Dear Dr. Nakayama,

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PLOS ONE

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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?

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Partly

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

**********

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.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

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

Reviewer #1: Overall impression:

• The manuscript addresses an important and novel topic.

• Major revisions are required for clarity, structure, and reproducibility, particularly in Methods and Results.

• Minor edits for grammar, terminology, and flow will enhance readability and impact.

• After revisions, the manuscript could provide a valuable contribution regarding FXIII deficiency in LIC and its clinical implications.

Suggestions:

Major

• Introduction lines 69-74: “These facts led us to survey the activity of FXIII … but the decrease in FXIII was limited”. Information provided is inappropriate for an Introduction and should rather feature under Results. The final paragraph should explicitly state the study aim/s and highlight how this study addresses the identified gap.

• Methods section: The paragraph is dense and difficult to follow. Suggest dividing it into paragraphs or subsections to improve clarity.

• Methods lines 76-79: This initial sentence is difficult to read. Suggest “Between July 2017 and March 2023, clinicians retrospectively identified patients with vascular anomalies or traumatic injuries who presented with bleeding symptoms and/or abnormal coagulation markers (e.g., elevated FDP)”

• Methods line 80: Explicitly state what the second set of dates were used for. Suggest: “Clinical records were accessed for research purposes between October 3, 2024, and December 11, 2024.”

• Methods section: This section is incomplete with the following details missing:

o Clear inclusion criteria (define abnormal coagulation markers; It is not clear whether both patients with vascular anomalies and those with traumatic injuries were included in the same cohort, or whether trauma patients served as a comparison group)

o Clearly indicate if whether exclusion criteria were applied

o Define “above a certain size” - line 86

o Clarify the timing of DIC scoring and FXIII levels

o Define how the following will be identified:

� Coagulopathy and chronic coagulopathy

� bleeding tendency

� fibrinolytic phenotype

• Statistical analysis section: This section is incomplete and does not cover all statistical analyses performed. Additional, statistical significance is not defined.

• Results section: Ensure statistical reporting is consistent (R values and P values for all correlations, where possible).

• Discussion section: Link the cases under Results to specific points in the Discussion.

• TABLE 1: Review abbreviations list in legend - AAA is incorrectly written in full as “thoracic aortic aneurysm”.

Minor

• Abstract line 30: Review the use of “;”. Suggest removing “;” to read “We collected plasma from 17 patients with LIC (9 with aneurysms and 8 with vessel malformations)…”

• Abstract line 32: suggest replacing “..measured FXIII contents” with “..measured FXIII levels”.

• Abstract line 33: suggest removing “actually” from “..13 of 17 patients actually showed bleeding tendency …”.

• Abstract line 41: Grammar – add “s” to “level”. Should be “… considered in LIC patients even with normal fibrinogen levels, who are…”

• Introduction line 59-60: regarding “However, LIC patients with normal levels of platelets and fibrinogen can be hemorrhagic for unknown reasons”, add a reference or clearly state that this is a personal clinical observation.

• Results lines 105 and 108: “..decreased (Table 1; 7 to 59%, mean 33.1%)”. Suggest revision of how results are written. Suggest “…decreased (mean 33.1%, range 7 to 59%) as shown in Table 1”. Review similar for line 108.

• Results line 114: “fibrinogen content” should rather be “fibrinogen level”

• Discussion section: Some sentences are overtly long and for readability, suggest long sentences are broken down to 2-3 sentences

Reviewer #2: The manuscript from Otsubo et al examines FXIII levels in patients with localized intravascular coagulopathy (LIC) vs those with trauma induced coagulopathy (TIC). The authors suggest that LIC is marked by profound FXIII reduction whereas TIC is not and that the level of FXIII in LIC patients positively correlated with circulating fibrinogen levels, but not other markers of coagulation factor levels and function. Two brief case reports are also presented. The strength of the manuscript is that this is one of the first to examine FXIII levels as a possibly being linked to bleeding in LIC. The weaknesses of the manuscript is the limited N number of patients in the cohorts, overstating of some conclusions, and that the case reports really provide nothing substantive to the report. I have several specific comments for authors to consider.

