Factor XI explained

Factor XI, or plasma thromboplastin antecedent, is the zymogen form of factor XIa, one of the enzymes involved in coagulation. Like many other coagulation factors, it is a serine protease. In humans, factor XI is encoded by F11 gene.^{[1] [2] [3] [4]}

Function

Factor XI (FXI) is produced by the liver and circulates as a homo-dimer in its inactive form.^[5] The plasma half-life of FXI is approximately 52 hours. The zymogen factor is activated into factor XIa by factor XIIa (FXIIa), thrombin, and FXIa itself; due to its activation by FXIIa, FXI is a member of the "contact pathway" (which includes HMWK, prekallikrein, factor XII, factor XI, and factor IX).^[6]

Factor XIa activates factor IX by selectively cleaving arg-ala and arg-val peptide bonds. Factor IXa, in turn, forms a complex with Factor VIIIa (FIXa-FVIIIa) and activates factor X.

Physiological inhibitors of factor XIa include protein Z-dependent protease inhibitor (ZPI, a member of the serine protease inhibitor/serpin class of proteins), which is independent of protein Z (its action on factor X, however, is protein Z-dependent, hence its name).

Structure

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.^{[2] [3]}

Factor XI consists of four apple domains, that create a disk-like platform around the base of a fifth, catalytic serine protease domain.One contains a binding site for thrombin, another for high molecular weight kininogen, a third one for factor IX, heparin and glycoprotein Ib and the fourth is implicated in forming the factor XI homodimer, including a cysteine residue that creates a disulfide bond.

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 or factor 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.^[7]

Role in disease

Deficiency of factor XI causes the rare hemophilia C; this mainly occurs in Ashkenazi Jews 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. It is an autosomal recessive disorder. There is little spontaneous bleeding, but surgical procedures may cause excessive blood loss, and prophylaxis is required.^[8]

Low levels of factor XI also occur in many other disease states, including Noonan syndrome.

High levels of factor XI have been implicated in thrombosis, 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 include the oral factor XIa inhibitors Asundexian (BAY 2433334) and Milvexian^[9] as well as the monoclonal anti-factor XI antibody Abelacimab (MAA868).^[10]

See also

• Contact activation pathway (also known as the intrinsic pathway)
• Tissue factor pathway (also known as the extrinsic pathway)

Further reading

• Gailani D, Zivelin A, Sinha D, Walsh PN . Do platelets synthesize factor XI? . Journal of Thrombosis and Haemostasis . 2 . 10 . 1709–12 . 2005 . 15456479 . 10.1111/j.1538-7836.2004.00935.x . 5962587 . free .
• Dossenbach-Glaninger A, Hopmeier P . Coagulation factor XI: a database of mutations and polymorphisms associated with factor XI deficiency . Blood Coagulation & Fibrinolysis . 16 . 4 . 231–8 . Jun 2005 . 15870541 . 10.1097/01.mbc.0000169214.62560.a5 . 23922781 .
• Seligsohn U . Factor XI in haemostasis and thrombosis: past, present and future . Thrombosis and Haemostasis . 98 . 1 . 84–9 . Jul 2007 . 17597996 . 10.1160/th07-04-0246 . free .
• Meijers JC, Davie EW, Chung DW . Expression of human blood coagulation factor XI: characterization of the defect in factor XI type III deficiency . Blood . 79 . 6 . 1435–40 . Mar 1992 . 1547342 . 10.1182/blood.V79.6.1435.1435. free .
• Gailani D, Broze GJ . Factor XI activation in a revised model of blood coagulation . Science . 253 . 5022 . 909–12 . Aug 1991 . 1652157 . 10.1126/science.1652157 . 1991Sci...253..909G . 9262836 .
• Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ . A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates . American Journal of Human Genetics . 48 . 5 . 911–25 . May 1991 . 1673289 . 1683054 .
• Bodfish P, Warne D, Watkins C, Nyberg K, Spurr NK . Dinucleotide repeat polymorphism in the human coagulation factor XI gene, intron B (F11), detected using the polymerase chain reaction . Nucleic Acids Research . 19 . 24 . 6979 . 1992 . 1762944 . 329377 . 10.1093/nar/19.24.6979-a .
• Clarkson K, Rosenfeld B, Fair J, Klein A, Bell W . Factor XI deficiency acquired by liver transplantation . Annals of Internal Medicine . 115 . 11 . 877–9 . Dec 1991 . 1952475 . 10.7326/0003-4819-115-11-877 .
• McMullen BA, Fujikawa K, Davie EW . Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains . Biochemistry . 30 . 8 . 2056–60 . Feb 1991 . 1998667 . 10.1021/bi00222a008 .
• Naito K, Fujikawa K . Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces . The Journal of Biological Chemistry . 266 . 12 . 7353–8 . Apr 1991 . 10.1016/S0021-9258(20)89453-8 . 2019570 . free .
• Asakai R, Chung DW, Davie EW, Seligsohn U . Factor XI deficiency in Ashkenazi Jews in Israel . The New England Journal of Medicine . 325 . 3 . 153–8 . Jul 1991 . 2052060 . 10.1056/NEJM199107183250303 . free .
• España F, Berrettini M, Griffin JH . Purification and characterization of plasma protein C inhibitor . . 55 . 3 . 369–84 . Aug 1989 . 2551064 . 10.1016/0049-3848(89)90069-8 .
• Asakai R, Chung DW, Ratnoff OD, Davie EW . Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations . Proceedings of the National Academy of Sciences of the United States of America . 86 . 20 . 7667–71 . Oct 1989 . 2813350 . 298131 . 10.1073/pnas.86.20.7667 . 1989PNAS...86.7667A . free .
• Asakai R, Davie EW, Chung DW . Organization of the gene for human factor XI . Biochemistry . 26 . 23 . 7221–8 . 1988 . 2827746 . 10.1021/bi00397a004 .
• Fujikawa K, Chung DW, Hendrickson LE, Davie EW . 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 . 2417–24 . May 1986 . 3636155 . 10.1021/bi00357a018 .
• Warn-Cramer BJ, Bajaj SP . Stoichiometry of binding of high molecular weight kininogen to factor XI/XIa . Biochemical and Biophysical Research Communications . 133 . 2 . 417–22 . 1986 . 3936495 . 10.1016/0006-291X(85)90922-2 .
• Bouma BN, Vlooswijk RA, Griffin JH . Immunologic studies of human coagulation factor XI and its complex with high molecular weight kininogen . Blood . 62 . 5 . 1123–31 . Nov 1983 . 6626744 . 10.1182/blood.V62.5.1123.1123. free .
• Tuszynski GP, Bevacqua SJ, Schmaier AH, Colman RW, Walsh PN . Factor XI antigen and activity in human platelets . Blood . 59 . 6 . 1148–56 . Jun 1982 . 7044446 . 10.1182/blood.V59.6.1148.1148. free .
• Imanaka Y, Lal K, Nishimura T, Bolton-Maggs PH, Tuddenham EG, McVey JH . Identification of two novel mutations in non-Jewish factor XI deficiency . British Journal of Haematology . 90 . 4 . 916–20 . Aug 1995 . 7669672 . 10.1111/j.1365-2141.1995.tb05215.x . 21900907 .
• Pugh RE, McVey JH, Tuddenham EG, Hancock JF . Six point mutations that cause factor XI deficiency . Blood . 85 . 6 . 1509–16 . Mar 1995 . 7888672 . 10.1182/blood.V85.6.1509.bloodjournal8561509. free .
• Riley PW, Cheng H, Samuel D, Roder H, Walsh PN . Dimer dissociation and unfolding mechanism of coagulation factor XI apple 4 domain: spectroscopic and mutational analysis . Journal of Molecular Biology . 367 . 2 . 558–73 . Mar 2007 . 17257616 . 1945241 . 10.1016/j.jmb.2006.12.066 .
• Samuel D, Cheng H, Riley PW, Canutescu AA, Nagaswami C, Weisel JW, Bu Z, Walsh PN, Roder H . Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation . Proceedings of the National Academy of Sciences of the United States of America . 104 . 40 . 15693–8 . Oct 2007 . 17884987 . 1987390 . 10.1073/pnas.0703080104 . 2007PNAS..10415693S . free .

