PONE-D-24-44281Enhanced prediction of thrombotic events in hospitalized COVID-19 patients with soluble thrombomodulin.PLOS ONE

Dear Dr. Padilla,

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2. Thank you for stating the following financial disclosure: This work was supported by Spanish National Plan for Scientific and Technical Research and Innovation, European Regional Development Fund (ERDF) and Instituto de Salud Carlos III (RD16/0025/0038, PI16/01740, PI18/01861, CM19/00160, CM20/00066, COV20/00005, CM21/00186, CM22/00026 and PI22/01949); Consorcio Centro de Investigación Biomédica en Red (CIBER), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and European Union – NextGenerationEU (CB21/13/00011); ILISABIO programme, UMH-FISABIO, Generalitat Valenciana (A-32 2020); Consellería de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana (AICO/2021/205); and funded by Conselleria de Sanitat Universal i Salut Pública (Generalitat Valenciana, Spain) and the EU Operational Program of the European Regional Development Fund (ERDF) for the Valencian Community 2014–2020, within the framework of the REACT-EU program, as the Union’s response to the COVID-19 pandemic (FEDER-COVID-23).  

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a nested case control study of patients with COVID-19 and examined the utility of sTM and ang2 as predictive markers for TE.

It is well executed and well written study, however, there are some major shortcomings that directly impact the scope of this work.

- In the introduction, authors have mentioned the limitations of D dimer and that it is non specific for thrombosis. I would argue the same is true for soluble thrombomodulin. It is a marker of endothelial injury, and as a result can be elevated at the time of thrombosis, multi-organ injury, respiratory failure, etc.

- Authors mentioned about routine CTPA to rule out PAT. How about 4 extremity doppler ultrasound? If that was not done routinely with CTPA, is there a chance that an extremity DVT was missed and people were inappropriately assigned to the no thrombosis category? Please clarify.

- Authors acknowledge that D dimer is a not a great marker for arterial thrombosis in their discussion. It will be helpful to compare ROC curves for D dimer with and without sTM to truly understand if indeed sTM is a better predictor for arterial thrombosis than D dimer or not.

Reviewer #2: The authors measured serum levels of sTM, Angiopoietin-2 and D-Dimers in 73 patients developing thrombotic events (TE) within 28 days of hospital admission and 297 patients without TE.

Comments:

1. The Biomarkers were measured closest to TE in the 73 positives, but at hospital admission for the other patients. This does not work. The analysis can either aim to be predictive, then all measurements have to take place at hospital admission. Or the analysis is diagnostic, then all measurements need to take place on matched days after hospital admission, or else a time course can be shown for all patients from hospital admission to days 5 - 10 - 28 comparing patients with and without TE.

2. The Discussion emphasizes the predictive nature of the results, then values measured at hospital admission have to be shown, but removal of the 20 patients with TEs after day 28 is not justifiable.

3. This correction of timing should also include all lab values (Table 1).

4. Multivariate logistic regressions include D-Dimers, sTM, IL-6 and RT-PCR-cycle threshold. I cannot understand this selection - either include clinically meaningful variables (age, sex, comorbidity etc.) or else include all variables significant in univariable logistic regression from Table 1.

5. Figures 1 and 2: TE until day28? Overall mortality is a time dependent event, Cox regression should be used.

6. Figure 3: sTM mono is lacking – any difference to sTM+D-Dimer?

7. Figure legends are too short and do not explain what was done and what is seen. Worst example is suppl. Figure 3, I do not understand it.

8. P8 line 197: no mortality risk of PAT is shown in suppl. Table 3.

9. P10 line 223: D-Dimers did not correlate with Angoipoietin-2.

10. Figure S4 – please find an easier way of labeling the plots with rho and p-values. Always give the values for p, no stars.

11. P10 line 234: give p-value for statement.

12. P10 line 235 – mortality is a time-dependent event, what exactly is reported?

13. Discussion: all arguments relate to a predictive value of the biomarkers, but this requires measurement at hospital admission.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-44281R1Enhanced prediction of thrombotic events in hospitalized COVID-19 patients with soluble thrombomodulin.PLOS ONE

Dear Dr. Padilla,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Mar 08 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Hideto Sano

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Please review the reviewers’ comments and make the necessary revisions.

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Reviewers' comments:

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1:  (No Response)

Reviewer #2:  Thank you for revising the manuscript.

I still have a problem with Figure 1, see my former comment 12.

Mortality is a time dependent event. For a KW-test looking at mortality in a binary way, the time frame for mortality has to be reported (e.g. 1-year mortality, then only include patients who died before or reached the landmark, take out patients with LFU before the landmark).

Figure legends are better now, but Figure 1 shows a and b, the legend reports a-d.

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Reviewer #1: No

Reviewer #2: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Enhanced prediction of thrombotic events in hospitalized COVID-19 patients with soluble thrombomodulin.

PONE-D-24-44281R2

Dear Dr. Padilla,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Hideto Sano

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: ok, no further comments

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Reviewer #2: No

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