Management and clinical outcomes for patients with gastrointestinal bleeding who decline transfusion

Jessica O. Asiedu; Ananda J. Thomas; Nicolas C. Cruz; Ryan Nicholson; Linda M. S. Resar; Mouen Khashab; Steven M. Frank

doi:10.1371/journal.pone.0290351

Peer Review History

Original SubmissionFebruary 23, 2023
16 Jun 2023 Decision Letter - Mabel Aoun, Editor PONE-D-23-05326Management and Clinical Outcomes for Patients with Gastrointestinal Bleeding who Decline TransfusionPLOS ONE Dear Dr. Frank, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please provide a point-by-point response to both reviewers' comments. Please submit your revised manuscript by Jul 13 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Mabel Aoun, MD, MPH Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. 2. Thank you for stating the following in the Competing Interests section: “S.M.F. serves on a scientific advisory board for Haemonetics.” We note that one or more of the authors are employed by a commercial company: Haemonetics a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests) . If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf. 3. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well 4. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for asking me to review this paper by Asiedu and colleagues. The authors have examined the management of patients admitted to their institution with GI bleeding who refused/declined red blood cell transfusions. Although most practitioners meet patients who would decline blood products, it remains relatively rare to face the situation of acute bleeding in this patient population. Although this series is small, it is nevertheless probably one of the largest and is informative. I have the following questions and comments for the authors: -Please comment on the choice of therapies (IV iron, folate, B12), which are all important in stimulating erythropoiesis over relatively long period of time. These therapies cannot mitigate the short-term impact of acute blood loss and I am left wondering about strategies to mitigate blood loss that are unique to this patient population. Were other products were used? Was there any use of pro-coagulant factors or drugs, etc. -Please clarify how many patients were seen multiple times and considered separate patients? Patients who are seen multiple times over a short period of time would be influenced/correlated to their previous admission (e.g. erythropoiesis would have already been stimulated, etc.). -Please comment on the indications for surgery and endoscopy (as well as more generally for the whole cohort), and whether these interventions were necessary solely on the basis of blood products refusal. It is indeed very unusual to have to carry out colectomies or even therapeutic lower endoscopies to stop bleeding these days. Most cases of lower GI bleeding will resolve with supportive management. Unnecessary surgery or therapeutic endoscopies would indeed be a major endpoint to consider if invasive procedures could have been avoided with blood products. Bleeding from diverticulosis would be a good example of a pathology for which surgery is almost never indicated. -Please include interventional radiology procedures in your description of invasive interventions. -The results of this series should be put into context of the broader literature pertaining to acute blood loss management in patients who decline blood transfusions. There are surely other series that should be cited and reviewed. There may be systematic reviews as well? Reviewer #2: This study focuses on the bloodless medicine approach to gastrointestinal bleeding patients who declined allogeneic blood transfusions. In addition, with the recent blood shortages resulting from the COVID-19 pandemic and the continuing increase in healthcare costs associated with allogeneic blood transfusions, the authors provide very important insight into reducing blood transfusions in all patients. Below are some points that need to be revised. ・Some types of blood transfusions may be acceptable for each patient Jehovah’s Witness patients will generally not accept red blood cells, plasma, platelets, or whole blood, other blood components. In some patients, however, may accept autologous blood storage or closed extracorporeal circulation with autotransfusion using a cell saver during the procedure. These options should not be completely ruled out. It is important to confirm the details of precisely which autologous blood transfusions and blood products the patient can accept. This should be added to the DISCUSSION. ・Add to Reference [Giving HBOCs also require a risk/benefit decision analysis, acknowledging that giving “too little, too late” may not help severely anemic patients, while giving HBOCs for mild or moderate anemia may not be helpful to improve outcomes.] (DISCUSSION, page 12-13) Please add references. ・Combination of intravenous iron and erythropoietin In some countries, medical insurance does not cover the use of erythropoietin for anemia due to bleeding. In this study, some or many cases were treated with iron and erythropoietin. Is the increase in Hb greater with iron plus erythropoietin than with iron alone? If possible, can the authors show the range of increase in Hb for each drug or combination used? ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Guillaume Martel Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0290351.r001
