Journal of

Clinical Medicine

Systematic Review
The Prognostic Role of Platelet-to-Lymphocyte Ratio in Acute
Coronary Syndromes: A Systematic Review and Meta-Analysis
Michal Pruc 1 , Frank William Peacock 2 , Zubaid Rafique 2 , Damian Swieczkowski 3 , Krzysztof Kurek 4 ,
Monika Tomaszewska 4 , Burak Katipoglu 5 , Maciej Koselak 6 , Basar Cander 7 and Lukasz Szarpak 2,4, *

1 Department of Public Health, International European University, 03187 Kyiv, Ukraine

2 Henry JN Taub Department of Emergency Medicine, Baylor College of Medicine, Houston, TX 77030, USA
3 Department of Toxicology, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland
4 Department of Clinical Research and Development, LUXMED Group, 02-676 Warsaw, Poland
5 Department of Emergency Medicine, Ufuk University Medical Faculty, 06510 Ankara, Turkey
6 Institute of Outcomes Research, Maria Sklodowska-Curie Medical Academy, 00-136 Warsaw, Poland
7 Department of Emergency Medicine, Bezmialem Vakif University, Fatih, 34093 Istanbul, Turkey
* Correspondence: lukasz.szarpak@gmail.com; Tel.: +48-500186225

Abstract: This study aimed to investigate the potential prognostic role of the platelet-to-lymphocyte
(PLR) ratio in patients presenting with suspected acute coronary syndromes (ACS). A systematic
search of PubMed Central, Scopus, EMBASE, and the Cochrane Library from conception through
20 August 2023 was conducted. We used odds ratios (OR) as the effect measure with 95% confidence
intervals (CIs) for dichotomous data and mean differences (MD) with a 95% CI for continuous
data. If I2 was less than 50% or the p value of the Q tests was less than 0.05, a random synthesis
analysis was conducted. Otherwise, a fixed pooled meta-analysis was performed. Nineteen studies
fulfilled the eligibility criteria and were included in the meta-analysis. PLR was higher in MACE-
Citation: Pruc, M.; Peacock, F.W.; positive (164.0 ± 68.6) than MACE-negative patients (115.3 ± 36.9; MD = 40.14; 95% CI: 22.76 to 57.52;
Rafique, Z.; Swieczkowski, D.; Kurek, p < 0.001). Pooled analysis showed that PLR was higher in AMI patients who died (183.3 ± 30.3),
K.; Tomaszewska, M.; Katipoglu, B.; compared to survivors (126.2 ± 16.8; MD = 39.07; 95% CI: 13.30 to 64.84; p = 0.003). It was also
Koselak, M.; Cander, B.; Szarpak, L. higher in the ACS vs. control group (168.2 ± 81.1 vs. 131.9 ± 37.7; MD = 39.01; 95% CI: 2.81 to
The Prognostic Role of 75.21; p = 0.03), STEMI vs. NSTEMI cohort (165.5 ± 92.7 vs. 159.5 ± 87.8; MD = 5.98; 95% CI: −15.09
Platelet-to-Lymphocyte Ratio in
to 27.04; p = 0.58), and MI vs. UAP populations (162.4 ± 90.0 vs. 128.2 ± 64.9; MD = 18.28; 95%
Acute Coronary Syndromes: A
CI: −8.16 to 44.71; p = 0.18). Overall, our findings confirmed the potential prognostic role of the
Systematic Review and
plate-let-to-lymphocyte (PLR) ratio in patients presenting with suspected acute coronary syndromes
Meta-Analysis. J. Clin. Med. 2023, 12,
(ACS). Its use as a risk stratification tool should be examined prospectively to define its capability for
6903. https://doi.org/10.3390/
jcm12216903
evaluation in cardiovascular patients.

