Coagulation abnormalities in children with uncorrected congenital heart defects seen at a teaching hospital in a developing country

Omotola O. Majiyagbe; Adeseye M. Akinsete; Titilope A. Adeyemo; Abideen O. Salako; Ekanem N. Ekure; Christy A. N. Okoromah

doi:10.1371/journal.pone.0263948

Peer Review History

Original SubmissionJanuary 29, 2022
16 Mar 2022 Decision Letter - Emanuele Bobbio, Editor PONE-D-22-02924Coagulation abnormalities in children with uncorrected congenital heart defects seen at a teaching hospital in a developing countryPLOS ONE Dear Dr. Majiyagbe, 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. ============================== ACADEMIC EDITOR: The paper is well written but, to be accepted for publication, should be able to answer the queries issued by the reviewers. To ensure the Editor and Reviewers will be able to recommend that your revised manuscript is accepted, please pay careful attention to each of the comments that have been pasted underneath this email. 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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. [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: Partly Reviewer #2: Partly Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know Reviewer #3: 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 Reviewer #3: 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 Reviewer #3: 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: 1. This manuscript reviews 70 cases of uncorrected congenital heart disease in patients 6 months to 17 years of age to establish the prevalence of coagulation defects looking at very basic parameters including CBC, PT, PTT and D-dimer. The study found a significantly elevated incidence of 37% when compared to a control population of 7% abnormalities. 2. The case:control ratio is only 1:1 which limits the reliability of the results, particularly in view of the fact that the controls had a relatively high and unexpected incidence of coagulation abnormalities. A ratio of at least 1:2 would be preferred. 3. The abbreviations CCHD and ACHD are used early in the article and not defined. It becomes apparent with further reading that it does refer to acyanotic and cyanotic heart disease, but it would be less confusion to define this earlier. 4. The details of how the blood samples on pages 9 and 10 were collected are somewhat excessive and could be condensed considerably. It is important to stress the different amount of coagulant required for patients with > 55% hematocrit. 5. There is variability in referring to coagulation abnormalities in the singular or pleural form and should be uniformly made in the pleural form, that is "abnormalities". 6. Many previous studies have shown that the major problems with coagulation occur with cyanotic congenital heart disease. This seems to be supported in this review which shows cyanotic lesions had a 37% incidence of abnormalities compared to a cyanotic lesions of 17%. However, most of the data discussion lumps acyanotic and cyanotic heart disease together and it would be important, even though the numbers are relatively small to break down the difference in these groups more clearly particularly in Table 1,3 and 4. It would also be important to include the pulse ox values in the acyanotic and cyanotic heart disease groups in addition to controls on Table 1. Including specific pulse ox data is critical since this is inherent in their conclusions of hypoxia being a primary factor in producing coagulation abnormalities. 7. In the discussion the authors describe the abnormalities of coagulation to 2 major factors, hypoxia and congestive heart failure. This speculation is intuitively correct, but should be expanded in more detail to include reference to low-grade DIC that is likely present with cyanotic patients. The link between congestive heart failure and probable hepatic hypoproduction of clotting factors should also be more clearly discussed. Reviewer #2: Thank you for the opportunity to review this interesting paper about coagulation disorders in patients with congenital, native heart defects from Nigeria. The paper is very well written and it is a pleasure to read the paper. However, there are some major concerns which have to be addressed: 1. The objective of the study was to determine the prevalence of coagulation abnormality in paediatric uncorrected CHD and to identify associated risk factors. If wonder if it is possible to calculate the prevalence of coagulation abnormalities in the given cohort of 70 consecutive children with CHD. Please give information about the statistic background. 2. Characteristics of CHD: Obviously, the definition of acyanotic and cyanotic CHD was given by diagnosis and not by saturations per se. How many patients in the acyanotic group had saturations below 90% , how many had severe pulmonary hypertension with Eisenmenger and were bad or no candidates for corrective surgery? 3. In the group of cyanotic CHD, patients with univentricular hearts which can be only palliated by Fontan Circulation are also included. Corrective surgery is not applicable for those. 4. Results: The statistics can be summarized and tables can be moved to the appendix. (Table 5, Table 6, table 8. 