Review Reports - Platelet-to-Lymphocyte Ratio—A Real or Fake Bridge Between Inflammation and Coagulation in COVID-19 Patients: A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Author,

We would like to thank the authors for submitting this comprehensive and timely scoping review addressing the role of the platelet-to-lymphocyte ratio (PLR) in COVID-19. The topic is clinically relevant, and the manuscript demonstrates substantial effort in compiling current evidence. However, several issues should be addressed to improve the scientific rigor, clarity, and overall impact of the study. I believe these changes will contribute to the literature.

This manuscript presents a scoping review evaluating the prognostic value of the platelet-to-lymphocyte ratio (PLR) in COVID-19. The topic is clinically relevant and timely, particularly in the context of immunothrombosis and accessible biomarkers. The manuscript is comprehensive; however, some issues limit its scientific rigor and clarity. Major revisions are required before the manuscript can be considered for publication.

Although the study is presented as a scoping review, the methodology partially overlaps with a systematic review (e.g., use of ROC, AUC comparison), yet lacks key elements of both approaches.

No clear justification for choosing a scoping review instead of a systematic review/meta-analysis
No critical appraisal of included studies (risk of bias missing)

Expand databases or clearly justify limitation in Discussion. If it is not possible, expand the limitation.

Only PubMed was used → major limitation
No use of Embase, Scopus, Web of Science

Explain why ROC-based studies were prioritized and discuss resulting bias more explicitly.
Add structured subgroup discussion:

severity definition-based
ICU vs non-ICU
age groups

Frequent repetition (e.g., inflammation–coagulation interplay)

Some grammatical issues:
“platelet and leukocyte” → platelets and leukocytes
“Total platelet and lymphocyte counts was” → were

Figures and tables

Forest plots mentioned but interpretation limited and tables are dense and difficult to follow

summarizing key findings visually
highlighting main ranges instead of raw data overload

Sincerely,

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Dear Author,

Author's Reply to the Review Report (Reviewer 1)

Comments 1: Although the study is presented as a scoping review, the methodology partially overlaps with a systematic review (e.g., use of ROC, AUC comparison), yet lacks key elements of both approaches. No clear justification for choosing a scoping review instead of a systematic review/meta-analysis. No critical appraisal of included studies (risk of bias missing)

Response 1: We thank the Reviewer for this valuable comment. Our study was conducted in accordance with the methodological framework for scoping reviews as outlined by PRISMA-ScR, and the corresponding checklist was provided to ensure transparency and completeness of reporting.

The primary objective of this work was to provide a preliminary and exploratory assessment of the platelet-to-lymphocyte ratio (PLR) and its potential clinical utility as a prognostic marker for COVID-19 severity and mortality. In this context, we examined how ROC analyses were reported across the included studies, with particular attention to AUC values, as these metrics are commonly used to describe discriminative performance in clinical research. This approach was intended to map the existing evidence rather than to formally synthesize diagnostic accuracy. Scoping reviews are, by definition, designed to provide a broad overview of a given topic, identify research gaps, and summarize the range and nature of available evidence. In line with established methodological guidance (Arksey and O’Malley framework and PRISMA-ScR), critical appraisal of included studies (e.g., risk of bias assessment) is not a mandatory component of a scoping review, as it is more characteristic of systematic reviews and meta-analyses.

Comments 2: Expand databases or clearly justify limitation in Discussion. If it is not possible, expand the limitation. Only PubMed was used → major limitation. No use of Embase, Scopus, Web of Science

Response 2: We appreciate this comment, as it has helped us improve the transparency and methodological clarity of our study. We acknowledge that limiting the search strategy to a single database may represent a methodological constraint. The decision to use PubMed was primarily based on its wide accessibility, comprehensive coverage of biomedical literature, and the fact that it provides free access to a substantial number of peer-reviewed articles. One of our intentions was also to reflect a pragmatic approach, demonstrating that even when using a single, widely available database, it is possible to identify consistent evidence regarding the potential clinical relevance of the platelet-to-lymphocyte ratio (PLR).

In accordance with the Reviewer’s suggestion, we have expanded the Discussion section to explicitly acknowledge this issue and its potential impact on the comprehensiveness of the evidence base. "An additional limitation is that our scoping review was based on the analysis of only one database (PubMed). However, the limited number of studies included in the analysis does not negate the fact that PLR shows diagnostic value, and further studies evaluating its usefulness in assessing COVID-19 severity and mortality are warranted." (Discussion, 430-434)

Comments 3: Explain why ROC-based studies were prioritized and discuss resulting bias more explicitly.

