factor XII

The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter).

Human Factor XII is 596 amino acids long and consists of two chains, the heavy chain (353 residues) and light chain (243 residues) held together by a disulfide bond. It is 80,000 daltons in molecular weight. The heavy chain contains two fibronectin-type domains (type I and II), two epidermal growth factor-like domains, a kringle domain, and a proline-rich region, while the light chain contains the protease domain. FXII can be cleaved sequentially at two sites, Arg353 and Arg334, with the second cleavage liberating the light chain and forming β-FXIIa.{{cite journal | vauthors = Ivanov I, Matafonov A, Gailani D | title = Single-chain factor XII: a new form of activated factor XII | journal = Current Opinion in Hematology | volume = 24 | issue = 5 | pages = 411–418 | date = September 2017 | pmid = 28604413 | doi = 10.1097/MOH.0000000000000363 | pmc = 5762122 }}

The structure of the FnI-EGF-like tandem domain of coagulation factor XII has been solved by X-ray crystallography.{{cite journal | vauthors = Stavrou E, Schmaier AH | title = Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis | journal = Thrombosis Research | volume = 125 | issue = 3 | pages = 210–215 | date = March 2010 | pmid = 20022081 | pmc = 2851158 | doi = 10.1016/j.thromres.2009.11.028 }}{{cite journal | vauthors = Beringer DX, Kroon-Batenburg LM | title = The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS | journal = Acta Crystallographica Section F | volume = 69 | issue = Pt 2 | pages = 94–102 | date = February 2013 | pmid = 23385745 | pmc = 3564606 | doi = 10.1107/S1744309113000286 }} Crystal structures of the FXII light chain have also been determined, both unbound (β-FXII) and bound (β-FXIIa) to inhibitors.{{cite journal | vauthors = Dementiev A, Silva A, Yee C, Li Z, Flavin MT, Sham H, Partridge JR | title = Structures of human plasma β-factor XIIa cocrystallized with potent inhibitors | journal = Blood Advances | volume = 2 | issue = 5 | pages = 549–558 | date = March 2018 | pmid = 29519898 | pmc = 5851424 | doi = 10.1182/bloodadvances.2018016337 }}{{cite journal | vauthors = Pathak M, Wilmann P, Awford J, Li C, Hamad BK, Fischer PM, Dreveny I, Dekker LV, Emsley J | title = Coagulation factor XII protease domain crystal structure | journal = Journal of Thrombosis and Haemostasis | volume = 13 | issue = 4 | pages = 580–591 | date = April 2015 | pmid = 25604127 | pmc = 4418343 | doi = 10.1111/jth.12849 }}{{cite journal | vauthors = Pathak M, Manna R, Li C, Kaira BG, Hamad BK, Belviso BD, Bonturi CR, Dreveny I, Fischer PM, Dekker LV, Oliva ML, Emsley J | title = Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics | journal = Acta Crystallographica Section D | volume = 75 | issue = Pt 6 | pages = 578–591 | date = June 2019 | pmid = 31205020 | doi = 10.1107/S2059798319006910 | s2cid = 189944782 | url = https://nottingham-repository.worktribe.com/output/2390798 }}

Image:Coagulation full.svg

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.{{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 }} FXII also plays a role in diagnostic coagulation assays called activated partial thromboplastin times (aPTT).{{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 }}

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 polyphosphates, which activate FXII, initiating the intrinsic pathway and contributing to fibrin formation and thrombus development.{{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 }} Polyphosphates also accelerate thrombin-induced activation of factor XI.{{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 }}

Polyphosphate forms calcium-rich nanoparticles 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.{{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 }} Targeting XPR1 increases polyphosphate levels, accelerating thrombosis in mouse models.{{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 }}

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.{{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 }}

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{{main|Factor XII deficiency}}

Factor XII deficiency is a rare disorder that is inherited in an autosomal recessive manner.{{cite journal | vauthors = Wagenman BL, Townsend KT, Mathew P, Crookston KP | title = The laboratory approach to inherited and acquired coagulation factor deficiencies | journal = Clinics in Laboratory Medicine | volume = 29 | issue = 2 | pages = 229–252 | date = June 2009 | pmid = 19665676 | doi = 10.1016/j.cll.2009.04.002 | url = https://zenodo.org/record/894920 }} Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding. Mice lacking the gene for factor XII, however, are less susceptible to thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall.{{cite journal | vauthors = Renné T, Pozgajová M, Grüner S, Schuh K, Pauer HU, Burfeind P, Gailani D, Nieswandt B | title = Defective thrombus formation in mice lacking coagulation factor XII | journal = The Journal of Experimental Medicine | volume = 202 | issue = 2 | pages = 271–281 | date = July 2005 | pmid = 16009717 | pmc = 2213000 | doi = 10.1084/jem.20050664 }}

Factor XII does play an important role in clot formation during in vitro measurements of the partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency. As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result. All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.

