Factor X

http://emedicine.medscape.com/article/209867-overview

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Factor X
Author: Robert A Schwartz, MD, MPH; Chief Editor: Emmanuel C Besa, MD more... Updated: Jul 12, 2012

Background
Clotting factor X, or Stuart-Prower factor, is a vitamin Kdependent serine protease that serves as the first enzyme in the common pathway of thrombus formation. Factor X deficiency is a bleeding disorder that can be inherited or acquired. This disorder is one of the world's most rare factor deficiencies. In the 1950s, 2 independent groups first identified factor X deficiency. Telfer and colleagues reported a bleeding tendency in a 22-year-old woman named Prower in 1956[1] ; Hougie and colleagues described abnormal coagulation profiles in a 36-year-old man named Stuart in 1957.[2] Experiments demonstrated that mixing plasma or serum from Stuart and Prower did not mutually correct the abnormality, thus showing that the 2 lacked an identical factor. Based on these common clotting test results, the factor was designated Stuart-Prower factor. Now, this factor is known as factor X. Inherited factor X deficiency is autosomal recessive, with heterozygotes most often remaining asymptomatic. Homozygous individuals may experience hemorrhagic symptoms, including easy bruising, hematuria, soft-tissue hemorrhages, hemarthroses, recurrent epistaxis, and menorrhagia.[3] Pedigree analysis of patients with congenital factor X deficiency often reveals consanguinity. Acquired factor X deficiency can be caused by severe liver disease, vitamin K deficiency, or anticoagulant drugs such as warfarin. Factor X deficiency has also been reported in association with a variety of medical conditions. The human gene encoding factor X is primarily expressed in the liver and is located on the long arm of chromosome 13, just downstream from the gene for factor VII.[4, 5] It is composed of 8 exons and contains 22 kilobases of DNA.[6] The gene encodes a signal region, a propeptide region, a glutamic acid domain, an "aromatic stack" region, 2 regions homologous to epidermal growth factor, and a catalytic domain.[7] The enzyme gamma-glutamyl carboxylase, in the presence of vitamin K, converts the glutamic acid residues to gamma-carboxyglutamic acid residues. These gamma-carboxyglutamic acid residues are necessary for the binding of prothrombin to phospholipids on platelet membranes. For excellent patient education resources, see eMedicineHealth's patient education article Blood in the Urine.

Pathophysiology
In the blood coagulation cascade, factor X is cleaved to form factor Xa, an active serine protease. As the first step in the common pathway to thrombus formation, factor X can be activated by products of both the intrinsic and extrinsic clotting cascades. Activation by the extrinsic pathway occurs via the complex of tissue factor and factor VIIa. Activation by the intrinsic pathway occurs via the interaction of factor IXa and factor VIIIa. Both pathways of activation require the

