Coagulation factor X(EC3.4.21.6), orStuart factor,is anenzymeof thecoagulation cascade,encoded in humans byF10gene.[5]It is aserine endopeptidase(protease group S1,PA clan). Factor X is synthesized in theliverand requiresvitamin Kfor its synthesis.
Factor X is activated, by hydrolysis, intofactor Xaby bothfactor IXwith its cofactor,factor VIIIin a complex known asintrinsic pathway;andfactor VIIwith its cofactor,tissue factorin a complex known asextrinsic pathway.[6]It is therefore the first member of thefinal common pathwayorthrombin pathway.
It acts by cleavingprothrombinin two places (anArg-Thrand then anArg-Ilebond), which yields the activethrombin.This process is optimized when factor Xa is complexed with activatedco-factor Vin theprothrombinasecomplex.
Factor Xa is inactivated byprotein Z-dependent protease inhibitor(ZPI), aserine protease inhibitor(serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence ofprotein Z,while it does not require protein Z for inactivation offactor XI.Defects in protein Z lead to increased factor Xa activity and a propensity for thrombosis. The half life of factor X is 40–45 hours.
Structure
editThe first crystal structure of human factor Xa was deposited in May 1993. To date, 191 crystal structures of factor Xa with various inhibitors have been deposited in the protein data bank. The active site of factor Xa is divided into four subpockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the "hydrophobic box", the "cationic hole" and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residuesAsp189,Ser195, andTyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99,Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites.[7]
Genetics
editThe human factor Xgeneis located onchromosome 13(13q34).
Role in disease
editInborn deficiency of factor X is very rare (1:1,000,000), and may present withepistaxis(nosebleeds),hemarthrosis(bleeding into joints) and gastrointestinal blood loss. Apart from congenital deficiency, low factor X levels may occur occasionally in a number of disease states. For example, factor X deficiency may be seen inamyloidosis,where factor X is adsorbed to the amyloid fibrils in the vasculature.
Deficiency of vitamin K or antagonism bywarfarin(or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to preventthrombosis.As of late 2007, four out of five emerginganti-coagulationtherapeutics targeted this enzyme.[8]
Inhibiting Factor Xa would offer an alternate method for anticoagulation.Direct Xa inhibitorsare popular anticoagulants.
Polymorphisms in Factor X have been associated with an increased prevalence in bacterial infections, suggesting a possible role directly regulating the immune response to bacterial pathogens.[9]
Therapeutic use
editFactor X is part offresh frozen plasmaand the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured byCSL Behring,[10]and high purity Factor XCoagadexproduced byBio Products Laboratoryand approved for use in the United States by the FDA in October 2015, and in the EU in March 2016, after earlier acceptance by CHMP and COMP.[11][12][13][14]
Kcentra, manufactured by CSL Behring, is a concentrate containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S.[15]
Use in biochemistry
editThe factor Xa protease can be used in biochemistry to cleave offprotein tagsthat improve expression or purification of a protein of interest. Its preferred cleavage site (after the arginine in the sequence Ile-Glu/Asp-Gly-Arg, IEGR or IDGR) can easily be engineered between a tag sequence and the protein of interest. After expression and purification, the tag is then proteolytically removed by factor Xa.
Factor Xa
edit
Factor Xa is the activated form of thecoagulation factorX, also known asthrombokinase.Factor X is anenzyme,aserine endopeptidase,which plays a key role at several stages of thecoagulation system.Factor X issynthesizedin theliver.The most commonly usedanticoagulantsin clinical practice,warfarinand theheparinseries of anticoagulants andfondaparinux,act to inhibit the action of Factor Xa in various degrees.
Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic(tissue factor (TF))pathway and the intrinsic pathway. These pathways converge to a common point, the formation of the Factor Xa/Va complex which together withcalciumand bound on aphospholipidssurface, generatethrombin (Factor IIa)fromprothrombin (Factor II).
A new model, the cell-based model of anticoagulation appears to explain more fully the steps in coagulation. This model has three stages: 1) initiation of coagulation on TF-bearing cells, 2) amplification of the procoagulant signal by thrombin generated on the TF-bearing cell and 3) propagation of thrombin generation on theplateletsurface. Factor Xa plays a key role in all three of these stages.[16]
In stage 1,Factor VIIbinds to thetransmembrane proteinTF on the surface of cells and is converted to Factor VIIa. The result is a Factor VIIa/TF complex, which catalyzes the activation of Factor X andFactor IX.Factor Xa formed on the surface of the TF-bearing cell interacts withFactor Vato form theprothrombinase complexwhich generates small amounts of thrombin on the surface of TF-bearing cells.
In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet-associatedcofactorsoccurs.
