Pulmonary Embolism in Antiphospholipid Syndrome (APS)—Where Are We and Where Are We Going?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I appreciated having the opportunity to review this manuscript about comprehensive and up-to-date narrative overview of pulmonary embolism in antiphospholipid syndrome. 

I just have some suggestions that I think can help improve the paper overall.

• The epidemiology section and the pathophysiology section have a lot of redundancy, please consider summarizing ranges and emphasizing trends rather than listing several registries with overlapping data, as well as avoiding restating the same prothrombotic effects across subsections.

• Although this is a narrative review, the inclusion of a PRISMA-like flowchart may be misleading. Either justify more clearly why this approach was chosen or simplify the methodology section to avoid confusion with a systematic review.

• Several associations (e.g., CTEPH frequency in APS, prognostic role of NETs, predictive value of isolated biomarkers) are presented in a very strong tone. Please clarify when evidence is derived from retrospective studies, small cohorts, or indirect data.
• Shorten long paragraphs, particularly in Sections 3–5, to improve readability.

Author Response

Reviuver 1

Point 1: I appreciated having the opportunity to review this manuscript about comprehensive and up-to-date narrative overview of pulmonary embolism in antiphospholipid syndrome. 

I just have some suggestions that I think can help improve the paper overall.

Response 1: We would like to sincerely thank the Reviewer for the time devoted to the evaluation of our manuscript and for the constructive and valuable comments provided. We greatly appreciate the opportunity to have our work reviewed. We hope that the suggested revisions and clarifications have helped to further improve the quality, clarity, and scientific value of the manuscript.

Point 2: The epidemiology section and the pathophysiology section have a lot of redundancy, please consider summarizing ranges and emphasizing trends rather than listing several registries with overlapping data, as well as avoiding restating the same prothrombotic effects across subsections.

Response 2: We sincerely thank the Reviewer for this valuable and insightful comment. In response, we have thoroughly revised both the epidemiology and pathophysiology sections. To reduce redundancy, we summarized epidemiological ranges and overarching trends instead of listing multiple registries with overlapping data. Additionally, repeated descriptions of prothrombotic mechanisms were consolidated into a single, coherent subsection to improve clarity and readability.

Point 3:Although this is a narrative review, the inclusion of a PRISMA-like flowchart may be misleading. Either justify more clearly why this approach was chosen or simplify the methodology section to avoid confusion with a systematic review.

Response 3: We thank the Reviewer for this comment. We agree that the inclusion of a PRISMA-like flow diagram in a narrative review may be misleading. In response, we have revised and simplified the methodology section to more clearly emphasize the narrative nature of the review and its alignment with the SANRA guidelines. The flow diagram (Figure 4) and all references to the study selection process have been removed to avoid any implication of a systematic review approach.

Point 4: Several associations (e.g., CTEPH frequency in APS, prognostic role of NETs, predictive value of isolated biomarkers) are presented in a very strong tone. Please clarify when evidence is derived from retrospective studies, small cohorts, or indirect data.

Response 4 : Thank you for this comments. We revised the manuscript to moderate the tone of several statements and explicitly clarify when conclusions are based on retrospective analyses, small cohorts, or indirect evidence, particularly with regard to CTEPH frequency, the role of NETs, and biomarker associations.

Point 5: Shorten long paragraphs, particularly in Sections 3–5, to improve readability.

Response 5: Thank you for this comments. We shortened and reorganized long paragraphs, especially in Sections 3–5, to improve readability and reduce redundancy.

Reviewer 2 Report

Comments and Suggestions for Authors

This is an interesting and updated review on pulmonary embolism in antiphospholipid syndrome patients.

No serious problems in the content but the paper should be reorganized to be consistent in the use of abbreviations, to condense some parts and to avoid repetitions

Sometimes, the paragraphs seem written by different people...

Even if the English is globally ok, some editing is needed

General comment

Please be consistent in the use of abbreviations. Introduce them the first time and then use them always.

