Factor XII: Difference between revisions

In vivo, factor XII is activated by binding (contact) to [[polyanions]] termed contact-activation. Multiple polymers, the white clay material kaolin and glass are non-physiological factor XII contact activators. Activated platelets release inorganic polymers, [[polyphosphate]]s. Contact to polyphosphates activates factor XII and initiates [[fibrin]] formation by the intrinsic pathway of coagulation with critical importance for [[thrombus]] formation and the factor XII-activated pro inflammatory kallikrein kinin-system. Targeting polyphosphates with [[phosphatase]]s interfered with procoagulant activity of activated [[platelet]]s and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of [[Hermansky–Pudlak syndrome]] patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a [[platelet plug]]) to secondary hemostasis (fibrin meshwork formation).<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 | display-authors = 6 | 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> Polyphosphate exerts differential effects on plasma clotting in test tubes ex vivo, depending on polymer size and it was shown in vitro that platelet-size soluble polyphosphates induce little activaton of factor XII in solution but that they are accelerators of 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 | display-authors = 6 | 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> The mystery was solved upon the discovery that short chain polyphosphate forms insoluble calcium-rich [[nanoparticle]]s in vivo. These aggregates accumulate on the platelet surface and activate factor XII independently of the chain length go the individual polymer.<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> Regulation of polyphosphates in platelets has remained poorly understood. Combinations of systems biology, genetics and functional analyses has identified the phosphate-exporter XPR1 as important regulator of polyphosphates in platelets. Targeting XPR1 increases polyphosphate content and leads to accelerated arterial and venous thrombosis in mouse models.<ref>{{cite journal | pmid=32932519 | year=2021 | last1=Mailer | first1=R. K. | last2=Allende | first2=M. | last3=Heestermans | first3=M. | last4=Schweizer | first4=M. | last5=Deppermann | first5=C. | last6=Frye | first6=M. | last7=Pula | first7=G. | last8=Odeberg | first8=J. | last9=Gelderblom | first9=M. | last10=Rose-John | first10=S. | last11=Sickmann | first11=A. | last12=Blankenberg | first12=S. | last13=Huber | first13=T. B. | last14=Kubisch | first14=C. | last15=Maas | first15=C. | last16=Gambaryan | first16=S. | last17=Firsov | first17=D. | last18=Stavrou | first18=E. X. | last19=Butler | first19=L. M. | last20=Renné | first20=T. | title=Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate | journal=Blood | volume=137 | issue=10 | pages=1392–1405 | doi=10.1182/blood.2019004617 | pmc=7955403 }}</ref>

 

 

== Genetics ==