Response 3: Thank you for this comment. We added a relevant section in the Introduction to guide the reader and clarify the main issue addressed in this scoping review. Differences in AUC values across studies are discussed in the Discussion section, with consideration of factors that may have influenced the observed variability. "We primarily focused on receiver operating characteristic (ROC) analysis and reported area under the curve (AUC) values in relation to COVID-19 severity or mortality, as this is a fundamental method for assessing diagnostic performance and is widely used in the evaluation of biomarkers."(Introduction, 165-168)

Comments 4: Add structured subgroup discussion: severity definition-based, ICU vs non-ICU, age groups

Response 4: Thank you for this suggestion. We have added a structured subgroup discussion in the Discussion section. For clarity and to improve reader navigation, the subgroup headings are as follows: Demographic heterogeneity across study populations, Variability in disease severity definitions across studies, Geographical and ethnic variability as sources of heterogeneity, and Clinical interpretation and limitations of PLR as a dynamic biomarker. (Discussion, 373, 385, 402, 408)

Comments 5: Frequent repetition (e.g., inflammation–coagulation interplay)

Some grammatical issues:
“platelet and leukocyte” → platelets and leukocytes
“Total platelet and lymphocyte counts was” → were

Response 5: Thank you for pointing out these errors. The manuscript has been carefully reviewed, and we hope that no similar errors remain.

Comments 6: Forest plots mentioned but interpretation limited and tables are dense and difficult to follow summarizing key findings visually highlighting main ranges instead of raw data overload

Response 6: We thank the Reviewer for this insightful suggestion. Forest plots visually present the distribution of PLR values across the studies included in the analysis. To facilitate their interpretation, we have added a section describing how to interpret AUC values. "Analysis of ROC curves and AUC values (Figure 3) illustrates the distribution of the diagnostic performance of PLR across the included studies. AUC values were interpreted according to commonly used criteria: 0.9–1.0 as excellent, 0.8–0.9 as good, 0.7–0.8 as fair, 0.6–0.7 as poor, and 0.5–0.6 as failed. This approach allows for a standardized assessment of the diagnostic accuracy of the evaluated marker across different COVID-19 patient populations." (Results, 292-297)

Regarding the tables, they were modeled on the presentation of data used in other scoping reviews. Our aim was to include the most relevant information needed to interpret the diagnostic value of PLR in patients with COVID-19. This allows the reader to clearly examine the results obtained across different studies. The forest plots summarize the distribution of AUC values. We would like to retain the tables in their current form, as the Results section is intended to present the findings of the scoping review. The interpretation of these data is discussed in detail in the Discussion section.

We truly appreciate your thoughtful feedback, which has enabled us to substantially enhance the scientific rigor and clarity of our study.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses a clinically relevant question: whether the platelet-to-lymphocyte ratio (PLR), a simple, accessible hematological marker derived from complete blood counts, can serve as a prognostic indicator of severity and mortality in patients with COVID-19, and whether it can be interpreted as an indirect link between inflammation and coagulation in the context of COVID-19-associated coagulopathy. The review includes 20 studies published between 2020 and 2025, with an emphasis on those that reported ROC analyses and AUC values, and that separated outcomes by severity and mortality. This approach is useful because it allows evaluation not only of the direction of the association between PLR and adverse outcomes, but also of PLR's discriminative performance as a clinical biomarker.

In its current form, the article oscillates between a descriptive scoping review and a review with the pretensions of diagnostic/prognostic evaluation. Still, it does not fully meet the methodological standards of either approach. Furthermore, the central claim that PLR could be a "bridge" between inflammation and coagulation requires considerable qualification, as the data presented do not demonstrate a direct mechanistic relationship but rather an indirect, heterogeneous association with clinical outcomes.

Major Comments

The first aspect that requires attention is the methodological definition of the study. The authors present the work as a scoping review, grounded in the Arksey and O'Malley frameworks and PRISMA-ScR. However, the manuscript focuses much of its analysis on AUC values, sensitivity, specificity, and cutoff points, which correspond more to a review of diagnostic or prognostic performance than to a purely exploratory scoping review. This methodological tension must be resolved. If the authors wish to maintain the scoping review approach, they must more clearly justify why this design is the most appropriate, limit inferences about diagnostic performance, and present the results as a mapping of the available evidence. Conversely, if the main objective is to evaluate the discriminative capacity of the PLR, it would be necessary to approach this more like a systematic review, ideally incorporating assessments of methodological quality and risk of bias, and a more formal discussion of heterogeneity.

The selection of studies should be described more rigorously. The manuscript reports that 75 articles were identified and 20 studies were ultimately included, but the exclusion process is not sufficiently detailed. It states that 46 articles were assessed in full text and that 26 were excluded because they lacked ROC analysis and AUC values. Still, it would be necessary to detail whether other studies were excluded because of a pediatric population, the absence of PLR on admission, lack of clinical outcomes, duplication of cohorts, or incompatible definitions of severity.

