Genotype-Specific Postural Control Deficits in Hemophilia A: Insights from Center of Pressure Analysis Beyond Radiographic Arthropathy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript examines postural balance strategies (the parameter of center of pressure) based on radiographic joint assessment with the Pettersson score (knee, ankle, and elbow joints) and frequency domain analysis (intron 22 and intron 1 inversion of the F8 gene). In conclusion, the authors state that CoP analysis reveals genotype-specific postural differences.

There are some significant shortcomings of this study:

1. There is no null hypothesis.
2. Compared groups are too small for significant comparison.
3. It is evident that hip, pelvis, and spine position determine posture and subsequently center of pressure. There are no data in the manuscript regarding hip, pelvis, and spine position. Furthermore, some limitations in range of motion in knee and ankle joints can result in functional lower limb discrepancy, but that parameter was not discussed.
4. The role of hip pathology is not negligible in hemophilia A. It should be studied and discussed in the study.
- Lyu TW, Chiu WY, Sun T, Chou SC. Bone Health in Adults With Severe Haemophilia Receiving Different Prophylactic Treatments. Haemophilia. 2026 Jan 19. doi: 10.1111/hae.70215. Epub ahead of print. PMID: 41549881.
- Wu C, Dai J, Chen Z, Shao Y, Wang X, He C. Robot-assisted total hip arthroplasty following gene therapy for hemophilia a arthropathy: a case report. Arthroplasty. 2025 Dec 3;7(1):61. doi: 10.1186/s42836-025-00348-5. PMID: 41331951; PMCID: PMC12673715.
- Dutta A, Shyam M, Borah P, Biswas S. Silent Avascular Necrosis of the Femoral Head in Severe Hemophilia A: A Case Report. Cureus. 2025 Sep 17;17(9):e92588. doi: 10.7759/cureus.92588. PMID: 41111790; PMCID: PMC12534721.
5. A simple statement of difference in postural strategies depending on F8 mutation type is not enough as a conclusion. Authors should provide some explanation(s) based on pathological and anatomical findings.

Author Response

Please see the attachment, thank you.

(We have updated the email address for the corresponding author, Shao-Li Han, in this revised version (Revision 2).)

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript appears to be interesting, relatively underexplored, and with potential future clinical relevance, particularly considering that newer hematological treatments in hemophilia increasingly require attention to comorbidities associated with aging and increased physical activity in daily life.

It is important to recognize that the current findings do not yet allow extrapolation to specific modifications in therapeutic strategies aimed at improving or preventing balance alterations, as we still do not have sufficient understanding of whether functional balance has a clinically relevant association with genotype. Nevertheless, I consider that these results may represent a first step in this line of research.

From this positive perspective and with a favorable view toward publication, I would like to point out several aspects which, in my opinion, represent minor revisions:

1. Regarding the statistical analysis, since only one frequency-domain parameter reached statistical significance, it may be useful to indicate the total number of comparisons performed (including adjustment for age) and to explicitly mention the exploratory nature of the analysis.

2. Concerning the frequency-domain analysis, and particularly the energy content above 2 Hz, a slightly more detailed description of the method used (for example, the spectral procedure applied) would contribute to improving the reproducibility of the study.

3. Postural instability was assessed exclusively during static bipedal stance with eyes open. As balance alterations in hemophilia—and in many other conditions—tend to become clinically relevant during dynamic activities, it may be advisable to acknowledge this aspect as a limitation in the Discussion and to suggest future research incorporating clinical balance scales or fall-related variables, which would help facilitate the clinical contextualization of these findings, which are currently primarily spectral in nature.

4. Postural control in hemophilia may be influenced by factors such as prophylactic regimen, habitual physical activity level, bleeding history, or the presence of active synovitis. Although these variables may not have been specifically collected in the present study, it may be advisable to acknowledge in the Discussion that they were not analyzed and could represent potential confounding factors in future research.

All these observations represent, in my opinion, minor revisions. Overall, this is a good study which, I reiterate, is interesting and may constitute a starting point for more in-depth investigations in the future.

Author Response

Please see the attachment, thank you.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

In the revised manuscript authors have recognized and discussed significant limitations of the study.

Anyway even scientific soundness is low of the study, the manuscript could be accepted for publication.