In stage 3, thrombin generation,Factor XIaactivates free Factor IX on the surface of activated platelets. The activated Factor IXa withFactor VIIIaforms the"tenase" complex.This "tenase" complex activates more Factor X, which in turn forms new prothrombinase complexes with Factor Va. Factor Xa is the prime component of the prothrombinase complex which converts large amounts ofprothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible forfibrinpolymerizationto form athrombus.
Factor Xa also plays a role in other biological processes that are not directly related to coagulation, like wound healing, tissue remodelling, inflammation, angiogenesis and atherosclerosis.
Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative ofcoumarin,is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumonandacenocoumarol) are used. These agents known asvitamin K antagonists(VKA), inhibit the vitamin K-dependent carboxylation of Factors II (prothrombin), VII, IX, X in the hepatocyte. This carboxylation after the translation is essential for the physiological activity.[17]
Heparin (unfractionated heparin) and its derivativeslow molecular weight heparin (LMWH)bind to aplasmacofactor,antithrombin (AT)to inactivate several coagulation factors IIa, Xa, XIa and XIIa. The affinity of unfractionated heparin and the various LMWHs for Factor Xa varies considerably. The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases. LMWH shows increased inactivation of Factor Xa compared to unfractionated heparin, and fondaparinux, an agent based on the critical pentasacharide sequence of heparin, shows more selectivity than LMWH. This inactivation of Factor Xa by heparins is termed "indirect" since it relies on the presence of AT and not a direct interaction with Factor Xa.
Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugsrivaroxaban,apixaban,betrixaban,LY517717,darexaban(YM150),edoxabanand 813893. These agents have several theoretical advantages over current therapy. They may be given orally. They have rapid onset of action. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex.[18]
History
editAmerican and British scientists described deficiency of factor X independently in 1953 and 1956, respectively. As with some other coagulation factors, the factor was initially named after these patients, a Mr Rufus Stuart (1921) and a Miss Audrey Prower (1934). At that time, those investigators could not know that the human genetic defect they had identified would be found in the previously characterized enzyme called thrombokinase.
Thrombokinase was the name coined by Paul Morawitz in 1904 to describe the substance that converted prothrombin to thrombin and caused blood to clot.[19]That name embodied an important new concept in understanding blood coagulation – that an enzyme was critically important in the activation of prothrombin. Morawitz believed that his enzyme came from cells such as platelets yet, in keeping with the state of knowledge about enzymes at that time, he had no clear idea about the chemical nature of his thrombokinase or its mechanism of action. Those uncertainties led to decades during which the terms thrombokinase and thromboplastin were both used to describe the activator of prothrombin and led to controversy about its chemical nature and origin.[20]
In 1947, J Haskell Milstone isolated a proenzyme from bovine plasma which, when activated, converted prothrombin to thrombin. Following Morawitz’s designation, he called it prothrombokinase[21]and by 1951 had purified the active enzyme, thrombokinase. Over the next several years he showed that thrombokinase was a proteolytic enzyme that, by itself, could activate prothrombin. Its activity was greatly enhanced by addition of calcium, other serum factors, and tissue extracts,[22]which represented the thromboplastins that promoted the conversion of prothrombin to thrombin by their interaction with thrombokinase. In 1964 Milstone summarized his work and that of others: “There are many chemical reactions which are so slow that they would not be of physiological use if they were not accelerated by enzymes. We are now confronted with a reaction, catalyzed by an enzyme, which is still too slow unless aided by accessory factors.”[23]
Interactions
editFactor X has been shown tointeractwithTissue factor pathway inhibitor.[24]
References
edit- ^abcGRCh38: Ensembl release 89: ENSG00000126218–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000031444–Ensembl,May 2017
- ^"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.
- ^"F10 gene: MedlinePlus Genetics".medlineplus.gov.
- ^Camire RM (August 2021)."Blood coagulation factor X: molecular biology, inherited disease, and engineered therapeutics".Journal of Thrombosis and Thrombolysis.52(2): 383–390.doi:10.1007/s11239-021-02456-w.PMC8531165.PMID33886037.
- ^"Presentation on Direct Factor Xa Inhibitors".Archived fromthe originalon 2016-03-03.Retrieved2010-04-08.
- ^Ron Winslow, Avery Johnson (2007-12-10)."Race Is on for the Next Blood Thinner".The Wall Street Journal.p. A12.Archivedfrom the original on 2016-03-10.Retrieved2008-01-06.
The flurry of interest reflects increasing understanding of what doctors call the coagulation cascade... Four new blood thinners target an enzyme called factor Xa, one of several enzymes that play an important role in the cascade.
- ^Choby JE, Monteith AJ, Himmel LE, Margaritis P, Shirey-Rice JK, Pruijssers A, et al. (March 2019)."A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X duringAcinetobacter baumanniiInfection ".Infection and Immunity.87(5): IAI.00031–19.doi:10.1128/IAI.00031-19.PMC6479028.PMID30782860.