Academic Editors: Roy Beigel, Keywords: platelet-to-lymphocyte ratio; PLR; acute coronary syndrome; diagnostic; biomarker;
Fernando Chernomordik and
meta-analysis
Alexander Fardman

Received: 9 October 2023

Revised: 31 October 2023
Accepted: 31 October 2023 1. Introduction
Published: 2 November 2023
The search for new biomarkers that allow the prediction of disease progression is
one of the main areas of development in basic and translational science. One widely
discussed biomarker is the platelet-to-lymphocyte ratio (PLR), a simple blood test that
Copyright: © 2023 by the authors.
measures the relationship between platelets and lymphocytes in the bloodstream. As a
Licensee MDPI, Basel, Switzerland. marker of inflammation and thus increased predominantly in diseases of pro-inflammatory
This article is an open access article etiology, the predictive value of PLR shows promise in onco-hematology, immunology, and
distributed under the terms and cardiovascular diseases.
conditions of the Creative Commons For instance, the utility of PLR as a prognostic biomarker has been evaluated in
Attribution (CC BY) license (https:// the area of pulmonary pathology, where Kumar et al. found that an increased PLR was
creativecommons.org/licenses/by/ associated with significantly higher 90-day mortality among patients diagnosed with acute
4.0/). exacerbations of chronic obstructive pulmonary disease [1]. However, its prognostic value

J. Clin. Med. 2023, 12, 6903. https://doi.org/10.3390/jcm12216903 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2023, 12, 6903 2 of 11

in pulmonary pathology was confounded by Pertiwi, who reported that in COVID-19

infection, other inflammatory markers, particularly a high CRP, may be more useful in
predicting the clinical course [2]. This seeming contradiction of deteriorating prognostic
ability of PLR in COVID-19 was addressed by Levy et al., who suggested that the PLR may
be more affected by older age and its associated frailty than by the severity of COVID-19 [3].
Consistent with the results of Kumar, a recently published meta-analysis of 32 studies
indicated that the PLR obtained at hospital admission correlated with increased mortality.
These authors did acknowledge that the studies they included exhibited a high risk of bias
and that the overall quality of the evidence was low, such that further investigation was
warranted. Finally, a challenging characteristic of newly evaluated biomarkers is the fact
that there is also no clear cut-off point for what determines a pathologic PLR, which may
explain some variation in reports of patients with a good prognosis and those at a high risk
of disease progression [4].
PLR is also being studied as a predictor in oncology. Zhang et al. revealed that a
high pre-treatment PLR was negatively related to the overall survival and progression-
free survival in patients diagnosed with limited-stage small-cell lung cancer [5]. Further,
the predictive value of PLR has been investigated in glioblastoma, where a relationship
between PLR and overall survival in treatment-naïve patients was reported [6]. Finally,
other cancers in which the role and potential utility of PLR are being currently investigated
include head and neck squamous cell carcinoma [7], uroepithelial carcinoma [8], gastric
cancer [9], and ovarian cancer [10].
Since pro-inflammatory factors have a significant impact on the development of
atherosclerotic processes in coronary arteries, PLR is also an object of interest in cardiology.
However, despite its pathologic relationship and the fact that it has been widely evaluated, a
consensus on its appropriate clinical use is yet to be established. Supporting its application,
Pinho et al. found, based on a retrospective analysis, that a high PLR is associated with
a higher risk of cardiovascular events in patients with primary hypertension. Further, in
heart failure, a high PLR was correlated with the risk of re-hospitalization due to worsening
of heart failure, although it was not useful as a diagnostic test [11,12].
Taking into consideration the above, we performed a meta-analysis with the aim of
investigating the potential prognostic role of the PLR ratio in patients presenting with
suspected acute coronary syndromes (ACS). Compared to previously published papers,
new outcomes, e.g., coronary flow vs. no reflow risk, were added to the current meta-
analysis.

2. Materials and Methods

2.1. Search Strategy
We performed this systematic review and meta-analysis based on the Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses (PRISMA; Table S1) [13]. The protocol
was registered with the PROSPERO database (registration number: CRD42023447572).

2.2. Literature Enrollment

A literature search was conducted for English-language articles up to 20 August 2023,
in the international databases of PubMed Central, Scopus, EMBASE, and the Cochrane
Library. The search strategy consisted of variations of the terms “platelet-to-lymphocyte
ratio” OR “platelet/lymphocyte ratio” OR “platelet to lymphocyte ratio” OR “platelet lym-
phocyte ratio” OR “PLR”, AND “acute coronary syndrome” OR “ACS” OR “STEMI” OR
“NSTEMI” OR “unstable angina” OR “UA” OR “myocardial infarction” OR “MI”, as both
medical subject headings and subject headings specific to each database and keywords or
free-text words that included a wide range of derivations to ensure an extensive search was
performed. A manual review of the Google Scholar search engine and references to relevant
articles was also performed to access any possibly missed studies. It is worth mentioning
that the protocol registered in the PROSPERO was not changed during the investigation.
J. Clin. Med. 2023, 12, 6903 3 of 11