There is confusion in the abbreviation "aPL". Sometimes you use it as "antiphospholipid" and you add "antibodies" (eg aPL antibodies) but elsewhere you use aPL also to indicate "antiphospholipid antibodies" (see list of abbreviations line 486). One possibility is to introduce the abbreviation "aPLA" for "antiphospholipid antibodies". 

Introduction

Lines 36-41

This part is rather confused. Please clearly state that the 3 distinct forms of APS are 1- primary, 2- secondary, 3- CAPS

Line 43: I would say "Most of them " and not "all"

Line 45: "anti-beta2-GPI" and not "beta2-GPI"

Lines 59-60 " developmental pathways" is unclear, please rephrase

2.1 Epidemiology of APS

The sentence  in line 63 "PE is often..." should be deleted because here you treat the epidemiology of APS in general, whereas the epidemiology of APS-PE is teated in paragraph 2.2

Lines 63-73: this part  is too detailed and could be condensed simply quotind data from the 3 areas.

Line 111: please introduce the concept of CTEPH 

Lines 112-113

"It is worth mentioning that PE-APS can be caused by one of the forms of APS – catastrophic antiphospholipid syndrome (CAPS)".  PE is not caused by CAPS. I would say that PE can occur in the context of all clinical types of APS, including CAPS.

Lines 116-118: "The incidence of CAPS is generally lower than that of APS; however, the incidence of PE is higher. An analysis by Ponce et al. showed that approximately 1% of the 805 CAPS ......" Please rephrase. APS and CAPS are not two different diseases but CAPS is a special type of APS

Lines 120-125 "It is worth noting that PE can develop in patients without aPL antibodies. For example, an analysis of PE-APS (n = 24) and unprovoked PE without aPL antibodies (n = 44) revealed a mean age of 39.7 years in the PE-APS group compared with 60.4 years in the non-PE-APS group. This study confirmed that younger age, the presence of hemoptysis, a low PESI score (Pulmonary Embolism Severity Index), and a prolonged APTT were the most sensitive predictors of APS [31]" 

The start sound rather strange! PE is not a feature of APS but a common disease. The period should be reorganize for clarity

Pathologic mechanisms..

line 148: I would add also neutrophils in the list

The main triggering...

line 173-174 "This characteristic of anti-β2GPI antibodies makes them one of the main pathological autoantigens in APS [5]. " This is a formal mistake. The antigen is β2GPI and not the antibodies. Please correct

lines 178-179. "Anti-β2GPI antibodies inhibit anticoagulation processes by decreasing factor X and increasing thrombin synthesis,...." 1- how they decrease factor X levels? Why lower levels of factor X should induce thrombosis? 2- thrombin is an enzyme deriving from prothrombin. There may be mechanisms increasing the synthesis of prothrombin or its activation to thrombin with increased levels of thrombin but you can never "increase the synthesis of an enzyme". Please amend the sentence

Lines 211-215. Sentences unclear which need to be rephrased

Figure 1  Several points to be amended/clarified:

For factor X decrease and increased thrombin synthesis see above

" ...release of tPA activator by ECs" ???  Probably "activator" must be deleted?

"cEC:TF synthesis and Endothelin-1 on the surface "  I cannot understand. Something lacking?

"Thrombogenic state"? or "Thrombophilic state"?

"Triggering factors of the second hit"???? or simply "Second hit"?

Legend to Fig 1 lines 223-226. What is the subject of the sentence? I think the subject should be  "aPL antibodies" plural whereas you say "stimulates, inhibits etc" which are singular. Please check and correct

Paragraph 6 Risk factors ...

Several concepts have been already written in the previous paragraphs. Please condense and delete some parts to avoid repetitions.

