Arterial Thrombosis in Severe Ulcerative Colitis: A Case-Based Narrative Review of Current Evidence

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

I have read with interest the review entitled “Arterial Thrombosis in Severe Ulcerative Colitis: A Case-Based Narrative Review of Current Evidence” by Djordje Kralj et al. The authors propose a large-scale analysis of cardiovascular risk in ulcerative colitis. This paper presents a comprehensive examination of the link between inflammation and the secondary thrombotic burden. I have some comments on it.

1 The author should provide information on the involvement of lymphocytes in the pathogenesis of IBD. In other words, inflammation is driven by an uncontrolled immune response to various antigens that penetrate the mucosal layer. The same phenomenon may arise regarding the activation of the hemostatic system. It seems that an exaggerated inflammatory response may be the principal cause of the thrombotic burden that the authors have analyzed in both their patient and the general population. It should be remembered that an ancestral link between inflammation and coagulation exists, aimed at protecting humans from viral, bacterial, and neoplastic cell invasion. This subtle and external equilibrium is disrupted when the subject loses both immune and hemostatic control, resulting in disastrous consequences. A brief representation of these mechanisms is desirable.  

2 I am not so sure that unfractionated heparin (UFH) is the anticoagulant of choice in arterial thrombosis, even though it is recommended by some guidelines, which, as we know, do not always represent what has been really ascertained in a determined topic. Often, they are not evidence-based, relying on personal belief or empirical data. The use of UFH is not easy in a medical ward because it requires close aPTT monitoring, which has never been well standardized, leading to wide, erratic responses from the lab and different decision-making depending on who the on-call doctor is. In this review, the authors should add these useful considerations to avoid misleading information on the use of UFH in general.      

3 In this paper, the role of thrombophilia has been correctly examined without giving it a pathogenically important role. Genotypes such as MTHFR and PAI-1 should not be a part of the thromophilic screening, which, per se, is not useful in arterial thrombosis except for high homocysteine levels and anti-phospholipid antibodies. Even this consideration should be added by the authors to the text.   

Author Response

Response to Reviewer

We sincerely thank the Reviewer for the careful evaluation of our manuscript entitled “Arterial Thrombosis in Severe Ulcerative Colitis: A Case-Based Narrative Review of Current Evidence.” We greatly appreciate the Reviewer’s insightful and constructive comments, which substantially improved the scientific depth, balance, and clinical relevance of the manuscript.
All revisions made in response to the Reviewer’s comments are highlighted in yellow in the revised manuscript.

 

Reviewer Comment 1

The author should provide information on the involvement of lymphocytes in the pathogenesis of IBD. In other words, inflammation is driven by an uncontrolled immune response to various antigens that penetrate the mucosal layer. The same phenomenon may arise regarding the activation of the hemostatic system. It seems that an exaggerated inflammatory response may be the principal cause of the thrombotic burden that the authors have analyzed in both their patient and the general population. It should be remembered that an ancestral link between inflammation and coagulation exists, aimed at protecting humans from viral, bacterial, and neoplastic cell invasion. This subtle and external equilibrium is disrupted when the subject loses both immune and hemostatic control, resulting in disastrous consequences. A brief representation of these mechanisms is desirable.

 

Response 1

We fully agree with the Reviewer and thank them for highlighting this important mechanistic aspect. In response, we substantially expanded Section 3.2 (Pathophysiological Mechanisms Linking IBD and Thrombosis) to include a detailed yet concise discussion of immune-driven hemostatic activation. Specifically, we added a description of the role of innate and adaptive immune cells, including lymphocytes, in promoting endothelial activation, tissue factor expression, platelet activation, and dysregulation of fibrinolysis. We also explicitly introduced the concept of immunothrombosis as an evolutionarily conserved defense mechanism linking inflammation and coagulation, and discussed how loss of immune–hemostatic balance in IBD converts this protective response into pathological thrombosis.

These additions directly address the Reviewer’s comment and provide a mechanistic framework linking exaggerated inflammatory responses to the arterial thrombotic burden observed in IBD. All newly added text is highlighted in yellow in the revised manuscript.

 

Reviewer Comment 2

I am not so sure that unfractionated heparin (UFH) is the anticoagulant of choice in arterial thrombosis, even though it is recommended by some guidelines, which, as we know, do not always represent what has been really ascertained in a determined topic. Often, they are not evidence-based, relying on personal belief or empirical data. The use of UFH is not easy in a medical ward because it requires close aPTT monitoring, which has never been well standardized, leading to wide, erratic responses from the lab and different decision-making depending on who the on-call doctor is. In this review, the authors should add these useful considerations to avoid misleading information on the use of UFH in general.

 

Response 2

We thank the Reviewer for this highly relevant and pragmatic comment. We agree that UFH should not be presented as a universal or unequivocal anticoagulant of choice in arterial thrombosis.