Excess levels of factor XII can predispose individuals towards greater risk of venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin.{{cite book |title= Manual of Coagulation Disorders| vauthors = Kroll MH |year= 2001|publisher= Blackwell Science|isbn= 0-86542-446-2|pages= 3–4, 206–207}}

Factor XII is also activated by endotoxins, especially lipid A in vitro. Experimental mouse models have suggested a role of FXII in multiple sclerosis.{{cite journal | vauthors = Göbel K, Pankratz S, Asaridou CM, Herrmann AM, Bittner S, Merker M, Ruck T, Glumm S, Langhauser F, Kraft P, Krug TF, Breuer J, Herold M, Gross CC, Beckmann D, Korb-Pap A, Schuhmann MK, Kuerten S, Mitroulis I, Ruppert C, Nolte MW, Panousis C, Klotz L, Kehrel B, Korn T, Langer HF, Pap T, Nieswandt B, Wiendl H, Chavakis T, Kleinschnitz C, Meuth SG | title = Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells | journal = Nature Communications | volume = 7 | issue = | pages = 11626 | date = May 2016 | pmid = 27188843| pmc = 4873982 | doi = 10.1038/ncomms11626 | bibcode = 2016NatCo...711626G }}

Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no hemorrhagic symptoms. Hageman was then examined by hematologist Oscar Ratnoff, who found that Hageman lacked a previously unidentified clotting factor.{{cite journal | vauthors = Ratnoff OD, Margolius A | title = Hageman trait: an asymptomatic disorder of blood coagulation | journal = Transactions of the Association of American Physicians | volume = 68 | pages = 149–154 | year = 1955 | pmid = 13299324 }} Ratnoff later found that the Hageman factor deficiency is an autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident in 1968. Since then, case studies and clinical studies identified an association between thrombosis and Factor XII deficiency. Hepatocytes express blood coagulation factor XII.{{cite journal | vauthors = Gordon EM, Gallagher CA, Johnson TR, Blossey BK, Ilan J | title = Hepatocytes express blood coagulation factor XII (Hageman factor) | journal = The Journal of Laboratory and Clinical Medicine | volume = 115 | issue = 4 | pages = 463–469 | date = April 1990 | pmid = 2324612 }}

Currently produced QuikClot products, produced and marketed primarily for use in battlefield medicine to treat penetrating trauma (such as gunshot wounds and stab wounds), and other injuries that are known to commonly cause exsanguination (such as blast injury), are used with the overarching goal of increasing the time between the blood loss occurring, and the patient succumbing to the blood loss. The purpose of increasing this time is so that the patient may reach a higher level of medical care before succumbing from their injuries. These products use a Kaolinite-based coating, applied to the bandages by the manufacturer before packaging and sale. This coating, when applied to an open wound via the application of the bandages, directly promotes blood clotting by activating Factor XII in the coagulation cascade.{{cite book | vauthors = Dee KC, Puleo DA, Bizios R, Madhavan G | title = Tissue-biomaterial interactions. | location = Hoboken | publisher = Wiley & Sons | date = 2002 | isbn = 978-0-471-46112-8 }} Also, due to the active ingredient nature of Kaolinite, the activation of the Factor XII occurs in both an earlier amount of time than it otherwise would, and at an increased, more rapid rate than it otherwise would.{{cite journal | vauthors = Trabattoni D, Montorsi P, Fabbiocchi F, Lualdi A, Gatto P, Bartorelli AL | title = A new kaolin-based haemostatic bandage compared with manual compression for bleeding control after percutaneous coronary procedures | journal = European Radiology | volume = 21 | issue = 8 | pages = 1687–1691 | date = August 2011 | pmid = 21476127 | doi = 10.1007/s00330-011-2117-3 | s2cid = 11755594 }}{{cite journal | vauthors = Politi L, Aprile A, Paganelli C, Amato A, Zoccai GB, Sgura F, Monopoli D, Rossi R, Modena MG, Sangiorgi GM | title = Randomized clinical trial on short-time compression with Kaolin-filled pad: a new strategy to avoid early bleeding and subacute radial artery occlusion after percutaneous coronary intervention | journal = Journal of Interventional Cardiology | volume = 24 | issue = 1 | pages = 65–72 | date = February 2011 | pmid = 20807305 | doi = 10.1111/j.1540-8183.2010.00584.x | hdl = 11380/649198 | hdl-access = free }} This coating is widely considered amongst combat medics to be vastly superior to the older QuikClot powder formulation, which was poured into wounds, due to the fact that the older formulation used bead-form Zeolite, a mineral which promotes the coagulation cascade, due to the fact that the reaction between the Zeolite powder and the blood inside the wound site was an Exothermic one, sometimes so intensely that it caused cases of second degree burns on the inside surface of the wound. This, obviously, caused extreme pain to the patient, often more-so than the initial injury was causing them at the time (assuming the patient was still conscious at the time of the application of the powder).{{cite journal | vauthors = Wright JK, Kalns J, Wolf EA, Traweek F, Schwarz S, Loeffler CK, Snyder W, Yantis LD, Eggers J | title = Thermal injury resulting from application of a granular mineral hemostatic agent | journal = The Journal of Trauma | volume = 57 | issue = 2 | pages = 224–230 | date = August 2004 | pmid = 15345965 | doi = 10.1097/01.ta.0000105916.30158.06 }} This effect is often seen in movies and TV programs, with the QuikClot powder being poured into wounds, and the patient screaming out in pain as their wounds were violently burned on the inside surface of the wounds. This created a common misconception, which persists to this day, that commonly used QuikClot products still use this method of clot promotion (Zeolite powder) to this day. However, Zeolite-based clotting products are no longer widely used by militaries and police departments throughout the western world, as they have been widely supplanted by the Kaolinite-based bandage products, which do not cause any exothermic reaction whatsoever, nor do they have the absolute-requirement of the application of the product exclusively to the inside-surface of the wound.

