{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T16:34:36Z","timestamp":1780677276907,"version":"3.54.1"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020480","name":"CSL Limited","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020480","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The management of factor Xa (FXa) inhibitor-associated bleeding remains a clinical challenge. Massive bleeding is often associated with complex coagulopathy and, thus, the sole reversal of FXa inhibitors might not be sufficient to restore hemostasis, requiring instead a multimodal approach. Four-factor prothrombin complex concentrate (4F-PCC) is widely recognized as a viable treatment option for FXa inhibitor-associated bleeding. Here, we applied computational models to explore the effect 4F-PCC has on the coagulation cascade and restoration of thrombin generation in a system that simulates a patient that has received a FXa inhibitor. The coagulation model is largely based on a previously developed model with modifications incorporated from various other published sources. The model was calibrated and validated using data from a phase 3 clinical trial of vitamin K antagonist reversal with 4F-PCC. Using the parameters and initial conditions determined during the calibration and validation process, the prothrombin time (PT) test simulations predicted a PT of 11.4 seconds. The model successfully simulated the effects of rivaroxaban and apixaban on total thrombin concentration and showed that 4F-PCC increased thrombin generation in the presence of rivaroxaban or apixaban.<\/jats:p>","DOI":"10.1371\/journal.pone.0310883","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T17:31:14Z","timestamp":1727458274000},"page":"e0310883","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modelling the effects of 4-factor prothrombin complex concentrate for the management of factor Xa-associated bleeding"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8209-1385","authenticated-orcid":true,"given":"Ineke","family":"Muir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Herzog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Brechmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Ghobrial","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Rezvani Sharif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureane","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"issue":"2 Suppl","key":"pone.0310883.ref001","doi-asserted-by":"crossref","first-page":"e120S","DOI":"10.1378\/chest.11-2294","article-title":"New antithrombotic drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines","volume":"141","author":"JI Weitz","year":"2012","journal-title":"Chest"},{"issue":"4","key":"pone.0310883.ref002","article-title":"Direct-Acting Oral Anticoagulants and Their Reversal Agents-An Update","volume":"6","author":"SA Kustos","year":"2019","journal-title":"Medicines (Basel)"},{"issue":"5","key":"pone.0310883.ref003","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1097\/ALN.0000000000002910","article-title":"Four-factor Prothrombin Complex Concentrate for the Management of Patients Receiving Direct Oral Activated Factor X Inhibitors","volume":"131","author":"O Grottke","year":"2019","journal-title":"Anesthesiology"},{"issue":"1","key":"pone.0310883.ref004","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12245-018-0215-6","article-title":"The impact of prothrombin complex concentrates when treating DOAC-associated bleeding: a review.","volume":"11","author":"M Hoffman","year":"2018","journal-title":"Int J Emerg Med"},{"issue":"22","key":"pone.0310883.ref005","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1182\/bloodadvances.2018024893","article-title":"American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy","volume":"2","author":"DM Witt","year":"2018","journal-title":"Blood Adv"},{"issue":"5","key":"pone.0310883.ref006","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.jacc.2020.04.053","article-title":"2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee","volume":"76","author":"GF Tomaselli","year":"2020","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"pone.0310883.ref007","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.annemergmed.2019.09.001","article-title":"Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel","volume":"76","author":"CW Baugh","year":"2020","journal-title":"Ann Emerg Med"},{"issue":"6","key":"pone.0310883.ref008","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1002\/ajh.25475","article-title":"Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum","volume":"94","author":"A Cuker","year":"2019","journal-title":"Am J Hematol"},{"issue":"16","key":"pone.0310883.ref009","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1093\/eurheartj\/ehy136","article-title":"The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation","volume":"39","author":"J