Factor XI, orplasma thromboplastin antecedent, is thezymogen form of factor XIa, one of theenzymes involved incoagulation. Like many other coagulation factors, it is aserine protease. In humans, factor XI is encoded byF11gene.[5][6][7][8]
Factor XI (FXI) is produced by theliver and circulates as ahomo-dimer in its inactive form.[9] The plasma half-life of FXI is approximately 52 hours. The zymogen factor is activated intofactor XIa byfactor XIIa (FXIIa),thrombin, and FXIa itself; due to its activation by FXIIa, FXI is a member of the "contact pathway" (which includesHMWK,prekallikrein,factor XII, factor XI, andfactor IX).[10]
Factor XIa activates factor IX by selectively cleavingarg-ala andarg-valpeptide bonds. Factor IXa, in turn, forms a complex with Factor VIIIa (FIXa-FVIIIa) and activatesfactor X.
Although synthesized as a single polypeptide chain, FXI circulates as a homodimer. Every chain has a relative molecular mass of approximately 80000. Typical plasma concentrations of FXI are 5 μg/mL, corresponding to a plasma concentration (of FXI dimers) of approximately 30 nM.The FXI gene is 23kb in length, has 15 exons, and is found on chromosome 4q32-35.[6][7]
In the homodimer, the apple domains create two disk-like platforms connected together at an angle, with the catalytic domains sticking out at each side of the dimer.
Activation by thrombin orfactor XIIa is achieved by cleavage of Arg369-Ile370 peptide bonds on both subunits of the dimer. This results in a partial detachment of the catalytic domain from the disk-like apple domains, still linked to the fourth domain with a disulfide bond, but now farther from the third domain.This is thought that this exposes the factor IX binding site of the third apple domain, allowing factor XI's protease activity on it.[11]
Deficiency of factor XI causes the rarehemophilia C; this mainly occurs inAshkenaziJews and is believed to affect approximately 8% of that population. Less commonly, hemophilia C can be found in Jews of Iraqi ancestry and in Israeli Arabs. The condition has been described in other populations at around 1% of cases. There is little spontaneous bleeding, but surgical procedures may cause excessive blood loss, and prophylaxis is required.[12]
Low levels of factor XI also occur in many other disease states, includingNoonan syndrome.
High levels of factor XI have been implicated inthrombosis, although it is uncertain what determines these levels and how serious the procoagulant state is.
Pharmacological inhibitors of factor XI that are under clinical development but not yet approved for treatment as of May 2022[update] include the oral factor XIa inhibitorsAsundexian (BAY 2433334)[13] andMilvexian[14] as well as the monoclonal anti-factor XI antibodyabelacimab (MAA868). The idea behind producing such an inhibitor is that XI is mostly involved in intrinsic/contact activation pathway,[15] which plays a bigger role inthrombosis as opposed tohemostasis, so targeting it may reduce clotting risks without a corresponding increase in bleeding.[16] Anabelacimab trial appears to have indeed produced this result.[17]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Fujikawa K, Chung DW, Hendrickson LE, Davie EW (May 1986). "Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein".Biochemistry.25 (9):2417–2424.doi:10.1021/bi00357a018.PMID3636155.
^abAsakai R, Davie EW, Chung DW (Nov 1987). "Organization of the gene for human factor XI".Biochemistry.26 (23):7221–7228.doi:10.1021/bi00397a004.PMID2827746.
^abKato A, Asakai R, Davie EW, Aoki N (1989). "Factor XI gene (F11) is located on the distal end of the long arm of human chromosome 4".Cytogenetics and Cell Genetics.52 (1–2):77–78.doi:10.1159/000132844.PMID2612218.
^Clinical trial numberNCT04304508 for "Study to Gather Information About Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following a Recent Non Cardioembolic Ischemic Stroke Which Occurs When a Blood Clot Has Formed Somewhere in the Human Body (But Not in the Heart) Travelled to the Brain. (PACIFIC-STROKE)" atClinicalTrials.gov
^Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, et al. (23 January 2025). "Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation".The New England Journal of Medicine.392 (4):361–371.doi:10.1056/NEJMoa2406674.PMID39842011.
Dossenbach-Glaninger A, Hopmeier P (Jun 2005). "Coagulation factor XI: a database of mutations and polymorphisms associated with factor XI deficiency".Blood Coagulation & Fibrinolysis.16 (4):231–238.doi:10.1097/01.mbc.0000169214.62560.a5.PMID15870541.S2CID23922781.
Clarkson K, Rosenfeld B, Fair J, Klein A, Bell W (Dec 1991). "Factor XI deficiency acquired by liver transplantation".Annals of Internal Medicine.115 (11):877–879.doi:10.7326/0003-4819-115-11-877.PMID1952475.
McMullen BA, Fujikawa K, Davie EW (Feb 1991). "Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains".Biochemistry.30 (8):2056–2060.doi:10.1021/bi00222a008.PMID1998667.
España F, Berrettini M, Griffin JH (Aug 1989). "Purification and characterization of plasma protein C inhibitor".Thrombosis Research.55 (3):369–384.doi:10.1016/0049-3848(89)90069-8.PMID2551064.
