{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T13:08:06Z","timestamp":1740143286406,"version":"3.37.3"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1848221"],"award-info":[{"award-number":["1848221"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["R01HL120728"],"award-info":[{"award-number":["R01HL120728"]}]},{"name":"NIH","award":["R01HL151984"],"award-info":[{"award-number":["R01HL151984"]}]},{"DOI":"10.13039\/100000183","name":"Army Research Office","doi-asserted-by":"publisher","award":["12369656"],"award-info":[{"award-number":["12369656"]}],"id":[{"id":"10.13039\/100000183","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Blood coagulation is a vital physiological process involving a complex network of biochemical reactions, which converge to form a blood clot that repairs vascular injury. This process unfolds in three phases: initiation, amplification, and propagation, ultimately leading to thrombin formation. Coagulation begins when tissue factor (TF) is exposed on an injured vessel\u2019s wall. The first step is when activated factor VII (VIIa) in the plasma binds to TF, forming complex TF:VIIa, which activates factor X. Activated factor X (Xa) is necessary for coagulation, so the regulation of its activation is crucial. Tissue Factor Pathway Inhibitor (TFPI) is a critical regulator of the initiation phase as it inhibits the activation of factor X. While previous studies have proposed two pathways\u2014direct and indirect binding\u2014for TFPI\u2019s inhibitory role, the specific biochemical reactions and their rates remain ambiguous. Many existing mathematical models only assume an indirect pathway, which may be less effective under physiological flow conditions. In this study, we revisit datasets from two experiments focused on activated factor X formation in the presence of TFPI. We employ an adaptive Metropolis method for parameter estimation to reinvestigate a previously proposed biochemical scheme and corresponding rates for both inhibition pathways. Our findings show that both pathways are essential to replicate the static experimental results. Previous studies have suggested that flow itself makes a significant contribution to the inhibition of factor X activation. We added flow to this model with our estimated parameters to determine the contribution of the two inhibition pathways under these conditions. We found that direct binding of TFPI is necessary for inhibition under flow. The indirect pathway has a weaker inhibitory effect due to removal of solution phase inhibitory complexes by flow.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012509","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T18:37:23Z","timestamp":1731695843000},"page":"e1012509","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A new look at TFPI inhibition of factor X activation"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5369-4128","authenticated-orcid":true,"given":"Fabian","family":"Santiago","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amandeep","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Bride","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0493-2943","authenticated-orcid":true,"given":"Dougald","family":"Monroe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4188-1305","authenticated-orcid":true,"given":"Karin","family":"Leiderman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2742-4332","authenticated-orcid":true,"given":"Suzanne","family":"Sindi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"pcbi.1012509.ref001","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.mcna.2013.07.004","article-title":"Patients 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Wood","year":"2014","journal-title":"Blood, The Journal of the American Society of Hematology"},{"issue":"8","key":"pcbi.1012509.ref009","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.1074\/jbc.273.8.4378","article-title":"Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor","volume":"273","author":"RJ Baugh","year":"1998","journal-title":"Journal of Biological Chemistry"},{"issue":"8","key":"pcbi.1012509.ref010","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1046\/j.1432-1033.2002.02818.x","article-title":"Tissue factor pathway inhibitor","volume":"269","author":"MA Panteleev","year":"2002","journal-title":"European Journal of Biochemistry"},{"issue":"2-3","key":"pcbi.1012509.ref011","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1159\/000089930","article-title":"Coagulation under flow: The influence of flow-mediated transport on the initiation and inhibition of coagulation","volume":"34","author":"AL 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