Mean Platelet Volume Used as a Potential Negative Predictor in Patients with Heart Failure; Hypothesis Based on Statistical Modeling

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comments 1: According to the retrospective study, the relationship between high MCV value and severe HF has been demonstrated. However, I doubt the word “predictor” used in the title. More evidence for the predictive value of MCV on heart failure should be provided.

Response 1: Thank you for pointing this out. I agree with the fact that the word “predictor” used in the title is probably too ambitious, but based on the arguments that I will present below we can sustain that mean platelet volume (MPV) could be a potential negative predictor in patients with heart failure (HF). The evidence by which it could be stated that MPV could be a potential negative predictor in HF is highlighted in the section Results regarding the relationship between MPV value and 3-month rehospitalization, 6-month rehospitalization, 1-year mortality and number of days of hospitalization (see in detail subsection 3.4, 3.5, 3.6, 3.7). As a conclusion from the above-mentioned subsections, the negative events represented by 3 and 6-month rehospitalization, 1-year mortality, and increased number of days of hospitalization are considered elements of poor prognosis in HF patients. The results from our research pointed out that patients with the above-mentioned events had an increased value of MPV and by applying regression model analysis the statistical results showed us that as the MPV value increases, there is an increased probability of patients with HF to be rehospitalized at 3 months, 6 months, to die at 1 year or to have an increased number of days of hospitalization. Therefore, based on these results, which were statistically significant since the p value for each result was below 0.05, we could state that MPV could be a potential negative predictor in HF patients. Based on your review I understand that it is wise to change the expression within the title into a suitable one (see the revisions within the title highlighted in red).

Comments 2: Based on the relationship between platelet and heart failure, is there other parameters of platelet been proved as an indicator of heart failure?

Response 2: Thank you for the question. Our study was focused only on mean platelet volume (MPV) in the population of patients with heart failure (HF). In the current medical literature, there are few studies cited (the study conducted by Hakki K. et al., Budak Y. et al., Kandis H. et al., Nassiba M. et al.– see the studies in detail in the Introduction section, paragraphs 73-109) which were focused only on MPV value, and which demonstrated that MPV could be a prognostic parameter in HF patients. Regarding the available studies focused on the relationship between other platelet indices and heart failure, there is only one study cited in the current medical literature such as the one conducted by Bianca Dahlen et al. who focused on MPV and platelet to leukocyte ratio, revealing that platelet indices are linked with worse cardiac function and adverse clinical outcome in HF patients (see study in detail in Introduction section – paragraphs 110-116). The main objective of our research was to add novelty to the current medical research regarding MPV as a prognostic parameter in HF. Knowing that a simple parameter such as MPV (which is found in the componence of any hemogram) could provide us knowledge regarding the prognosis of HF patients, is an element of importance because through it we could identify the HF patients at risk and therefore treat them in advance to prevent negative events.

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comments 1: Lot of typo errors.

Response 1: Thank you for pointing this out. I revised the typing errors and made the necessary corrections (see the corrections highlighted in red in the revised manuscript).

Comments 2:  Images are so poor quality.

Response 2: Thank you for the review. I agree that the images from the Manuscript are of poor quality probably due to the manuscript format. Therefore, I have uploaded the Supplementary files represented by the figures in pdf. format which is of better quality. 

Comments 3: Supplementary files and Main manuscript files are same, so confusing to correlate.

Response 3: Thank you for pointing this out. I agree that the Supplementary files and Main manuscript files are the same and I apologize if this was confusing. The reason for this aspect was due to the poor quality of the images within the Manuscript, therefore the reason for providing Supplementary files with the figures in pdf. format which is of better quality. 

Comments 4: Rewrite the discussion and conclusion.

Response 4: Thank you for the suggestion. I followed your advice and rewrote the discussion and conclusions in a proper manner (please see section 4. Discussion and 5. Conclusions with the corresponding revisions highlighted in red).

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comments 1: Selection of several patients is fixed, or any sample size calculation?

Response 1: Thank you for pointing this out. Regarding the sample size, we included in our database all the patients admitted to the Cardiology Department of the Emergency Clinical Hospital Bagdasar-Arseni, between January 2017 and January 2019, of which we selected 260 patients who met the inclusion criteria for the variables that we have proposed to analyze (see the revisions highlighted in the Methodology section, paragraphs 139-162).

Comments 2:  The authors put an equation for calculating probabilities in the result section. I recommend adding it to the methodology section itself for better understanding.

Response 2: Thank you for the suggestion. I followed your advice and added the calculating mathematical formula and equation in the methodology section for better understanding (see paragraphs 188-192 highlighted in red in the Revised Manuscript uploaded).

Comments 3: Introduction needs to be improved by putting more recent publication and their interpretation.

Response 3: Thank you for pointing this out and thank you for the suggestion. I followed your advice and improved the Introduction section (see paragraphs 73-122 highlighted in red in the Revised Manuscript uploaded).

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comments and suggestions for authors:

Suggestion 1: Abstract: Indicate methods the type of study developed; in the results section, add the statistical significance reported.

Response 1: Thank you for the suggestion. The revisions suggested can be found highlighted in red in the Abstract.

Suggestion 2: Introduction: The medical and health context related to heart failure should be briefly presented, highlighting its clinical importance and challenges. The relevance of research in the field of heart failure and how it can contribute to improving the management of this disease should be enhanced. Concisely summarize previous knowledge on heart failure and any existing literature related to mean platelet volume as a possible predictor. Finally, identify the lack of information or limitations in previous research that led to the need for this study.

Response 2: Thank you for the suggestion. I followed your advice and made the necessary revisions in the Introduction section. The revisions are highlighted in red, paragraphs 73-122.

Suggestion 3: Methodology:  The organization should be improved. I suggest establishing study design and study population, data collection, statistical analysis, and ethical information. The wording is not clear. Precise inclusion and exclusion criteria should be established. Establish your sample size calculation and type of sampling. A specific table can be organized for chronic, stable, or decompensated heart failure criteria.

Response 3: Thank you for the suggestion. I followed your advice and improved the organization in the Methodology section. The revision suggested could be found highlighted in red (paragraphs 124-192).

Suggestion 4: Results: Should be presented with greater clarity. Review the acronyms used.

Response 4: Thank you for pointing this out and thank you for the suggestions. I have reviewed the acronyms and made the necessary corrections (highlighted in red).

Suggestion 5: Discussion: Establish a greater comparison of the main results with other published studies. The limitations and strengths of the study should be indicated. In addition, recommendations for future studies and the impact of the results as evidence in clinical practice.

Response 5: Thank you for the suggestions. I followed your advice and improved the Discussion section and added the strengths and limitations of the study. The revision suggested could be found highlighted in red (paragraphs 502-584).