Interpreting platelet-rich plasma (PRP) as a bridge between inflammation and coagulation requires a conceptual reformulation. The title poses an intriguing, yet somewhat dichotomous and potentially excessive question: "a real or fake bridge." The data presented do not allow us to determine whether PRP is a genuine or a fake bridge between these two processes. PRP combines two hematological parameters: platelets and lymphocytes, but this alone does not demonstrate a functional connection between immunothrombosis, platelet activation, lymphopenia, and coagulopathy. The manuscript should clearly distinguish between an indirect marker, an associated marker, a prognostic biomarker, and a mechanistic marker. Based on the evidence presented, PRP can be considered an indirect index of inflammatory and immunohematological alterations associated with COVID-19, but not a specific marker of coagulopathy nor direct evidence of the inflammation-coagulation interaction.

The discussion should delve deeper into the clinical and statistical heterogeneity of the included studies. The authors acknowledge differences in age, sex, comorbidities, severity criteria, viral variants, vaccination coverage, and geographic location, but address these factors in a general, repetitive manner. It would be important to reorganize this section to explain how each source of heterogeneity can affect PLR performance. For example, advanced age can alter baseline lymphocyte and platelet counts; cardiovascular, metabolic, autoimmune, or neoplastic comorbidities can elevate or depress the PLR independently of COVID-19; vaccination and viral variants can modify clinical severity; and early hospital treatment, including corticosteroids, anticoagulation, or antivirals, can affect outcomes. This discussion would allow for a more cautious interpretation of the wide range of AUCs reported.

The results suggest limited to moderate prognostic utility of the PLR, and this conclusion should be expressed more precisely. In terms of severity, reported AUCs range from 0.559 to 0.811; for mortality, from 0.474 to 0.758. These values indicate that some studies show reasonable performance, but others show poor discriminatory capacity, even lower than expected for a clinically useful marker. Therefore, statements such as "PLR demonstrates clinical significance as a biomarker" should be softened. It would be more appropriate to state that PLR is associated with a worse clinical outcome, but its usefulness as an independent and generalizable marker remains uncertain. The conclusion should avoid overinterpreting the consistency of the association when the diagnostic/prognostic performance is heterogeneous.

The use of forest plots for AUC should be explained in more detail. Figure 3 presents the AUCs of the included studies, which are informative. Still, the manuscript does not clearly describe how these forest plots were generated, whether confidence intervals reported directly by the studies were used, whether derived estimates were used, or whether any meta-analytic interpretation was avoided. If a formal meta-analysis was not performed, the authors should explicitly state that the forest plots are descriptive and do not constitute a pooled estimate. Otherwise, it would be necessary to describe the statistical model used, the heterogeneity, and the justification for combining studies with such different definitions of severity and mortality.

The tables are useful, but they require refinement and standardization. Tables 2 and 3 have inconsistencies in format, abbreviations, country names, statistical symbols, and the presentation of values. Furthermore, some data are difficult to compare because the studies report PLR as mean ± standard deviation, median with interquartile range, categories by cut-off point, or without complete values. The authors should add a methodological note explaining how they handled these differences and avoid directly comparing values expressed in different statistical formats. It would also be advisable to clearly separate studies that assess clinical severity, ICU admission, ventilatory support, pulmonary thromboembolism, septic shock, or mortality, as these outcomes do not all have the same clinical significance.

The abstract should be rewritten to better reflect bettert the study's limitations. It conveys the idea that PLR has diagnostic utility but also acknowledges significant inconsistencies. It would be preferable to structure it more clearly: objective, methods, number of studies, outcomes assessed, AUC range for severity and mortality, critical interpretation, and nuanced conclusion. The final section should make it clear that PLR should not be considered a sufficiently robust independent biomarker, but rather a complementary marker that requires further validation, standardization of cut-off points, and analyses adjusted for age, comorbidities, vaccination status, and baseline severity.

Minor Comments

The introduction is lengthy and contains general information about COVID-19 that could be condensed. The description of the pandemic, the general pathogenesis of SARS-CoV-2, and some aspects of adaptive immunity take up too much space before addressing the specific issue of the PLR. To improve flow, the authors should reduce the introductory material and focus the argument more quickly on three main points: COVID-19-associated coagulopathy, platelet and lymphocyte alterations, and the justification for PLR as a composite index.

The section on COVID-19-associated coagulopathy contains relevant information, but it needs to be better linked to the PLR. Currently, it describes endothelial activation, platelet aggregation, P-selectin, CD40L, CLEC-2, thrombin, and immunothrombus formation, but the link to the clinical interpretation of PLR is presented abruptly. It would be helpful to conclude this subsection with an explicit transition explaining why an index derived from platelets and lymphocytes could reflect, albeit indirectly, these processes.

