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Thrombin cleaves soluble fibrinogen into fibrin, which polymerizes and forms an insoluble, stabilizing gel around the growing clot. A small fraction of circulating fibrinogen is the variant <jats:italic>\u03b3<\/jats:italic><jats:sub><jats:italic>A<\/jats:italic><\/jats:sub>\/<jats:italic>\u03b3<\/jats:italic>\u2032, which has been associated with high-affinity thrombin binding and implicated as a risk factor for myocardial infarctions, deep vein thrombosis, and coronary artery disease. Thrombin is also known to be strongly sequestered by polymerized fibrin for extended periods of time in a way that is partially regulated by <jats:italic>\u03b3<\/jats:italic><jats:sub><jats:italic>A<\/jats:italic><\/jats:sub>\/<jats:italic>\u03b3<\/jats:italic>\u2032. However, the role of <jats:italic>\u03b3<\/jats:italic><jats:sub><jats:italic>A<\/jats:italic><\/jats:sub>\/<jats:italic>\u03b3<\/jats:italic>\u2032-thrombin interactions during fibrin polymerization is not fully understood. Here, we present a mathematical model of fibrin polymerization that considered the interactions between thrombin, fibrinogen, and fibrin, including those with <jats:italic>\u03b3<\/jats:italic><jats:sub><jats:italic>A<\/jats:italic><\/jats:sub>\/<jats:italic>\u03b3<\/jats:italic>\u2032. In our model, bivalent thrombin-fibrin binding greatly increased thrombin residency times and allowed for thrombin-trapping during fibrin polymerization. Results from the model showed that early in fibrin polymerization, <jats:italic>\u03b3<\/jats:italic>\u2032 binding to thrombin served to localize the thrombin to the fibrin(ogen), which effectively enhanced the enzymatic conversion of fibrinogen to fibrin. When all the fibrin was fully generated, however, the fibrin-thrombin binding persisted but the effect of fibrin on thrombin switched quickly to serve as a sink, essentially removing all free thrombin from the system. This dual role for <jats:italic>\u03b3<\/jats:italic>\u2032-thrombin binding during polymerization led to a paradoxical decrease in trapped thrombin as the amount of <jats:italic>\u03b3<\/jats:italic>\u2032 was increased. The model highlighted biochemical and biophysical roles for fibrin-thrombin interactions during polymerization and agreed well with experimental observations.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010414","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T17:30:44Z","timestamp":1663263044000},"page":"e1010414","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization"],"prefix":"10.1371","volume":"18","author":[{"given":"Michael 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