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Factor X

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presence of calcium ions and a phospholipid surface. Once formed, factor Xa is then responsible for the conversion of prothrombin to its active form, thrombin, which is responsible for activating fibrinogen and allowing clot formation. It also functions in a positive feedback loop by activating factor V, factor VII, and factor VIII. Factor Xa can suppress the coagulation cascade by inactivating both factor VIII and tissue factor. Factor Xa is ultimately inactivated by forming a complex with antithrombin, which then undergoes hepatic clearance. Factor X deficiency may arise because of reduced synthesis of the protein, which is known as type I deficiency state, or because of production of a dysfunctional molecule, which is known as type II deficiency state. Authorities believe that a complete absence of factor X is incompatible with life. Studies of knockout mice have revealed a lethal phenotype, with death occurring in utero or within a few days of birth.[8] Most often, missense mutations are the cause of congenital factor X deficiency.[9, 10] Several specific mutations have been reported.[9] Relatively recently identified mutations include Gly366Ser, Arg347His, Phe31Ser, Gly133Arg, Val196Met, Gly204Arg, Glu51Lys, and Cys364Arg.[11, 12, 13, 14, 15, 16, 17] The Gla-domain of factor X, a 39 residue peptide that is part of its light chain, may have mutations; at least 15 cases of factor X deficiency have been documented to be mutated in this area.[18] In a Japanese patient with factor X deficiency, molecular analysis revealed a homozygous glutamine-to-glycine mutation at residue 32, which normally undergoes gamma-carboxylation within the gamma-carboxyglutamic acidrich domain.[19] A factor Xdeficient woman from France was identified as homozygous for a mutation in exon VIII, resulting in the substitution of serine 334 by proline.[20] This mutation is probably responsible for altering the orientation of the cleavage site of factor X, preventing activation of the molecule. Other reported consequences of this mutation include interference with protein folding, disruption of disulfide bonds, and inhibition of factor binding sites. Acquired factor X deficiency has several possible etiologies. Because factor X is synthesized in the liver, severe hepatic disease can have a dramatic impact on protein levels. Vitamin K deficiency can also result in decreased factor X levels. Vitamin K, which is produced by enteric flora, can be affected by intestinal malabsorption, bile duct obstruction, or antibiotic administration. Vitamin K deficiency can be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. Vitamin K deficiency can also be observed in neonates. In general, liver disease and insufficient vitamin K levels produce deficiencies of several clotting factors. Factor X deficiency has been reported in association with a number of other medical conditions. Factor X deficiency occurs in an estimated 8% of patients with amyloidosis.[7, 21, 22] Factor X binds to deposited amyloid fibrils and has a shortened half-life in the plasma.[23, 24] . Factor X deficiency has also been reported in association with myeloma, presumably because of binding of the protein to circulating light chains.[25] Decreases in factor X levels have been noted in association with Mycoplasma pneumoniae infection,[26] lupus anticoagulant,[27] sodium valproate administration,[28] upper respiratory tract infection,[29] and leprosy.[30] Other reports link the development of acquired factor X deficiency in children with severe burns[31] and topical thrombin administration.[32] Acquired factor X deficiency has also been reported in association with leukemia and other neoplastic processes.[33, 34]

Epidemiology
Frequency
United States The US prevalence of factor X deficiency presumably mirrors international rates. International Congenital factor X deficiency is among the most rare factor disorders, affecting an estimated 1 individual per 500,000-1,000,000 population worldwide.[35] Only 50 cases of congenital factor X deficiency have been documented worldwide.

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Mortality/Morbidity
Congenital factor X deficiency is a lifelong bleeding disorder. Death can occur owing to massive hemorrhage resulting from trauma. Hemorrhage can also occur as a result of surgery if proper precautions are not taken. Cases of both fatal and nonfatal perinatal and infant intracranial hemorrhages have been reported.[36, 37, 38] Disabling hemarthroses can also occur.

Race
Factor X deficiency has no known racial or ethnic predilection.

Sex
Males and females are equally affected in cases of factor X deficiency.

Age
Patients with congenital factor X deficiency can present at any age. Generally, patients with more severe cases present during infancy. Acquired forms may affect persons of any age group.

Contributor Information and Disclosures

Author Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi Disclosure: Nothing to disclose. Coauthor(s) Christopher J Steen, MD Dermatologist, Private Practice Christopher J Steen, MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi Disclosure: Nothing to disclose. Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi Disclosure: Nothing to disclose. Specialty Editor Board Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment

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Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences Disclosure: Nothing to disclose.

References
1. Telfer TP, Denson KW, Wright DR. A new coagulation defect. Br J Haematol . Jul 1956;2(3):308-16. [Medline]. 2. Hougie C, Barrow EM, Graham JB. Stuart clotting defect. I. Segregation of an hereditary hemorrhagic state from the heterogeneous group heretofore called stable factor (SPCA, proconvertin, factor VII) deficiency. J Clin Invest. Mar 1957;36(3):485-96. [Medline]. [Full Text]. 3. Uprichard J, Perry DJ. Factor X deficiency. Blood Rev . Jun 2002;16(2):97-110. [Medline]. 4. Pfeiffer RA, Ott R, Gilgenkrantz S, Alexandre P. Deficiency of coagulation factors VII and X associated with deletion of a chromosome 13 (q34). Evidence from two cases with 46,XY,t(13;Y)(q11;q34). Hum Genet. 1982;62(4):358-60. [Medline]. 5. Pfeiffer RA, Ott R, Taben KD. Clotting factors VII and X as useful markers of terminal deletion of chromosome 13. Hum Genet. 1985;69(2):192. [Medline]. 6. Ott R, Pfeiffer RA. Evidence that activities of coagulation factors VII and X are linked to chromosome 13 (q34). Hum Hered. 1984;34(2):123-6. [Medline]. 7. Furie B, Furie BC. The molecular basis of blood coagulation. Cell . May 20 1988;53(4):505-18. [Medline]. 8. Dewerchin M, Liang Z, Moons L, et al. Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost. Feb 2000;83(2):185-90. [Medline]. 9. Peyvandi F, Menegatti M, Santagostino E, et al. Gene mutations and three-dimensional structural analysis in 13 families with severe factor X deficiency. Br J Haematol . Jun 2002;117(3):685-92. [Medline]. 10. Morishita E, Yamaguchi K, Asakura H, et al. One missense mutation in the factor X gene causing factor X deficiency--factor X Kanazawa. Int J Hematol . Apr 2001;73(3):390-2. [Medline]. 11. Isshiki I, Favier R, Moriki T, et al. Genetic analysis of hereditary factor X deficiency in a French patient of Sri

