PONE-D-22-09809Incidence of Sinus Thrombosis with Thrombocytopenia - a Nation-wide Register StudyPLOS ONE

Dear Dr. Hovi,

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.

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PLOS ONE

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The current study received no external funding outside THL and there are no conflicting interests. Finnish Institute for Health and Welfare (THL) conducts Public-Private Partnership with vaccine manufacturers and has received research funding from Sanofi Inc., Pfizer Inc., and GlaxoSmithKline Biologicals SA.  AAP, TN, JJ, ER, and TK have been investigators in these studies, but they have received no personal remuneration. P.H. reports being, in 2016 and 2017, a member in an expert group “Future Rheumatology Advisory Board”, funded by Pfizer.

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The current study received no external funding outside THL and there are no conflicting interests. Finnish Institute for Health and Welfare (THL) conducts Public-Private Partnership with vaccine manufacturers and has received research funding from Sanofi Inc., Pfizer Inc., and GlaxoSmithKline Biologicals SA.  AAP, TN, JJ, ER, and TK have been investigators in these studies, but they have received no personal remuneration. P.H. reports being, in 2016 and 2017, a member in an expert group “Future Rheumatology Advisory Board”, funded by Pfizer.

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Reviewers' comments:

Reviewer's Responses to Questions

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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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3. 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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4. 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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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: The introduction of thrombosis in unusual regions, including cerebral venous sinus thrombosis(CVST), by SARS-CoV-2 vaccines, caused a major public concern. Although vaccine-induced CVST is rare, for instance, 0.55 per 100,000 person-months in the first month after 7,126,434 vaccination in Germany, the affliction of young and previously healthy people makes it a critical area of research.

 This is a cohort study to investigate the association between COVID-vaccination and the evolution of CVST. Authors showed that only 2 out of 117 patients with CVST fulfill the criteria of CVST associated with vaccine-induced thrombosis and thrombocytopenia(VITT). In the other word, the rate of CVST-VITT was about 1 per 100.00 adult population. 

Research design is sound. Methods are adequately described, and results are clearly presented. Some significant issues should be addressed, though:

Method:

-“ The date of the first contact to hospital resulting in a relevant CVST diagnosis indicated disease onset” seems to be obscure. The authors should clearly differentiate between the date of admission and the date of first clinical presentation ( the date of onset)

-“Original radiological images were not reviewed.”. it should be considered a drawback.

- It should be mentioned that using the nationwide registry supervised by reviewers decreased the risk of false positives; however, some false-negative cases, particularly mild cases of CVST with an isolated headache, might be overlooked.

-Were there any patients diagnosed only by antigen detection method rather than PCR?

Results

-“We detected 167 register-based CVST episodes in 156 subjects”. Seven percent risk of recurrence in a 15-month period of observation is unusual. Authors should justify this result.

-Table-2

Concomitant diseases, which were mentioned in table-2 are not the most important predisposing factors for CVST. Provocative predisposing factors for CVST include pregnancy, puerperium, OCPs, infections, head injury, and dehydration. Non-provocative factors include inherent conditions such as acquired or genetic thrombophilia, malignancies, hematologic diseases, and inflammatory diseases. Some of them, such as SLE, antiphospholipid antibody syndrome, leukemia, and some medications, can induce both CVST and thrombocytopenia; and should be excluded for diagnosing VITT. However, they were not mentioned in the manuscript.

- The status of anti-platelet factor 4(PF4) antibodies was mentioned

Discussion:

The discussion part is too long.

Limitations of the study were not mentioned.

Reviewer #2: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the adenoviral vector based SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford–AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Using nationwide registers, the authors estimated the incidence of CVT and CVT with thrombocytopenia since 2020 to established whether vaccines against SARS-CoV-2 were associated with increased risk of CVT with thrombocytopenia.

Comments and suggestions are listed below:

1. Thrombocytopenia is a key feature of the vaccine-induced immune thrombotic thromcytopenia syndrome (VITT). However, the authors have not addressed this in their analysis of ADRs. This should be acknowledged as a major limitation.

2. The authors say in the results that CVT occurring within 28 days was considered. However, this is not detailed in the methods. Case definition and adjudication should be better described in the methods section.

3. the number of events is small (only 2 patients with CVT and thrombocytopenia after vaccination, only 200.000 subjects vaccinated with ChAdOx 1 nCov-19). For this reason, there is substantial imprecision in the estimates that are provided (very large confidence intervals). The discussion on the study limitations should be expanded.

4. Three physicians revised all suspected clinical cases. Please explain whether these clinicians were neurologists or physicians with a special expertise in cerebrovascular diseases.

5. If possible, the authors should consider describing what were the causes/comorbidities in patients with thrombocytopenia and CVT, particularly those that may justify concomitant thrombocytopenia. Information on the range of platelet values would be also useful (less severe thrombocytopenia in patients without VITT?)

6. A more recent study which was based on pharmacovigilance data from the EEA (doi: 10.1212/WNL.0000000000013148) provides more updated information than the EMA report that has been cited in Supplementary table 1 (reference 6). Consider updating that.

7. Previous studies, such as doi: 10.1212/WNL.0000000000013148, have also not found an increased risk of CVT in recipients of mRNA vaccines against SARS-CoV-2. Consider discussing that.

8. No data is provided for Ad26.COV2.S. The reasons for this should be explained.

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Reviewer #1: Yes: Afshin Borhani Haghighi

Reviewer #2: No

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PONE-D-22-09809R1Incidence of sinus thrombosis with thrombocytopenia: A nationwide register studyPLOS ONE

Dear Dr. Hovi,

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 by one of the reviewers.

Please submit your revised manuscript by the Feb 19 2023 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,

Roza Chaireti

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 #1: All comments have been addressed

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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

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 #1: Yes

Reviewer #2: No

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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

**********

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: Dear Editor,

I still have some concerns about the manuscript:

Response #1 – 5

The authors response is ambiguous. They should directly declare in the manuscript why

they had 167 register-based CVST episodes in 156 subjects in a 15-month period of observation in the first revision.

The changed manuscript “In our data, 2 of the 117 patients presented with more than a single [confirmed CVST] episode during the study period.” did not reply my argument

Response #1 – 6:

I agree that “We only detected two cases and were unable to perform formal analysis that take concomitant disease into account”. However, the authors should clearly declare in the method part that conditions which can induce both CVST and thrombocytopenia was excluded for diagnosing VITT.

Reviewer #2: Thank you for the revised manuscript and for your responses to each of the comments made in the previous review of this submission.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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.

Incidence of sinus thrombosis with thrombocytopenia: A nationwide register study

PONE-D-22-09809R2

Dear Dr. Hovi,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Roza Chaireti

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #1: (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: (No Response)

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

Reviewer #1: (No Response)

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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: (No Response)

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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: (No Response)

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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)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Afshin Borhani-Haghighi

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