Year of publication limits were not applied to capture any potential studies that
may have been missed in the original review. Searches were limited to English language
and adult human subjects. The following inclusion PICOS criteria were applied for the
eligible studies: (1) patient, i.e., patients diagnosed with Acute Coronary Syndrome (STEMI,
NSTEMI, and unstable angina), (2) intervention, i.e., PLR determination, (3) control, i.e., not
applicable, (4) outcomes, i.e., no-flow vs. normal flow after PCI, MACE positive vs. MACE
negative, and (5) study, i.e., observational studies (including cross-sectional studies) and
non-randomized and randomized clinical trials (if applicable). Meanwhile, the exclusion
criteria were as follows: (1) studies in pediatric population/children (age < 18 years);
(2) case series, case reports, correspondence, letters to editors, editorials, or review articles;
(3) studies that are not available in full-text form or that have not been published; and
(4) studies with insufficient data to assess PLR levels.
First, the screening process began by comparing the suitability of the titles and/or
abstracts against our eligibility criteria. Any original publications that were cited in the
systematic reviews or meta-analyses but missed by the initial search would also be included
if they met our inclusion/exclusion criteria. All duplicate articles were removed. The
process was then followed by a comprehensive assessment of full-text articles. All of these
processes were carried out independently by two reviewers (M.P. and M.T.). If disagreement
was found during the screening process, it was resolved by seeking the opinion of a third
reviewer (L.S. or D.S.).

2.3. Data Extraction and Quality Assessment

Two authors (M.P. and M.T.) separately extracted data from individual reports and
recorded the data in an Excel sheet. Any disagreement between the two reviewers in
the process of data extraction was resolved by a third reviewer (L.S.). The extracted data
included the first author, year of publication, study design, country, sample size, age,
gender, comorbidities, ACS types, and PLR values. For publications lacking sufficient
information on predictive accuracy to calculate the 2 × 2 contingency tables, we asked the
corresponding author for help via email. Studies were excluded if a second email received
no response.
Once eligible studies were identified, two researchers (M.P. and D.S.) independently
assessed each article for methodological quality and risk of bias using the Newcastle-
Ottawa Scale (NOS) [14]. Quality rating disagreements were resolved by discussion with
the third researcher (L.S.). The NOS is categorized into three sections: (1) selection of
study groups; (2) comparability of groups; and (3) ascertainment of the outcome of interest.
The total scores that can be obtained using this tool were in the range of 0–9. A study
investigation that obtained a cumulative score of 7 or above was deemed to possess a low
likelihood of bias [15]. In cases where a study obtained a cumulative score of 6 or less, it
was deemed to possess bias and was excluded from the analysis.

2.4. Statistical Analysis

Statistical analysis was conducted with STATA (Software for Statistics and Data Sci-
ence) software version 17.0 (StataCorp LLC, Lakeway Dr, College Station, TX, USA) and
Review Manager software version 5.4 (Nordic Cochrane Centre, Cochrane Collaboration,
Copenhagen, Denmark). All statistical tests were two-sided, and the significance level was
defined as p < 0.05. We used odds ratios (OR) as the effect measure with 95% confidence in-
tervals (CIs) for dichotomous data and mean differences (MD) with a 95% CI for continuous
data. If continuous outcomes were reported as median, range, and interquartile range, we
estimated means and standard deviations using the formula described by Hozo et al. [16].
The Q test and I2 statistics were used to check for heterogeneity. If I2 was less than 50% or
the p value of the Q tests was less than 0.05, a random synthesis analysis was conducted.
Otherwise, a fixed pooled meta-analysis was performed [17]. We utilized Egger’s test
and funnel plots to check for possible bias and funnel plot tests for asymmetry to assess
potential publication bias if more than ten trials were included in a single meta-analysis.
J. Clin. Med. 2023, 12, 6903 4 of 11

A sensitivity analysis using leave-one-out was performed to test for the robustness of
the findings.