Asakai R, Davie EW, Chung DW (1988). "Organization of the gene for human factor XI".Biochemistry.26 (23):7221–7228.doi:10.1021/bi00397a004.PMID2827746.
Fujikawa K, Chung DW, Hendrickson LE, Davie EW (May 1986). "Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein".Biochemistry.25 (9):2417–2424.doi:10.1021/bi00357a018.PMID3636155.
Imanaka Y, Lal K, Nishimura T, Bolton-Maggs PH, Tuddenham EG, McVey JH (Aug 1995). "Identification of two novel mutations in non-Jewish factor XI deficiency".British Journal of Haematology.90 (4):916–920.doi:10.1111/j.1365-2141.1995.tb05215.x.PMID7669672.S2CID21900907.
1xx9: Crystal Structure of the FXIa Catalytic Domain in Complex with EcotinM84R
1xxd: Crystal Structure of the FXIa Catalytic Domain in Complex with mutated Ecotin
1xxf: Crystal Structure of the FXIa Catalytic Domain in Complex with Ecotin Mutant (EcotinP)
1zhm: Crystal Structure of the Catalytic Domain of the Coagulation Factor XIa in Complex with Benzamidine (S434A-T475A-K437 Mutant)
1zhp: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-K505 Mutant)
1zhr: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)
1zjd: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Kunitz Protease Inhibitor Domain of Protease Nexin II
1zlr: Factor XI catalytic domain complexed with 2-guanidino-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl nicotinate
1zmj: Crystal Structure of the Catalytic Domain of Factor XI in complex with 4-(guanidinomethyl)-phenylboronic acid
1zml: Crystal Structure of the Catalytic Domain of Factor XI in complex with (R)-1-(4-(4-(hydroxymethyl)-1,3,2-dioxaborolan-2-yl)phenethyl)guanidine
1zmn: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with (R)-1-(4-(4-(hydroxymethyl)-1,3,2-dioxaborolan-2-yl)phenyl)guanidine
1zom: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in complex with a peptidomimetic Inhibitor
1zpb: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 4-Methyl-pentanoic acid {1-[4-guanidino-1-(thiazole-2-carbonyl)-butylcarbamoyl]-2-methyl-propyl}-amide
1zpc: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 2-[2-(3-Chloro-phenyl)-2-hydroxy-acetylamino]-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-3-methyl-butyramide
1zpz: Factor XI catalytic domain complexed with N-((R)-1-(4-bromophenyl)ethyl)urea-Asn-Val-Arg-alpha-ketothiazole
1zrk: Factor XI complexed with 3-hydroxypropyl 3-(7-amidinonaphthalene-1-carboxamido)benzenesulfonate
1zsj: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in complex with N-(7-Carbamimidoyl-naphthalen-1-yl)-3-hydroxy-2-methyl-benzamide
1zsk: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 6-Carbamimidoyl-4-(3-hydroxy-2-methyl-benzoylamino)-naphthalene-2-carboxylic acid methyl ester
1zsl: Factor XI complexed with a pyrimidinone inhibitor
1ztj: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 2-(5-Benzylamino-2-methylsulfanyl-6-oxo-6H-pyrimidin-1-yl)-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide
1ztk: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 2-(5-Amino-6-oxo-2-m-tolyl-6H-pyrimidin-1-yl)-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide
1ztl: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with N-[4-Guanidino-1-(thiazole-2-carbonyl)-butyl]-2-{6-oxo-5-[(quinolin-8-ylmethyl)-amino]-2-m-tolyl-6H-pyrimidin-1-yl}-acetamide
2f83: Crystal structure at 2.9 Angstroms resolution of human plasma coagulation factor XI zymogen
2fda: Crystal Structure of the Catalytic Domain of Human Coagulation Factor XIa in Complex with alpha-Ketothiazole Arginine Derived Ligand
![1zpb: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 4-Methyl-pentanoic acid {1-[4-guanidino-1-(thiazole-2-carbonyl)-butylcarbamoyl]-2-methyl-propyl}-amide](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.m.wikipedia.org%2fwiki%2fFile%3aPDB_1zpb_EBI.png)
![1zpc: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 2-[2-(3-Chloro-phenyl)-2-hydroxy-acetylamino]-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-3-methyl-butyramide](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.m.wikipedia.org%2fwiki%2fFile%3aPDB_1zpc_EBI.png)
![1ztj: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 2-(5-Benzylamino-2-methylsulfanyl-6-oxo-6H-pyrimidin-1-yl)-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.m.wikipedia.org%2fwiki%2fFile%3aPDB_1ztj_EBI.png)
![1ztk: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with 2-(5-Amino-6-oxo-2-m-tolyl-6H-pyrimidin-1-yl)-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.m.wikipedia.org%2fwiki%2fFile%3aPDB_1ztk_EBI.png)
![1ztl: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with N-[4-Guanidino-1-(thiazole-2-carbonyl)-butyl]-2-{6-oxo-5-[(quinolin-8-ylmethyl)-amino]-2-m-tolyl-6H-pyrimidin-1-yl}-acetamide](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.m.wikipedia.org%2fwiki%2fFile%3aPDB_1ztl_EBI.png)
