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.
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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
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Christopher J Steen, MD Dermatologist, Private Practice
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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
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Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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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
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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
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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
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Factor X Deficiency
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