{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T10:54:25Z","timestamp":1767178465738,"version":"build-2238731810"},"update-to":[{"DOI":"10.12688\/f1000research.146710.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000}},{"DOI":"10.12688\/f1000research.146710.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000}}],"reference-count":15,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.<\/ns3:p>","DOI":"10.12688\/f1000research.146710.3","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T11:10:09Z","timestamp":1731323409000},"page":"887","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19"],"prefix":"10.12688","volume":"13","author":[{"given":"Lantarima","family":"Bhoopat","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia","family":"Martynova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"April","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pattharawin","family":"Pattharanitima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Semi","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senxi","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibrahim","family":"Syed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther E","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zea","family":"Borok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice","family":"Liebler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa Lee","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pichaya","family":"Tantiyavarong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey O","family":"Connell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"100434","DOI":"10.1016\/j.eclinm.2020.100434","article-title":"Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series.","volume":"24","author":"A Rapkiewicz","year":"2020","journal-title":"EClinicalMedicine."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1054-1062","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.","volume":"395","author":"F Zhou","year":"2020","journal-title":"Lancet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1094-1099","DOI":"10.1111\/jth.14817","article-title":"Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.","volume":"18","author":"N Tang","year":"2020","journal-title":"J. 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Res."},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.12687462","author":"L Bhoopat","year":"2024","journal-title":"Zenodo."},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.12730540","article-title":"STROBE checklist for A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19.","author":"L Bhoopat","year":"2024","journal-title":"Zenodo."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/13-887\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/13-887\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/13-887\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T11:10:10Z","timestamp":1731323410000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/13-887\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,11]]},"references-count":15,"URL":"https:\/\/doi.org\/10.12688\/f1000research.146710.3","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/f1000research.146710.2","asserted-by":"subject"},{"id-type":"doi","id":"10.12688\/f1000research.146710.1","asserted-by":"subject"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,11]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/13-887\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.171179.r320738, Prof. NOPPACHARN UAPRASERT, Chulalongkorn University, Bangkok, Bangkok, 18 Sep 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/13-887\/v2#referee-response-320738","order":0,"name":"referee-response-320738","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.171179.r324950, Adisak Tantiworawit, Chiang Mai University, Chiang Mai, Chiang Mai, 10 Oct 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/13-887\/v2#referee-response-324950","order":1,"name":"referee-response-324950","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Lantarima Bhoopat<\/b>; \n<i>Posted: 16 Oct 2024<\/i>; I would like to thank you the reviewer for the review and comments. I would address the queries as below. 1. Which factors was used to analyze in the multivariable Cox regression for survival outcome?  \n<i>We evaluated the following potential covariates: D-dimer levels, age, ethnicity, BMI, comorbidities, ICU admission, mechanical ventilation, HFNC, SIC score, COVID treatment, thrombosis, and bleeding events in the multivariable Cox regression for survival outcome.<\/i>  2. Why does azithromycin treatment was the factors associated for survival outcome, please give more discussion and answer?  \n<i>We have certain limitations in answering this question. As we did not collect data on the timing of treatment initiation, we are unable to evaluate the clinical condition at the time azithromycin was started, or whether it was administered too late in the course of the disease.<\/i>  3. Please give and discuss more about the limitation of the study such as - The imbalance characteristics between group such as steroid treatment, antiviral treatment  \n<i>The imbalance in treatment characteristics between the groups could be explained by the difference in severity between them. Patients who received anticoagulant adjustment were treated more aggressively for COVID-19 infection, with therapies such as remdesivir, azithromycin, hydroxychloroquine, convalescent plasma, and steroids, in response to their severe clinical course. The severity of patients in the anticoagulant adjustment group was reflected in higher rates of ICU admission, high-flow nasal cannula (HFNC) requirement, mechanical ventilator (MV) requirement, and vasopressor use compared to the fixed anticoagulant group. The sepsis-induced coagulopathy scores (SICS) were also significantly higher in this group, correlating with higher lactate dehydrogenase (LDH) levels and d-dimer levels both at baseline and at their peak during admission.<\/i>  - The survival outcome may effect by other treatment, not only anticoagulant treatment  \n<i>Although steroid treatment was associated with lower in-hospital mortality (HR 0.39, 95% CI: 0.16, 0.96), we demonstrated that receiving up-titrated heparin was an independent factor associated with reduced in-hospital mortality. This was confirmed using Schoenfeld residuals tested in the final model, which showed that the proportional hazards assumption was valid, allowing us to interpret the independent effect of the up-titrated group separately from the effect of steroids.