Review for 10.1186/s12876-024-03253-4 (2024)

Title: A new model of portal vein thrombosis in rats with cirrhosis induced by partial portal
vein ligation plus carbon tetrachloride and intervened with rivaroxaban
Version: 3 Date: 12 Apr 2024
Reviewer's report:
In this paper, Guo and Dong, et. al., describe a combined carbon tetrachloride and PPVL model
of cirrhosis with portal vein thrombosis in the rat. Animal models of cirrhotic portal vein
thrombosis are lacking and I believe this study has important value in terms of the development
of tools for basic research in portal vein thrombosis in cirrhosis.
In reviewing past reviewer comments, it is challenging to understand why some things asked
for multiple times, including detailed data on animal survival, are included in the comments
to reviewers but no the paper. Sections of the discussion that the authors said were revised are
hard to find in the main text, and concerns about anticoagulant parameters remain incompletely
addressed. In addition, more issues are present as detailed below. In this situation, I believe the
manuscript cannot be accepted given ongoing issues.
- It should not limit publication of the manuscript, but throughout the language is difficult to
understand and some sentences do not make sense. I felt I was able to understand the meaning
of the paper but this should be generally refined
- The introduction and conclusion should discuss the prior study of rivaroxaban in cirrhosis
(for example, Vilaseca, et. al.) and perhaps the background of anticoagulation as a therapeutic
strategy in cirrhosis more broadly. The authors cite the rivaroxaban administration from the
Vilaseca study without discussing any findings of the study at all
- The same kit is described as having two different catalog numbers (C009-1 and C010-1) in
the methods (Drugs and main agents section), is this correct? Glutathione is also not mentioned
again in the paper so why was this used?
- The experimental design could more clearly describe that the rivaroxaban treated rats are also
receiving 10 weeks of carbon tetrachloride. The rivaroxaban treatment can also be shown in the
flowchart
- AST and ALT definitions are not correct AST = aspartate aminotransferase, ALT = alanine
aminotransferase
- The histological images are all very small and the image quality makes zooming in not possible.
This means it is hard to evaluate some of the authors’ claims. For examples, they say fibrinogen
marks microvascular thrombi, but to me it looks like it is mostly in hepatocytes. They should
show higher magnification of the histology to show if it is truly in the microvasculature
- The authors claim platelets are present in the portal vein thrombus but do not show any platelet
staining. They could do IHC for CD61 or CD41 to confirm the presence of platelets
- If possible, the authors should measure Protein C and Protein S levels in their coagulation
parameters. Ideally they could also measure Factor VIII
- The vWF immunofluorescence images do not look very different to me between groups, but
perhaps it is a function of image quality. Please check these images
- Figure 4 Fibrin and PAI-1 images should show enlarged regions to determine if the Fibrin is
in the microvasculature and if the PAI-1 involves the endothelial cells
- The Vilaseca study should be discussed in the discussion section given its similarity to this
study. Perhaps some role for hepatic stellate cells in the observed pathology should be considered
- The last sentence of the discussion says the downregulatino of vWF can promote the
degradation of fibrin by inhibiting PAI-1 with no citation. I’m not aware of this mechanism,
please clarify
- The limitations and perspective section is very challenging to understand and should be
clarified. No molecular mechanism is really defined in this study