5. Discussion and conclusion: The discussion must be more coherend and shorter.. Due to the wide range of age some of the patients with ACHD are expected to have pulmonary hypertension and Eisenmenger which is known to result in severe coagulation abnormalities. This has to be worked up and discussed. That population is different to the population with CCHD and severe cyanosis, but without pulmonary arterial hypertension. Furthermore, there is a lack of therapeutic concepts that justify regular routine laboratory tests in patients, as the coagulopathies are a consequence of non-operated congenital heart disease. The only possible therapy is either corrective or palliative surgery to improve oxygenation (in CCHD) or prevent Eisenmenger as well as prevention of iron deficiency anemia. Hematological data must be available from the complete blood count. The data can be incorporate in the study or at least discussed. This is a major draw-back of the current version of the article and cannot be justified by the data. 6. Limitations: The number of patients is limited to calculate a prevalence. This scientific work is very interesting and well done, but it does not justify the conclusion, I would recommend sticking only to the descriptive description Reviewer #3: The authors present an interesting study regarding Coagulation abnormalities in a cohort of 70 children with uncorrected CHD in a developing country. They compared the results with controls. They show that uncorrected CHD displays higher probability of coagulopathy, and among CHDs, Cyanotic ones are more likely going to develop such abnormalities. Paper is well written, although there are minor spell mistakes to ammend. - Please specify that patients were not on anticoagulant or antiplatelets other than aspirin - Specify also other kind of medication patients were on, because many drugs can influence coagulation cascade - Did you perform or are you willing to perform thromboelastogram to assess platelets funcion? In fact more than the number of platelets, is the activity which counts. - Do you have data on liver function? ****** 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: No Reviewer #2: Yes:** Ulrike Herberg Reviewer #3: 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.0263948.r001
Revision 1
22 Apr 2022 Author Response I appreciate all the comments from the Reviewers as they have helped to enrich the manuscript. Reviewer #1: 1. This manuscript reviews 70 cases of uncorrected congenital heart disease in patients 6 months to 17 years of age to establish the prevalence of coagulation defects looking at very basic parameters including CBC, PT, PTT and D-dimer. The study found a significantly elevated incidence of 37% when compared to a control population of 7% abnormalities. 2. The case:control ratio is only 1:1 which limits the reliability of the results, particularly in view of the fact that the controls had a relatively high and unexpected incidence of coagulation abnormalities. A ratio of at least 1:2 would be preferred. RESPONSE: Thank you very much for the comments. At the commencement of the comparative study, ratio of 1:1 was done to appropriately match the children for age and sex. The finding in healthy controls was unexpected and may be a limitation of the study. 3. The abbreviations CCHD and ACHD are used early in the article and not defined. It becomes apparent with further reading that it does refer to acyanotic and cyanotic heart disease, but it would be less confusion to define this earlier. RESPONSE: The comments are duly noted and amendments made. 4. The details of how the blood samples on pages 9 and 10 were collected are somewhat excessive and could be condensed considerably. It is important to stress the different amount of coagulant required for patients with > 55% hematocrit. RESPONSE: Thank you for the comment. The details of the blood sample collection has been modified and the amount of anticoagulant added for patients with >55% hematocrit, the formula, has been included. 5. There is variability in referring to coagulation abnormalities in the singular or pleural form and should be uniformly made in the pleural form, that is "abnormalities". RESPONSE: The comments are noted and have been corrected. 6. Many previous studies have shown that the major problems with coagulation occur with cyanotic congenital heart disease. This seems to be supported in this review which shows cyanotic lesions had a 37% incidence of abnormalities compared to a cyanotic lesions of 17%. However, most of the data discussion lumps acyanotic and cyanotic heart disease together and it would be important, even though the numbers are relatively small to break down the difference in these groups more clearly particularly in Table 1,3 and 4. It would also be important to include the pulse ox values in the acyanotic and cyanotic heart disease groups in addition to controls on Table 1. Including specific pulse ox data is critical since this is inherent in their conclusions of hypoxia being a primary factor in producing coagulation abnormalities. RESPONSE: The data discussion has been separated as requested. The pulse oximetry has also been added to Tables 1 and 4. 7. In the discussion the authors describe the abnormalities of coagulation to 2 major factors, hypoxia and congestive heart failure. This speculation is intuitively correct, but should be expanded in more detail to include reference to low-grade DIC that is likely present with cyanotic patients. The link between congestive heart failure and probable hepatic hypoproduction of clotting factors should also be more clearly discussed. RESPONSE: The discussion on hypoxia and congestive heart failure with reference to low grade/sub-clinical DIC has been expanded. So also, the link between congestive heart failure and hepatic production of clotting factors. Reviewer #2: Thank you for the opportunity to review this interesting paper about coagulation disorders in patients with congenital, native heart defects from Nigeria. The paper is very well written and it is a pleasure to read the paper. RESPONSE: Thank you so much for the comments. However, there are some major concerns which have to be addressed: 1. The objective of the study was to determine the prevalence of coagulation abnormality in paediatric uncorrected CHD and to identify associated risk factors. If wonder if it is possible to calculate the prevalence of coagulation abnormalities in the given cohort of 70 consecutive children with CHD. Please give information about the statistic background. RESPONSE: The static background (sample size calculation for difference in two proportion) has been added to the methodology. 