<\/i>","URL":"https:\/\/f1000research.com\/articles\/13-887\/v3#referee-comment-12654","order":2,"name":"referee-comment-12654","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Lantarima Bhoopat<\/b>; \n<i>Posted: 20 Oct 2024<\/i>; I re-analyzed the data today and now have more supporting evidence to answer the reviewer's second question regarding why azithromycin treatment was a factor associated with survival outcomes, as outlined below  Initially, we did not classify the patients according to standard guidelines, which categorize the severity as follows: mild for those with mild symptoms; moderate disease is defined by the presence of clinical or radiographic evidence of lower respiratory tract disease but with a blood oxygen saturation of 94% or higher and requiring hospitalization; severe disease is indicated by hypoxemia with oxygen saturation \u226493% or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen &lt;300; and critical illness is defined by respiratory failure requiring mechanical ventilation or shock requiring vasopressors.  After reclassifying the patients according to standard guidelines and including the new severity classification as a factor in the multivariate analysis of the survival model, we found that azithromycin treatment had no effect on survival. However, critical patients became an independent factor affecting the outcome, which may support the assumption that the effect of azithromycin on survival was confounded by patient severity.","URL":"https:\/\/f1000research.com\/articles\/13-887\/v3#referee-comment-12684","order":3,"name":"referee-comment-12684","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.171179.r324949, Bundarika Suwanawiboon, Mahidol University, Salaya, Nakhon Pathom, 16 Oct 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/13-887\/v2#referee-response-324949","order":4,"name":"referee-response-324949","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Lantarima Bhoopat<\/b>; \n<i>Posted: 03 Nov 2024<\/i>; I would like to thank you the reviewer for the review and comments. I would address the queries as below. 1. The authors acknowledged the study's limitations in determining causes of death through autopsies. However, could the authors provide information on the most common causes of death, if possible? Were there any differences in thromboembolism-related mortality between the two treatment groups?  \n<i>All causes of death are determined to be due to COVID infection. We apologize for not collecting specific data on thromboembolism-related mortality. However, there were 2 non-surviving patients who were confirmed breakthrough thrombosis: 1 with deep vein thrombosis (DVT) and another with pulmonary embolism along with DVT.<\/i>  2. In addition to the fixed doses of anticoagulation and insuppressible trend of D-dimer levels in deceased patients, as shown in Figure 3B, were there any differences between deceased patients in the fixed-dose group and those with the up-titrating group regarding factors that might affect survival outcomes, for example, age, the clinical severity of COVID-19 according to the standard classification, and COVID-19 treatment?  \n<i>When defining COVID-19 severity according to standard guidelines, the severity is classified as mild for those with mild symptoms. Moderate disease is defined by the presence of clinical or radiographic evidence of lower respiratory tract disease but with a blood oxygen saturation of 94% or higher, and it requires hospitalization. Indicators of severe disease include hypoxemia with oxygen saturation \u226493% or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen &lt;300. Critical illness is defined by respiratory failure requiring mechanical ventilation or shock requiring vasopressors.<\/i> \n<i>Among non-surviving patients, we found that 31.2% of patients in the fixed-dose group were classified as severe and 68.2% as critical, while all of the non-surviving patients in the up-titrated group were classified as critical illness.<\/i> \n<i>After reclassifying the patients according to standard guidelines and including the severity classification as a factor in the multivariate analysis of the survival model, we found that critical illness became an independent factor affecting the outcome, and azithromycin treatment had no effect on survival. Therefore, the effect of azithromycin on survival was confounded by patient severity.<\/i> \n<i>Other factors affecting survival that showed statistically significant differences between non-surviving patients in both groups included age and steroid treatment. The fixed-dose group had a higher median age of 82 years (range 37-97), while the up-titrated group had a median age of 59 years (range 30-76). However, non-surviving patients in the up-titrated group received more steroid treatment (70.6%) compared to 25% in the fixed-dose group.<\/i>  3. The authors addressed the limitations of the study, such as the inconsistent diagnostic evaluation of VTE in COVID-19 patients and the absence of autopsies to confirm the causes of death. Furthermore, the mean D-dimer levels over time in deceased patients treated with fixed-dose thromboprophylaxis (Figure 3B) seemed to fall within the D-dimer range associated with pulmonary embolism (2.0-9.6 mcg\/ml FEU), as mentioned in the introduction. Would the authors consider the possibility that deceased patients in the fixed-dose group might have had untreated asymptomatic pulmonary embolisms, which might result in lower in-hospital survival compared with those in the up-titrating group?  \n<i>It is possible that deceased patients in the fixed-dose group might have had untreated asymptomatic pulmonary embolisms. According to previous reports, the incidence of VTE among critically ill patients is around 50%, compared to 2.7% in our study, where most of the population could be classified as critically ill according to standard guidelines. The overall incidence of breakthrough thrombosis in our study is notably low. These patients might have required earlier titration of anticoagulants, and I will include an additional discussion on this in the discussion section.<\/i>  4. If the data was available, was there any correlation between the suppressible trend of D-dimer levels and the levels of other inflammatory markers, for example, LDH and CRP?  \n<i>There are some correlations between the suppressible trend of D-dimer levels and the levels of other inflammatory markers, especially CRP, as shown in the figure below.<\/i>","URL":"https:\/\/f1000research.com\/articles\/13-887\/v3#referee-comment-12772","order":5,"name":"referee-comment-12772","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Lantarima Bhoopat<\/b>; \n<i>Posted: 03 Nov 2024<\/i>; There are some correlations between the suppressible trend of D-dimer levels and the levels of other inflammatory markers, especially CRP, as shown in the figure below.  \n<i>https:\/\/f1000research.s3.amazonaws.com\/linked\/688634.146710-Figure_files.pdf<\/i>","URL":"https:\/\/f1000research.com\/articles\/13-887\/v3#referee-comment-12773","order":6,"name":"referee-comment-12773","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":7,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}