Accordingly, we revised Section 3.4.2 (Acute Phase Management) to clearly state that the use of UFH in this case was context-specific and individualized, rather than guideline-driven or broadly generalizable. We explicitly discuss the limitations of UFH, including the need for continuous infusion, reliance on aPTT monitoring with significant inter- and intra-laboratory variability, operator-dependent dosing, and the risk of heparin-induced thrombocytopenia.

At the same time, we clarify why UFH was selected in this specific clinical scenario—namely, its short half-life, full reversibility, and titratability in a patient with severe active ulcerative colitis and high bleeding risk. Importantly, we explicitly state that this management approach should not be interpreted as a general endorsement of UFH for arterial thrombosis.

These clarifications were added to avoid any misleading interpretation and are highlighted in yellow in the revised manuscript.

 

Reviewer Comment 3

In this paper, the role of thrombophilia has been correctly examined without giving it a pathogenically important role. Genotypes such as MTHFR and PAI-1 should not be a part of the thrombotic screening, which, per se, is not useful in arterial thrombosis except for high homocysteine levels and anti-phospholipid antibodies. Even this consideration should be added by the authors to the text.

 

Response 3

We fully agree with the Reviewer’s assessment and appreciate this important clarification. In response, we revised Section 3.3.5 (Inherited and Acquired Thrombophilia) to explicitly state that MTHFR and PAI-1 genotyping should not be included in routine thrombophilia screening, particularly in the context of arterial thrombosis.

We emphasize that thrombophilia testing in arterial events is generally of limited clinical utility, with the exception of plasma homocysteine levels and antiphospholipid antibodies, which retain established clinical relevance. We further clarify that MTHFR and PAI-1 polymorphisms are highly prevalent in the general population and should not be interpreted as causal explanations for thrombotic events.

While we acknowledge population-specific and APS-related associations reported in the literature, these are clearly framed as modulatory and non-causal, and current guideline recommendations against routine testing are explicitly stated. All relevant additions and revisions are highlighted in yellow in the revised manuscript.

Once again, we sincerely thank the Reviewer for their thoughtful and constructive comments, which significantly improved the manuscript's mechanistic clarity, clinical nuance, and overall quality.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

This manuscript presents a case report of diffuse arterial thrombosis in a patient with severe ulcerative colitis (UC), coupled with an extensive literature review on arterial thrombotic risk in inflammatory bowel disease (IBD). The manuscript provides a clear, evidence-based synthesis of the epidemiology, pathophysiological mechanisms, and key risk factors, and offers a valuable, practical clinical commentary on diagnosis, acute management, and long-term therapeutic strategy, including a thoughtful discussion on the vascular safety profiles of various IBD medications.

1, The literature review section is overly detailed, particularly the paragraphs on traditional cardiovascular risk factors, which have weak relevance to IBD. This results in verbose prose and a lack of focus; it could be further streamlined to better highlight the core issues.

2, The discussion on anticoagulation therapy is rather general; providing more specific clinical recommendations would significantly enhance its practical utility.

Author Response

Response to Reviewer 2

We sincerely thank Reviewer 2 for the careful reading of our manuscript and for the positive overall assessment, as well as for the constructive comments that helped us further improve the focus and clinical relevance of the review. In response to these comments, we have revised the manuscript accordingly. All changes are highlighted in yellow in the revised version.

 

Reviewer 2 - General Comment

This manuscript presents a case report of diffuse arterial thrombosis in a patient with severe ulcerative colitis (UC), coupled with an extensive literature review on arterial thrombotic risk in inflammatory bowel disease (IBD). The manuscript provides a clear, evidence-based synthesis of the epidemiology, pathophysiological mechanisms, and key risk factors, and offers a valuable, practical clinical commentary on diagnosis, acute management, and long-term therapeutic strategy, including a thoughtful discussion on the vascular safety profiles of various IBD medications.

 

Response:
We thank the Reviewer for this encouraging and thoughtful assessment of our work. We are pleased that the Reviewer found the synthesis of current evidence and the clinical discussion to be useful and balanced.

 

Reviewer 2 - Comment 1

The literature review section is overly detailed, particularly the paragraphs on traditional cardiovascular risk factors, which have weak relevance to IBD. This results in verbose prose and a lack of focus; it could be further streamlined to better highlight the core issues.

 

Response:
We fully agree with the Reviewer that excessive detail regarding traditional cardiovascular risk factors may detract from the central message of the manuscript. In response, we have substantially streamlined the section on traditional cardiovascular risk factors (Section 3.3.2).

Specifically, we condensed the discussion to retain only the key mechanistic concepts and epidemiological observations directly relevant to IBD, while removing extensive general cardiovascular pathophysiology that is well established and not specific to this population. The revised text now emphasizes that, despite their well-known role in the general population, traditional risk factors appear attenuated in IBD and do not fully explain the increased burden of arterial thrombosis, thereby reinforcing the primacy of inflammation-driven mechanisms.