The discussion adequately compares PLR with NLR, but this aspect could be strengthened. The explanation for why NLR can show a stronger signal than PLR is interesting: in NLR, neutrophils typically increase while lymphocytes decrease, amplifying the ratio; in PLR, platelets and lymphocytes can decrease simultaneously, complicating interpretation. This insight is valuable and should be presented earlier and more forcefully, as it helps explain why PLR may be biologically plausible but clinically less robust.

Author Response

Author's Reply to the Review Report (Reviewer 2)

Comments 1: The first aspect that requires attention is the methodological definition of the study. The authors present the work as a scoping review, grounded in the Arksey and O'Malley frameworks and PRISMA-ScR. However, the manuscript focuses much of its analysis on AUC values, sensitivity, specificity, and cutoff points, which correspond more to a review of diagnostic or prognostic performance than to a purely exploratory scoping review. This methodological tension must be resolved. If the authors wish to maintain the scoping review approach, they must more clearly justify why this design is the most appropriate, limit inferences about diagnostic performance, and present the results as a mapping of the available evidence. Conversely, if the main objective is to evaluate the discriminative capacity of the PLR, it would be necessary to approach this more like a systematic review, ideally incorporating assessments of methodological quality and risk of bias, and a more formal discussion of heterogeneity.

Response 1: Thank you for this important comment. The primary aim of our study was to assess the diagnostic value of PLR in patients with COVID-19 and to evaluate its usefulness in predicting disease severity and mortality. To achieve this, we conducted a literature search in the PubMed database in accordance with PRISMA-ScR guidelines. After applying the inclusion and exclusion criteria, a limited number of studies were identified and subsequently analyzed and interpreted. We acknowledge that our manuscript may not fit perfectly within the framework of a single review type. However, we aimed to maintain the scoping review format, as we believe it is appropriate for mapping the available evidence on this topic. Our study provides a structured overview of the existing literature and highlights the potential diagnostic relevance of PLR, encouraging further investigation in this area.

As our scoping review does not include a formal assessment of methodological quality, it cannot be considered a systematic review; however, this does not preclude its classification as a scoping review. We believe that our approach remains consistent with the purpose of scoping reviews. The Results section presents the extracted data from the included studies, while the Discussion focuses primarily on factors that may explain the variability in AUC values across studies. In our opinion, the extent of inference regarding the diagnostic value of PLR does not exceed what is appropriate for a scoping review. We hope that the reviewers will find this approach acceptable.

Comments 2: The selection of studies should be described more rigorously. The manuscript reports that 75 articles were identified and 20 studies were ultimately included, but the exclusion process is not sufficiently detailed. It states that 46 articles were assessed in full text and that 26 were excluded because they lacked ROC analysis and AUC values. Still, it would be necessary to detail whether other studies were excluded because of a pediatric population, the absence of PLR on admission, lack of clinical outcomes, duplication of cohorts, or incompatible definitions of severity.

Response 2: Thank you for this important comment. We fully agree that our manuscript should include this information. Therefore, we have clarified the additional exclusion criteria beyond the absence of ROC curve analysis and AUC values. We have added the following paragraph: "Studies were excluded if they focused on highly specific patient subgroups, including those with particular comorbidities, as such populations were not representative of the general COVID-19 cohort considered in this review. We also excluded studies evaluating the diagnostic value of PLR during different waves of the COVID-19 pandemic, as temporal variations in disease characteristics and management could affect comparability. Furthermore, studies restricted to specific populations, such as elderly individuals or pregnant women, were not included to maintain greater consistency across the analyzed cohorts. These criteria were applied to ensure a more homogeneous study population and to improve the comparability of AUC values across the included studies." (Results, 242-250)

Comments 3: Interpreting platelet-rich plasma (PRP) as a bridge between inflammation and coagulation requires a conceptual reformulation. The title poses an intriguing, yet somewhat dichotomous and potentially excessive question: "a real or fake bridge." The data presented do not allow us to determine whether PRP is a genuine or a fake bridge between these two processes. PRP combines two hematological parameters: platelets and lymphocytes, but this alone does not demonstrate a functional connection between immunothrombosis, platelet activation, lymphopenia, and coagulopathy. The manuscript should clearly distinguish between an indirect marker, an associated marker, a prognostic biomarker, and a mechanistic marker. Based on the evidence presented, PRP can be considered an indirect index of inflammatory and immunohematological alterations associated with COVID-19, but not a specific marker of coagulopathy nor direct evidence of the inflammation-coagulation interaction.

Response 3: Thank you for this comment. However, we respectfully disagree with this interpretation. The aim of our study was to evaluate the platelet-to-lymphocyte ratio (PLR), not platelet-rich plasma (PRP), as a bridge between coagulation and inflammation. The data presented focus on whether PLR, reflecting both platelet and lymphocyte counts, may be considered a potential link between these processes. The association between PLR and both disease severity and mortality in COVID-19 cannot be ignored. PLR can be considered an indirect bridge reflecting the interplay between inflammation and coagulation during COVID-19 progression. While it is not a direct marker of clinical deterioration, it indirectly reflects the involvement of both platelets and lymphocytes in immune-thrombotic processes, although its clinical utility still requires further investigation.

