Factor XI#Inhibition

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.{{cite journal | vauthors = Fujikawa K, Chung DW, Hendrickson LE, Davie EW | title = Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein | journal = Biochemistry | volume = 25 | issue = 9 | pages = 2417–2424 | date = May 1986 | pmid = 3636155 | doi = 10.1021/bi00357a018 }}{{cite journal | vauthors = Asakai R, Davie EW, Chung DW | title = Organization of the gene for human factor XI | journal = Biochemistry | volume = 26 | issue = 23 | pages = 7221–7228 | date = Nov 1987 | pmid = 2827746 | doi = 10.1021/bi00397a004 }}{{cite journal | vauthors = Kato A, Asakai R, Davie EW, Aoki N | title = Factor XI gene (F11) is located on the distal end of the long arm of human chromosome 4 | journal = Cytogenetics and Cell Genetics | volume = 52 | issue = 1–2 | pages = 77–78 | year = 1989 | pmid = 2612218 | doi = 10.1159/000132844 }}{{cite journal | vauthors = Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ | title = A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates | journal = American Journal of Human Genetics | volume = 48 | issue = 5 | pages = 911–925 | date = May 1991 | pmid = 1673289 | pmc = 1683054 }}

Function

Factor XI (FXI) is produced by the liver and circulates as a homo-dimer in its inactive form.{{cite journal | vauthors = Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN | title = Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa | journal = The Journal of Biological Chemistry | volume = 283 | issue = 27 | pages = 18655–18664 | date = Jul 2008 | pmid = 18441012 | pmc = 2441546 | doi = 10.1074/jbc.M802275200 | doi-access = free }} 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).{{cite journal | vauthors = Walsh PN | title = Roles of platelets and factor XI in the initiation of blood coagulation by thrombin | journal = Thrombosis and Haemostasis | volume = 86 | issue = 1 | pages = 75–82 | date = Jul 2001 | pmid = 11487044 | doi = 10.1055/s-0037-1616203 | s2cid = 32572142 | url = http://www.schattauer.de/index.php?id=1268&pii=th01070007&no_cache=1 | access-date = 2009-01-07 | archive-url = https://web.archive.org/web/20160416092638/http://www.schattauer.de/index.php?id=1268&pii=th01070007&no_cache=1 | archive-date = 2016-04-16 | url-status = dead }}

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.

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.

{{cite journal | vauthors = Emsley J, McEwan PA, Gailani D | title = Structure and function of factor XI | journal = Blood | volume = 115 | issue = 13 | pages = 2569–2577 | date = Apr 2010 | pmid = 20110423 | pmc = 4828079 | doi = 10.1182/blood-2009-09-199182 }}

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.{{cite journal | vauthors = Bolton-Maggs PH | title = Factor XI deficiency | journal = Bailliere's Clinical Haematology | volume = 9 | issue = 2 | pages = 355–368 | date = Jun 1996 | pmid = 8800510 | doi = 10.1016/S0950-3536(96)80068-0 }}

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.

= Inhibition =

Pharmacological inhibitors of factor XI that are under clinical development but not yet approved for treatment {{as of|2022|05|lc=y}} include the oral factor XIa inhibitors Asundexian (BAY 2433334){{ClinicalTrialsGov|NCT04304508|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)}} and Milvexian{{cite journal | vauthors = Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, Mahaffey KW, Notani RS, Roberts R, Segers A, Raskob GE | title = Milvexian for the Prevention of Venous Thromboembolism | journal = The New England Journal of Medicine | volume = 385 | issue = 23 | pages = 2161–2172 | date = November 2021 | pmid = 34780683 | pmc = 9540352 | doi = 10.1056/NEJMoa2113194 | s2cid = 244132392 }} as well as the monoclonal anti-factor XI antibody abelacimab (MAA868). The idea behind producing such an inhibitor is that XI is mostly involved in intrinsic/contact activation pathway,{{cite journal | vauthors = Long AT, Kenne E, Jung R, Fuchs TA, Renné T | title = Contact system revisited: an interface between inflammation, coagulation, and innate immunity | journal = Journal of Thrombosis and Haemostasis | volume = 14 | issue = 3 | pages = 427–437 | date = March 2016 | pmid = 26707513 | doi = 10.1111/jth.13235 | doi-access = free }} which plays a bigger role in thrombosis as opposed to hemostasis, so targeting it may reduce clotting risks without a corresponding increase in bleeding.{{cite journal | vauthors = Verhamme P, Yi BA, Segers A, Salter J, Bloomfield D, Buller HR, Raskob GE, Weitz JI | title = Abelacimab for Prevention of Venous Thromboembolism | journal = The New England Journal of Medicine | volume = 385 | issue = 7 | pages = 609–617 | date = 12 August 2021 | pmid = 34297496 | doi = 10.1056/NEJMoa2105872 | s2cid = 236198598 | doi-access = free }} An abelacimab trial appears to have indeed produced this result.{{cite journal | vauthors = Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, Goodrich EL, Chen SA, Goodman SG, Joung B, Kiss RG, Spinar J, Wojakowski W, Weitz JI, Murphy SA, Wiviott SD, Parkar S, Bloomfield D, Sabatine MS | title = Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation | journal = The New England Journal of Medicine | volume = 392 | issue = 4 | pages = 361–371 | date = 23 January 2025 | pmid = 39842011 | doi = 10.1056/NEJMoa2406674 }}

References

External links

The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.213 S01.213] {{Webarchive|url=https://web.archive.org/web/20200529050416/https://www.ebi.ac.uk/merops/ |date=2020-05-29 }}

Category:EC 3.4.21

Category:Coagulation system

Category:Zymogens