Steffel","year":"2018","journal-title":"Eur Heart J"},{"issue":"6","key":"pone.0310883.ref010","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1097\/EJA.0000000000000630","article-title":"Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016","volume":"34","author":"SA Kozek-Langenecker","year":"2017","journal-title":"Eur J Anaesthesiol"},{"issue":"1","key":"pone.0310883.ref011","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13054-019-2347-3","article-title":"The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition","volume":"23","author":"DR Spahn","year":"2019","journal-title":"Crit Care"},{"issue":"3","key":"pone.0310883.ref012","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1055\/a-1369-5274","article-title":"Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline\u2014Update 2021","volume":"53","author":"IM Gralnek","year":"2021","journal-title":"Endoscopy"},{"issue":"3","key":"pone.0310883.ref013","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1177\/1747493020968424","article-title":"Canadian stroke best practice recommendations: Management of Spontaneous Intracerebral Hemorrhage, 7th Edition Update 2020","volume":"16","author":"A Shoamanesh","year":"2021","journal-title":"Int J Stroke"},{"issue":"7","key":"pone.0310883.ref014","doi-asserted-by":"crossref","first-page":"e282","DOI":"10.1161\/STR.0000000000000407","article-title":"2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association\/American Stroke Association","volume":"53","author":"SM Greenberg","year":"2022","journal-title":"Stroke"},{"issue":"10","key":"pone.0310883.ref015","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1111\/j.1742-1241.2008.01859.x","article-title":"Biochemical comparison of seven commercially available prothrombin complex concentrates","volume":"62","author":"U Kalina","year":"2008","journal-title":"Int J Clin Pract"},{"key":"pone.0310883.ref016","unstructured":"CSL Behring. (2018). Kcentra prescribing information [Available from: https:\/\/labeling.cslbehring.com\/PI\/US\/Kcentra\/EN\/Kcentra-prescribing-information.pdf."},{"issue":"4","key":"pone.0310883.ref017","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1097\/ALN.0000000000003899","article-title":"Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model","volume":"135","author":"F Rayatdoost","year":"2021","journal-title":"Anesthesiology"},{"issue":"2","key":"pone.0310883.ref018","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/ALN.0000000000000520","article-title":"Effective reversal of edoxaban-associated bleeding with four-factor prothrombin complex concentrate in a rabbit model of acute hemorrhage","volume":"122","author":"E Herzog","year":"2015","journal-title":"Anesthesiology"},{"issue":"1","key":"pone.0310883.ref019","doi-asserted-by":"crossref","first-page":"13029","DOI":"10.1038\/s41598-019-49552-9","article-title":"Prothrombin, alone or in complex concentrates or plasma, reduces bleeding in a mouse model of blood exchange-induced coagulopathy","volume":"9","author":"LJ Eltringham-Smith","year":"2019","journal-title":"Sci Rep"},{"issue":"9","key":"pone.0310883.ref020","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1111\/j.1538-7836.2012.04859.x","article-title":"Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P\/N) in a rabbit model","volume":"10","author":"I Pragst","year":"2012","journal-title":"J Thromb Haemost"},{"issue":"11","key":"pone.0310883.ref021","doi-asserted-by":"crossref","first-page":"e78696","DOI":"10.1371\/journal.pone.0078696","article-title":"Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood","volume":"8","author":"G Escolar","year":"2013","journal-title":"PLoS One"},{"issue":"4","key":"pone.0310883.ref022","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.thromres.2014.01.017","article-title":"Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro","volume":"133","author":"E Perzborn","year":"2014","journal-title":"Thromb Res"},{"issue":"3","key":"pone.0310883.ref023","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.thromres.2015.01.007","article-title":"Correlation of coagulation markers and 4F-PCC-mediated reversal of rivaroxaban in a rabbit model of acute bleeding","volume":"135","author":"E Herzog","year":"2015","journal-title":"Thromb Res"},{"issue":"5","key":"pone.0310883.ref024","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1055\/s-0038-1636541","article-title":"Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study","volume":"118","author":"S Schulman","year":"2018","journal-title":"Thromb Haemost"},{"issue":"15","key":"pone.0310883.ref025","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1182\/blood-2017-05-782060","article-title":"Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study","volume":"130","author":"A