Review for 10.1186/s12876-025-04208-z (2025)

Title: Efficacy and Safety of Reduced Thromboprophylaxis with Low Molecular Weight
Heparin for Hepatocellular Carcinoma after conversion therapy
Version: 0 Date: 08 Jun 2025
Reviewer's report:
This retrospective cohort study examines the safety and efficacy of reduced-dose low molecular
weight heparin (LMWH) for thromboprophylaxis following neoadjuvant Lenvatinib therapy
and hepatectomy in hepatocellular carcinoma (HCC) patients. The study included 140 patients,
comparing those who received reduced LMWH prophylaxis postoperatively to those who did
not. The primary outcome was the incidence of thrombotic and hemorrhagic complications, and
secondary outcomes included overall survival (OS). The authors concluded that reduced LMWH
dosing does not increase thrombotic risk or compromise survival, and may reduce hemorrhagic
complications.
Major Concerns:
1. Study Design and Confounding Control:
While the study is based on a well-defined clinical question, its retrospective, non-randomized
design limits the ability to draw definitive causal inferences. Potential confounders such as extent
of surgery, tumor burden, and patient comorbidities (e.g., cardiovascular disease, cirrhosis) were
not adequately adjusted for using multivariate methods or propensity score matching. Logistic
regression was applied, but results remain susceptible to selection bias due to non-randomized
group allocation.
2. Definition of “Reduced Thromboprophylaxis”:
The definition of “reduced” prophylaxis (#100 IU/kg LMWH for <5 days) seems arbitrary and
is not clearly justified in the context of international guidelines. The comparator group also
includes patients who received no LMWH, which introduces heterogeneity in exposure. This
undermines the clarity of the primary intervention and control arms.
3. Sample Size and Statistical Power:
Although 140 patients were enrolled, the study is likely underpowered for rare events like venous
thromboembolism (VTE) and major hemorrhage, as acknowledged by the wide confidence
intervals and lack of statistical significance in primary outcomes. A post hoc power analysis is
warranted.
4. Survival Analysis Interpretation:
The authors claim that reduced prophylaxis does not affect survival. However, OS is not
significantly different between groups, and the study does not appear adequately powered
or designed to assess survival outcomes. Moreover, the HR for Lenvatinib use (2.73) and
cardiovascular comorbidity (2.20) requires cautious interpretation due to potential confounding
and wide CIs.
5. Figure and Table Presentation:
Figure 1 and corresponding legends are not sufficiently informative. The Kaplan-Meier survival
curve lacks labeling of risk tables or number-at-risk per timepoint. Additionally, tables are
embedded within the manuscript rather than formatted per journal style.
Minor Concerns:
1. Clarity and Redundancy:
Several sections, particularly the Discussion, are redundant and overly speculative (e.g.,
comments on prolonged Lenvatinib use and its implications on hepatic reserve). These
interpretations should be restrained and grounded in the study’s own findings.
2. Literature Citations:
Some references (e.g., [6–8]) refer to cardiovascular risks and FXa inhibition by TKIs but are
not directly relevant to the thromboprophylaxis context. A more targeted review of current
thromboprophylaxis guidelines in oncologic liver surgery is advised.
3. Methodological Details:
• The protocol for diagnosing VTE (imaging modalities and timing) should be elaborated.
• Details about how bleeding events were adjudicated (e.g., by blinded committee or based on
clinical notes) are lacking.
• Missing explanation on whether LMWH dose was weight-based or fixed across all patients
in the reduced group.
4. Ethical Considerations:
The ethics approval and waiver of consent are adequately mentioned. However, the declaration
“no conflict of interest” should be standardized per journal template.
The authors do not explicitly acknowledge several key limitations:
• Lack of standardized LMWH dosing and unclear adherence.
• Absence of biochemical markers or coagulation profiles to support bleeding risk analysis.
• Heterogeneity in the definition of VTE and bleeding events.
• Retrospective design and single-center scope limit external validity.
The manuscript would benefit from professional language editing. Issues include inconsistent
verb tenses, unclear phrasing (e.g., “prolonged Lenvatinib use would not improve rather
than worsen survival”), and incorrect or awkward expressions. References are inconsistently
formatted (e.g., missing periods, unstandardized journal abbreviations) and should be revised to
comply with BMC Gastroenterology referencing style.