Based on the findings of our scoping review, we suggest that PLR may act as an indirect bridge, which is reflected in our conclusions. Importantly, we do not consider PLR a direct or mechanistic marker. Rather, we emphasize its indirect and not fully consistent diagnostic value and highlight the need for further studies addressing current limitations. Such research may help establish more reliable cut-off values and support the potential incorporation of PLR into routine clinical assessment.

Comments 4: The discussion should delve deeper into the clinical and statistical heterogeneity of the included studies. The authors acknowledge differences in age, sex, comorbidities, severity criteria, viral variants, vaccination coverage, and geographic location, but address these factors in a general, repetitive manner. It would be important to reorganize this section to explain how each source of heterogeneity can affect PLR performance. For example, advanced age can alter baseline lymphocyte and platelet counts; cardiovascular, metabolic, autoimmune, or neoplastic comorbidities can elevate or depress the PLR independently of COVID-19; vaccination and viral variants can modify clinical severity; and early hospital treatment, including corticosteroids, anticoagulation, or antivirals, can affect outcomes. This discussion would allow for a more cautious interpretation of the wide range of AUCs reported.

Response 4: We thank the Reviewer for this insightful suggestion. In order to demonstrate greater caution in the evaluation of the diagnostic performance of PLR, we have added a paragraph expanding on the influence of various factors on the variability of AUC values across the included studies. This allows for a more cautious interpretation of this marker and highlights potential directions for future research aimed at reducing sources of variability in reported AUC values. "Heterogeneity in study populations represents an important source of variability and may partly explain discrepancies in reported AUC values across studies. Total platelet counts and lymphocyte counts may be lower in elderly patients due to age-related hematological changes and immunosenescence; therefore, the age distribution across individual studies should be carefully considered when interpreting PLR values. Moreover, the included studies did not exclusively involve patients without comorbidities, which further limits comparability. As a result, the potential impact of underlying diseases on PLR values should also be acknowledged. Elevated PLR values have been reported in a range of chronic inflammatory and systemic conditions, including malignancies, cardiovascular diseases, viral infections, autoimmune disorders, and other pulmonary diseases. Therefore, the lack of studies focusing on patients without comorbidities represents a significant limitation in the interpretation of PLR in COVID-19. In addition, the absence of detailed clinical background information further constrains interpretation, as vaccination status, treatment regimens, and the specific SARS-CoV-2 variant responsible for infection were not consistently reported across studies. These factors may have substantially influenced both disease severity and inflammatory marker profiles." (Discussion, 411-427)

Comments 5: The results suggest limited to moderate prognostic utility of the PLR, and this conclusion should be expressed more precisely. In terms of severity, reported AUCs range from 0.559 to 0.811; for mortality, from 0.474 to 0.758. These values indicate that some studies show reasonable performance, but others show poor discriminatory capacity, even lower than expected for a clinically useful marker. Therefore, statements such as "PLR demonstrates clinical significance as a biomarker" should be softened. It would be more appropriate to state that PLR is associated with a worse clinical outcome, but its usefulness as an independent and generalizable marker remains uncertain. The conclusion should avoid overinterpreting the consistency of the association when the diagnostic/prognostic performance is heterogeneous.

Response 5: We thank the Reviewer for this important observation. We have revised this statement and adopted a more cautious approach to the definitive assessment of the diagnostic value of the PLR. Both in the Results and in the Discussion and Conclusion sections, we repeatedly emphasize the heterogeneity of the studied populations. In the summary, we state that PLR may be considered an indirect bridge rather than a direct marker, as it reflects the interplay between inflammation and coagulation during COVID-19 progression. While it is not a direct marker of clinical deterioration, it indirectly reflects the involvement of both platelets and lymphocytes in immune-thrombotic processes; however, its clinical utility still requires further investigation. "It has been associated with worse clinical outcomes; however, its usefulness as an independent and generalizable marker remains uncertain" (Conclusion, 447-448)

Comments 6: The use of forest plots for AUC should be explained in more detail. Figure 3 presents the AUCs of the included studies, which are informative. Still, the manuscript does not clearly describe how these forest plots were generated, whether confidence intervals reported directly by the studies were used, whether derived estimates were used, or whether any meta-analytic interpretation was avoided. If a formal meta-analysis was not performed, the authors should explicitly state that the forest plots are descriptive and do not constitute a pooled estimate. Otherwise, it would be necessary to describe the statistical model used, the heterogeneity, and the justification for combining studies with such different definitions of severity and mortality.