Revision 1
14 Jul 2023 Author Response We thank the Editor and Reviewers for the time and effort taken to suggest edits to improve our manuscript. Below is a point-by-point response addressing these revisions and describing how they were made. All edits in the revised manuscript are shown in underlined, red-colored font. Reviewer #1 Comment- Please comment on the choice of therapies (IV iron, folate, B12), which are all important in stimulating erythropoiesis over relatively long period of time. These therapies cannot mitigate the short-term impact of acute blood loss and I am left wondering about strategies to mitigate blood loss that are unique to this patient population. Were other products were used? Was there any use of pro-coagulant factors or drugs, etc. Response- We appreciate the reviewer’s insightful comment regarding the erythropoietic therapies we described in our manuscript and how these therapies do not acutely benefit the patient who is bleeding from the gastrointestinal tract. The same is true for erythropoietin as well. For this reason, the number one priority in patients who will not accept allogeneic transfusion is to stop the bleeding. We call this priority “keeping the blood in the patient”. After all possible efforts are made to stop the bleeding, then we focus on stimulating RBC production (erythropoiesis). Although the benefits of IV iron, folate, and B12 are not acute, we have seen increases in the hemoglobin concentration by 1-2 g/dL per week, which is important for achieving overall positive patient outcomes. Other products utilized in the management of these patients included tranexamic acid (an antifibrinolytic) and Hemopure (a bovine Hb-based oxygen carrier). These concepts are clarified and emphasized in the revised version of the manuscript in the edits on pages 12-14. Comment- Please clarify how many patients were seen multiple times and considered separate patients? Patients who are seen multiple times over a short period of time would be influenced/correlated to their previous admission (e.g. erythropoiesis would have already been stimulated, etc.). Response- The reviewer raises a valid point about how previous therapeutic interventions for patients with recurrent GIB may influence their outcomes in subsequent encounters, particularly for encounters close in time when a patient may still be receiving some erythropoiesis-stimulating supplements. The number of patients who were seen multiple times for GIB during our study period have been noted on page 7 of the revised manuscript. Of note, two of the three repeat patients had encounters 9-13 months apart and are unlikely to be markedly influenced by previous therapeutic interventions. Comment- Please comment on the indications for surgery and endoscopy (as well as more generally for the whole cohort), and whether these interventions were necessary solely on the basis of blood products refusal. It is indeed very unusual to have to carry out colectomies or even therapeutic lower endoscopies to stop bleeding these days. Most cases of lower GI bleeding will resolve with supportive management. Unnecessary surgery or therapeutic endoscopies would indeed be a major endpoint to consider if invasive procedures could have been avoided with blood products. Bleeding from diverticulosis would be a good example of a pathology for which surgery is almost never indicated. Response- The reviewer raises an important topic which is the specific indication for surgery or endoscopy in our GIB patients. As we now emphasize in the revised version of the manuscript, and in the above response to reviewers’, the number one priority is stopping the bleed. If this can be done by endoscopy for example by cauterizing a bleeding source in the colon, this is a low risk, high benefit approach. Therefore, endoscopy is far more commonly utilized than surgery (e.g., colectomy). Another low risk, high benefit procedure is an interventional radiology procedure to embolize the source of bleeding. This is usually a second-choice approach after endoscopy. The third choice and as the reviewer alludes to, uncommonly performed, is surgical approach to stop the bleed. Rarely do we need to take these patients to surgery, in fact only four of our twenty-seven patients received such treatment. These details described here have been added to the revised version of the manuscript on page 10. Comment- Please include interventional radiology procedures in your description of invasive interventions. Response- Two out of twenty-seven patients in our case series required interventional radiology procedures. Although this approach to finding and stopping the bleed seems reasonable, it is not uncommon for the proceduralist to have difficulty finding the exact location and