External links

• The MEROPS online database for peptidases and their inhibitors: S01.213

Notes and References

1. Fujikawa K, Chung DW, Hendrickson LE, Davie EW . 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 . 2417–24 . May 1986 . 3636155 . 10.1021/bi00357a018 .
2. Asakai R, Davie EW, Chung DW . Organization of the gene for human factor XI . Biochemistry . 26 . 23 . 7221–8 . Nov 1987 . 2827746 . 10.1021/bi00397a004 .
3. Kato A, Asakai R, Davie EW, Aoki N . 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 . 77–8 . 1989 . 2612218 . 10.1159/000132844 .
4. Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ . A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates . American Journal of Human Genetics . 48 . 5 . 911–25 . May 1991 . 1673289 . 1683054 .
5. Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN . Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa . The Journal of Biological Chemistry . 283 . 27 . 18655–64 . Jul 2008 . 18441012 . 2441546 . 10.1074/jbc.M802275200 . free .
6. Walsh PN . Roles of platelets and factor XI in the initiation of blood coagulation by thrombin . Thrombosis and Haemostasis . 86 . 1 . 75–82 . Jul 2001 . 11487044 . 10.1055/s-0037-1616203. 32572142 . 2009-01-07 . https://web.archive.org/web/20160416092638/http://www.schattauer.de/index.php?id=1268&pii=th01070007&no_cache=1 . 2016-04-16 . dead .
7. Emsley J, McEwan PA, Gailani D . Structure and function of factor XI . Blood . Apr 2010 . 115 . 13 . 2569–77 . 20110423 . 10.1182/blood-2009-09-199182 . 4828079.
8. Bolton-Maggs PH . Factor XI deficiency . Baillière's Clinical Haematology . 9 . 2 . 355–68 . Jun 1996 . 8800510 . 10.1016/S0950-3536(96)80068-0 .
9. Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, Mahaffey KW, Notani RS, Roberts R, Segers A, Raskob GE . 6 . Milvexian for the Prevention of Venous Thromboembolism . The New England Journal of Medicine . November 2021 . 385 . 23 . 2161–2172 . 34780683 . 10.1056/NEJMoa2113194 . 9540352 . 244132392 .
10. Verhamme . Peter . Yi . B. Alexander . Segers . Annelise . Salter . Janeen . Bloomfield . Daniel . Büller . Harry R. . Raskob . Gary E. . Weitz . Jeffrey I. . Abelacimab for Prevention of Venous Thromboembolism . New England Journal of Medicine . 12 August 2021 . 385 . 7 . 609–617 . 10.1056/NEJMoa2105872 . 34297496. 236198598 . free .