{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T20:50:41Z","timestamp":1785876641989,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012552","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000}}],"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The kallikrein-kinin system (KKS) is a complex biochemical pathway that plays a crucial role in regulating several physiological processes, including inflammation, coagulation, and blood pressure. Dysregulation of the KKS has been associated with several pathological conditions such as hereditary angioedema (HAE), hypertension, and stroke. Developing an accurate quantitative model of the KKS may provide a better understanding of its role in health and disease and facilitate the rapid and targeted development of effective therapies for KKS-related disorders.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objectives<\/jats:title>\n<jats:p>Here, we present a novel, detailed mechanistic model of the plasma KKS, elucidating the processes of Factor XII (FXII) activation, the kallikrein feedback loop, cleavage of high molecular weight kininogen leading to bradykinin (BK) production, and the impact of inhibitors.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The model incorporates both surface and solution-phase reactions of all proteins in the KKS, describing how binding site concentration affects the rate of surface reactions. The model was calibrated and validated using a variety of published and in-house experimental datasets, which encompass a range of dextran sulphate (DXS) concentrations to initiate contact activation and various KKS inhibitors to block bradykinin production.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>Our mathematical model showed that a trace amount of activated FXII is required for subsequent FXII activation. The model also reveals a bell-shaped curve relationship between the activation of the KKS and the number of DXS surface binding sites. Simulations of BK generation in healthy and HAE plasma demonstrated the impact of C1 esterase inhibitor (C1inh) deficiency via increased peak BK levels and accelerated formation in HAE plasma. The efficacy of KKS inhibitors, such as CSL312, ecallantide, and C1inh, was also evaluated, with CSL312 showing the most potent inhibition of BK generation.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pcbi.1012552","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T18:40:17Z","timestamp":1730745617000},"page":"e1012552","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6595-2596","authenticated-orcid":true,"given":"Alireza","family":"Rezvani-Sharif","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Lioe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven K.","family":"Dower","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Pelzing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Con","family":"Panousis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalton J. E.","family":"Harvie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8209-1385","authenticated-orcid":true,"given":"Ineke L.","family":"Muir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,11,4]]},"reference":[{"key":"pcbi.1012552.ref001","doi-asserted-by":"crossref","first-page":"234","DOI":"10.2174\/187152509789105444","article-title":"Human Plasma Kallikrein-Kinin System: Physiological and Biochemical Parameters.","volume":"7","author":"J Bryant","year":"2009","journal-title":"Cardiovasc Hematological Agents Medicinal Chem"},{"key":"pcbi.1012552.ref002","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/jth.13235","article-title":"Contact system revisited: an interface between inflammation, coagulation, and innate immunity","volume":"14","author":"AT Long","year":"2016","journal-title":"J Thromb Haemost"},{"key":"pcbi.1012552.ref003","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/B978-0-12-800100-4.00002-7","article-title":"Chapter Two Pathogenic Mechanisms of Bradykinin Mediated Diseases Dysregulation of an Innate Inflammatory Pathway","volume":"121","author":"AP Kaplan","year":"2014","journal-title":"Adv Immunol"},{"key":"pcbi.1012552.ref004","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jaci.2016.02.041","article-title":"Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process","volume":"138","author":"ZLM Hofman","year":"2016","journal-title":"J Allergy Clin Immun"},{"key":"pcbi.1012552.ref005","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s40629-018-0088-5","article-title":"Guideline: Hereditary angioedema due to C1 inhibitor deficiency.","volume":"28","author":"K Bork","year":"2019","journal-title":"Allergo J Int"},{"key":"pcbi.1012552.ref006","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1007\/s12325-022-02401-0","article-title":"Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology.","volume":"40","author":"ES Sinnathamby","year":"2023","journal-title":"Adv Ther"},{"key":"pcbi.1012552.ref007","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.jaip.2021.11.011","article-title":"Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade","volume":"10","author":"P Busse","year":"2022","journal-title":"J Allergy Clin Immunol Pract"},{"key":"pcbi.1012552.ref008","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.jaci.2018.06.014","article-title":"Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation","volume":"142","author":"H Cao","year":"2018","journal-title":"J Allergy Clin Immun"},{"key":"pcbi.1012552.ref009","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/S0140-6736(23)00350-1","article-title":"Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.","volume":"401","author":"TJ Craig","year":"2023","journal-title":"Lancet"},{"key":"pcbi.1012552.ref010","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1080\/17512433.2016.1182425","article-title":"Icatibant as acute treatment for hereditary angioedema in adults.","volume":"9","author":"H. 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