PONE-D-24-43881Type 1 diabetes mellitus patients had lower total vitamin K levels and increased sensitivity to direct anticoagulantsPLOS 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?

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

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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

Reviewer #3: No

Reviewer #4: No

Reviewer #5: 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: No

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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: Goodpaperwith enough information. However there is an important issue. For these outcome measures, the sample size is so limited. Because of lots of dropouts , it was needed to have more participants. You did not mention how to estimate sample size in method section. Moreover, I did not see the limitation part.

Reviewer #2: This manuscript, titled "Type 1 Diabetes Mellitus Patients Had Lower Total Vitamin K Levels and Increased Sensitivity to Direct Anticoagulants," explores an intriguing and clinically significant intersection between diabetes mellitus, coagulation pathways, and the efficacy of anticoagulants. The study aims to shed light on potential differences in anticoagulant sensitivity between patients with type 1 diabetes mellitus (DMT1) and healthy individuals, while also examining the role of vitamin K levels in mediating these differences.

The research is notable for its direct comparison of different classes of anticoagulants and its attempt to correlate biochemical markers with coagulation outcomes. However, the manuscript, as submitted, has several areas that warrant substantial revision. Addressing these issues will not only enhance the scientific rigor of the work but also its potential impact on clinical practice and public health.

The following detailed review outlines specific recommendations for improving the manuscript:

Abstract

p. 2, lines 25–46:

The abstract lacks a concise statement of the clinical or public health relevance of the findings. How these findings might influence current clinical practices is not well articulated.

Terms like "paradoxically better lipid profiles" need clarification; such phrasing is ambiguous without context.

The results are described without confidence intervals, p-values, or other statistical measures, which are essential to substantiate claims.

Introduction

p. 3, lines 61–66:

The introduction does not sufficiently highlight gaps in existing literature to justify the study’s necessity. It assumes the audience is already aware of the limitations in current research on DMT1 and anticoagulation.

p. 3, lines 66–70:

Statements regarding the suitability of direct anticoagulants for DMT1 patients are broad and unsupported by specific prior studies or references.

p. 3, lines 78–90:

The description of coagulation assays lacks precision. Specific references to how these tests uniquely contribute to the study goals could strengthen the argument.

Methods

p. 5, lines 99–102:

No rationale is provided for choosing 50 participants per group. Was a power calculation conducted to ensure adequate sample size?

p. 5, lines 101–105:

The criteria are described but lack justification. For instance, why were individuals with hypothyroidism or hypertension included if these conditions could influence coagulation?

Control Selection:

The control group, described as “generally healthy,” is not defined rigorously. Are they comparable to DMT1 patients in lifestyle and diet?

Confounding Variables:

The study fails to address the influence of potential confounders such as inflammatory markers, diet, or medication use.

Results

p. 8–12:

The narrative description of results omits some key statistical details. For example, confidence intervals for effect sizes are not reported.

p. 9–12:

There is minimal discussion of non-significant findings. This could introduce bias in interpreting the data.

Ambiguity in Causality:

Correlations between vitamin K levels and coagulation outcomes are mentioned, but causation is implied without robust evidence.

Demographic Stratification:

While stratified analyses by age and BMI are conducted, their clinical implications are not clearly discussed.

Discussion

p. 14–17:

Claims regarding the protective effects of lower cholesterol and vitamin K levels in DMT1 lack robust evidence. The discussion overstates the findings’ implications.

Confounding Factors:

The potential influence of unmeasured variables (e.g., inflammatory states or micronutrient deficiencies) is not adequately acknowledged.

Comparison to Prior Studies (p. 14):

The discussion does not sufficiently critique or compare the study's results with contradictory findings from other research.

Limitations (p. 17):

Limitations are inadequately addressed. For example, no mention of the small sample size or lack of long-term follow-up is made.

p. 18:

The conclusion is overly broad and lacks actionable insights for clinical practice.

Reviewer #3: The authors performed an interesting study. There are potential issues in methodology and thus interpretation of results. Specifically, I have the following comments:

1. I am not sure whether PT/APTT are regularly used to assess the prothrombotic burden

2. Similarly, PT/APTT may not be the standardised way to measure the anticoagulation effect of DOACs

3. Similarly, APTT instead of PT should be used to measure the effect of heparin

4. As the authors have noted, it was quite surprising that DMT1 individuals had lower levels of total cholesterol and LDL. Any possible explanation?