These revisions reduce redundancy, improve focus, and better align the literature review with the core objectives of the manuscript. All modifications are highlighted in yellow in the revised text.

 

Reviewer 2  Comment 2

The discussion on anticoagulation therapy is rather general; providing more specific clinical recommendations would significantly enhance its practical utility.

 

Response:
We appreciate this important suggestion and agree that greater clinical specificity enhances the practical value of a case-based review. In response, we substantially expanded and refined the discussion of anticoagulation therapy in Section 3.4.2 (Acute Phase Management) based on both reviewers suggestions..

The revised text now provides a more detailed, context-driven rationale for anticoagulant selection, explicitly addressing the choice of unfractionated heparin (UFH) in this case. We clarify that UFH was selected based on patient-specific considerations, namely severe active ulcerative colitis, high bleeding risk, and the need for rapid reversibility and titratability, rather than as a general recommendation for arterial thrombosis. We also explicitly discuss the limitations of UFH, including the need for continuous infusion, non-standardized aPTT monitoring, operator dependence, and the risk of heparin-induced thrombocytopenia, to avoid any misleading generalization. In addition, we expanded the discussion of alternative strategies, including low-molecular-weight heparin, invasive and endovascular approaches, and thrombolysis, clearly outlining why these options were not pursued in this clinical context. This approach provides concrete clinical guidance while emphasizing individualized decision-making rather than protocol-driven management. All additions and clarifications are highlighted in yellow in the revised manuscript.

 

Once again, we sincerely thank the Reviewer for the constructive and insightful comments, which significantly improved the clarity, focus, and clinical applicability of the manuscript.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript describes a rare and clinically important case of extensive arterial thrombosis complicating acute severe ulcerative colitis in the context of combined MTHFR and PAI-1 polymorphisms. It is accompanied by a broad and well-referenced review of the literature on arterial events in IBD and the role of genetic polymorphisms in thrombosis. The manuscript provides comprehensive literature review with up-to-date references, including mechanistic insights and therapeutic implications.

Revisions:

1- The role of MTHFR and PAI-1 polymorphisms is overemphasized. The discussion must be rebalanced to highlight that their contribution is modest and context-dependent, avoiding the impression that these variants are strong causal drivers.

2- At present, the case report and the literature review read almost as two separate papers.  Revision should focus on explicitly linking the case to the literature. This integration will improve coherence and impact.

3- Figures: Legends need to be expanded to be more self-explanatory (so readers can interpret them without reading the main text).

4- The sections on MTHFR and PAI-1 polymorphisms are long and somewhat repetitive. 

5-

Reviewer 2 Report

Comments and Suggestions for Authors

I read the case report by Milic et al entitled “Arterial Thrombosis in Severe Ulcerative Colitis with combined MTHFR and PAI-1 Mutations: A Case-Illustrated Review of Current Evidence “. The case reported by the authors is interesting but I cannot accept the prothrombotic role of both MTHFR and PAI-genotypes. Recently, a call for action has been published aiming to avoid the request for the MTHFR genotype if a thrombophilia screening is demanded (Deloughery TG, Hunt BJ, Barnes GD, Connors JM; WTD Steering Committee. A call to action: MTHFR polymorphisms should not be a part of inherited thrombophilia testing. Res Pract Thromb Haemost. 2022 Jun 8;6(4):e12739). This is because it has been definitively proven that MTHFR genotypes are not a thrombotic risk factor. As the authors of that paper state, eliminating MTHFR from thrombophilia testing is important because it alleviates patients' concerns and reduces healthcare costs. The same is to be applied to the PAI1 genotypes not recognized as a risk factor for thrombosis (Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost. 2016 Jan;115(1):25-30). It is known that both MTHFR and PAI-1vgenotypes (4G-5G) can be found in the healthy population in a large proportion, up to 40%. It is, therefore, greatly misleading to propose these genotypes as a further reason to explain why the patient here described suffered from multiple thrombotic arterial events. The authors, in other words, speculate too much. However, they report an interesting review of the arterial thrombotic risk during UC disease, including the pharmacologic treatment of the disease that significantly contributed to achieving remission of the patient’s conditions. This is what the readers would appreciate. It is known that inflammation and blood coagulation are strictly linked (Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 2005;15(07): 254–259), and inflammatory bowel diseases are, unfortunately, an example of this ancestral relationship. Why, therefore, should we search for other negligible risk factors? The authors should reflect on this essential concept. They should radically revise the manuscript to propose a mini-review on the burden of arterial and venous thrombosis in Ulcerative Colitis, without attributing the role to thrombophilia, which is really inappropriate.      

Comments on the Quality of English Language

I am not an English mother tongue so I have difficulties in judging the style of English..