations of COPD.¹⁰ It has been highlighted that hypoxia can induce the expression of PSA in human prostate carcinoma cells.¹⁶ It has also been reported that hypoxia facilitates PSA transcription by inducing histone acetylation of PSA enhancers.¹⁷ Moreover, hypoxia increases the androgen receptor-induced promoter activity of the human PSA gene.¹⁸ Therefore, acute hypoxemia may promote the expression and release of PSA in prostatic epithelial cells and elevate serum tPSA levels in patients with PE.

Elevated serum tPSA levels may not only be explained by hypoxemia but also by systemic inflammation, which may also contribute to increased serum PSA levels in patients with PE. Systemic pro-inflammatory cytokines are critical factors in acute PE.¹⁹ The systemic immune inflammatory index, as an inflammatory marker, is a predictor of disease severity in patients with acute PE, and serum C-reactive protein (CRP) is independently associated with massive acute PE.¹⁹ Ma et al suggested that increased serum CRP was a useful screening marker for patients with PE.²⁰ Therefore, these studies support the possibility that a systemic inflammatory cascade facilitates the development of PE. Interesting, a positive association between serum PSA levels and systemic inflammatory markers has been demonstrated in healthy population.²¹ Similarly, systemic inflammatory markers are associated with elevated serum PSA levels in males without known prostatic diseases.²² Serum PSA levels have been suggested to be positively correlated with CRP levels in the general population.²³ These evidences hence suggest that systemic inflammation may increase serum PSA levels.

In this study, we observed increased serum tPSA levels in patients with PE, but not serum fPSA. When PSA, a kallikrein-like serine protease, is secreted by prostate epithelial cells into the peripheral circulation and rapidly binds to protease inhibitors, primarily alpha1-antichymotrypsin, and a fraction is inactivated by proteolysis and circulates as fPSA.²⁴ Protease activity has been implicated in the pathogenesis of thrombosis, and proteolysis is associated with the regulation of blood coagulation function.^25,26 Thus, abnormal proteolysis may inhibit the formation of fPSA in patients with PE.

Our study also found a significant association between elevated serum tPSA levels and a history of COPD in patients with PE, some of whom may experience more severe hypoxia, which may further increase tPSA levels. Li et al²⁷ found an inverse association between serum tPSA and smoking. Results of the current study confirmed that smoking may reduce serum tPSA levels in patients with PE. This may be related to the toxic effects of harmful cigarette substances on prostate epithelial cells.

The present investigation had several limitations, the first of which was its small sample size. Second, this study did not directly assess prostate volume in patients with PE. However, we adjusted for age and BMI in the multivariate analysis to minimize the effects of prostate volume on serum PSA levels because age and BMI are closely associated with prostate volume.^28,29 Third, serum PSA is also expressed in females³⁰; however, the serum PSA levels were not measured in female patients with PE. Fourth, we did not examine serum PSA levels in patients with PE after treatment.

Conclusion

In summary, elevated serum tPSA levels were observed in male patients with PE compared with healthy controls; however, fPSA was not affected, suggesting that PE may increase serum tPSA levels and that measures of tPSA should be interpreted with caution for prostate disease screening in patients with PE. However, further investigations with larger sample sizes are needed to confirm these findings.

Footnotes

Availability of Data and Material

The data can be obtained by corresponding author upon reasonable request.

Consent to Participation

Informed consent was waived by the Ethics Committee of the Affiliated Hospital of Youjiang Medical University for Nationalities due to the retrospective nature of the study.

Consent for Publication

All authors agreed with publish this work.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

The study was approved by the Ethics Committee of the Affiliated Hospital of Youjiang Medical University for Nationalities, and conformed to the principles of the Declaration of Helsinki.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

You-Fan Peng

References

Lilja

. Biology of prostate-specific antigen. Urology. 2003;62(5):27-33.

Catalona

. Clinical utility of measurements of free and total prostate-specific antigen (PSA): a review. Prostate. 1996;29(S7):64-69.

Montironi

Mazzucchelli

Algaba

, et al. Prostate-specific antigen as a marker of prostate disease. Virchows Arch. 2000;436(4):297-304.

Williams

Singh

Isaacs

, et al.

Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer?

Prostate. 2007;67(3):312-329.

Sindhwani

Wilson

. Prostatitis and serum prostate-specific antigen. Curr Urol Rep. 2005;6(4):307-312.

