Introduction
Venous thromboembolism (VTE), clinically presenting as deep venous thrombosis (DVT) or acute pulmonary thromboembolism (aPTE), is the third most frequent cause of cardiovascular death after stroke and myocardial infarction.1 The incidence of APTE has been increasing over time. This increase may explain an improvement in life expectancy. Also, this result may be related to a lower threshold of clinical suspicion and the standard use of computed tomographic pulmonary angiography.2
Mortality rates in the acute phase vary widely. Overall mortality rates with PTE are around 40% and can reach up to 71.4% for massive cases.3 Clinicians need accurate parameters for improving survival. Several tests like C-reactive protein, troponin, D-dimer, and N-terminal proB-Type natriuretic peptide have been studied.4 Patients can be stratified based on hemodynamic stability, the Pulmonary Embolism Severity Index (PESI), echocardiographic examination, and biomarkers like troponin indicating right ventricular ischemia or brain natriuretic peptide.5 However, many of these indicators are challenging to apply in clinical settings or are not routinely measured.6 Moreover, the predictive values of these expensive biomarkers are often low.7
Inflammation plays a significant role in the pathophysiology of PTE.8 Recent studies have shown the potential prognostic role of NLR and PLR in patients with PE.9 Neutrophils (NEU) migrate at the side of PTE and release proinflammatory mediators and procoagulants that cause oxidative and proteolytic injury.10,11 Increased platelet (PLT) count corresponds to increased thrombocyte activity that causes a destructive proinflammatory and prothrombotic response.12 Lymphocytes (LYM) counter this reaction, controlling and restraining the inflammatory process.13 This acute inflammatory response has been associated with poor prognoses in PTE patients. PLR and NLR can be obtained through hemogram analysis. Both PLR and NLR are promising markers for assessing inflammation status, and they may also enhance the risk classification of aPTE cases.14 In PTE cases with a high risk of death, identifying prognostic markers is crucial. Recent studies have highlighted the prognostic importance of composite markers like the triglyceride glucose index and pan-immune-inflammation value in cases with thromboembolic diseases.15
Since the high mortality rate and high prevalence of aPTE, clinicians need helpful prognostication of patients to improve survival. It is important to estimate its prognosis and take possible precautions in this direction to reduce mortality. Besides clinical variables, it may be useful to use simple and cheaply obtained parameters, for example like hemogram analysis. In our APTE cases, we aimed to evaluate the effects of various parameters in hemogram analysis, especially NLR and PLR, on mortality and to determine simple laboratory or clinical findings that can be used to predict prognosis in the acute or late periods in emergencies.
Materials and Methods
This study was conducted in a tertiary-level reference hospital and received approval from the local ethical board (No: E-49109414-604.02 from Izmir Katip Celebi University Health Research Ethics Committee). Since it was a retrospective study, the informed consent form was not obtained from the patients. In this context, an official permission was obtained from the administration of the reference hospital. Izmir Katip Çelebi University Health Research Ethics Committee waived the requirement for informed consent because it was a retrospective study. The confidentiality of patients’ data has been carefully protected.
Patients
A total of 346 aPTE adult cases were included in this retrospective cohort study. Patients with acute coronary syndrome, pregnancy, younger than 18 years/old, acute renal failure, malignancy, infection, or acute trauma were excluded. In all cases, the diagnosis was confirmed by filling defects of pulmonary arteries in computed tomography pulmonary angiography (CTPA) or mismatched defects seen in ventilation and perfusion pulmonary scintigraphy. Medical files of the cases were examined. Information such as age, sex, date of diagnosis, vital status, last follow-up date, intensive care unit admission, hemogram analysis, and lower extremity venous Doppler ultrasonography results were also recorded. WBC, PLT, NEU, and LYM (103/µL) counts and hemoglobin (g/dL) levels were obtained from hemogram analysis results, and PLR and NLR were calculated according to these results. In addition, the status of the patients at the end of the first week, first month, and sixth month was recorded.
Sample size calculation: A post-hoc power analysis was performed using the powerSurvEpi package in R version 4.3.0 to assess the study’s statistical power, considering the effect size of ICU admission on mortality. With a hazard ratio (HR) of 12.74 for ICU admission, a prevalence of 25%, and a squared correlation coefficient (rho2) of 0.04796, the power analysis estimated a power of 91.2% (alpha = 0.05). This suggests that the study has a relatively high probability of detecting a significant effect of ICU admission on mortality, assuming such an effect exists.
Statistical Analysis
PLR and NLR were calculated. Descriptive statistics were presented as numbers and percentages for categorical variables and mean ± SD and/or median (min-max) for continuous variables. To assess normality, the Kolmogorov–Smirnov/Shapiro–Wilk’s tests were used for all continuous variables, and it was observed that they did not follow a normal distribution. A Chi-Square test was employed to compare categorical groups about vital status, while the Mann–Whitney U-test was used to analyze continuous parameters. Cox regression analysis was performed to identify prognostic factors associated with mortality at three different time points. Hazard ratios and a 95% confidence interval (CI) were reported. The significance level was set at p < 0.05 for all analyses. All statistical procedures were conducted using SPSS 26.0 (Statistical Package for the Social Sciences; software version 26, SPSS Inc).
