Home » Posts tagged 'Factor X Deficiency Overview'
Tag Archives: Factor X Deficiency Overview
Factor X Deficiency
Clotting factor X, or Stuart-Prower factor, is a vitamin K–dependent 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.
Inherited factor X deficiency is autosomal recessive, with heterozygotes most often remaining asymptomatic or having only a mild bleeding tendency.  Homozygous individuals may experience hemorrhagic symptoms, including easy bruising, hematuria, soft-tissue hemorrhages, hemarthroses, recurrent epistaxis, and menorrhagia.  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 (eg, systemic light-chain amyloidosis,  atypical chronic lymphoid leukemia  ).
Treatment of factor X deficiency is individualized, but restoring circulating factor X levels to 10-40% of normal is usually adequate. Additionally, in patients with acquired factor X deficiency, treatment of the underlying cause may resolve the disorder. Treatment options include factor X concentrate, fresh frozen plasma, and prothrombin complex concentrates (PCCs). Vitamin K is ineffective in hereditary factor X deficiency but may be useful in certain acquired cases. (See Treatment and Medication.)
In the 1950s, two independent groups first identified factor X deficiency. Telfer and colleagues reported a bleeding tendency in a 22-year-old woman named Prower in 1956  ; Hougie and colleagues described abnormal coagulation profiles in a 36-year-old man named Stuart in 1957.  Experiments demonstrated that mixing plasma or serum from Stuart and Prower did not mutually correct the abnormality, thus showing that the two lacked an identical factor. Based on these common clotting test results, the factor was designated Stuart-Prower factor. This factor became known as factor X.
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. [7, 8] It is composed of 8 exons and contains 22 kilobases of DNA.  The gene encodes the following  :
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.
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 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.  Most often, missense mutations are the cause of congenital factor X deficiency. [12, 13]
Several specific mutations have been reported.  Relatively recently identified mutations include Gly366Ser, Arg347His, Phe31Ser, Gly133Arg, Val196Met, Gly204Arg, Glu51Lys, and Cys364Arg. [14, 15, 16, 17, 18, 19, 20] Mutations in the Gla-domain of factor X, a 39 residue peptide that is part of its light chain, have been documented in at least 15 cases of factor X deficiency. 
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 acid–rich domain.  A factor X–deficient woman from France was identified as homozygous for a mutation in exon VIII, resulting in the substitution of serine 334 by proline.  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.
Factor X has a natural variant carrying the Asp-185 deletion. Paradoxically, this variant may be associated with only mild bleeding despite a severe factor X deficiency. 
Acquired factor X deficiency has a variety of 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. In general, liver disease and insufficient vitamin K levels produce deficiencies of several clotting factors, not just factor X.
Vitamin K is produced by enteric flora, and vitamin K levels can be reduced by intestinal malabsorption, bile duct obstruction, or antibiotic administration. Vitamin K deficiency can also be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. Vitamin K deficiency can also be observed in neonates.
Acquired 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, including immunoglobulin light chain (AL) amyloidosis. [10, 25, 26, 27] Factor X binds to deposited amyloid fibrils and has a shortened half-life in the plasma. [28, 29]
Factor X deficiency has also been reported in association with myeloma, presumably because of binding of the protein to circulating light chains.  Acquired factor X deficiency has also been reported in association with leukemia and other neoplastic processes. [31, 32]
Decreases in factor X levels have also been noted in association with the following:
Mycoplasma pneumoniae infection 
Lupus anticoagulant 
Sodium valproate administration 
Upper respiratory tract infection 
Severe burns in a child 
Topical thrombin administration 
Congenital factor X deficiency is among the most rare factor disorders, affecting an estimated one individual per 500,000-1,000,000 population worldwide.  The prevalence of factor X deficiency in the United States presumably mirrors international rates.
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. [41, 42, 43] Disabling hemarthroses can also occur.
Factor X deficiency has no known racial or ethnic predilection. Males and females are equally affected.
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.