3. Results
3.1. Study Selection and Baseline Characteristics
The literature search is illustrated in Figure 1. A total of 2236 records were initially
retrieved. Of these, 982 duplicate publications were excluded. After an initial screening
of titles and abstracts, 43 articles were selected for assessment of full texts, resulting in
a further exclusion of 24 studies. Finally, a total of 19 studies were eventually included
in the review (Table 1) [18–36]. Five prospective and fourteen retrospective studies were
published from 2015 to 2023, with sample sizes between 170 and 2230. The participants
were from Turkey, Pakistan, China, Poland, Indonesia, Iran, and Yemen. Results of the
risk of bias assessment of individual studies can be found in Table 1. All studies were of
sufficient quality to be included in the review. Additional information about the studies
included in the systematic review is provided in the supplementary file (Table S2). Table S2
includes additional information on the studies: number of patients diagnosed with STEMI,
NSTEMI, and UA, detailed comparative characteristics of the study group vs. control
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 6 of 12
group, PLR determination (time), and information on MACE (how MACE was defined in
the study).

Figure1.1.Flow
Figure Flowdiagram
diagramofofthe
thesearch
searchstrategy
strategyand
andstudy
studyselection.
selection.

3.2. Meta-Analysis
Five trials reported PLR values as related to coronary blood flow and presented the
data stratified as no-flow vs. normal flow. Pooled analysis showed that PLR values were
higher in those with no vs. normal flow (166.3 ± 77.3 vs. 116.5 ± 43.4, respectively, MD =
J. Clin. Med. 2023, 12, 6903 5 of 11

Table 1. Baseline characteristics of included trials.

No of NOS
Study Country Study Design Study Group Age, Years Sex, Male, n, %
Patient’s Score
72
Normal flow 88 60.2 ± 14.3
(81.8%)
Acet et al., 2015 [18] Turkey Retrospective study 9
165
No-flow 236 62.1 ± 13.9
(69.9%)
68
MACE-positive 102 54.49 ± 11.41
Adam et al., 2018 [19] Prospective cohort study (66.7%) 8
Pakistan
MACE-negative 195 55.82 ± 10.50 120 (61.5%)
AMI 284 61.27 ± 12.01 237 (83.45%)
Cao et al., 2023 [20] China Retrospective study 9
No-AMI 91 59.10 ± 11.96 51 (56.04%)
Normal flow 198 62 ± 11 144 (72.7%)
Celık et al., 2016 [21] Turkey Retrospective study 8
No-flow 382 58 ± 12 307 (80.4%)

Single-center, observational, AMI With Death 94 76.61 ± 11.98 53 (56.38%)

Chen et al., 2023 [22] China 8
retro- spective study AMI Without Death 94 76.88 ± 9.04 48 (51.06%)
AMI 103 73.1 ± 9.9 NS
Dziedzic et al., 2023 [23] Poland Retrospective study 8
No-AMI 135 71.1 ± 8.3 NS
10
AMI With Death 22 68.09 + 18.7
(45.5%)
Guclu et al., 2020 [24] Turkey Prospective cohort study 9
120
AMI Without Death 148 61.5 + 10.6
(81.1%)
AMI 223 NS 151 (67.71%)
Harun et al., 2016 [25] Indonesia Retrospective study 7
No-AMI 198 NS 84 (42.42%)

Retrospective, MACE-positive 195 65.3 ± 10.8 123 (63.1%)

Karadeniz et al., 2023 [26] Turkey 8
cross-sectional study MACE-negative 908 76.6 ± 11.3 636 (70.0%)
Normal flow 403 58 ± 12 311 (77.2%)
Retrospective,
Kurtul et al., 2014 [27] Turkey 74 8
cross-sectional study No-flow 117 68 ± 13
(63.2%)
MACE-positive 81 NS NS
Li et al., 2020 [28] China Retrospective study 7
MACE-negative 421 NS NS
78
Single-center prospective MACE-positive 107 NS
Li et al., 2022 [29] (72.9%) 8
China observational study
MACE-negative 1594 NS 1227 (77.0%)
38
Retrospective, MACE-positive 47 63.13 ± 13.14
Pashapour et al., 2019 [30] Iran (80.9%) 8
cross-sectional study
MACE-negative 270 59.54 ± 11.70 225 (83.3%)
152
Normal flow 204 57.29 ± 13.14
(74.5%)
Senoz et al., 2021 [31] Turkey Retrospective study 9
27
No-flow 43 61.74 ± 12.47
(62.8%)
12
STEMI 24 71.1 ± 9.8
(50.0%)