Results
The study encompassed patients enrolled between 15 February 2010 and 19 November 2014 and followed up from 21 February 2010 to 1 June 2016. The median follow-up period was 898.5 days (0 to 2298 days). The mean age of the cases was 62.7 ± 17.3 years, and 176 of the cases (50.9%) were female. Table 1 provides a summary of the patient’s characteristics. Among the cases, 125 (36.1%) were deceased.
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Table 1 The Data of Study Population
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Sex was found to have no significant impact on mortality. However, it was observed that the cases who died within the first and sixth months were older than the survivors. In the first week, ICU admission rates were higher in cases who died, and DVT was detected less frequently in deceased cases than in survivors. Moreover, NLR was higher in deceased patients than in survivors, and PLR was elevated in deceased cases in the first and sixth months. The median counts of PLT, NEU, and LYM for each group are shown in Tables 2–4, respectively.
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Table 2 Comparison Characteristics of Patients at Baseline by Survival Status at First week
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Table 3 Comparison Characteristics of Patients at Baseline by Survival Status at First month
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Table 4 Comparison Characteristics of Patients at Baseline by Survival Status at Sixth month
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In Table 5, significant prognostic factors for mortality were summarized. ICU admission and DVT status were the only variables in the model for all three times. ICU admission was a poor prognostic factor, with HR ranging from a maximum of 26.692 to a minimum of 3.661, while DVT was a good prognostic one, with HR ranging from 0.087 to 0.487. NLR was a good prognostic factor for the first-month mortality (HR 1.090, 95% CI: 1.017–1.168; p= 0.014). PLR with an HR of 1.003 and age with an HR of 1.028 were poor prognostic factors, but PLT with an HR of 0.996 was a favorable prognostic factor for survival in the 6th month. The Cox regression analysis revealed significant prognostic factors for mortality in patients with aPTE. ICU admission and DVT status were consistently associated with mortality across all three time points. ICU admission was a strong predictor of mortality, with higher HRs ranging from 3.661 to 26.692, depending on the period. DVT status had a protective effect on survival, with HRs ranging from 0.087 to 0.487, indicating a lower risk of death in patients with DVT. NLR was identified as a good prognostic factor for the first month, with an HR of 1.090, suggesting that higher NLR values were associated with increased mortality risk within the first month. PLR and age were poor prognostic factors, with HR of 1.003 and 1.028, respectively, indicating increased mortality risk in patients with higher PLR values and older age. However, platelet count was a favorable prognostic factor for survival in the sixth month, with an HR of 0.996, suggesting higher platelet counts were associated with reduced mortality risk at this time point.
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Table 5 Prognostic Factors for Survival Status Patients with Acute Pulmonary Embolism by Three Different Times
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Discussion
In this study, we emphasized and tried to clarify the effect of several inflammatory markers, demographic predictors, ICU admission, and DVT on mortality in aPTE cases. According to our results, ICU admission and DVT were consistently associated with survival across all three time points. ICU admission was a strong predictor of mortality, and DVT status had a protective effect on survival. NLR was identified as a good prognostic factor for the first month. PLR and age were poor prognostic factors, indicating increased mortality risk in patients with higher PLR values and older age. PLT count was a favorable prognostic factor for survival in the sixth month; higher platelet counts were associated with reduced mortality risk.
Although the mean age of the cases who died in the acute period and the survivors were similar, the cases who died in the 6th month were older than the survivors. This result is consistent with the literature.6 In our study, we also determined that advanced age is a poor prognostic factor for death.
The all-cause short-term mortality rate of PE varies widely, ranging from 2% to 95%, depending on disease severity.16 In our cases, the short-term mortality rate within the first week was 6.1%. Eckelt et al reported an early mortality rate occurring within 30 days after PE as 8.7%,17 which was 19.7% for our cases.