Response 6: Thank you for this important comment. We clarify that no formal meta-analysis was performed in this study. The forest plots presented in Figure 3 are purely descriptive and were generated using the AUC values and confidence intervals reported directly in the included studies “For graphical comparison of the AUC values, forest plots were generated separately for studies focusing on disease severity and mortality in COVID-19 patients”. No derived estimates were calculated, and no statistical pooling of results was conducted. Accordingly, the forest plots do not represent a combined or pooled estimate but rather a visual summary of the reported diagnostic performance across studies. We have clarified this in the revised manuscript to avoid any potential misinterpretation. We have also added a paragraph describing the commonly accepted criteria for interpreting ROC curves. "Analysis of ROC curves and AUC values (Figure 3) illustrates the distribution of the diagnostic performance of PLR across the included studies. AUC values were interpreted according to commonly used criteria: 0.9–1.0 as excellent, 0.8–0.9 as good, 0.7–0.8 as fair, 0.6–0.7 as poor, and 0.5–0.6 as failed. This approach allows for a standardized assessment of the diagnostic accuracy of the evaluated marker across different COVID-19 patient populations." (Results, 292-297)

Comments 7: The tables are useful, but they require refinement and standardization. Tables 2 and 3 have inconsistencies in format, abbreviations, country names, statistical symbols, and the presentation of values. Furthermore, some data are difficult to compare because the studies report PLR as mean ± standard deviation, median with interquartile range, categories by cut-off point, or without complete values. The authors should add a methodological note explaining how they handled these differences and avoid directly comparing values expressed in different statistical formats. It would also be advisable to clearly separate studies that assess clinical severity, ICU admission, ventilatory support, pulmonary thromboembolism, septic shock, or mortality, as these outcomes do not all have the same clinical significance.

Response 7: We thank the Reviewer for this helpful remark. The tables present raw data extracted directly from the studies included in the analysis. Unfortunately, we had no influence on how these data were originally reported in the source articles. Nevertheless, the tables allow the reader to examine how different studies assessed the evaluated parameters and to compare the reported findings across publications.

Comments 8: The abstract should be rewritten to better reflect bettert the study's limitations. It conveys the idea that PLR has diagnostic utility but also acknowledges significant inconsistencies. It would be preferable to structure it more clearly: objective, methods, number of studies, outcomes assessed, AUC range for severity and mortality, critical interpretation, and nuanced conclusion. The final section should make it clear that PLR should not be considered a sufficiently robust independent biomarker, but rather a complementary marker that requires further validation, standardization of cut-off points, and analyses adjusted for age, comorbidities, vaccination status, and baseline severity.

Response 8: We thank the Reviewer for this valuable comment. Our abstract already includes the information highlighted by the reviewer. It states the objective of the scoping review, which was to assess the diagnostic value of PLR in COVID-19 patients for evaluating disease severity and mortality. In terms of methods, it describes the use of the PubMed database and the inclusion of 20 studies in the final analysis, with a focus on AUC values. The range of AUC values for severity and mortality is also reported, together with the indication that heterogeneity between study populations likely contributed to the observed variability.

We have, however, revised the conclusion section to make it more explicit, stating that PLR should be considered a complementary biomarker. It is described as an indirect rather than a direct bridge, and we emphasize that further studies are required to confirm its clinical utility. "It is a complementary marker that may assist clinicians in assessing COVID-19 patients but still requires further investigation." (Abstract, 29-31)

Comments 9: The introduction is lengthy and contains general information about COVID-19 that could be condensed. The description of the pandemic, the general pathogenesis of SARS-CoV-2, and some aspects of adaptive immunity take up too much space before addressing the specific issue of the PLR. To improve flow, the authors should reduce the introductory material and focus the argument more quickly on three main points: COVID-19-associated coagulopathy, platelet and lymphocyte alterations, and the justification for PLR as a composite index.

Response 9: We thank the Reviewer for this helpful remark. We have shortened the section on the COVID-19 pandemic, retaining only a brief introduction to the current situation and a concise description of immunothrombosis-related changes associated with SARS-CoV-2 infection. (Introduction, 36-55)

Comments 10: The section on COVID-19-associated coagulopathy contains relevant information, but it needs to be better linked to the PLR. Currently, it describes endothelial activation, platelet aggregation, P-selectin, CD40L, CLEC-2, thrombin, and immunothrombus formation, but the link to the clinical interpretation of PLR is presented abruptly. It would be helpful to conclude this subsection with an explicit transition explaining why an index derived from platelets and lymphocytes could reflect, albeit indirectly, these processes.