Sheng et al., 2021 [32] Prospective cohort study 18

China NSTEMI 25 66.5 ± 10.8 8
(72.0%)
108
UA 156 63.6 ± 10.6
(69.5%)
60
AMI 100 55.5 ± 15
(60.0%)
Shumilah et al., 2021 [33] Yemen Case–control study 7
60
No-AMI 100 54.1 ± 15
(60.0%)
Normal flow 515 62 ± 13 368 (71.5%)
Wang et al., 2018 [34] China Retrospective study 29 8
No-flow 97 63 ± 16
(69.1%)

Prospective observational MACE-positive 96 71 (63~78) NS

Wang et al., 2021 [35] China 7
study MACE-negative 291 67 (59~75) NS
MACE-positive 572 62.93 ± 11.18 361 (63.11%)
Zhou et al., 2016 [36] China Retrospective study 8
MACE-negative 1658 58.12 ± 11.31 934 (56.33%)
Legend: AMI: acute myocardial infarction; DM: diabetes mellitus; MACE: major advance cardiac event;
NOS: Newcastle Ottawa Scale; NS: not specified; and UA: unstable angina.
J. Clin. Med. 2023, 12, 6903 6 of 11
Figure 1. Flow diagram of the search strategy and study selection.

3.2. Meta-Analysis
3.2. Meta-Analysis
Five trials reported PLR values as related to coronary blood flow and presented the
Five trials reported PLR values as related to coronary blood flow and presented the
data stratified as no-flow vs. normal flow. Pooled analysis showed that PLR values were
data stratified as no-flow vs. normal flow. Pooled analysis showed that PLR values were
higher in those with no vs. normal flow (166.3 ± 77.3 vs. 116.5 ± 43.4, respectively, MD =
higher in those with no vs. normal flow (166.3 ± 77.3 vs. 116.5 ± 43.4, respectively,
48.29;
MD = 95% CI:
48.29; 24.52
95% CI:to 72.06;
24.52 to p72.06;
< 0.001;
p < Figure 2).
0.001; Figure 2).

Figure 2. Forest
Figure 2. Forest plot
plotofofPLR
PLRlevels
levelsamong
among no-flow
no-flow vs.vs. normal
normal flow
flow acute
acute coronary
coronary syndrome
syndrome pa-
patients.
tients. The center of each square represents the mean differences for individual trials, and
The center of each square represents the mean differences for individual trials, and the correspond- the cor-
responding horizontal line stands for a 95% confidence interval. The diamonds represent pooled
ing horizontal line stands for a 95% confidence interval. The diamonds represent pooled results.
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 7 of 12
results. Acet et al., 2015 [18]; Celık et al., 2016 [21]; Kurtul et al., 2014 [27]; Wang et al., 2018 [34];
Acet et al., 2015 [18]; Celık et al., 2016 [21]; Kurtul et al., 2014 [27]; Wang et al., 2018 [34]; Senoz et al.,
Senoz et al., 2021 [31].
2021 [31].

Seven studies
Seven studies reported
reported PLR
PLR values
values in
in MACE-positive
MACE-positive vs.vs. -negative
-negative patient
patient groups.
groups.
Pooled analysis
Pooled analysis showed
showed PLRPLR was
was higher
higher in
in MACE-positive
MACE-positive (164.0
(164.0 ±± 68.6)
68.6) than
than MACE-
MACE-
negative patients
negative patients (115.3
(115.3 ±±36.9;
36.9;MD
MD= 40.14; 95%
= 40.14; CI:CI:
95% 22.76 to 57.52;
22.76 p < p0.001;
to 57.52; Figure
< 0.001; 3). 3).
Figure