Ornstein

Pruthi

. Prostate-specific antigen. Expert Opin Pharmacother. 2000;1(7):1399-1411.

Durmaz

Ayhan

Keleş

, et al.

Is there a relationship between acute coronary syndrome and prostate specific antigen level?

Urol J. 2014;11(1):1278-1286.

Koreny

Koller-Strametz

Geppert

, et al. Elevation of prostatic markers following cardiogenic shock. Intensive Care Med. 2001;27(2):447.

Koller-Strametz

Fritzer

Gwechenberger

, et al. Elevation of prostate-specific markers after cardiopulmonary resuscitation. Circulation. 2000;102(3):290-293.

10.

Ozge

Bozlu

Ozgur

, et al. The impact of hypoxemia on serum total and free prostate-specific antigen levels in patients with chronic obstructive pulmonary disease. Med Oncol. 2015;32(5):156.

11.

Toplis

Mortimore

. The diagnosis and management of pulmonary embolism. Br J Nurs. 2020;29(1):22-26.

12.

Fernandes

Luppino Assad

Alves

Jr , et al. Pulmonary embolism and gas exchange. Respiration. 2019;98(3):253-262.

13.

Konstantinides

Meyer

Becattini

, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54(3):1901647.

14.

Qanadli

El Hajjam

Vieillard-Baron

, et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. AJR Am J Roentgenol. 2001;176(6):1415-1420.

15.

Kiran

. Markedly raised serum prostate specific antigen levels. Prostatic infarction rather than malignancy? Aust Fam Physician. 2001;30(5):458-460.

16.

Chung

Tsui

Feng

, et al. Curcumin provides potential protection against the activation of hypoxia and prolyl 4-hydroxylase inhibitors on prostate-specific antigen expression in human prostate carcinoma cells. Mol Nutr Food Res. 2011;55(11):1666-1676.

17.

Lee

Yang

Park

. Hypoxia enhances the expression of prostate-specific antigen by modifying the quantity and catalytic activity of Jumonji C domain-containing histone demethylases. Carcinogenesis. 2013;34(12):2706-2715.

18.

Horii

Suzuki

Kondo

, et al. Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells. Mol Cancer Res. 2007;5(4):383-391.

19.

Gok

Kurtul

. A novel marker for predicting severity of acute pulmonary embolism: systemic immune-inflammation index. Scand Cardiovasc J. 2021;55(2):91-96.

20.

Liu

Zhi

, et al. Risk factors of pulmonary embolism in the elderly patients: a retrospective study. Aging Clin Exp Res. 2022;34(5):1133-1137.

21.

Yun

Lee

Yang

. Association between systemic inflammation and serum prostate-specific antigen in a healthy Korean population. Turk J Urol. 2017;43(3):284-288.

22.

McDonald

Vira

Vidal

, et al. Association between systemic inflammatory markers and serum prostate-specific antigen in men without prostatic disease-the 2001-2008 National Health and Nutrition Examination Survey. Prostate. 2014;74(5):561-567.

23.

Lippi

Montagnana

Guidi

. Epidemiological association between C-reactive protein and prostate-specific antigen. Cancer. 2009;115(5):1132.

24.

Balk

Bubley

. Biology of prostate-specific antigen. J Clin Oncol. 2003;21(2):383-391.

25.

Slack

Gordon

. Protease activity in vascular disease. Arterioscler Thromb Vasc Biol. 2019;39(10):e210-e218.

26.

Ten Cate

Hackeng

García de Frutos

. Coagulation factor and protease pathways in thrombosis and cardiovascular disease. Thromb Haemost. 2017;117(7):1265-1271.

27.

Thompson

Joseph

, et al. Association between smoking status, and free, total and percent free prostate specific antigen. J Urol. 2012;187(4):1228-1233.

28.

Rahmani

Haghighian Roudsari

Bawadi

, et al. Relationship between body mass index, risk of venous thromboembolism and pulmonary embolism: a systematic review and dose–response meta-analysis of cohort studies among four million participants. Thromb Res. 2020;192:64-72.

29.

Khezri

Shirazi

Ayatollahi

, et al. Age specific reference levels of serum prostate-specific antigen, prostate volume and prostate specific antigen density in healthy Iranian men. Iran J Immunol. 2009;6(1):40-48.

30.

Berkel

. Prostate-specific antigen (PSA) in women. J La State Med Soc. 1999;151(4):209-213.

Elevation of Serum Prostate-Specific Antigen Levels in Males With Pulmonary Embolism