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Lankan ancestry: in vitro expression study identified Gly366Ser substitution as the molecular basis of the dysfunctional factor X. Blood Coagul Fibrinolysis . Jan 2005;16(1):9-16. [Medline]. 12. Wang WB, Fu QH, Zhou RF, et al. Molecular characterization of two novel mutations causing factor X deficiency in a Chinese pedigree. Haemophilia. Jan 2005;11(1):31-7. [Medline]. 13. Jayandharan G, Viswabandya A, Baidya S, et al. Six novel mutations including triple heterozygosity for Phe31Ser, 514delT and 516T-->G factor X gene mutations are responsible for congenital factor X deficiency in patients of Nepali and Indian origin. J Thromb Haemost. Jul 2005;3(7):1482-7. [Medline]. [Full Text]. 14. Shinohara K, Adachi M, Matsui K, et al. A case of factor X (FX) deficiency due to novel mutation V196M, FX Hofu. Int J Hematol . Apr 2008;87(3):256-9. [Medline]. 15. Bereczky Z, Bardos H, Komaromi I, et al. Factor X Debrecen: Gly204Arg mutation in factor X causes the synthesis of a non-secretable protein and severe factor X deficiency. Haematologica. Feb 2008;93(2):299-302. [Medline]. [Full Text]. 16. Al-Hilali A, Wulff K, Abdel-Razeq H, et al. Analysis of the novel factor X gene mutation Glu51Lys in two families with factor X-Riyadh anomaly. Thromb Haemost. Apr 2007;97(4):542-5. [Medline]. 17. Todd T, Perry DJ, Hayman E, et al. Severe factor X deficiency due to a homozygous mutation (Cys364Arg) that disrupts a disulphide bond in the catalytic domain. Haemophilia. Nov 2006;12(6):621-4. [Medline]. 18. Girolami A, Allemand E, Scandellari R, Lombardi AM, Girolami B. The clinical and laboratory significance of cases of congenital FX deficiency due to defects in the Gla-domain. Hematology . Jun 2009;14(3):177-81. [Medline]. 19. Zama T, Murata M, Watanabe R, et al. A family with hereditary factor X deficiency with a point mutation Gla32 to Gln in the Gla domain (factor X Tokyo). Br J Haematol . Sep 1999;106(3):809-11. [Medline]. 20. Bezeaud A, Miyata T, Helley D, et al. Functional consequences of the Ser334-->Pro mutation in a human factor X variant (factor X Marseille). Eur J Biochem . Nov 15 1995;234(1):140-7. [Medline]. [Full Text]. 21. Choufani EB, Sanchorawala V, Ernst T, et al. Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy. Blood. Mar 15 2001;97(6):1885-7. [Medline]. [Full Text]. 22. Manikkan AT. Factor X deficiency: An uncommon presentation of AL amyloidosis. Ups J Med Sci . Jun 1 2012;[Medline]. 23. Furie B, Voo L, McAdam KP, Furie BC. Mechanism of factor X deficiency in systemic amyloidosis. N Engl J Med. Apr 2 1981;304(14):827-30. [Medline]. 24. Perez Martinez J, Llamas F, Lopez Montes A, et al. [Primary amyloidosis associated to severe factor X deficiency] [Spanish]. Nefrologia. 2004;24(5):493-8. [Medline]. 25. Schwarzinger I, Stain-Kos M, Bettelheim P, et al. Recurrent, isolated factor X deficiency in myeloma: repeated normalization of factor X levels after cytostatic chemotherapy followed by late treatment failure associated with the development of systemic amyloidosis. Thromb Haemost. Dec 7 1992;68(6):648-51. [Medline]. 26. Peuscher FW, van Aken WG, van Mourik JA, et al. Acquired, transient factor X (Stuart factor) deficiency in patient with mycoplasma pneumonial infection. Scand J Haematol . Oct 1979;23(4):257-64. [Medline]. 27. Ashrani AA, Aysola A, Al-Khatib H, Nichols WL, Key NS. Lupus anticoagulant associated with transient severe factor X deficiency: a report of two patients presenting with major bleeding complications. Br J Haematol . May 2003;121(4):639-42. [Medline]. 28. Gallais V, Bredoux H, le Roux G, Laroche L. Acquired and transient factor X deficiency associated with sodium valproate treatment. Eur J Haematol . Oct 1996;57(4):330. [Medline]. 29. Mulhare PE, Tracy PB, Golden EA, Branda RF, Bovill EG. A case of acquired factor X deficiency with in vivo and in vitro evidence of inhibitor activity directed against factor X. Am J Clin Pathol . Aug 1991;96(2):196-200. [Medline]. 30. Ness PM, Hymas PG, Gesme D, Perkins HA. An unusual factor-X inhibitor in leprosy. Am J Hematol .