Figure 3.
Figure 3. Forest
Forest plot
plot ofof PLR
PLR levels
levels among
among MACE-positive
MACE-positive vs. vs. -negative
-negative acute
acute coronary
coronary syndrome
syndrome
patients. The
patients. The center
center of each square
of each square represents
represents the
the mean
mean differences
differences for for individual
individual trials,
trials, and
and the
the
corresponding horizontal line stands for a 95% confidence interval. The diamonds
corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled represent pooled
results. Adam
results. Adam et et al.,
al., 2018
2018 [19];
[19]; Karadeniz
Karadeniz et et al.,
al., 2023
2023 [26];
[26]; Li
Li et
et al.,
al., 2020
2020 [28];
[28]; Li
Li et
et al.,
al., 2022
2022 [29];
[29];
Pashapour et al., 2019 [30]; Wang et al., 2021 [35]; Zhou et al., 2016 [36].
Pashapour et al., 2019 [30]; Wang et al., 2021 [35]; Zhou et al., 2016 [36].

Pooled analysis
Pooled analysis showed
showed thatthat PLR
PLR was
was higher
higher inin AMI
AMI patients
patientswhowhodied
died(183.3
(183.3±30.3),
±30.3),
compared to survivors (126.2 ± 16.8; MD = 39.07; 95% CI: 13.30 to 64.84;
compared to survivors (126.2 ± 16.8; MD = 39.07; 95% CI: 13.30 to 64.84; p = 0.003). p = 0.003). It was
It
also higher in the ACS vs. control group (168.2 ± 81.1 vs. 131.9 ± 37.7; MD
was also higher in the ACS vs. control group (168.2 ± 81.1 vs. 131.9 ± 37.7; MD = 39.01; = 39.01; 95% CI:
2.81 to
95% CI:75.21;
2.81 top =75.21;
0.03),pSTEMI
= 0.03),vs. NSTEMI
STEMI cohort (165.5
vs. NSTEMI ± 92.7
cohort vs. ±
(165.5 159.5
92.7±vs.
87.8; MD±= 87.8;
159.5 5.98;
95%=CI:
MD −15.09
5.98; 95%toCI:27.04; p = to
−15.09 0.58), and
27.04; p=MI0.58),
vs. UAP populations
and MI (162.4 ± 90.0(162.4
vs. UAP populations vs. 128.2 ± 64.9;
± 90.0 vs.
MD =±18.28;
128.2 95% =CI:
64.9; MD −8.16
18.28; to 44.71;
95% p = to
CI: −8.16 0.18). Sensitivity
44.71; p = 0.18).analysis based
Sensitivity on the
analysis leave-one-
based on the
out analysis showed
leave-one-out analysisthat the pooled
showed results
that the pooled were not influenced
results by a single
were not influenced bytrial.
a single trial.

4. Discussion
Our meta-analysis
meta-analysis revealed that the PLR is higher
higher inin MACE
MACE patients
patients compared
compared to to
those without MACE. Moreover, the PLR PLR in
in AMI patients
patients who died
died was
was higher
higher than inin
survivors. In terms of coronary blood flow, the PLR was lower in the normal-flow
flow, the PLR was lower in the normal-flow cohort cohort
compared to those
those with
with complete
complete blockage.
blockage. It is worth mentioning that no reflowreflow was
was
found to have
have a post-PCI
post-PCI TIMI
TIMI flow
flow grade
grade of
of 0,
0, 1,
1, or
or 2,
2, and
and aa TIMI
TIMI flow
flow grade
grade of
of 3.
3.
Some previously conducted studies aimed at detecting the difference between PLR
and clinical prognosis in patients with acute coronary syndrome. Li et al. published a
meta-analysis demonstrating that individuals with higher PLR had a higher risk of in-
hospital adverse outcomes and long-term adverse events [37], including all-cause mortal-
ity and CV events among patients with ACS [38]. In a meta-analysis, Dong et al. reported
J. Clin. Med. 2023, 12, 6903 7 of 11