Response 10: Thank you for this suggestion. In line with the reviewer’s comment, we have added a paragraph that provides a smoother transition from the topic of COVID-19-Associated Coagulopathy to the key components of PLR, namely platelets and lymphocytes. "Changes in coagulation and inflammatory responses induced by SARS-CoV-2 infection are reflected in alterations in platelet and lymphocyte counts. As PLR captures both platelet activation and lymphocyte dynamics, it may serve as an indirect indicator of these processes. Therefore, particular attention should be given to changes in these components as the key constituents of PLR in the context of COVID-19-Aassociated Coagulopathy." (Introduction, 94-98)

Comments 11: The discussion adequately compares PLR with NLR, but this aspect could be strengthened. The explanation for why NLR can show a stronger signal than PLR is interesting: in NLR, neutrophils typically increase while lymphocytes decrease, amplifying the ratio; in PLR, platelets and lymphocytes can decrease simultaneously, complicating interpretation. This insight is valuable and should be presented earlier and more forcefully, as it helps explain why PLR may be biologically plausible but clinically less robust.

Response 11: Thank you for this comment. We have moved this section from the end to the beginning of the Discussion to better highlight why PLR may be less diagnostically useful than NLR, despite being based on lymphocyte counts, which play a key role in the immune response to viral infection. (Discussion, 328-345)

We truly appreciate your thoughtful feedback, which has enabled us to substantially enhance the scientific rigor and clarity of our study.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Author,

Thank you for explaining the necessary revisions. I believe the article is acceptable with these revisions.

Sincerely,

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Dear Reviewer,

We sincerely thank you for your positive evaluation of our manuscript entitled "Platelet-to-Lymphocyte Ratio – a Real or Fake Bridge Between Inflammation and Coagulation in COVID-19 Patients: A Scoping Review" and for your constructive feedback.

The topic is clinically relevant, and the manuscript provides a comprehensive synthesis of the current evidence. We would therefore be pleased to have it considered for publication in Diagnostics, Section Diagnostic Microbiology and Infectious Disease, Special Issue New Diagnostic and Testing Strategies for Infectious Diseases. We are sincerely grateful for the acceptance of our manuscript, which represents a significant recognition of our work. We would also like to express our gratitude for the time devoted to the review process and for the constructive assistance in editing the manuscript, as well as for the valuable suggestions, which have undoubtedly improved the quality and scientific value of our work.

Sincerely,

Maja Aleksandra Oksentowicz

Reviewer 2 Report

Comments and Suggestions for Authors

I thank the authors for addressing the previous observations. I believe the manuscript has been significantly strengthened, particularly in the more cautious presentation of the PLR value, the description of heterogeneity across studies, and the clarification of the descriptive nature of the AUC graphs. However, before considering the manuscript in its final version, I still recommend correcting a few specific aspects.

First, the entire text should be carefully reviewed to avoid any statements that present PLR as a direct or mechanistic “bridge” between inflammation and coagulation. The most appropriate interpretation, according to the evidence presented, is that PLR may act as an indirect, composite, and nonspecific marker associated with inflammatory and immunohematological alterations in COVID-19. Therefore, the statements in the abstract, introduction, discussion, and conclusion should be consistent with this more cautious interpretation.

Second, I recommend adding an explicit methodological note to the tables or results section indicating that PLR values are not directly comparable across all included studies due to differences in statistical reporting formats and the heterogeneity of the clinical outcomes assessed, including severity, ICU admission, ventilatory support, pulmonary thromboembolism, septic shock, and mortality.

Third, I suggest reinforcing the methods and/or limitations section by stating that a formal assessment of the methodological quality and risk of bias of the included studies was not performed. Consequently, inferences about the diagnostic or prognostic performance of PLR should be presented as exploratory and descriptive, not as definitive conclusions about its independent or generalizable clinical utility.

Author Response

Dear Reviewer,

We sincerely thank you for your constructive feedback.

We have implemented the suggested changes accordingly. We hope that these revisions will enhance the quality of our manuscript entitled "Platelet-to-Lymphocyte Ratio – a Real or Fake Bridge Between Inflammation and Coagulation in COVID-19 Patients: A Scoping Review", and contribute to the positive consideration of our submission for publication in Diagnostics, Section Diagnostic Microbiology and Infectious Disease, Special Issue New Diagnostic and Testing Strategies for Infectious Diseases.

Comments 1: First, the entire text should be carefully reviewed to avoid any statements that present PLR as a direct or mechanistic “bridge” between inflammation and coagulation. The most appropriate interpretation, according to the evidence presented, is that PLR may act as an indirect, composite, and nonspecific marker associated with inflammatory and immunohematological alterations in COVID-19. Therefore, the statements in the abstract, introduction, discussion, and conclusion should be consistent with this more cautious interpretation.

Response 1: We thank the Reviewer for this important observation. We carefully reviewed our manuscript to eliminate terms suggesting a direct or mechanistic “bridge” between inflammation and coagulation. The evidence presented indicates variable utility of PLR; therefore, we have focused on describing PLR as a biomarker that may support diagnostic processes and assist clinicians in predicting disease severity and mortality in patients with COVID-19. Reflecting changes in both platelet and lymphocyte counts, PLR may serve as a complementary parameter that aids in the interpretation of immune–hematological alterations observed in COVID-19-Associated Coagulopathy; however, further investigation is required. We believe that this revision adequately addresses the reviewer’s comments and meets the required standards.