Majeed","year":"2017","journal-title":"Blood"},{"issue":"2","key":"pone.0310883.ref026","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1182\/bloodadvances.2018024133","article-title":"Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis","volume":"3","author":"S Piran","year":"2019","journal-title":"Blood Adv"},{"issue":"6","key":"pone.0310883.ref027","first-page":"2637","article-title":"Prothrombin complex concentrates and andexanet for management of direct factor Xa inhibitor related bleeding: a meta-analysis","volume":"25","author":"C Luo","year":"2021","journal-title":"Eur Rev Med Pharmacol Sci"},{"issue":"24","key":"pone.0310883.ref028","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1016\/j.jacc.2021.04.061","article-title":"Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants","volume":"77","author":"A Gomez-Outes","year":"2021","journal-title":"J Am Coll Cardiol"},{"issue":"2","key":"pone.0310883.ref029","doi-asserted-by":"crossref","first-page":"e190","DOI":"10.1055\/s-0038-1649507","article-title":"Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation","volume":"2","author":"PY Kim","year":"2018","journal-title":"TH Open"},{"key":"pone.0310883.ref030","first-page":"25","article-title":"Computational model for drug research","author":"X Chen","year":"2024","journal-title":"Brief Bioinform"},{"key":"pone.0310883.ref031","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.phrs.2015.06.002","article-title":"Molecular mechanism matters: Benefits of mechanistic computational models for drug development","volume":"99","author":"LE Clegg","year":"2015","journal-title":"Pharmacol Res"},{"issue":"2","key":"pone.0310883.ref032","doi-asserted-by":"crossref","DOI":"10.3390\/jpm12020166","article-title":"Computational Models for Clinical Applications in Personalized Medicine-Guidelines and Recommendations for Data Integration and Model Validation","volume":"12","author":"CB Collin","year":"2022","journal-title":"J Pers Med"},{"issue":"21","key":"pone.0310883.ref033","doi-asserted-by":"crossref","first-page":"18322","DOI":"10.1074\/jbc.M201173200","article-title":"A model for the stoichiometric regulation of blood coagulation","volume":"277","author":"MF Hockin","year":"2002","journal-title":"J Biol Chem"},{"issue":"9","key":"pone.0310883.ref034","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1000950","article-title":"Systems biology of coagulation initiation: kinetics of thrombin generation in resting and activated human blood","volume":"6","author":"MS Chatterjee","year":"2010","journal-title":"PLoS Comput Biol"},{"issue":"4","key":"pone.0310883.ref035","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0049-3848(00)00405-9","article-title":"Analysis of the activated partial thromboplastin time test using mathematical modeling","volume":"101","author":"AE Kogan","year":"2001","journal-title":"Thromb Res"},{"issue":"1","key":"pone.0310883.ref036","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/imammb\/20.1.105","article-title":"A mathematical model of lipid-mediated thrombin generation","volume":"20","author":"SD Bungay","year":"2003","journal-title":"Math Med Biol"},{"issue":"7","key":"pone.0310883.ref037","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1046\/j.1538-7836.2003.00298.x","article-title":"What is all that thrombin for?","volume":"1","author":"KG Mann","year":"2003","journal-title":"J Thromb Haemost"},{"key":"pone.0310883.ref038","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2423(10)51001-1","article-title":"Prothrombin fragments in cardiovascular disease","volume":"51","author":"JA P\u00e1ramo","year":"2010","journal-title":"Adv Clin Chem"},{"issue":"4","key":"pone.0310883.ref039","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1111\/j.1538-7836.2008.02904.x","article-title":"Prothrombin complex concentrate (Beriplex P\/N) for emergency anticoagulation reversal: a prospective multinational clinical trial","volume":"6","author":"I Pabinger","year":"2008","journal-title":"J Thromb Haemost"},{"issue":"1","key":"pone.0310883.ref040","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/rth2.12048","article-title":"A review of commercially available thrombin generation assays","volume":"2","author":"J Kintigh","year":"2018","journal-title":"Res Pract Thromb Haemost"},{"issue":"1","key":"pone.0310883.ref041","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12959-021-00312-8","article-title":"Calibrated automated thrombogram II: removing barriers for thrombin generation measurements","volume":"19","author":"PLA Giesen","year":"2021","journal-title":"Thromb J"},{"issue":"1","key":"pone.0310883.ref042","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/rth2.12455","article-title":"ST Genesia reference values of 117 healthy donors measured with STG-BleedScreen, STG-DrugScreen and STG-ThromboScreen