Girolami A, Cosi E, Santarossa C, Ferrari S, Girolami B, Lombardi AM. Prevalence of bleeding manifestations in 128 heterozygotes for Factor X deficiency, mainly for FX Friuli, matched vs 128 unaffected family members, during a long sequential observation period (23.5 years). Eur J Haematol. 2016 Apr 28. [Medline].
Uprichard J, Perry DJ. Factor X deficiency. Blood Rev. 2002 Jun. 16(2):97-110. [Medline].
Mahmood S, Blundell J, Drebes A, Hawkins PN, Wechalekar AD. Utility of factor X concentrate for the treatment of acquired factor X deficiency in systemic light-chain amyloidosis. Blood. 2014 May 1. 123 (18):2899-900. [Medline]. [Full Text].
Kulkarni R, James AH, Norton M, Shapiro A. Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in women and girls with hereditary factor X deficiency. J Thromb Haemost. 2018 Feb 20. [Medline].
Telfer TP, Denson KW, Wright DR. A new coagulation defect. Br J Haematol. 1956 Jul. 2(3):308-16. [Medline].
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. 1957 Mar. 36(3):485-96. [Medline]. [Full Text].
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].
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].
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].
Furie B, Furie BC. The molecular basis of blood coagulation. Cell. 1988 May 20. 53(4):505-18. [Medline].
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. 2000 Feb. 83(2):185-90. [Medline].
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. 2002 Jun. 117(3):685-92. [Medline].
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. 2001 Apr. 73(3):390-2. [Medline].
Isshiki I, Favier R, Moriki T, et al. Genetic analysis of hereditary factor X deficiency in a French patient of Sri Lankan ancestry: in vitro expression study identified Gly366Ser substitution as the molecular basis of the dysfunctional factor X. Blood Coagul Fibrinolysis. 2005 Jan. 16(1):9-16. [Medline].
Wang WB, Fu QH, Zhou RF, et al. Molecular characterization of two novel mutations causing factor X deficiency in a Chinese pedigree. Haemophilia. 2005 Jan. 11(1):31-7. [Medline].
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. 2005 Jul. 3(7):1482-7. [Medline]. [Full Text].
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. 2008 Apr. 87(3):256-9. [Medline].
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. 2008 Feb. 93(2):299-302. [Medline]. [Full Text].
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. 2007 Apr. 97(4):542-5. [Medline].
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. 2006 Nov. 12(6):621-4. [Medline].
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. 2009 Jun. 14(3):177-81. [Medline].
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. 1999 Sep. 106(3):809-11. [Medline].
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. 1995 Nov 15. 234(1):140-7. [Medline]. [Full Text].
Lu Q, Yang L, Manithody C, Wang X, Rezaie AR. Molecular basis of the clotting defect in a bleeding patient missing the Asp-185 codon in the factor X gene. Thromb Res. 2014 Aug 20. [Medline].
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. 2001 Mar 15. 97(6):1885-7. [Medline]. [Full Text].
Manikkan AT. Factor X deficiency: An uncommon presentation of AL amyloidosis. Ups J Med Sci. 2012 Jun 1. [Medline].
Furuhata M, Doki N, Hishima T, Okamoto T, Koyama T, Kaito S, et al. Acquired factor X deficiency associated with atypical AL-amyloidosis. Intern Med. 2014. 53(16):1841-5. [Medline].
Furie B, Voo L, McAdam KP, Furie BC. Mechanism of factor X deficiency in systemic amyloidosis. N Engl J Med. 1981 Apr 2. 304(14):827-30. [Medline].
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].
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. 1992 Dec 7. 68(6):648-51. [Medline].
Nora RE, Bell WR, Noe DA, Sholar PW. Novel factor X deficiency. Normal partial thromboplastin time and associated spindle cell thymoma. Am J Med. 1985 Jul. 79(1):122-6. [Medline].
Caimi MT, Redaelli R, Cattaneo D, et al. Acquired selective factor X deficiency in acute nonlymphocytic leukemia. Am J Hematol. 1991 Jan. 36(1):65-6. [Medline].
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. 1979 Oct. 23(4):257-64. [Medline].