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• {{cite journal | vauthors = Girolami A, Randi ML, Gavasso S, Lombardi AM, Spiezia F | title = The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature | journal = Journal of Thrombosis and Thrombolysis | volume = 17 | issue = 2 | pages = 139–143 | date = April 2004 | pmid = 15306750 | doi = 10.1023/B:THRO.0000037670.42776.cd | s2cid = 19336633 }}
• {{cite journal | vauthors = Renné T, Gailani D | title = Role of Factor XII in hemostasis and thrombosis: clinical implications | journal = Expert Review of Cardiovascular Therapy | volume = 5 | issue = 4 | pages = 733–741 | date = July 2007 | pmid = 17605651 | doi = 10.1586/14779072.5.4.733 | s2cid = 41250936 }}
• {{cite journal | vauthors = Harris RJ, Ling VT, Spellman MW | title = O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C | journal = The Journal of Biological Chemistry | volume = 267 | issue = 8 | pages = 5102–5107 | date = March 1992 | pmid = 1544894 | doi = 10.1016/S0021-9258(18)42736-6 | doi-access = free }}
• {{cite journal | vauthors = McMullen BA, Fujikawa K, Davie EW | title = Location of the disulfide bonds in human plasma prekallikrein: the presence of four novel apple domains in the amino-terminal portion of the molecule | journal = Biochemistry | volume = 30 | issue = 8 | pages = 2050–2056 | date = February 1991 | pmid = 1998666 | doi = 10.1021/bi00222a007 }}
• {{cite journal | vauthors = Miyata T, Kawabata S, Iwanaga S, Takahashi I, Alving B, Saito H | title = Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor XIIa results from Cys-571----Ser substitution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 21 | pages = 8319–8322 | date = November 1989 | pmid = 2510163 | pmc = 298272 | doi = 10.1073/pnas.86.21.8319 | doi-access = free | bibcode = 1989PNAS...86.8319M }}
• {{cite journal | vauthors = Bernardi F, Marchetti G, Patracchini P, del Senno L, Tripodi M, Fantoni A, Bartolai S, Vannini F, Felloni L, Rossi L | title = Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme | journal = Blood | volume = 69 | issue = 5 | pages = 1421–1424 | date = May 1987 | pmid = 2882793 | doi = 10.1182/blood.V69.5.1421.1421 | doi-access = free }}
• {{cite journal | vauthors = Cool DE, MacGillivray RT | title = Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region | journal = The Journal of Biological Chemistry | volume = 262 | issue = 28 | pages = 13662–13673 | date = October 1987 | pmid = 2888762 | doi = 10.1016/S0021-9258(19)76478-3 | doi-access = free }}
• {{cite journal | vauthors = Que BG, Davie EW | title = Characterization of a cDNA coding for human factor XII (Hageman factor) | journal = Biochemistry | volume = 25 | issue = 7 | pages = 1525–1528 | date = April 1986 | pmid = 3011063 | doi = 10.1021/bi00355a009 }}
• {{cite journal | vauthors = Royle NJ, Nigli M, Cool D, MacGillivray RT, Hamerton JL | title = Structural gene encoding human factor XII is located at 5q33-qter | journal = Somatic Cell and Molecular Genetics | volume = 14 | issue = 2 | pages = 217–221 | date = March 1988 | pmid = 3162339 | doi = 10.1007/BF01534407 | s2cid = 7868690 }}
• {{cite journal | vauthors = Citarella F, Tripodi M, Fantoni A, Bernardi F, Romeo G, Rocchi M | title = Assignment of human coagulation factor XII (fXII) to chromosome 5 by cDNA hybridization to DNA from somatic cell hybrids | journal = Human Genetics | volume = 80 | issue = 4 | pages = 397–398 | date = December 1988 | pmid = 3198120 | doi = 10.1007/BF00273661 | s2cid = 13428786 }}
• {{cite journal | vauthors = Henry ML, Everson B, Ratnoff OD | title = Inhibition of the activation of Hageman factor (factor XII) by beta 2-glycoprotein I | journal = The Journal of Laboratory and Clinical Medicine | volume = 111 | issue = 5 | pages = 519–523 | date = May 1988 | pmid = 3361230 }}
