Editing Factor XII (section)

== Function ==
[[Image:Coagulation full.svg|thumb|left|400px|The coagulation cascade.]]

Factor XII (FXII, Hageman factor) is a plasma glycoprotein of approximately 90 kDa and is part of the [[coagulation]] cascade. It activates [[factor XI]] and [[prekallikrein]] in vitro. FXII is activated to FXIIa by negatively charged surfaces such as glass, initiating the intrinsic pathway.<ref>{{cite book | url = https://www.moscmm.org/pdf/Guyton%20physiology.pdf | title = Textbook of Medical Physiology | edition = 11th | vauthors = Guyton AC, Hall JE | date = 2006 | pages = 462–463 | publisher = Elsevier España | isbn = 0-7216-0240-1 | access-date = 2021-01-25 | archive-date = 2020-07-14 | archive-url = https://web.archive.org/web/20200714104902/https://www.moscmm.org/pdf/Guyton%20physiology.pdf | url-status = dead }}</ref> FXII also plays a role in diagnostic coagulation assays called activated partial thromboplastin times (aPTT).<ref name="pmid22993391">{{cite journal | vauthors = Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C | title = In vivo roles of factor XII | journal = Blood | volume = 120 | issue = 22 | pages = 4296–4303 | date = November 2012 | pmid = 22993391 | pmc = 3507141 | doi = 10.1182/blood-2012-07-292094 }}</ref>

In vivo, FXII is activated by binding to [[polyanions]] in a process termed contact activation. Various polymers, such as kaolin and glass, act as non-physiological activators of FXII. Activated platelets release inorganic [[polyphosphate]]s, which activate FXII, initiating the intrinsic pathway and contributing to [[fibrin]] formation and thrombus development.<ref name="pmid20005807">{{cite journal | vauthors = Müller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, Schmidbauer S, Gahl WA, Morrissey JH, Renné T | title = Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo | journal = Cell | volume = 139 | issue = 6 | pages = 1143–1156 | date = December 2009 | pmid = 20005807 | pmc = 2796262 | doi = 10.1016/j.cell.2009.11.001 }}</ref> Polyphosphates also accelerate thrombin-induced activation of factor XI.<ref>{{cite journal | vauthors = Smith SA, Choi SH, Davis-Harrison R, Huyck J, Boettcher J, Rienstra CM, Reinstra CM, Morrissey JH | title = Polyphosphate exerts differential effects on blood clotting, depending on polymer size | journal = Blood | volume = 116 | issue = 20 | pages = 4353–4359 | date = November 2010 | pmid = 20709905 | doi = 10.1182/blood-2010-01-266791 | pmc = 2993633 }}</ref>

Polyphosphate forms calcium-rich [[nanoparticle]]s in vivo, which accumulate on platelets and activate FXII. The regulation of platelet polyphosphates is still not fully understood, but the phosphate-exporter XPR1 has been identified as a key regulator.<ref name="pmid28049643">{{cite journal | vauthors = Verhoef J, Barendrecht A, Nickel KF, Dijkxhoorn K, Kenne E, Labberton L, McCarty O, Schiffelers R, Heijnen H, Hendrickx A, Schellekens H, Fens MH, de Maat S, Renné T, Maas C | title = Polyphosphate nanoparticles on the platelet surface trigger contact system activation | journal = Blood | volume = 129 | issue = 23 | pages = 1707–1717 | date = January 2017 | pmid = 28049643 | pmc = 5364341 | doi = 10.1182/blood-2016-08-734988 }}</ref> Targeting XPR1 increases polyphosphate levels, accelerating thrombosis in mouse models.<ref>{{cite journal | vauthors = Mailer RK, Allende M, Heestermans M, Schweizer M, Deppermann C, Frye M, Pula G, Odeberg J, Gelderblom M, Rose-John S, Sickmann A, Blankenberg S, Huber TB, Kubisch C, Maas C, Gambaryan S, Firsov D, Stavrou EX, Butler LM, Renné T | title = Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate | journal = Blood | volume = 137 | issue = 10 | pages = 1392–1405 | date = March 2021 | pmid = 32932519 | pmc = 7955403 | doi = 10.1182/blood.2019004617 }}</ref>

Given FXII’s role in thrombosis while sparing hemostasis, it has become a target for anticoagulant drug development. Inhibitors targeting FXII are in clinical trials.<ref>{{cite journal | vauthors = Davoine C, Bouckaert C, Fillet M, Pochet L | title = Factor XII/XIIa inhibitors: Their discovery, development, and potential indications | journal = European Journal of Medicinal Chemistry | volume = 208 | pages = 112753 | date = December 2020 | pmid = 32883641 | doi = 10.1016/j.ejmech.2020.112753 | hdl-access = free | s2cid = 221496237 | hdl = 2268/251278 }}</ref>
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