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. 2003 May. 121(4):639-42. [Medline].
Gallais V, Bredoux H, le Roux G, Laroche L. Acquired and transient factor X deficiency associated with sodium valproate treatment. Eur J Haematol. 1996 Oct. 57(4):330. [Medline].
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. 1991 Aug. 96(2):196-200. [Medline].
Ness PM, Hymas PG, Gesme D, Perkins HA. An unusual factor-X inhibitor in leprosy. Am J Hematol. 1980. 8(4):397-402. [Medline].
Matsunaga AT, Shafer FE. An acquired inhibitor to factor X in a pediatric patient with extensive burns. J Pediatr Hematol Oncol. 1996 May. 18(2):223-6. [Medline].
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. 1997 Sep. 131(3):480-3. [Medline].
Girolami A, Cosi E, Santarossa C, Ferrari S, Girolami B, Lombardi AM. Prevalence of bleeding manifestations in 128 heterozygotes for Factor X deficiency, mainly for FX Friuli, matched versus 128 unaffected family members, during a long sequential observation period (23.5 years). Eur J Haematol. 2016 Dec. 97 (6):547-553. [Medline].
Citak A, Ucsel R, Karabocuoglu M, Unuvar A, Uzel N. A rare cause of intracranial hemorrhage: factor X deficiency. Pediatr Emerg Care. 2001 Oct. 17(5):349-50. [Medline].
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. 2005 Jan. 146(1):128-30. [Medline].
Singh V, Kakkar T, Digra SK, Kakkar M. Factor X Deficiency: A Rare Cause of Puberty Menorrhagia. Indian J Pediatr. 2012 Jun 14. [Medline].
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].
Coagadex (coagulation factor X [human]) [package insert]. Durham, NC: Bio Products Laboratory USA, Inc. October, 2015. Available at [Full Text].
Escobar MA, Auerswald G, Austin S, Huang JN, Norton M, Millar CM. Experience of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency undergoing surgery. Haemophilia. 2016 May 24. [Medline].
Litvak A, Kumar A, Wong RJ, Smith L, Hassou H, Soff G. Successful perioperative use of prothrombin complex concentrate in the treatment of acquired factor X deficiency in the setting of systemic light-chain (AL) amyloidosis. Am J Hematol. 2014 Jul 24. [Medline].
Greipp PR, Kyle RA, Bowie EJ. Factor X deficiency in primary amyloidosis: resolution after splenectomy. N Engl J Med. 1979 Nov 8. 301(19):1050-1. [Medline].
Rosenstein ED, Itzkowitz SH, Penziner AS, Cohen JI, Mornaghi RA. Resolution of factor X deficiency in primary amyloidosis following splenectomy. Arch Intern Med. 1983 Mar. 143(3):597-9. [Medline].
Coucke L, Trenson S, Deeren D, Van Haute I, Devreese K. Life-threatening bleeding tendency provoked by an acquired isolated factor X deficiency associated with respiratory infection. Ann Hematol. 2013 Oct. 92(10):1437-8. [Medline].
Orgul G, Aktoz F, Beksac MS. Impact of Rare Bleeding Disorders during Pregnancy on Maternal and Fetal Outcomes: Review of 29 Pregnancies at a Single Center. Rev Bras Ginecol Obstet. 2017 Jan. 39 (1):4-8. [Medline].
Boudin L, Patient M, Roméo E, Bladé JS, Gisserot O, de Jauréguiberry JP. [Acquired, non-amyloid related factor X deficiency: A first case associated with atypical chronic lymphocytic leukemia and literature review]. Rev Med Interne. 2017 Jan 19. [Medline].
Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration
Disclosure: Nothing to disclose.
Christopher J Steen, MD Dermatologist, Private Practice
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
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: Received salary from Medscape for employment. for: Medscape.
Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MBBCh, FRCPC, DTM&H 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, Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.
Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center
Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians
Disclosure: Nothing to disclose.
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
Disclosure: Nothing to disclose.
Factor X Deficiency
Research & References of Factor X Deficiency|A&C Accounting And Tax Services