Lines 376-378.  Monitoring is not required in DOAC treatment. You probably mean that the measurement of DOAC levels with specific tests, when needed, may have special problems in the presence of aPL antibodies (specially LA). Please rephrase

Paragraph 8

Usually Methods are reported in the first part of a review

Conclusions

Line 456 "non APS-PE is a very strange definition. I suggest to simply say "PE occurring in patients non affected by APS" or something like this

Few minor typos in the Reference list. Please check

Author Response

Reviuver 2

Point 1: This is an interesting and updated review on pulmonary embolism in antiphospholipid syndrome patients.

No serious problems in the content but the paper should be reorganized to be consistent in the use of abbreviations, to condense some parts and to avoid repetitions

Sometimes, the paragraphs seem written by different people...

Even if the English is globally ok, some editing is needed

Response 1: We sincerely thank the Reviewer for the time devoted to the evaluation of our manuscript and for the constructive and valuable comments. In response, the manuscript has been carefully revised to improve structural coherence, ensure consistent use of abbreviations, reduce redundancy, and shorten selected sections as suggested. The text was also edited to enhance linguistic consistency and overall readability. We hope that these revisions have addressed the Reviewer’s concerns and that the manuscript is now clearer, more coherent, and improved in its final form.

Point 2: Please be consistent in the use of abbreviations. Introduce them the first time and then use them always. There is confusion in the abbreviation "aPL". Sometimes you use it as "antiphospholipid" and you add "antibodies" (eg aPL antibodies) but elsewhere you use aPL also to indicate "antiphospholipid antibodies" (see list of abbreviations line 486). One possibility is to introduce the abbreviation "aPLA" for "antiphospholipid antibodies". 

Response 2 Thank you for this important comment. In response, we standardized the use of abbreviations throughout the manuscript by introducing aPLA to denote antiphospholipid antibodies and using it consistently in the text, figures, and tables. The list of abbreviations was updated accordingly.

Point 3 Introduction

Lines 36-41

This part is rather confused. Please clearly state that the 3 distinct forms of APS are 1- primary, 2- secondary, 3- CAPS

Line 43: I would say "Most of them " and not "all"

Line 45: "anti-beta2-GPI" and not "beta2-GPI"

Lines 59-60 " developmental pathways" is unclear, please rephrase

Response 3: Thank you for this helpful and detailed comment. In response, we have revised the Introduction to clearly and explicitly define the three distinct forms of antiphospholipid syndrome: primary APS, secondary APS, and catastrophic APS (CAPS). We have corrected the wording to “most of these complications” instead of “all,” replaced “β2-GPI” with the correct term “anti-β2-glycoprotein I,” and rephrased the unclear expression “developmental pathways” to more precisely describe the mechanisms involved in disease progression

Point 4  2.1 Epidemiology of APS

The sentence  in line 63 "PE is often..." should be deleted because here you treat the epidemiology of APS in general, whereas the epidemiology of APS-PE is teated in paragraph 2.2

Lines 63-73: this part  is too detailed and could be condensed simply quotind data from the 3 areas.

Line 111: please introduce the concept of CTEPH 

Lines 112-113

"It is worth mentioning that PE-APS can be caused by one of the forms of APS – catastrophic antiphospholipid syndrome (CAPS)".  PE is not caused by CAPS. I would say that PE can occur in the context of all clinical types of APS, including CAPS.

Lines 116-118: "The incidence of CAPS is generally lower than that of APS; however, the incidence of PE is higher. An analysis by Ponce et al. showed that approximately 1% of the 805 CAPS ......" Please rephrase. APS and CAPS are not two different diseases but CAPS is a special type of APS

Lines 120-125 "It is worth noting that PE can develop in patients without aPL antibodies. For example, an analysis of PE-APS (n = 24) and unprovoked PE without aPL antibodies (n = 44) revealed a mean age of 39.7 years in the PE-APS group compared with 60.4 years in the non-PE-APS group. This study confirmed that younger age, the presence of hemoptysis, a low PESI score (Pulmonary Embolism Severity Index), and a prolonged APTT were the most sensitive predictors of APS [31]" 

The start sound rather strange! PE is not a feature of APS but a common disease. The period should be reorganize for clarity

Response 4: Thank you for the helpful suggestions. In response, we revised and shortened the Epidemiology section to improve clarity, reduce redundancy, and more clearly distinguish between APS epidemiology and APS-associated pulmonary embolism.