reagents","volume":"5","author":"M Ninivaggi","year":"2021","journal-title":"Res Pract Thromb Haemost"},{"issue":"1","key":"pone.0310883.ref043","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.thromres.2015.04.020","article-title":"Establishing a reference range for thrombin generation using a standard plasma significantly improves assay precision","volume":"136","author":"CN Bagot","year":"2015","journal-title":"Thromb Res"},{"issue":"3","key":"pone.0310883.ref044","doi-asserted-by":"crossref","first-page":"e12699","DOI":"10.1002\/rth2.12699","article-title":"Reversing direct factor Xa or thrombin inhibitors: Factor V addition to prothrombin complex concentrate is beneficial in vitro","volume":"6","author":"HJM Brinkman","year":"2022","journal-title":"Res Pract Thromb Haemost"},{"issue":"4","key":"pone.0310883.ref045","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1093\/labmed\/lmx050","article-title":"Coagulation Testing in the Core Laboratory","volume":"48","author":"WE Winter","year":"2017","journal-title":"Lab Med"},{"issue":"3","key":"pone.0310883.ref046","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1055\/s-0038-1627480","article-title":"International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants","volume":"118","author":"RC Gosselin","year":"2018","journal-title":"Thromb Haemost"},{"issue":"1","key":"pone.0310883.ref047","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40262-013-0100-7","article-title":"Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban","volume":"53","author":"W Mueck","year":"2014","journal-title":"Clin Pharmacokinet"},{"issue":"10","key":"pone.0310883.ref048","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1007\/s40262-019-00775-z","article-title":"Apixaban: A clinical pharmacokinetic and pharmacodynamic review","volume":"58","author":"W Byon","year":"2019","journal-title":"Clin Pharmacokinet"},{"issue":"1","key":"pone.0310883.ref049","doi-asserted-by":"crossref","first-page":"e122","DOI":"10.1097\/FJC.0000000000001038","article-title":"Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study","volume":"78","author":"I Skornova","year":"2021","journal-title":"J Cardiovasc Pharmacol"},{"issue":"5","key":"pone.0310883.ref050","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines9050445","article-title":"Laboratory Monitoring of Direct Oral Anticoagulants (DOACs)","volume":"9","author":"C. Dunois","year":"2021","journal-title":"Biomedicines"},{"key":"pone.0310883.ref051","doi-asserted-by":"crossref","first-page":"457","DOI":"10.2147\/VHRM.S126265","article-title":"Practical guidance on the use of laboratory testing in the management of bleeding in patients receiving direct oral anticoagulants","volume":"13","author":"H Ten Cate","year":"2017","journal-title":"Vasc Health Risk Manag"},{"issue":"5","key":"pone.0310883.ref052","first-page":"1087","article-title":"Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis","volume":"134","author":"TA Drake","year":"1989","journal-title":"Am J Pathol"},{"issue":"6","key":"pone.0310883.ref053","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1161\/01.ATV.0000130465.23430.74","article-title":"Role of tissue factor in hemostasis, thrombosis, and vascular development","volume":"24","author":"N. Mackman","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"12","key":"pone.0310883.ref054","doi-asserted-by":"crossref","first-page":"4746","DOI":"10.1182\/blood-2005-11-4674","article-title":"Cellular localization and trafficking of tissue factor","volume":"107","author":"SK Mandal","year":"2006","journal-title":"Blood"},{"issue":"14","key":"pone.0310883.ref055","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1056\/NEJMoa1814051","article-title":"Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors","volume":"380","author":"SJ Connolly","year":"2019","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0310883.ref056","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41572-021-00264-3","article-title":"Trauma-induced coagulopathy","volume":"7","author":"EE Moore","year":"2021","journal-title":"Nat Rev Dis Primers"},{"issue":"4","key":"pone.0310883.ref057","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1365-2125.2011.04001.x","article-title":"Inhibitors of propagation of coagulation: factors V and X","volume":"72","author":"V Toschi","year":"2011","journal-title":"Br J Clin Pharmacol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0310883","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T17:31:27Z","timestamp":1727458287000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0310883"}},"subtitle":[],"editor":[{"given":"Samiullah","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,9,27]]},"references-count":57,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0310883","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,27]]}}}