Upper extremity deep vein thrombosis in COVID-19: Incidence and correlated risk factors in a cohort of non-ICU patients

Nicola Mumoli; Francesco Dentali; Giulia Conte; Alessandra Colombo; Riccardo Capra; Cesare Porta; Giuseppe Rotiroti; Francesca Zuretti; Marco Cei; Flavio Tangianu; Isabella Evangelista; Josè Vitale; Antonino Mazzone; Igor Giarretta

doi:10.1371/journal.pone.0262522

Peer Review History

Original SubmissionJuly 12, 2021
15 Dec 2021 Decision Letter - Amit Bahl, Editor PONE-D-21-22254Upper extremity deep vein thrombosis in COVID-19: incidence and correlated risk factors in a cohort of non-ICU patientsPLOS ONE Dear Dr. Mumoli, 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 see reviewer comments below. Minor modifications are needed. Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. For Lab, Study and Registered Report Protocols: These article types are not expected to include results but may include pilot data. ============================== Please submit your revised manuscript by Jan 29 2022 11:59PM. 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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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Comments: - Venous CUS of the upper and lower extremities was performed on all enrolled patients between the 1st and the 30th day of hospitalization (median 7; IQR 4-9). This procedure of screening for DVT needs to be better described. When exactly was it done? Why was it done at that time? What exactly does it say in “the local COVID-19 patient management protocol”? - The most striking finding of this work is the presence of a majority of isolated axillary vein thrombosis (which is an unusual presentation of UEDVT), of whom a high proportion are bilateral, and occur in the absence of central venous catheters. So the mechanical/haemodynamic effect of compression of the axillary veins by the anchoring system of the helmet CPAP system is likely to play a central role and be the main provoking factor for these unusual UEDVTs. This should be highlighted more clearly throughout the manuscript. - One important limitation is that the results and findings apply only to patients with helmet CPAP. To be stated more clearly. Reviewer #2: Interesting manuscript, well supported with clear discussion. The paper is well written and formally correct and it is clear its clinical relevance, and what this article should add to the body of knowledge on this topic. Minor Comments: - In this study most DVTs are UEDVT and in particular axillary venous thrombosis, there are several possible explanations for this finding. Is the UEDVT due to the increase in venous pressure induced by the application of Helmet CPAP or is it strictly related to the mechanical compression of caused by the anchor strips? Authors should discuss this. - In the paragraph Conclusion the authors state that the hypothesis that an intermediate dose of heparin may be effective in COVID-19 patients at high risk of DVT not hospitalized in intensive care and with an early stage of the disease may still be valid. However, a number of recent publications seem to disagree with this. For example, a recent article by Samdja et al. reported that among COVID-19 patients admitted to medical wards, intermediate-dose prophylactic anticoagulation versus standard-dose prophylactic anticoagulation did not result in a significant difference in hospital mortality. This document needs to be cited and discussed. - In this study, obesity, which has been associated with a worse prognosis in COVID-19 infection, is not associated with UEDVT, it can be hypothesized that a larger arm diameter may be "protective" on axillary vein compression caused by the helmet straps? ****** 6. 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Revision 1
21 Dec 2021 Author Response Dicember 20th 2021 Dr. Amit Bahl Academic Editor PLOS ONE Re: PONE-D-21-22254 Dear Dr. Bahl, I am writing in response to your email of December 14th 2021 regarding the above-mentioned manuscript. We are grateful that Reviewers for their positive comments to our paper and for defining it as interesting and well supported with clear data. We are also grateful to the Reviewers for their constructive criticisms. Therefore, we have edited the manuscript according to their suggestions. Below, our answers to all the Reviewers’ comments are listed point-by-point, along with a description of the changes that were made to the previous version of the manuscript. We hope that this manuscript in now acceptable for publication in the Plos One. Sincerely, Nicola Mumoli Reviewer: 1 1. Venous CUS of the upper and lower extremities was performed on all enrolled patients between the 1st and the 30th day of hospitalization (median 7; IQR 4-9). This procedure of screening for DVT needs to be better described. When exactly was it done? Why was it done at that time? What exactly does it say in “the local COVID-19 patient management protocol”? According to our local protocol, CUS was performed in each patient upon application of the c-pap helmet and repeated after 7 days of ventilation. In case of shorter duration of treatment with C-PAP, the examination was repeated when the helmet was removed. In addition, the examination was anticipated or possibly repeated in case of clinical suspicion of DVT. If DVT was