the anatomic vessels that need to be embolized to stop the bleed. Most likely stopping a GI bleed is more difficult that stopping bleeding from other sources such as the uterus in menorrhagia, since the vascular supply to the GI tract is so much more extensive and complex. Interventional radiology procedures have been described on page 10 and included in Table 2 of the revised manuscript. Comment- The results of this series should be put into context of the broader literature pertaining to acute blood loss management in patients who decline blood transfusions. There are surely other series that should be cited and reviewed. There may be systematic reviews as well? Response- In response to the above comment and on pages 12-14 of the manuscript, we have elaborated on some of the methods related to the management of blood loss in patient who decline blood transfusions. A lot of these methods revolve around minimizing blood loss and stimulating erythropoiesis. Some literature dive into other methods not discussed in our paper such as the use of hypotension to reduce blood loss or anesthesia to decrease oxygen consumption. While these methods are important to consider in the management of patients who decline transfusion, they are more applicable to patients undergoing major surgeries, which is not as reflective of our cohort. We have also included revisions to expand on how our results relate to previous studies done in this field. Reviewer #2: Comment- Some types of blood transfusions may be acceptable for each patient Jehovah’s Witness patients will generally not accept red blood cells, plasma, platelets, or whole blood, other blood components. In some patients, however, may accept autologous blood storage or closed extracorporeal circulation with autotransfusion using a cell saver during the procedure. These options should not be completely ruled out. It is important to confirm the details of precisely which autologous blood transfusions and blood products the patient can accept. This should be added to the DISCUSSION. Response- The reviewer raises a valid point about the alternative blood products and components that may be acceptable to Jehovah’s Witness patients. In general, these patients do not accept primary blood components such as RBCs, platelets, or plasma. They may be more open to minor blood components like cryoprecipitate, albumin, clotting factors, but this determination is made on an individual basis. Some Jehovah Witness patients are also willing to accept autologous blood salvage and intraoperative hemodilution as these can be performed such that blood remains physically contiguous w/ one’s body. These details have been expounded upon in the revisions of page 14 of the edited manuscript. Comment- Add to Reference.[Giving HBOCs also require a risk/benefit decision analysis, acknowledging that giving “too little, too late” may not help severely anemic patients, while giving HBOCs for mild or moderate anemia may not be helpful to improve outcomes.] (DISCUSSION, page 12-13). Please add references. Response- As an experimental therapy, Hemopure is used on a compassionate use basis and requires a risk/benefit decision analysis of factors such as the severity of the patient’s anemia, timely and efficacious administration, and risk factors associated with administration such as increased vasoconstriction and hypertension. Such considerations have been further elaborated in the edits to the revised manuscript on page 14 with additional references (19, 20) cited for deeper exploration of this topic. Comment- Combination of intravenous iron and erythropoietin In some countries, medical insurance does not cover the use of erythropoietin for anemia due to bleeding. In this study, some or many cases were treated with iron and erythropoietin. Is the increase in Hb greater with iron plus erythropoietin than with iron alone? If possible, can the authors show the range of increase in Hb for each drug or combination used? Response- We appreciate the reviewer’s insightful comment about the use of EPO and iron for the correction of anemia and the role that medical insurance might play in the protocol to use either or a combination of both. Patients in our cohort received many different combinations of therapies. As such, it is difficult to isolate the contribution of any one therapy such as of iron, B12, or EPO. Moreover, current literature does not show a consensus concerning whether treatment of anemia is more efficacious with a combination of iron and EPO or iron alone. Some studies demonstrate that there is no difference in the requirement for transfusions when patients are treated with EPO and iron compared to iron alone. Other studies demonstrate that the addition of EPO to iron leads to a greater and faster increase in Hb in anemic patients compared to iron alone. As such, further studies are required to make any decisive conclusions about this, and we have not edited the manuscript based on this comment. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0290351.r002