Point 5:  Pathologic mechanisms.. line 148: I would add also neutrophils in the list

Response 5: Thank you for this comment. In accordance with the Reviewer’s suggestion, we have expanded the description of the pathophysiological mechanisms to include neutrophils and clarified their role in APS-related immunothrombosis, particularly through the formation of neutrophil extracellular traps (NETs).

Point 6 The main triggering...

line 173-174 "This characteristic of anti-β2GPI antibodies makes them one of the main pathological autoantigens in APS [5]. " This is a formal mistake. The antigen is β2GPI and not the antibodies. Please correct

lines 178-179. "Anti-β2GPI antibodies inhibit anticoagulation processes by decreasing factor X and increasing thrombin synthesis,...." 1- how they decrease factor X levels? Why lower levels of factor X should induce thrombosis? 2- thrombin is an enzyme deriving from prothrombin. There may be mechanisms increasing the synthesis of prothrombin or its activation to thrombin with increased levels of thrombin but you can never "increase the synthesis of an enzyme". Please amend the sentence

Lines 211-215. Sentences unclear which need to be rephrased

Response 6: We thank the Reviewer for these detailed and important remarks. In response, we implemented the following revisions:
(1) we corrected the formal inaccuracy by clearly identifying β2-glycoprotein I (β2GPI), rather than anti-β2GPI antibodies, as the principal autoantigen in APS;
(2) we amended the description of coagulation mechanisms by removing incorrect statements regarding factor X reduction and “thrombin synthesis,” replacing them with a precise explanation of enhanced thrombin generation through increased activation of prothrombin;
(3) we rephrased the previously unclear sentences (lines 211–215) to improve clarity and scientific accuracy.

 

Point7 : Figure 1  Several points to be amended/clarified:

For factor X decrease and increased thrombin synthesis see above

" ...release of tPA activator by ECs" ???  Probably "activator" must be deleted?

"cEC:TF synthesis and Endothelin-1 on the surface "  I cannot understand. Something lacking?

"Thrombogenic state"? or "Thrombophilic state"?

"Triggering factors of the second hit"???? or simply "Second hit"?

Legend to Fig 1 lines 223-226. What is the subject of the sentence? I think the subject should be  "aPL antibodies" plural whereas you say "stimulates, inhibits etc" which are singular. Please check and correct

Response 7 Thank you for these helpful comments. We revised Figure 1 and its legend in line with all suggestions by correcting coagulation-related terminology, clarifying endothelial cell–related descriptions, standardizing the use of “prothrombotic state” and “Second hit,” and ensuring grammatical consistency by using plural forms for antiphospholipid antibodies throughout.

Point 8 Paragraph 6 Risk factors ... Several concepts have been already written in the previous paragraphs. Please condense and delete some parts to avoid repetitions.

Lines 376-378.  Monitoring is not required in DOAC treatment. You probably mean that the measurement of DOAC levels with specific tests, when needed, may have special problems in the presence of aPL antibodies (specially LA). Please rephrase

Response 8: Thank you for this comment. In response, we revised and condensed the Risk Factors section to eliminate redundancy, improve clarity, and correct the description regarding direct oral anticoagulants

Point 9: Paragraph 8Usually Methods are reported in the first part of a review

Response 9 Thank you for this comment. In accordance with the Reviewer’s suggestion, we have relocated the Methods section to immediately follow the Introduction (paragraph 8), aligning the manuscript structure with standard conventions in review articles. Thank you for this comment. In accordance with the Reviewer’s suggestion, we have relocated the Methods section to immediately follow the Introduction (paragraph 8), aligning the manuscript structure with standard conventions in review articles.

