Excerpt from Factor X

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Background

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.

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; 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. 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 (Uprichard, 2002). 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 (Pfeiffer, 1982; Pfeiffer, 1985). It is composed of 8 exons and contains 22 kilobases of DNA (Ott, 1984). 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 (Furie, 1988). 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.

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 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 reveal a lethal phenotype, with death occurring in utero or within a few days of birth (Dewerchin, 2000). Most often, missense mutations are the cause of congenital factor X deficiency.

Several specific mutations have been reported (Peyvandi, 2002). Recently identified mutations include Gly366Ser, Arg347His, Phe31Ser, and Gly133Arg (Isshiki, 2005; Wang, 2005; Jayandharan, 2005). 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 (Zama, 1999). 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 (Bezeaud, 1995). 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 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 (Furie, 1981; Choufani, 2001; Perez, 2004). Factor X binds to deposited amyloid fibrils and has a shortened half-life in the plasma. Factor X deficiency has also been reported in association with myeloma, presumably because of binding of the protein to circulating light chains (Schwarzinger, 1992). Decreases in factor X levels have been noted in association with Mycoplasma pneumoniae infection (Peuscher, 1979), lupus anticoagulant (Ashrani, 2003), sodium valproate administration (Gallais, 1996), upper respiratory tract infection (Mulhare, 1991), and leprosy (Ness, 1980).

Other reports link the development of acquired factor X deficiency in children with severe burns (Matsunaga, 1996) and topical thrombin administration (Israels, 1997). Acquired deficiency has also been reported in association with leukemia and other neoplastic processes (Nora, 1985; Caimi, 1991).

Frequency

United States

US prevalence 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 (Peyvandi, 1999). Only 50 cases of congenital factor X deficiency have been documented worldwide.

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 (Citak, 2001; Young, 2003; Herrmann, 2005). Disabling hemarthroses can also occur.

Race

This disorder has no known racial or ethnic predilection.

Sex

Males and females are equally affected.

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.

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