5. It was unclear why the authors performed subgroup analysis according to BMI. More elaboration is needed

6. Did the authors perform analysis correlating the strength of (anti-)coagulation and markers of insulin resistance?

7. Were there studies reporting an association between shortened PT/APTT and atherosclerotic risk?

8. Testing of anticoagulant level seems clinically more relevant than testing the effect at equimolar concentrations

9. The authors may consider performing a mediation analysis to support the findings

10. Please elaborate more on potential clinical implications and limitations

Reviewer #4: 1. Grammatical and Orthographic Review:

The manuscript is largely well-written with minor grammatical issues and awkward phrasing in some places. These areas could benefit from small revisions for clarity and flow:

Abstract: The sentence "There is, however, no effect comparison among different direct anticoagulants" could be more clearly phrased as "However, no comparative studies have been conducted on the effects of different direct anticoagulants."

Introduction: The transition from general coagulation background to diabetes is slightly abrupt. A smoother transition, linking diabetes-specific coagulation issues with broader coagulation principles, would improve clarity.

Methods: The description of chemical treatments and drug concentrations is concise, but the sentence "Heparin and dabigatran treatment resulted in longer coagulation in DMT1 when compared to healthy individual in both tests" can be improved to "Heparin and dabigatran treatments resulted in prolonged coagulation in DMT1 patients compared to healthy individuals in both tests."

Figures and Tables: Ensure that figure legends are consistently formatted. For example, "heparin (final concentration of 5 IU/mL)" could be "Heparin (5 IU/mL final concentration)" for consistency.

Results: In the sentence "There were however clear differences in vitamin K levels," adding a comma after "were" would enhance readability: "There were, however, clear differences in vitamin K levels."

2. Scientific Rigor:

Design and Methodology: The study is well-designed, using both control and experimental groups, and applies standard biochemical methods. However, it could benefit from more detailed information regarding the statistical tests used for each analysis. For example, when reporting results from the Student's t-test or the Mann-Whitney test, it's important to note the specific assumptions or conditions under which each test was applied, particularly since they differ in handling data distribution.

Cohort: The study is limited to a sample size of 50 DMT1 patients and 50 healthy controls. While this is a reasonable sample size for pilot studies, larger cohorts may be required to validate the findings robustly and examine variability across different subgroups (age, gender, comorbidities).

Data Presentation: The data is presented well in tables and figures, but ensuring that all statistical analyses are well-documented in the methods section (for reproducibility) is crucial. The authors might also consider adding confidence intervals for their estimates, which would provide more transparency and insight into the statistical reliability of their findings.

Vitamin K Levels: The study finds that DMT1 patients have lower total vitamin K levels compared to healthy controls, which is an intriguing result. However, the authors could further discuss the possible mechanisms behind this, referencing other literature on vitamin K and diabetes, especially in terms of bioavailability or altered metabolic pathways in DMT1 patients.

3. Scientific Impact:

The paper provides valuable insights into how DMT1 patients may experience altered coagulation and increased sensitivity to anticoagulants. The finding that vitamin K may play a role in coagulation disorders within DMT1 patients has significant potential for both clinical applications and further research.

The study also opens the door for exploring the relationship between lipid profiles, vitamin K, and anticoagulation therapies in DMT1 patients. This could have important implications for managing cardiovascular risks in these patients.

4. Questions for Authors and Further Research:

On Vitamin K and DMT1: What mechanisms do you propose for the observed lower levels of vitamin K in DMT1 patients? Could this be linked to altered dietary intake, absorption, or metabolic processing of vitamin K in these individuals?

On Lipid Profiles: The study found a paradoxical better lipid profile in DMT1 patients. Can you discuss in more detail how lipid metabolism in DMT1 may influence the coagulation system? Are these findings consistent with other studies, and how might they impact the broader therapeutic approach for managing DMT1?

On Anticoagulant Use: While the study shows increased sensitivity to direct anticoagulants in DMT1 patients, what are the potential clinical risks or benefits of using these anticoagulants in this population? Do the authors suggest any modifications to current anticoagulant dosing practices for DMT1 patients, considering their altered coagulation profiles?

On Age and BMI Effects: How do the effects of age and BMI on coagulation profiles compare to other factors such as lipid profiles or medication adherence in DMT1 patients? Could these factors confound the results, and how might they be better controlled in future studies?