In the context of thrombosis-associated diseases, including PE, inflammation-related markers in the circulation have emerged as promising prognostic factors. Among these biomarkers, NLR and PLR were suggested to help predict the prognosis of aPTE patients.18 NLR and PLR are promising biomarkers that may enhance risk prediction and help guide aPTE management.14
In our cases, NLR was significantly higher among non-survivors than among survivors, consistent with prior reports.6,18 Although NLR was not determined as a prognostic factor in acute deaths in our study, the detection of higher NLR in deceased cases holds clinical importance. Another study by Kose et al reported NLR as an independent poor prognostic factor in moderate-low and low-risk PTE patients.19 The increased NLR is attributed to elevated NEU counts and decreased LYM counts. Jo et al’s study observed increased NEU count and decreased LYM count within the deceased group, but in our research, the NEU count was higher, and the LYM count was lower in both acute and nonacute deaths.20
PLR is a marker of systemic inflammation similar to NLR,12 and it has been demonstrated to have good predictive value in predicting cardiovascular diseases.21 Ma et al reported significantly higher PLR values in cases of death within 30 days of hospital admission.6 In Phan et al’s study, both NLR and PLR were significantly elevated in non-survivors compared to survivors, and similar results were observed in our study. Additionally, consistent with Phan et al’s findings, the LYM count was lower in deceased individuals.14 However, this finding differs from other studies that have reported elevated NEU counts in the presence of decreased lymphocytes among PE non-survivors.6,18 Karatas et al also reported that NLR and PLR were defined as independent prognostic factors of both short- and long-term mortality, and in the same research, NLR was a better prognostic marker than PLR.18 Similar findings about the predictive role of NLR and PLR were reported in several other studies, and these results suggest their potential utility in the prognostic assessment of PE.22–24
Although the predictive values of NLR and PLR in aPTE are not fully understood, PLR was defined as a poor prognostic factor for non-acute death in our study.14 Telo et al showed that PLR and NLR were increased in high-risk PE patients. They indicated that PLR may have a predictive value to predict 3-month mortality, whereas NLR may have a predictive value for in-hospital, the third month, and total 3-month mortality.25 Tang et al showed that high NLR is a significant predictor of mortality in aPTE, but no relationship was noted with PLR.26 These results partially conform with the meta-analysis of Wang et al. Their meta-analysis indicates that both high levels of NLR and PLR are related to increased risk for short-term mortality and overall mortality.22
A meta-analysis reported this year says that PLR is not a significant predictor of mortality in patients with PE, and this can be related to the limited number of studies available for PLR. Only NLR is reported as an independent marker of mortality.26 Among our cases, NLR was higher in deceased patients than in survivors in all three periods compared to survivors. PLR was higher in survivors than in cases who died at 1 and 6 months. NLR was a good prognostic factor for mortality in the first month, and PLR was a poor prognostic factor for mortality in the sixth month. The prognostic effects of PLR and NLR on mortality at 1st and 6th months have been determined, but since it is difficult to interpret these two parameters for mortality in the acute period, their clinical usefulness is limited.
The patient’s gender also plays a role in APTE. Barrios et al found that female sex was an independent predictor of all-cause and PTE-specific mortality.27 Similarly, Agarwal et al reported a significantly higher hospital mortality rate among females.28 However, gender was reported as an insignificant factor in Ma et al’s study; we did not find any difference between male and female patients.6
In patients with symptomatic aPTE, venous thrombosis can be detected in 30 to 70%,29 so it is reasonable to use venous Doppler ultrasonography, especially of the lower limbs, to add diagnostic information in suspected aPTE cases. Dubois et al reported that patients with acute symptomatic aPTE and concomitant lower-limb DVT had an increased all-cause and PE-related mortality within 30 days, and they suggested assessment of DVT symptoms could assist with risk stratification of these patients.30 Meta-analysis of 9 studies with 7868 PE patients has demonstrated that patients with concomitant DVT had higher 30-day mortality.31 In our cases, deep venous Doppler ultrasonography was performed in 345 cases, and 140 of them (40.5%) had DVT. DVT was a good prognostic factor for all periods of death in our cases. This result may be related to early clinical suspicion for PE. The presence of DVT may be useful in predicting prognosis both in the acute and late phases, just like the results obtained for ICU admission.
Limitations
Although several parameters like age, DVT, and ICU admission were evaluated, one of the most important limitations of this study is that the evaluation is predominantly limited to hemogram analysis. The lack of results regarding additional parameters that may have an impact on mortality, such as clinical, echocardiographic, or underlying diseases are main limitation. This can be overcome by prospective studies that the cases included into the study by a standard data collection method.
Conclusion
Because of the prognostic effects of PLR and NLR on mortality at 1st and 6th months, it is not possible to comment on mortality in the acute period; their clinical utility for the acute phase is limited. However, detection of DVT and ICU admission may be useful in emergencies and can be used to predict prognosis in both acute and delayed terms. DVT is an important prognostic factor, possibly attributed to its potential for early diagnosis. The association of DVT with a low risk of mortality is an important result since few studies have been conducted in this field. Complete blood count is an inexpensive and easily accessible routine test that can be used as a predictive test to determine, especially late-term mortality in patients with aPTE.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethical Approval
We received approval from the local ethical board for this study (No: E-49109414-604.02).
Ethics Statement
All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed Consent Form
Since the study was a retrospective and informed consent was not obtained from the participants, the consent form was not obtained from the participants. In this context, an official permission was obtained from the administration of the reference hospital.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this study.
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