diagnosed, no further CUS was performed. Furthermore, the c-pap helmet was not always applied at hospitalization but in a percentage of cases it was prescribed for evidence of respiratory distress. This approach explains the large interval on the day of CUS administration, however the median exam day was 7th with 75% of the population ranging from 4th to 9th day. 2. The most striking finding of this work is the presence of a majority of isolated axillary vein thrombosis (which is an unusual presentation of UEDVT), of whom a high proportion are bilateral, and occur in the absence of central venous catheters. So the mechanical/haemodynamic effect of compression of the axillary veins by the anchoring system of the helmet CPAP system is likely to play a central role and be the main provoking factor for these unusual UEDVTs. This should be highlighted more clearly throughout the manuscript. We thank the reviewer for this comment and we also agree with his statement. Accordingly we added to the discussion the following sentence:…Interestingly, most UEDVTs were isolated axillary venous thrombosis which is an unusual presentation of UEDVT, of which a high percentage were bilateral and occurred in the absence of central venous catheters. These evidences suggest that the mechanical and hemodynamic effect of the compression of the axillary veins by the CPAP helmet anchorage system appears to play a central role and to be the main provoking factor for these high numbers of UEDVTs… We also removed the following sentence from the text: “According to this hypothesis we also found a higher incidence of UESVT compared to LESVT” which seems to be pleonastic after the suggested changes. 3. One important limitation is that the results and findings apply only to patients with helmet CPAP. To be stated more clearly. We agree with this reviewer 1 comment, however we must point-out that, as reported in the text, the majority of COVID-19 patients are ventilated with helmet-CPAP for a number of reasons so our findings appear to be clinical relevant. We integrated the text as follows: “Unfortunately, we cannot compare the incidence of UEDVT in our cohort of COVID-19 patients with that by a hypothetical group of patients treated with facemask-CPAP, therefore our findings apply only to patients with helmet-CPAP and this is one of the limitations of this study”. Reviewer: 2 1. In this study most DVTs are UEDVT and in particular axillary venous thrombosis, there are several possible explanations for this finding. Is the UEDVT due to the increase in venous pressure induced by the application of Helmet CPAP or is it strictly related to the mechanical compression of caused by the anchor strips? Authors should discuss this. Se answer 2 to reviewer 1. 2. In the paragraph Conclusion the authors state that the hypothesis that an intermediate dose of heparin may be effective in COVID-19 patients at high risk of DVT not hospitalized in intensive care and with an early stage of the disease may still be valid. However, a number of recent publications seem to disagree with this. For example, a recent article by Samdja et al. reported that among COVID-19 patients admitted to medical wards, intermediate-dose prophylactic anticoagulation versus standard-dose prophylactic anticoagulation did not result in a significant difference in hospital mortality. This document needs to be cited and discussed. We are grateful to the reviewer for this comment. The text has been revised with the addition of the following sentence and the inclusion of the suggested article in the references: “Smadja and coll. have reported that among COVID-19 patients hospitalized in medical wards, intermediate-dose anticoagulant compared with standard-dose anticoagulant did not result in a significant difference in in-hospital mortality, however only the 3,3% of the patients included in their retrospective analysis required CPAP ventilation and less than 20% had severe disease at lung CT-scan”. 3. In this study, obesity, which has been associated with a worse prognosis in COVID-19 infection, is not associated with UEDVT, it can be hypothesized that a larger arm diameter may be "protective" on axillary vein compression caused by the helmet straps? This is a very interesting hypothesis raised by the Reviewer 2, which seems to be reasonable but hardly to demonstrate. In addition, only 14% of the patients included in our study had a BMI greater than 30 therefore, we do not consider it appropriate to discuss this hypothesis in the main text. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0262522.r002
28 Dec 2021 Decision Letter - Amit Bahl, Editor Upper extremity deep vein thrombosis in COVID-19: incidence and correlated risk factors in a cohort of non-ICU patients PONE-D-21-22254R1 Dear Dr. Mumoli, 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, Amit Bahl Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0262522.r003
Formally Accepted
3 Jan 2022 Acceptance Letter - Amit Bahl, Editor PONE-D-21-22254R1 Upper extremity deep vein thrombosis in COVID-19: incidence and correlated risk factors in a cohort of non-ICU patients Dear Dr. Mumoli: 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. Amit Bahl Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0262522.r004

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