• {{cite journal | vauthors = Chung DW, Fujikawa K, McMullen BA, Davie EW | title = Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats | journal = Biochemistry | volume = 25 | issue = 9 | pages = 2410–2417 | date = May 1986 | pmid = 3521732 | doi = 10.1021/bi00357a017 }}
• {{cite journal | vauthors = Tripodi M, Citarella F, Guida S, Galeffi P, Fantoni A, Cortese R | title = cDNA sequence coding for human coagulation factor XII (Hageman) | journal = Nucleic Acids Research | volume = 14 | issue = 7 | pages = 3146 | date = April 1986 | pmid = 3754331 | pmc = 339730 | doi = 10.1093/nar/14.7.3146 }}
• {{cite journal | vauthors = Cool DE, Edgell CJ, Louie GV, Zoller MJ, Brayer GD, MacGillivray RT | title = Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of beta-factor XIIa | journal = The Journal of Biological Chemistry | volume = 260 | issue = 25 | pages = 13666–13676 | date = November 1985 | pmid = 3877053 | doi = 10.1016/S0021-9258(17)38776-8 | doi-access = free }}
• {{cite journal | vauthors = McMullen BA, Fujikawa K | title = Amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor) | journal = The Journal of Biological Chemistry | volume = 260 | issue = 9 | pages = 5328–5341 | date = May 1985 | pmid = 3886654 | doi = 10.1016/S0021-9258(18)89026-3 | doi-access = free }}
• {{cite journal | vauthors = de Grouchy J, Turleau C | title = Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band | journal = Humangenetik | volume = 24 | issue = 3 | pages = 197–200 | year = 1975 | pmid = 4140832 | doi = 10.1007/bf00283584 | s2cid = 11075182 }}
• {{cite journal | vauthors = Fujikawa K, McMullen BA | title = Amino acid sequence of human beta-factor XIIa | journal = The Journal of Biological Chemistry | volume = 258 | issue = 18 | pages = 10924–10933 | date = September 1983 | pmid = 6604055 | doi = 10.1016/S0021-9258(17)44364-X | doi-access = free }}
• {{cite journal | vauthors = Hovinga JK, Schaller J, Stricker H, Wuillemin WA, Furlan M, Lämmle B | title = Coagulation factor XII Locarno: the functional defect is caused by the amino acid substitution Arg 353-->Pro leading to loss of a kallikrein cleavage site | journal = Blood | volume = 84 | issue = 4 | pages = 1173–1181 | date = August 1994 | pmid = 8049433 | doi = 10.1182/blood.V84.4.1173.1173 | doi-access = free }}
• {{cite journal | vauthors = Schloesser M, Hofferbert S, Bartz U, Lutze G, Lämmle B, Engel W | title = The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients | journal = Human Molecular Genetics | volume = 4 | issue = 7 | pages = 1235–1237 | date = July 1995 | pmid = 8528215 | doi = 10.1093/hmg/4.7.1235 }}
• {{cite journal | vauthors = Hofferbert S, Müller J, Köstering H, von Ohlen WD, Schloesser M | title = A novel 5'-upstream mutation in the factor XII gene is associated with a TaqI restriction site in an Alu repeat in factor XII-deficient patients | journal = Human Genetics | volume = 97 | issue = 6 | pages = 838–841 | date = June 1996 | pmid = 8641707 | doi = 10.1007/BF02346200 | s2cid = 9589165 }}

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• {{cite web | title = Summary for peptidase S01.211: coagulation factor XIIa | work = The MEROPS online database for peptidases and their inhibitors | url = https://www.ebi.ac.uk/merops/cgi-bin/pepsum?id=S01.211 | url-status = live | archive-url = https://web.archive.org/web/20211012174247/https://www.ebi.ac.uk/merops/cgi-bin/pepsum?id=S01.211 | archive-date=12 October 2021 }}
• {{MeshName|Factor+XII}}
• {{PDBe-KB2|P00748|Coagulation factor XII}}

{{Coagulation}}

{{Serine endopeptidases}}

{{Enzymes}}

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{{DEFAULTSORT:Factor Xii}}

Category:Coagulation system

Category:EC 3.4.21

Category:Zymogens