2. Characteristics of CHD: Obviously, the definition of acyanotic and cyanotic CHD was given by diagnosis and not by saturations per se. How many patients in the acyanotic group had saturations below 90% , how many had severe pulmonary hypertension with Eisenmenger and were bad or no candidates for corrective surgery? RESPONSE: The comments are duly noted. Seven patients with ACHD had oxygen saturation less than 90%. One patient with ACHD had severe pulmonary hypertension. 3. In the group of cyanotic CHD, patients with univentricular hearts which can be only palliated by Fontan Circulation are also included. Corrective surgery is not applicable for those. RESPONSE: Comments noted with thanks. Such group of patients can only have palliative surgeries and the correction has been made. 4. Results: The statistics can be summarized and tables can be moved to the appendix. (Table 5, Table 6, table 8. RESPONSE: Comments noted and effected. 5. Discussion and conclusion: The discussion must be more coherent and shorter. Due to the wide range of age some of the patients with ACHD are expected to have pulmonary hypertension and Eisenmenger which is known to result in severe coagulation abnormalities. This has to be worked up and discussed. That population is different to the population with CCHD and severe cyanosis, but without pulmonary arterial hypertension. Furthermore, there is a lack of therapeutic concepts that justify regular routine laboratory tests in patients, as the coagulopathies are a consequence of non-operated congenital heart disease. The only possible therapy is either corrective or palliative surgery to improve oxygenation (in CCHD) or prevent Eisenmenger as well as prevention of iron deficiency anemia. Hematological data must be available from the complete blood count. The data can be incorporate in the study or at least discussed. This is a major draw-back of the current version of the article and cannot be justified by the data. RESPONSE: Thank you for the comments. The proportion of ACHD with severe pulmonary hypertension has been discussed. The recommendation on therapy is also noted. Iron deficiency and other hematological indices were not evaluated in this study, as the study focused on coagulation abnormalities. It is however a possibility for future research. 6. Limitations: The number of patients is limited to calculate a prevalence. This scientific work is very interesting and well done, but it does not justify the conclusion, I would recommend sticking only to the descriptive description RESPONSE: Thank you for the comments. The recommendations are duly noted. Reviewer #3: The authors present an interesting study regarding Coagulation abnormalities in a cohort of 70 children with uncorrected CHD in a developing country. They compared the results with controls. They show that uncorrected CHD displays higher probability of coagulopathy, and among CHDs, Cyanotic ones are more likely going to develop such abnormalities. Paper is well written, although there are minor spell mistakes to amend. RESPONSE: Thank you for the comments. - Please specify that patients were not on anticoagulant or antiplatelets other than aspirin. RESPONSE: The patients were not on anticoagulants nor antiplatelets. This has been included in the methodology. - Specify also other kind of medication patients were on, because many drugs can influence coagulation cascade RESPONSE: The patients were on frusemide, spironolactone and propranolol. This has been included in the methodology. - Did you perform or are you willing to perform thromboelastogram to assess platelets funcion? In fact more than the number of platelets is the activity which counts. RESPONSE: Thank you for the comment. Only platelet count was evaluated in this study. Thromboelastogram is not available in our environment, and was stated as a limitation to the current study. It is however noted as a possible area of future research. - Do you have data on liver function? RESPONSE: Liver function test was not performed in this study. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0263948.r002
1 May 2022 Decision Letter - Emanuele Bobbio, Editor Coagulation abnormalities in children with uncorrected congenital heart defects seen at a teaching hospital in a developing country PONE-D-22-02924R1 Dear Dr. Omotola O Majiyagbe, 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, Emanuele Bobbio, M.D. Section Editor PLOS ONE Additional Editor Comments: Congratulations on your manuscript which is very well written and further improved. Reviewers' comments: https://doi.org/10.1371/journal.pone.0263948.r003
Formally Accepted
30 May 2022 Acceptance Letter - Emanuele Bobbio, Editor PONE-D-22-02924R1 Coagulation abnormalities in children with uncorrected congenital heart defects seen at a teaching hospital in a developing country. Dear Dr. Majiyagbe: 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. Emanuele Bobbio Section Editor PLOS ONE https://doi.org/10.1371/journal.pone.0263948.r004

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