The following changes were made throughout the manuscript:

In the Introduction, “(…) represent a significant prognostic marker during COVID-19.” was revised to “(…)represent a significant, non-specific prognostic marker during COVID-19” (Introduction, 104–105), and “(…) PLR can be considered a bridge linking inflammation and coagulation in COVID-19-Associated Coagulopathy.” was modified to “(…) PLR may be considered an indirect link between inflammation and coagulation in COVID-19-Associated Coagulopathy.” (Introduction, 159–161).

In the Results section, “(…) PLR demonstrates variable clinical relevance and as a biomarker measured (…)” was revised to “(…) PLR demonstrates variable clinical relevance as an indirect, non-specific biomarker measured (…)” (Results, 267–268).

In the Discussion, “PLR has been shown to reflect systemic inflammation and is associated with patient prognosis, making it a valuable prognostic marker” was revised to “PLR has been shown to reflect systemic inflammation and is associated with patient prognosis, suggesting that it may serve as a supportive parameter in predicting patient outcomes” (Discussion, 371–373), and “These findings highlight the potential of PLR as a valuable prognostic biomarker for evaluating the severity and risk of mortality in COVID-19 patients” was revised to “These findings highlight the potential of PLR as a parameter that may support the assessment of disease severity and mortality risk in COVID-19 patients” (Discussion, 378–379).

Finally, in the Conclusion, “PLR can serve as a predictive marker of COVID-19 progression, as it increases with disease severity.” was revised to “PLR can serve as an indirect, composite and non-specific marker of COVID-19 progression, as it increases with disease severity.” (Conclusion, 445–446), and “PLR can be considered an indirect bridge (…)” was revised to “PLR can be considered an indirect biomarker (…)” (Conclusion, 458).

Comments 2: Second, I recommend adding an explicit methodological note to the tables or results section indicating that PLR values are not directly comparable across all included studies due to differences in statistical reporting formats and the heterogeneity of the clinical outcomes assessed, including severity, ICU admission, ventilatory support, pulmonary thromboembolism, septic shock, and mortality.

Response 2: This is a highly valuable comment. It will undoubtedly enhance the quality of our manuscript and help clarify the inherent difficulties in direct interpretation of PLR across studies. The suggestion is highly pertinent and strengthens the methodological aspect of our work. In response to this comment, we have added a new paragraph at the end of the Results section. We hope that it will serve as a concluding remark to the interpretation of the obtained results and function as a limitation of the study.

Accordingly, we have added:

“Platelet-to-lymphocyte ratio values are not directly comparable across the included studies due to heterogeneity in study populations, including demographic differences, variability in disease severity definitions, and inconsistencies in statistical reporting formats. Despite the application of strict inclusion criteria, interpretation of PLR values should be undertaken with caution. Nevertheless, these limitations do not negate the potential diagnostic and prognostic value of PLR.” (Result, 320-325)

Comments 3: Third, I suggest reinforcing the methods and/or limitations section by stating that a formal assessment of the methodological quality and risk of bias of the included studies was not performed. Consequently, inferences about the diagnostic or prognostic performance of PLR should be presented as exploratory and descriptive, not as definitive conclusions about its independent or generalizable clinical utility.

Response 3: We thank the reviewer for this valuable comment. We agree that it is important to explicitly highlight that a formal assessment of methodological quality and risk of bias of the included studies was not performed. Accordingly, we have added the following statement to the Methods section: “A formal assessment of the methodological quality and risk of bias of the included studies was not performed.” (Methods, Statistical Analysis, 212–213).

In addition, we have expanded the Discussion section to clarify how this limitation affects the interpretation of our findings. This statement has been incorporated into the paragraph addressing the use of a single database, as both issues collectively represent methodological constraints that may hinder direct interpretation of the data.

“These sources of variability limit the comparability of AUC values and represent key limitations of our analysis, so conclusions about the predictive performance of PLR should be interpreted with caution. An additional limitation is that our scoping review was based on the analysis of only one database (PubMed). Furthermore, no formal assessment of methodological quality or risk of bias of the included studies was performed; therefore, the findings should be interpreted as preliminary and descriptive, providing a basis for future investigations into the utility of PLR.

Given the alterations in both immunological and hemostatic processes, which underlie immuno-thrombosis during COVID-19-Associated Coagulopathy, further research is warranted to clarify the diagnostic significance of PLR in COVID-19 patients.” (Discussion, 434-443)

We sincerely thank the reviewer for the constructive and insightful comments, which have significantly improved the quality of our manuscript.

Kind regards,

Maja Aleksandra Oksentowicz