- ^Brooker M (April 2008).Registry of Clotting Factor Concentrates(Eighth ed.).World Federation of Hemophilia.
- ^"FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder"(Press release). US FDA. October 20, 2015. Archived fromthe originalon October 21, 2015.RetrievedOctober 21,2015.
Until today's orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.
- ^"Coagadex".U.S. Food and Drug Administration.28 June 2017. Archived from the original on 22 July 2017.Retrieved2 April2020.
{{cite web}}:CS1 maint: unfit URL (link) - ^"Coagadex".U.S. Food and Drug Administration.21 September 2018.Archivedfrom the original on 17 December 2019.Retrieved2 April2020.
- ^"Coagadex EPAR".European Medicines Agency(EMA).17 September 2018.Archivedfrom the original on 30 December 2019.Retrieved21 April2020.
- ^"Kcentra- prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water kit".DailyMed.22 October 2018.Archivedfrom the original on 25 March 2021.Retrieved21 April2020.
- ^Hoffman M, Monroe DM (February 2007). "Coagulation 2006: a modern view of hemostasis".Hematology/Oncology Clinics of North America.21(1): 1–11.doi:10.1016/j.hoc.2006.11.004.PMID17258114.
- ^Golan DE (2012).Principles of Pharmacology The Pathophysiologic Basis of Drug Therapy.Philadelphia: Lippincott Williams & Wilkins. p. 387.ISBN978-1-4511-1805-6.
- ^Turpie AG (June 2007). "Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases".Arteriosclerosis, Thrombosis, and Vascular Biology.27(6): 1238–1247.CiteSeerX10.1.1.536.872.doi:10.1161/ATVBAHA.107.139402.PMID17379841.S2CID2998452.
- ^Morawitz P. "Beitrage zur Kenntnis der Blutgerinnung".Deutsches Archiv für Klinische Medizin.79:432–442.
- ^Milstone JH (December 1952)."On the evolution of blood clotting theory".Medicine.31(4): 411–447.doi:10.1097/00005792-195212000-00004.PMID13012730.
- ^Milstone JH (December 1947). "Prothrombokinase and the Three Stages of Blood Coagulation".Science.106(2762): 546–547.Bibcode:1947Sci...106..546M.doi:10.1126/science.106.2762.546-a.PMID17741228.S2CID35643683.
- ^Milstone LM (August 2021). "Factor Xa: Thrombokinase from Paul Morawitz to J Haskell Milstone".Journal of Thrombosis and Thrombolysis.52(2): 364–370.doi:10.1007/s11239-021-02387-6.PMID33484373.S2CID231682954.
- ^Milstone JH, Oulianoff N, Milstone VK (November 1963)."Thrombokinase as prime activator of prothrombin: historical perspectives and present status".The Journal of General Physiology.47(2): 315–327.doi:10.1085/jgp.47.2.315.PMC2195336.PMID14080818.
- ^Broze GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP (February 1988)."The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action".Blood.71(2): 335–343.doi:10.1182/blood.V71.2.335.335.PMID3422166.
Further reading
edit- Cooper DN, Millar DS, Wacey A, Pemberton S, Tuddenham EG (July 1997). "Inherited factor X deficiency: molecular genetics and pathophysiology".Thrombosis and Haemostasis.78(1): 161–172.doi:10.1055/s-0038-1657520.PMID9198147.S2CID27129058.
- Hassan HJ, Leonardi A, Chelucci C, Mattia G, Macioce G, Guerriero R, et al. (September 1990)."Blood coagulation factors in human embryonic-fetal development: preferential expression of the FVII/tissue factor pathway".Blood.76(6): 1158–1164.doi:10.1182/blood.V76.6.1158.1158.PMID1698100.
- Messier TL, Pittman DD, Long GL, Kaufman RJ, Church WR (March 1991). "Cloning and expression in COS-1 cells of a full-length cDNA encoding human coagulation factor X".Gene.99(2): 291–294.doi:10.1016/0378-1119(91)90141-W.PMID1902434.
- Krishnaswamy S (March 1990)."Prothrombinase complex assembly. Contributions of protein-protein and protein-membrane interactions toward complex formation".The Journal of Biological Chemistry.265(7): 3708–3718.doi:10.1016/S0021-9258(19)39652-8.PMID2303476.
- España F, Berrettini M, Griffin JH (August 1989). "Purification and characterization of plasma protein C inhibitor".Thrombosis Research.55(3): 369–384.doi:10.1016/0049-3848(89)90069-8.PMID2551064.
- Fung MR, Hay CW, MacGillivray RT (June 1985)."Characterization of an almost full-length cDNA coding for human blood coagulation factor X".Proceedings of the National Academy of Sciences of the United States of America.82(11): 3591–3595.Bibcode:1985PNAS...82.3591F.doi:10.1073/pnas.82.11.3591.PMC397831.PMID2582420.