Literature Gaps: There seems to be a lack of studies directly comparing coagulation in DMT1 patients with those of other diabetic subtypes (e.g., type 2 diabetes). Could the authors expand on the differences or similarities in coagulation patterns between DMT1 and type 2 diabetes, citing other relevant research?

5. Final Recommendation:

The manuscript presents an intriguing and relevant exploration of the coagulation profiles in type 1 diabetes mellitus patients, particularly focusing on the role of vitamin K and its impact on anticoagulation sensitivity. However, I recommend addressing the minor grammatical issues and providing additional clarity on the mechanisms behind the findings. Expanding the discussion on the clinical implications of these results, particularly for anticoagulant treatment in DMT1 patients, would enhance the manuscript's impact.

Reviewer #5: The study by Carazo A et al, titled “Type 1 diabetes mellitus patients had lower total vitamin K levels 2 and increased sensitivity to direct anticoagulants” aims to evaluate the importance vitamin K/ lipids in Type 1 diabetic coagulopathy. They have shown that anticoagulant treatment increases the coagulation time in patients with diabetes mellitus. While I find this finding intriguing, I have some concerns about the article.

Table 1: I wondered why the author did not measure glycated hemoglobin in healthy donors.

Author treated plasma with glucose and measured aPTT, PT, and TT. It would be interesting to treat plasma with triglycerides and cholesterol, and then measure the same parameters (aPTT, PT, and TT).

What is the D-dimer concentrations in healthy donors compared to patients with diabetes mellitus? It would be worthwhile to correlate glucose, glycated hemoglobin, LDL, HDL, and TAG levels with D-dimer concentrations.

Table 2: I am interested in understanding how the external addition of heparin or Factor Xa inhibitors affects the r/p-value compared to DMSO alone (with glucose).

Authors should specify the type of statistical analysis used in the figure legend.

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Reviewer #1: Yes:  Laleh Abadi marand

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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PONE-D-24-43881R1

Type 1 diabetes mellitus patients had lower total vitamin K levels and increased sensitivity to direct anticoagulants

PLOS ONE

Dear Dr. Přemysl Mladěnka ,

Thank you for your revised submission of the manuscript entitled ”Type 1 diabetes mellitus patients had lower total vitamin K levels and increased sensitivity to direct anticoagulants” to PLOS One. After careful consideration of the reviewers’ comments and your thorough responses, I am pleased to inform you that your manuscript has been accepted for publication.

While Reviewer #4 recommended rejection based on specific methodological concerns, I carefully reviewed both their critique and your detailed, point-by-point responses. In my judgment, these concerns were appropriately and comprehensively addressed through robust clarifications, relevant literature citations, and meaningful revisions throughout the manuscript. It is also important to note that your study does not seek immediate clinical application, but rather provides novel comparative data that contribute to hypothesis generation and lay groundwork for future research in this field. I would also like to take this opportunity to acknowledge and sincerely thank Reviewer #4 for their detailed and constructive critique, which—despite their final recommendation—contributed significantly to improving the manuscript’s clarity and scientific rigor.

Based on the overall merit of the revised manuscript, the scientific value of the findings, and your thoughtful engagement with the reviewers’ feedback, I have made the decision to accept your manuscript for publication in PLOS One.

Congratulations again on your acceptance, and thank you for choosing PLOS One as the venue for your work.

Best regards,

Yousef Khazaei Monfared 

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

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: 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

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: 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.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: 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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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: Thank you. The paper is completed and all the comments have been addressed. After receiving the other reviewers responses,it's ready to publish.

Reviewer #2: I have no further comments. Thank you for addressing my comments carefully for a more sound manuscript.

Reviewer #3: The authors made an attempt to address the comments. However, the aims/objectives are still not clear. If the authors want to investigate the effect of different NOACs, then reporting APTT/PT is not enough. Although one may argue that there is correlation, still, measuring the NOAC levels and clinical event is necessary.

It is also unclear for the clinical implications. The authors reported that prolonged APTT/PT is associated with higher atherosclerotic risk. So taking NOACs will result in higher atherosclerotic risks? There are many patients with AF and CAD taking NOACs for prevention of cardiovascular event.

Reviewer #4: (No Response)

Reviewer #5: The revised manuscript has undergone significant improvements and is now suitable for publication.

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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:  Laleh Abadi marand

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes:  Kandahalli Venkataranganayaka Abhilasha

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