Some previously conducted studies aimed at detecting the difference between PLR
and clinical prognosis in patients with acute coronary syndrome. Li et al. published a meta-
analysis demonstrating that individuals with higher PLR had a higher risk of in-hospital
adverse outcomes and long-term adverse events [37], including all-cause mortality and
CV events among patients with ACS [38]. In a meta-analysis, Dong et al. reported results
that were similar. Based on data from 12,619 patients, they found that pre-procedural PLR
values were linked to major adverse cardiovascular events in the hospital, death from any
cause, and no reflow after percutaneous coronary intervention. Long-term follow-up (up to
82 months after discharge) had similar associations between increased MACE and all-cause
mortality [39]. Other meta-analyses [40] have reported findings that are similar.
PLR is not without confounders. Kazem et al. showed that the PLR is an age-
independent predictor of cardiovascular mortality, but only in the longer term (adj. HR per
1 SD of 1.04 (95% CI: 1.00–1.08); p = 0.039) [41]. PLR may also be important in the prediction
of patients with ACS who are more at risk of contrast-induced acute kidney injury (CI-AKI),
although, in this case, the prognostic value of the indicator is similar to other biomarkers of
inflammation [42,43].
The pathophysiology associated with PLR during atherosclerotic processes in coronary
artery disease and acute coronary syndrome is complicated. Reactive platelet activation at
the time of ACS may lead to a temporary increase in the absolute platelet count. In turn, the
damage resulting from acute myocardial infarction may activate lymphocytes that migrate
to the site of injury, consequently reducing their absolute number in the bloodstream.
Finally, the stress reaction and systematic inflammation may also disturb the number of
morphotic elements. And ultimately, an interaction between lymphocytes and platelets
cannot be excluded [44]. Different types of leukocytes contribute to pro-atherosclerotic
mechanisms in different ways and to varying degrees. Monocytes, especially in the pro-
inflammatory cascade pathway, are the source of Tissue Factor (TF), factor III, which initiates
the process of transformation of prothrombin into thrombin. Neutrophils, and to a lesser
extent monocytes, release metalloproteinases [45–49]. As a result of apoptosis, e.g., due
to sudden hypoxia, neutrophils release neutrophil extracellular traps (NET), an important
component of coagulation activation. Endothelial inflammation is indirectly related to the
activity of T- and B-lymphocytes. T-lymphocytes activate macrophages, leading to the
production of pro-inflammatory cytokines (including IL-1α, IL-6, IL-12, etc.) and tumor
necrosis factor (TNF-α), which not only increases inflammation by activating other pro-
inflammatory pathways but also hinders healing within the endothelium and contributes
to the instability of an atherosclerotic plaque. The role of eosinophils in the development of
atherosclerosis is less known. They are suspected of reducing thrombus stability.
In general, the value of the PLR index is related to the immune response, showing the
degree of the inflammatory response. An increased PLR index may indicate ongoing pro-
inflammatory processes. This, in turn, may contribute to the instability of an atherosclerotic
plaque, which may lead to major cardiovascular events. Furthermore, an increased PLR
value may result from an increased number of thrombocytes, thereby increasing the risk
of thromboembolism. Moreover, an increased number of platelets promotes endothelial
damage. A high value of the PLR index may, therefore, be the result of multidirectional
changes occurring in the body related to the markers of inflammation [50].
However, before the PLR can be routinely included in the decision-making process,
the first challenge is to define a cut-off point for the PLR value that allows the stratification
of patients. In addition, further studies need to describe how PLR differs from other similar
indicators in practice, e.g., monocyte-to-lymphocyte ratio (MLR), derived neutrophil-to-
lymphocyte ratio (dNLR), neutrophil-to-lymphocyte platelet ratio (NLPR), or systemic
inflammatory index (SII). Another area of interest may be to define if the systematic
immune response can be modified with treatment, if the effect is beneficial, and whether
the reduction in inflammation can be measured with the PLR. If so, the PLR biomarker
could be used to measure the degree of adherence to therapeutic recommendations or the
individual variability of response to the intervention. Single scientific reports show, for
J. Clin. Med. 2023, 12, 6903 8 of 11