- The authors claim that “FXIII levels in plasma obtained from all 17 patients were significantly decreased.” However, 4 of the 17 patients have a reduction of FXIII less than 50%. Should that be considered a significant reduction? This reviewer is skeptical.

- The authors claim that TIC patients “FXIII levels were only slightly decreased”. However, but there is significant overlap in the data between LIC and TIC, thus the conclusions drawn between the two groups appears to be overstated.

- No statistical analyses are performed to attempt to document bona fide differences in FXIII between the 2 groups. This is likely due to limited N numbers of patients in each group. Additional N should be evaluated to draw definitive conclusions.

- For Figure 1, the different graphs should be labeled A, B, C, etc. In addition, P values and R values for each analysis should be displayed on the graphs.

- The strongest correlation is between FXIII levels and fibrinogen levels. However, this is not surprising as effectively all FXIII A2-B2 circulates bound to fibrinogen. If fibrinogen is lost/consumed FXIII will be as well. This should be noted.

- The case presentations add nothing to this report as they are anecdotal and fail to individually support the conclusions of the authors. In case 1 both fibrinogen and FXIII is administered, thus it is difficult to know whether it was FXIII specifically that restored hemostatic potential. For case 2, FXIII was clearly administered but were other therapies also given that could improve in neurological symptoms documented. More information is needed to determine whether this case is an example of FXIII conferring a benefit or not.

Reviewer #3: The authors describe a case series of 17 patients with localized intravascular coagulopathy and investigate the role of Factor XIII in these disorders. The authors find decreased FXIII levels in these patients. They also find that FXIII and fibrinogen levels correlate in LIC patients.

While the manuscript is overall interesting, it is very descriptive and needs further work:

Line 62: Please explain the role of FXIII in the coagulation cascade in more detail, especially its interaction with fibrinogen

Line 92: Did you assess other coagulation factors, Willebrand factor and platelet function?

Table 1: thoracic instead of thorasic, also please specify all abbreviations you have used in this table. It might be helpful to also show normal ranges for each assessed lab value.

Line 132: please list the amount per kg of FXIII.

Line 150: you are referring to several case reports, but you are only citing one reference here.

Line 165: please go into more detail why there might be a correlation between FXIII and fibrinogen

Reviewer #4: In general, this manuscript describes FXIII activity levels in patients with localized intravascular coagulopathy (LIC, n=17) and those with trauma-induced coagulopathy (TIC, n=7), along with a description of their bleeding tendencies and other coagulation parameters. The results show that FXIII activity is critically decreased in patients with LIC, but not in those with TIC. The authors also report a new correlation between FXIII activity and fibrinogen levels in LIC patients.

These findings represent the main contribution of the manuscript and constitute a novel and valuable observation that merits publication.

In the second part of the manuscript, the authors provide a more detailed description of two LIC clinical cases. FXIII concentrate was administered, in addition to other hemostatic products, due to intraoperative excessive bleeding (case 1) and chronic subdural hematoma (case 2), with good bleeding control in both cases. Based on these observations, the author’s state that “FXIII supplementation must also be required for patients with LIC undergoing emergency surgery or experiencing bleeding” (lines 196–198 of the Discussion).

However, these conclusions cannot be supported based on the observation of only two clinical cases. In particular, in case 1, the patient presented several coexisting factors that could have contributed to bleeding (low fibrinogen levels and thrombocytopenia). In case 2, the etiology of the chronic subdural hematoma is not clearly explained—was it spontaneous or traumatic? Furthermore, in case 2, the use of FXIII supplementation is highly debatable, since the FXIII level (41%) is above the minimal hemostatic threshold.

The description of these two clinical cases represents the weakest section of the manuscript and requires revision.

More detailed revision is below, and is divided into two sections: Major Revisions and Minor Revisions.