- Jagadeeswaran P, Reddy SV, Rao KJ, Hamsabhushanam K, Lyman G (December 1989). "Cloning and characterization of the 5' end (exon 1) of the gene encoding human factor X".Gene.84(2): 517–519.doi:10.1016/0378-1119(89)90529-5.PMID2612918.
- Reddy SV, Zhou ZQ, Rao KJ, Scott JP, Watzke H, High KA, et al. (October 1989)."Molecular characterization of human factor XSan Antonio".Blood.74(5): 1486–1490.doi:10.1182/blood.V74.5.1486.1486.PMID2790181.
- Kaul RK, Hildebrand B, Roberts S, Jagadeeswaran P (1986). "Isolation and characterization of human blood-coagulation factor X cDNA".Gene.41(2–3): 311–314.doi:10.1016/0378-1119(86)90112-5.PMID3011603.
- Broze GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP (February 1988)."The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action".Blood.71(2): 335–343.doi:10.1182/blood.V71.2.335.335.PMID3422166.
- Gilgenkrantz S, Briquel ME, André E, Alexandre P, Jalbert P, Le Marec B, et al. (1986). "Structural genes of coagulation factors VII and X located on 13q34".Annales de Génétique.29(1): 32–35.PMID3487272.
- Leytus SP, Foster DC, Kurachi K, Davie EW (September 1986). "Gene for human factor X: a blood coagulation factor whose gene organization is essentially identical with that of factor IX and protein C".Biochemistry.25(18): 5098–5102.doi:10.1021/bi00366a018.PMID3768336.
- Leytus SP, Chung DW, Kisiel W, Kurachi K, Davie EW (June 1984)."Characterization of a cDNA coding for human factor X".Proceedings of the National Academy of Sciences of the United States of America.81(12): 3699–3702.Bibcode:1984PNAS...81.3699L.doi:10.1073/pnas.81.12.3699.PMC345286.PMID6587384.
- McMullen BA, Fujikawa K, Kisiel W, Sasagawa T, Howald WN, Kwa EY, et al. (June 1983). "Complete amino acid sequence of the light chain of human blood coagulation factor X: evidence for identification of residue 63 as beta-hydroxyaspartic acid".Biochemistry.22(12): 2875–2884.doi:10.1021/bi00281a016.PMID6871167.
- Marchetti G, Castaman G, Pinotti M, Lunghi B, Di Iasio MG, Ruggieri M, et al. (August 1995). "Molecular bases of CRM+ factor X deficiency: a frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glu102Lys) in the second EGF-like domain".British Journal of Haematology.90(4): 910–915.doi:10.1111/j.1365-2141.1995.tb05214.x.PMID7669671.S2CID29324903.
- Morgenstern KA, Sprecher C, Holth L, Foster D, Grant FJ, Ching A, et al. (March 1994). "Complementary DNA cloning and kinetic characterization of a novel intracellular serine proteinase inhibitor: mechanism of action with trypsin and factor Xa as model proteinases".Biochemistry.33(11): 3432–3441.doi:10.1021/bi00177a037.PMID8136380.
- Heeb MJ, Rosing J, Bakker HM, Fernandez JA, Tans G, Griffin JH (March 1994)."Protein S binds to and inhibits factor Xa".Proceedings of the National Academy of Sciences of the United States of America.91(7): 2728–2732.Bibcode:1994PNAS...91.2728H.doi:10.1073/pnas.91.7.2728.PMC43443.PMID8146182.
- Inoue K, Morita T (November 1993)."Identification of O-linked oligosaccharide chains in the activation peptides of blood coagulation factor X. The role of the carbohydrate moieties in the activation of factor X".European Journal of Biochemistry.218(1): 153–163.doi:10.1111/j.1432-1033.1993.tb18361.x.PMID8243461.
- Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, et al. (August 1993). "Structure of human des(1-45) factor Xa at 2.2 A resolution".Journal of Molecular Biology.232(3): 947–966.doi:10.1006/jmbi.1993.1441.PMID8355279.
- Sinha U, Wolf DL (February 1993)."Carbohydrate residues modulate the activation of coagulation factor X".The Journal of Biological Chemistry.268(5): 3048–3051.doi:10.1016/S0021-9258(18)53657-7.PMID8428982.
Further reading
edit- Schwartz RA, Steen CJ, Gascon P, Schick P (18 March 2024). Talavera F, Sacher RA, Thiagarajan P (eds.)."Factor X Deficiency".MedScape.WebMD LLC.
External links
edit- "Summary for peptidase S01.216: coagulation factor Xa".MEROPS.European Molecular Biology Laboratory (EMBL).
- "Factor X deficiency".Canadian Hemophilia Society.