31 Jul 2023 Decision Letter - Mabel Aoun, Editor PONE-D-23-05326R1Management and Clinical Outcomes for Patients with Gastrointestinal Bleeding who Decline TransfusionPLOS ONE Dear Dr. Frank, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please address the comment of Reviewer #2. Please submit your revised manuscript by Sep 14 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Mabel Aoun, MD, MPH Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: [ ] are my new comments. Reviewer #2: Comment- Some types of blood transfusions may be acceptable for each patient Jehovah’s Witness patients will generally not accept red blood cells, plasma, platelets, or whole blood, other blood components. In some patients, however, may accept autologous blood storage or closed extracorporeal circulation with autotransfusion using a cell saver during the procedure. These options should not be completely ruled out. It is important to confirm the details of precisely which autologous blood transfusions and blood products the patient can accept. This should be added to the DISCUSSION. Response- The reviewer raises a valid point about the alternative blood products and components that may be acceptable to Jehovah’s Witness patients. In general, these patients do not accept primary blood components such as RBCs, platelets, or plasma. They may be more open to minor blood components like cryoprecipitate, albumin, clotting factors, but this determination is made on an individual basis. Some Jehovah Witness patients are also willing to accept autologous blood salvage and intraoperative hemodilution as these can be performed such that blood remains physically contiguous w/ one’s body. These details have been expounded upon in the revisions of page 14 of the edited manuscript. [Thank you for correcting and adding references to alternative blood products and components. It is important to confirm these options for each Jehovah's Witness patient. Therefore, if possible, please add to the Discussion, "It is important to confirm the details of which autologous blood transfusions and blood products the patient can accept.] Comment- Add to Reference. “Giving HBOCs also require a risk/benefit decision analysis, acknowledging that giving “too little, too late” may not help severely anemic patients, while giving HBOCs for mild or moderate anemia may not be helpful to improve outcomes.” (DISCUSSION, page 12-13). Please add references. Response- As an experimental therapy, Hemopure is used on a compassionate use basis and requires a risk/benefit decision analysis of factors such as the severity of the patient’s anemia, timely and efficacious administration, and risk factors associated with administration such as increased vasoconstriction and hypertension. Such considerations have been further elaborated in the edits to the revised manuscript on page 14 with additional references (19, 20) cited for deeper exploration of this topic. [Thank you for the correction. The references are added and will help the reader.] Comment- Combination of intravenous iron and erythropoietin In some countries, medical insurance does not cover the use of erythropoietin for anemia due to bleeding. In this study, some or many cases were treated with iron and erythropoietin. Is the increase in Hb greater with iron plus erythropoietin than with iron alone? If possible, can the authors show the range of increase in Hb for each drug or combination used? Response- We appreciate the reviewer’s insightful comment about the use of EPO and iron for the correction of anemia and the role that medical insurance might play in the protocol to use either or a combination of both. Patients in our cohort received many different combinations of therapies. As such, it is difficult to isolate the contribution of any one therapy such as of iron, B12, or EPO. Moreover, current literature does not show a consensus concerning whether treatment of anemia is more efficacious with a combination of iron and EPO or iron alone. Some studies demonstrate that there is no difference in the requirement for transfusions when patients are treated with EPO and iron compared to iron alone. Other studies demonstrate that the addition of EPO to iron leads to a greater and faster increase in Hb in anemic patients compared to iron alone. As such, further studies are required to make any decisive conclusions about this, and we have not edited the manuscript based on this comment. [For the reader, it should be added in the Discussion with references that no conclusion has been reached as to whether the combination of EPO and iron or iron alone is more beneficial.] ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Guillaume Martel Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0290351.r003
Revision 2