MAJOR REVISIONS

1. FXIII supplementation as a hemostatic agent

The main and most controversial issue concerns the recommendation of FXIII supplementation. The manuscript does not provide sufficient evidence to justify recommending FXIII supplementation for bleeding management in LIC patients. The two clinical cases described involve multiple bleeding risk factors, and while bleeding improvement following FXIII administration may suggest a possible effect, this interpretation remains highly questionable. In particular, in case 2, an FXIII level of 41% cannot be considered indicative of a deficiency requiring replacement therapy.

Therefore, the conclusion stated in lines 196–198 should be revised.

It is important to note that the role of FXIII supplementation in acquired FXIII deficiency remains controversial. The International Society on Thrombosis and Haemostasis (ISTH) specifically recommends against the use of FXIII concentrates for the management of perioperative bleeding, as the benefits are unproven in acquired FXIII deficiency contexts [Godier A, Greinacher A, Faraoni D, Levy JH, Samama CM. Use of factor concentrates for the management of perioperative bleeding: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16(1):170–174].

The inclusion of this reference in the bibliography is recommended.

2. Title

The reference to “FXIII supplementation” in the title should be removed, as the manuscript does not present sufficient data to support its use. The title should instead emphasize the main findings—the differences in FXIII levels between LIC and TIC patients.

3. Introduction

The section addressing acquired FXIII deficiency (lines 65–68) should be expanded. A more comprehensive discussion of the literature is needed, including information on conditions in which FXIII supplementation has been proposed, the FXIII activity thresholds that justify supplementation, and the minimal hemostatic levels reported in the literature.

4. Patients and Methods

The method used to assess FXIII activity should be clearly stated.

MINOR REVISIONS

1. Patients and Methods: When referring to DIC scores, it is recommended to include more recent references (see below).

Suggested references:

• Wada H, Thachil J, Di Nisio M, et al. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11: 761-767.

• Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br J Haematol 2009; 145(01): 24-33.

2. Results: The correlation between FXIII activity and coagulation parameters in patients with TIC should be addressed, since this group serves as the control population being compared with LIC patients.

3. It is suggested that the table titles be improved for greater clarity.

Suggestion: “Clinical and laboratory profiles of patients with localized intravascular coagulopathy/trauma-induced coagulopathy”

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

**********

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Dear Dr. Nakayama,

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.. 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.. 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.. 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.

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• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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 . 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 . 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 . 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,

Mehmet Baysal

Academic Editor

PLOS One

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. 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.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: 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.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

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

Reviewer #1: Some minor comments:

- Suggest the study aim/s is/are clearly stated in a sentence in the final paragraph of the Introduction rather than just summarizing the findings.

-Given the small sample size, suggest adding a sentence indicating that the statistical analyses are exploratory and hypothesis-generating.

Reviewer #2: The authors were partially responsive to critiques from review of the original manuscript. Minor changes were made to the manuscript but the fatal flaws still exist. The study is significantly underpowered to draw meaningful conclusions and the case reports continue to be anecdotal.

For the statistical analysis of the FXIII levels in LIC vs TIC patients, the authors used a student T-test. This relies on a normal distribution of the data. The authors should have performed normality testing to determine if the T-test was valid as opposed to a nonparametric analysis.

Reviewer #3: Thanks for changing the manuscript, which has improved its overall quality. For the p-values, I would appreciate a tiered report with an additional description in the methods, such as statistically significant = <0.05, reporting p-values ≥0.05 to 0.1, and writing n.s. for p-values ≥0.1. Thanks.

Reviewer #4: General Comments

The authors have substantially revised the manuscript and have addressed most of the reviewer’s comments. However, some minor issues and corrections remain, mainly within the Discussion section, in order to clarify specific points related to FXIII levels and FXIII supplementation.

These issues are detailed below.

________________________________________

1. Introduction

1.1. In Major Comments, point 3, the reviewer requested that the minimal hemostatic levels of FXIII reported in the literature be stated. This information is still missing in the revised version of the manuscript.

It is recommended that this data be added at the end of line 80.