Point 10  ConclusionsLine 456 "non APS-PE is a very strange definition. I suggest to simply say "PE occurring in patients non affected by APS" or something like this

Response 10: Thank you for this comment. In accordance with the Reviewer’s suggestion, we revised the wording in the Conclusions section to replace the unclear phrase with a clearer formulation referring to pulmonary embolism occurring in patients without APS.

Point 11: Few minor typos in the Reference list. Please check

Response 11: Thank you for this comment. We have carefully reviewed the Reference list, corrected minor typographical errors, and ensured that the numbering and formatting of references are consistent throughout the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

i am ok with the changes made.

Author Response

We sincerely thank the Reviewer for the positive evaluation and for confirming acceptance of the changes made. We greatly appreciate the time devoted to the review process and the constructive feedback provided.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors, I still think that this is an interesting paper with values. This second draft is significantly improved. The paper is better organized.

There are still some major points to improve:

• I attach the figure 1 in which there are a lot of problems (typos, unclear points..). For instance, on the right of "fibrinolytic activity"  you start with an. increase in PAI-1 , then there is an arrow going to right and then "release of PA by endothelial cells" Do you mean t-PA or you refer to other PA (Plasminogen activators)? Again, the two boxes to explain Direct intracellular interactions (intracellular or intercellular?) look more or less the same. In the previous draft one box referred to EC and one to platelets. There is something wrong
• The second point is that the use of abbreviations is still completely crazy. Throughout the paper  you find pulmonary embolism alternated with PE and this happens also for other terms 
• Moreover there still typos.

A reviewer is not a proof-reader but also a professional proof-reader should work on a draft written at the best quality level by Authors. Please be more careful in editing the paper!

It is a pity because this paper is really interesting and useful for scientific readership

Comments for author File: Comments.pdf

Author Response

 

We sincerely thank the Reviewer for the thorough evaluation of our manuscript, the constructive comments, and the time devoted to improving our work. We are grateful for the positive assessment of the scientific value of the paper and for acknowledging the improvements introduced in the revised version. The Reviewer’s remarks were invaluable and helped us further enhance the clarity and quality of the manuscript.

 

Point 1: I attach the figure 1 in which there are a lot of problems (typos, unclear points..). For instance, on the right of "fibrinolytic activity"  you start with an. increase in PAI-1 , then there is an arrow going to right and then "release of PA by endothelial cells" Do you mean t-PA or you refer to other PA (Plasminogen activators)? Again, the two boxes to explain Direct intracellular interactions (intracellular or intercellular?) look more or less the same. In the previous draft one box referred to EC and one to platelets. There is something wrong

 

Response 1: Thank you for your suggestions. The figure has been improved. We have added an extra explanation:  aPL antibodies can directly interact with endothelial cells (ECs) and monocytes through specific receptors. aPL stimulates the expression of tissue factor (TF) and endothelin-1 in endothelial cells (ECs) and monocytes [45,46]. β2GPI can bind GPIbα, a subunit of the platelet adhesion molecule. This enables the binding of anti-β2GPI antibodies, thereby influencing platelet activation. Increased thromboxane synthesis and activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway lead to platelet adhesion and aggregation [47].

 

Point 2: The second point is that the use of abbreviations is still completely crazy. Throughout the paper  you find pulmonary embolism alternated with PE and this happens also for other terms 

Response 2:Thank you for your suggestion. We have used the abbreviation PE throughout the manuscript. Only where the full name is used. We have also corrected the use of other abbreviations.

 

Point 3: Moreover there still typos.

Response 3: We apologize for these oversights. The manuscript has been thoroughly proofread, and all identified typographical and language errors have been corrected.

 

We are very grateful to the Reviewer for the insightful comments and guidance, which significantly contributed to improving the overall quality of our manuscript.

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for changes. No further comments