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Factor X

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1980;8(4):397-402. [Medline]. 31. Matsunaga AT, Shafer FE. An acquired inhibitor to factor X in a pediatric patient with extensive burns. J Pediatr Hematol Oncol . May 1996;18(2):223-6. [Medline]. 32. Israels SJ, Leaker MT. Acquired inhibitors to factors V and X after exposure to topical thrombin: interference with monitoring of low molecular weight heparin and warfarin. J Pediatr. Sep 1997;131(3):480-3. [Medline]. 33. Nora RE, Bell WR, Noe DA, Sholar PW. Novel factor X deficiency. Normal partial thromboplastin time and associated spindle cell thymoma. Am J Med. Jul 1985;79(1):122-6. [Medline]. 34. Caimi MT, Redaelli R, Cattaneo D, et al. Acquired selective factor X deficiency in acute nonlymphocytic leukemia. Am J Hematol . Jan 1991;36(1):65-6. [Medline]. 35. Peyvandi F, Mannucci PM. Rare coagulation disorders. Thromb Haemost. Oct 1999;82(4):1207-14. [Medline]. 36. Citak A, Ucsel R, Karabocuoglu M, Unuvar A, Uzel N. A rare cause of intracranial hemorrhage: factor X deficiency. Pediatr Emerg Care. Oct 2001;17(5):349-50. [Medline]. 37. Young TM, Chitnavis BP, Swallow EB, Arya R, Vadher BD. Intracerebral haemorrhage in an adult due to transient factor X deficiency. J R Soc Med. Jul 2003;96(7):355-6. [Medline]. [Full Text]. 38. Herrmann FH, Navarette M, Salazar-Sanchez L, et al. Homozygous Factor X gene mutations Gly380Arg and Tyr163delAT are associated with perinatal intracranial hemorrhage. J Pediatr. Jan 2005;146(1):128-30. [Medline]. 39. Singh V, Kakkar T, Digra SK, Kakkar M. Factor X Deficiency: A Rare Cause of Puberty Menorrhagia. Indian J Pediatr. Jun 14 2012;[Medline]. 40. Senturk S, Guzel E, Bayrak AH, Bukte Y, Guzel A. Factor X deficiency presenting with bilateral chronic subdural hematoma. Pediatr Neurosurg. 2010;46(1):54-7. [Medline]. 41. Greipp PR, Kyle RA, Bowie EJ. Factor X deficiency in primary amyloidosis: resolution after splenectomy. N Engl J Med. Nov 8 1979;301(19):1050-1. [Medline]. 42. Rosenstein ED, Itzkowitz SH, Penziner AS, Cohen JI, Mornaghi RA. Resolution of factor X deficiency in primary amyloidosis following splenectomy. Arch Intern Med. Mar 1983;143(3):597-9. [Medline]. 43. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. Feb 18 2011;62:41-57. [Medline]. 44. McMahon C, Smith J, Goonan C, Byrne M, Smith OP. The role of primary prophylactic factor replacement therapy in children with severe factor X deficiency. Br J Haematol . Dec 2002;119(3):789-91. [Medline]. Medscape Reference 2011 WebMD, LLC

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