example, that ticagrelor may improve the parameters of inflammation compared to another
antiplatelet drug, i.e., clopidogrel [51]. Finally, the cost-effectiveness of the PLR has not
been defined. If the diagnostic or predictive properties of PLR are confirmed, it may be a
cost-effective solution, at least partially limiting the use of expensive technologies, which
may be particularly important in rural areas or less developed countries [52].
Other new potential markers include neutrophil-to-lymphocyte ratio, eosinophil-to-
leukocyte ratio, eosinophil-to-lymphocyte ratio, eosinophil-to-neutrophil ratio, lymphocyte-
to-monocyte ratio, and neutrophil-to-lymphocyte ratio. Patients with acute decompensated
heart failure and reduced ejection fraction who experienced a major cardiovascular event
(MACE) within 6 months of the index hospitalization had lower eosinophil-to-monocyte
ratio and eosinophil-to-lymphocyte ratio values. However, their neutrophil-to-eosinophil
ratio and leukocyte-to-eosinophil ratio were higher compared to patients without MACE.
Further research is necessary to determine which biomarkers demonstrate the best predic-
tive properties, preferably in a head-to-head comparison [53].
Gender-specific characteristics in the development of the immune system response
during the development of cardiovascular diseases remains an area of research. Epidemio-
logical studies have shown that among patients diagnosed with type 2 diabetes, women
have a much worse prognosis than men. One hypothesis is that the difference in the
immune response between women and men may contribute to a worse prognosis. The
increase in the number of platelet–neutrophil conjugates may be one of the factors of the
immune response. Also, hormones such as estradiol may determine the specificity of the
hormonal response in women. In the context of new biomarkers, careful analyses should
be carried out to determine whether there are different cut-offs for women and men [54].
Our meta-analysis has several limitations. These include the lack of a standardized
performance platform. This is likely to create variability in comparative numeric values
obtained from different data sources. Despite this, we were able to demonstrate clear
prognostic associations between abnormal PLR results and both short- and long-term
outcomes. Second, we were not able to evaluate the impact of age on outcome events.
However, whether age must be included in the interpretation of PLR testing is unclear.
Additionally, the effects of hematologic disorders and medications altering hematopoiesis
on the PLR accuracy need further evaluation. Furthermore, no study presented here
evaluated the consequence of care alterations determined with PLR testing.
The meta-analysis does not take into account some variables that may affect the useful-
ness of the PLR biomarker as a predictor. These include diagnosis (STEMI, NSTEMI, UA),
how the comparison group was constructed in the studies included in the meta-analysis, the
baseline characteristics of the patients, among others. Different ways of describing baseline
characteristics, in particular capturing very different information, make it significantly
difficult to present the characteristics of participants included in the studies. Moreover,
a comparison of morphological and other laboratory parameters between publications
would be burdened with a significant systematic error due to the possible different methods
of determining parameters and the lack of reference standards in the publications. The
meta-analysis did not take into account information about what proportion of patients
underwent PCI. Further limitations are associated with the time of PLR determination and
MACE definition. To address all the above aspects, Table S2 was added.
Finally, interventional studies, with clinical care changes based on PLR values, are
needed before this biomarker can be used in clinical practice.

5. Conclusions
This is the largest evaluation of PLR to date. Overall, our findings confirmed the
potential prognostic role of the platelet-to-lymphocyte (PLR) ratio in patients presenting
with suspected acute coronary syndromes (ACS). Its use as a risk stratification tool should
be examined prospectively to define its capability for evaluation in cardiovascular patients.
PLR might serve as a surrogate marker of microvascular obstruction and no-reflow risk,
with a potential impact on the management of high-risk patients (including gp IIb/IIIa
J. Clin. Med. 2023, 12, 6903 9 of 11

inhibitors). In addition, there is a clinical struggle to identify high-risk patients with no-
reflow, which subsequently may contribute to potential efficient strategies to prevent or
treat no-reflow, finally leading to short and long-term mortality.

Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/jcm12216903/s1, Table S1: PRISMA checklist; Table S2. Detailed
characteristics of the studies included in the meta-analysis.
Author Contributions: Conceptualization, M.P. and K.K.; methodology, M.P. and L.S.; software, M.P.,
M.T. and L.S.; validation, M.P., K.K. and M.K.; formal analysis, L.S., M.P. and B.K.; investigation, M.P.,
M.T., L.S. and D.S.; resources, M.P., K.K. and M.T.; data curation, M.P., L.S. and B.C.; writing—original
draft preparation, M.P., L.S. and D.S.; writing—review and editing, M.P., F.W.P., Z.R., D.S., K.K., M.T.,
B.K., M.K., B.C. and L.S.; visualization, M.P.; supervision, L.S., B.C. and F.W.P.; project administration,
M.P. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data that support the findings of this study are available on request
from the corresponding author (L.S.).
Acknowledgments: The study was supported by the ERC Research Net, the WACEM Research Net
and by the Polish Society of Disaster Medicine.
Conflicts of Interest: The authors declare no conflict of interest.

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