1.2. Lines 70–71: There is a repetition of words that should be corrected.

2. Patients and Methods

Blood Testing

It should be stated that some patients also underwent measurements of von Willebrand factor (vWF), as this parameter is mentioned in the Results section (lines 140–142). Please specify which test was used (e.g., vWF activity, vWF antigen [vWF:Ag], vWF ristocetin cofactor activity [vWF:RCo], or another assay).

In line 140, the phrase “activities of von Willebrand factor” should be corrected to either “von Willebrand factor activity” or “von Willebrand factor level”.

3. Results

The sentences from lines 152 to 155 are unclear due to issues with the English language. Please revise this paragraph to improve clarity and readability.

4. Discussion

Several deficiencies remain in the Discussion section.

4.1. The sentence in lines 190–192:

“Kleber et al. suggested that a cut-off for FXIII activity of <50–70% may be appropriate to diagnose acquired FXIII deficiency, although opinions and protocols may vary [16].”

Should be revised to:

Kleber et al. suggested that a cut-off for FXIII activity of <50–70% may be appropriate to diagnose acquired FXIII deficiency; however, this range is very broad, and opinions and diagnostic protocols may vary [16].

4.2. The sentence in lines 193–195:

“Here, we showed that FXIII was considerably decreased in all cases with vascular anomalies (Table 1; mean 33.1%, range 7–59%) while acquired FXIII deficiency was limited in TIC patients (Table 2; mean 67.4%, range 39–98%), as reported previously.”

Should be revised to:

Here, we showed that FXIII was decreased in some cases with vascular anomalies (Table 1; mean 33.1%, range 7–59%), whereas acquired FXIII deficiency was not present in TIC patients (Table 2; mean 67.4%, range 39–98%), consistent with previous reports.

4.3. Line 198: Please remove the word “substantial”.

4.4. Lines 209–213:

Instead of:

“In TIC patients, FXIII levels were most strongly correlated with APTT (R = −0.884, P < 0.05) and PT-INR (R = −0.798, P < 0.05), as described above. These results suggest that LIC and TIC show similar fibrinolytic phenotypes, but the underlying mechanism is quite different.”

Use:

In TIC patients, FXIII levels did not correlate with fibrinogen levels and were most strongly correlated with APTT (R = −0.884, P < 0.05) and PT-INR (R = −0.798, P < 0.05), as described above. These findings suggest that LIC and TIC may exhibit similar fibrinolytic phenotypes; however, the underlying pathogenic mechanisms are quite different.

4.5. Line 214: Please remove the expression “as to”.

4.6. Line 215: Please remove the word “the” in the phrase “the proposition”.

4.7. Lines 238–239:

The following sentence should be divided into two sentences:

“However, the role of FXIII supplementation in acquired FXIII deficiency remains controversial as the International Society on of Thrombosis and Haemostasis specifically recommends against the use of FXIII concentrates for the management of perioperative bleeding because the benefits are still unproven [11].”

Suggested revision:

However, the role of FXIII supplementation in acquired FXIII deficiency remains controversial. The International Society on Thrombosis and Haemostasis specifically recommends against the use of FXIII concentrates for the management of perioperative bleeding, as the clinical benefits remain unproven [11].

**********

what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

**********

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Attachments

Attachment

Submitted filename: Second Reviewer Comments PONE-D-25-44108R1.docx

<p>Low FXIII activity levels in patients with vascular anomalies, not in patients with trauma-induced coagulopathy

PONE-D-25-44108R2

Dear Dr. Nakayama,

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.

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Mehmet Baysal

Academic Editor

PLOS One

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

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

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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.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 #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: No

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Reviewer #1: This is a clinically relevant study, but conclusions are too strong - the data show an association between low FXIII and LIC, not that it causes bleeding, especially without comparing bleeding vs non-bleeding patients. Also the case reports cannot prove that FXIII treatment was effective. The results are hypothesis-generating and should be interpreted more cautiously. Otherwise, no further edits needed in my opinion.

Reviewer #3: The authors have addressed all issues raised by the four reviewers in the last revision. Therefore, the I accept this revision for publication.

Reviewer #4: The revised manuscript is significantly clearer and provides more detailed information, which greatly enhances the understanding of the work.

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Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

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