Factor X

Factor X, also known by the is_associated_with::eponym Stuart–Prower factor or as prothrombinase, thrombokinase or thromboplastin, is an is_associated_with::enzyme of the coagulation cascade. It is a serine endopeptidase (protease group S1, is_associated_with::PA clan).

Physiology
Factor X is synthesized in the is_associated_with::liver and requires is_associated_with::vitamin K for its synthesis.

Factor X is activated into factor Xa by both is_associated_with::factor IX (with its cofactor, is_associated_with::factor VIII in a complex known as intrinsic Xase) and is_associated_with::factor VII with its cofactor, is_associated_with::tissue factor (a complex known as extrinsic Xase). It is therefore the first member of the final common pathway or thrombin pathway.

It acts by cleaving is_associated_with::prothrombin in two places (an arg-thr and then an arg-ile bond), which yields the active is_associated_with::thrombin. This process is optimized when factor Xa is complexed with activated co-factor V in the is_associated_with::prothrombinase complex.

Factor Xa is inactivated by is_associated_with::protein Z-dependent protease inhibitor (ZPI), a is_associated_with::serine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence of is_associated_with::protein Z, while it does not require protein Z for inactivation of is_associated_with::factor 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 of factor Xa
The 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 sub pockets 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 residues Asp189, Ser195, and Tyr228, 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.

Genetics
The human factor X is_associated_with::gene is located on the thirteenth is_associated_with::chromosome (13q34).

Role in disease
Inborn deficiency of factor X is very rare (1:500,000), and may present with is_associated_with::epistaxis (nosebleeds), is_associated_with::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 in is_associated_with::amyloidosis, where factor X is adsorbed to the amyloid fibrils in the vasculature.

Deficiency of vitamin K or antagonism by is_associated_with::warfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to prevent is_associated_with::thrombosis. As of late 2007, four out of five emerging anti-coagulation therapeutics targeted this enzyme.

Inhibiting Factor Xa would offer an alternate method for anticoagulation. is_associated_with::Direct Xa inhibitors are popular anticoagulants.

Therapeutic use
Factor X is part of is_associated_with::fresh frozen plasma and the prothrombinase complex. The only commercially available concentrate is 'Factor X P Behring' manufactured by is_associated_with::CSL Behring. Although Bio Products Laboratory has a high purity Factor X product being evaluated by FDA as of October 2013. See press release http://www.bpl.co.uk/about-bpl/news/q/date/2013/11/04/bpl-announces-strong-progress-on-the-world-s-first-licensed-factor-x-product/

Use in biochemistry
The factor Xa protease can be used in biochemistry to cleave off protein tags that 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
Factor Xa is the activated form of the is_associated_with::coagulation factor is_associated_with::thrombokinase, known eponymously as Stuart-Prower factor. Factor X is an is_associated_with::enzyme, a is_associated_with::serine endopeptidase, which plays a key role at several stages of the is_associated_with::coagulation system. Factor X is synthesized in the is_associated_with::liver. The most commonly used is_associated_with::anticoagulants in clinical practice, is_associated_with::warfarin and the is_associated_with::heparin series of anticoagulants and is_associated_with::fondaparinux, 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 with is_associated_with::calcium and bound on a is_associated_with::phospholipids surface generate thrombin (Factor IIa) from prothrombin (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 the is_associated_with::platelet surface. Factor Xa plays a key role in all three of these stages.

In stage 1, is_associated_with::Factor VII binds to the is_associated_with::transmembrane protein TF 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 and is_associated_with::Factor IX. Factor Xa formed on the surface of the TF-bearing cell interacts with is_associated_with::Factor Va to form the prothrombinase complex which 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 associated cofactors occurs.

In stage 3, thrombin generation, is_associated_with::Factor XIa activates free Factor IX on the surface of activated platelets. The activated Factor IXa with is_associated_with::Factor VIIIa forms 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 of prothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible for is_associated_with::fibrin is_associated_with::polymerization to form a is_associated_with::thrombus.

Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of is_associated_with::coumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (is_associated_with::phenprocoumon and is_associated_with::acenocoumarol) are used. These agents are vitamin K antagonists (VKA). Vitamin K is essential for the hepatic synthesis of Factors II (prothrombin), VII, IX and X.

Heparin (unfractionated heparin) and its derivatives low molecular weight heparin (LMWH) bind to a plasma cofactor, 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 drugs is_associated_with::rivaroxaban, is_associated_with::apixaban, is_associated_with::betrixaban, LY517717, is_associated_with::darexaban (YM150), is_associated_with::edoxaban and 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.

History
American 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).

Interactions
Factor X has been shown to interact with is_associated_with::Tissue factor pathway inhibitor.