2 Aug 2023 Author Response We thank the Editor and Reviewers for the time and effort taken to suggest edits to improve our manuscript. Below is a point-by-point response addressing these revisions and describing how they were made. All edits in the revised manuscript are shown in underlined, red-colored font. Reviewer #1 (No additional comments) Reviewer #2: Comment- Some types of blood transfusions may be acceptable for each patient Jehovah’s Witness patients will generally not accept red blood cells, plasma, platelets, or whole blood, other blood components. In some patients, however, may accept autologous blood storage or closed extracorporeal circulation with autotransfusion using a cell saver during the procedure. These options should not be completely ruled out. It is important to confirm the details of precisely which autologous blood transfusions and blood products the patient can accept. This should be added to the DISCUSSION. Response- The reviewer raises a valid point about the alternative blood products and components that may be acceptable to Jehovah’s Witness patients. In general, these patients do not accept primary blood components such as RBCs, platelets, or plasma. They may be more open to minor blood components like cryoprecipitate, albumin, clotting factors, but this determination is made on an individual basis. Some Jehovah Witness patients are also willing to accept autologous blood salvage and intraoperative hemodilution as these can be performed such that blood remains physically contiguous w/ one’s body. These details have been expounded upon in the revisions of page 14 of the edited manuscript. [Thank you for correcting and adding references to alternative blood products and components. It is important to confirm these options for each Jehovah's Witness patient. Therefore, if possible, please add to the Discussion, "It is important to confirm the details of which autologous blood transfusions and blood products the patient can accept. Response- Thank you. This detail has been added to page 15] Comment- Add to Reference. “Giving HBOCs also require a risk/benefit decision analysis, acknowledging that giving “too little, too late” may not help severely anemic patients, while giving HBOCs for mild or moderate anemia may not be helpful to improve outcomes.” (DISCUSSION, page 12-13). Please add references. Response- As an experimental therapy, Hemopure is used on a compassionate use basis and requires a risk/benefit decision analysis of factors such as the severity of the patient’s anemia, timely and efficacious administration, and risk factors associated with administration such as increased vasoconstriction and hypertension. Such considerations have been further elaborated in the edits to the revised manuscript on page 14 with additional references (19, 20) cited for deeper exploration of this topic. [Thank you for the correction. The references are added and will help the reader.] Comment- Combination of intravenous iron and erythropoietin In some countries, medical insurance does not cover the use of erythropoietin for anemia due to bleeding. In this study, some or many cases were treated with iron and erythropoietin. Is the increase in Hb greater with iron plus erythropoietin than with iron alone? If possible, can the authors show the range of increase in Hb for each drug or combination used? Response- We appreciate the reviewer’s insightful comment about the use of EPO and iron for the correction of anemia and the role that medical insurance might play in the protocol to use either or a combination of both. Patients in our cohort received many different combinations of therapies. As such, it is difficult to isolate the contribution of any one therapy such as of iron, B12, or EPO. Moreover, current literature does not show a consensus concerning whether treatment of anemia is more efficacious with a combination of iron and EPO or iron alone. Some studies demonstrate that there is no difference in the requirement for transfusions when patients are treated with EPO and iron compared to iron alone. Other studies demonstrate that the addition of EPO to iron leads to a greater and faster increase in Hb in anemic patients compared to iron alone. As such, further studies are required to make any decisive conclusions about this, and we have not edited the manuscript based on this comment. [For the reader, it should be added in the Discussion with references that no conclusion has been reached as to whether the combination of EPO and iron or iron alone is more beneficial. Response- This is indeed a crucial subject that may inform future protocol. These details have been expounded upon on page 13 with the appropriate references 14-16 added.] Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0290351.r004
7 Aug 2023 Decision Letter - Mabel Aoun, Editor Management and Clinical Outcomes for Patients with Gastrointestinal Bleeding who Decline Transfusion PONE-D-23-05326R2 Dear Dr. Frank, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Mabel Aoun, MD, MPH Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0290351.r005
Formally Accepted
15 Aug 2023 Acceptance Letter - Mabel Aoun, Editor PONE-D-23-05326R2 Management and Clinical Outcomes for Patients with Gastrointestinal Bleeding who Decline Transfusion Dear Dr. Frank: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Mabel Aoun Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0290351.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .