Factor V

Factor V (pronounced factor five) is a is_associated_with::protein of the is_associated_with::coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for is_associated_with::hemorrhage, while some mutations (most notably is_associated_with::factor V Leiden) predispose for is_associated_with::thrombosis.

Genetics
The is_associated_with::gene for factor V is located on the is_associated_with::first chromosome (1q23). It is genomically related to the family of is_associated_with::multicopper oxidases, and is homologous to coagulation is_associated_with::factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.

Physiology
Factor V synthesis occurs in the liver, principally. The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.

Factor V is able to bind to activated is_associated_with::platelets and is activated by is_associated_with::thrombin. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium. The thereby activated factor V (now called FVa) is a cofactor of the is_associated_with::prothrombinase complex: The activated is_associated_with::factor X (FXa) enzyme requires calcium and activated factor V to convert prothrombin to is_associated_with::thrombin on the cell surface membrane.

Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation. In the presence of is_associated_with::thrombomodulin, thrombin acts to decrease clotting by activating Protein C; therefore, the concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation.

Role in disease
Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of is_associated_with::hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an is_associated_with::autosomal recessive fashion.

Other is_associated_with::mutations of factor V are associated with is_associated_with::venous thrombosis. They are the most common hereditary causes for is_associated_with::thrombophilia (a tendency to form is_associated_with::blood clots). The most common one of these, is_associated_with::factor V Leiden, is due to the replacement of an is_associated_with::arginine residue with is_associated_with::glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation.

History
Until the discovery of factor V, coagulation was regarded as a product of four factors: is_associated_with::calcium (IV) and thrombokinase (III) together acting on is_associated_with::prothrombin (II) to produce is_associated_with::fibrinogen (I); this model had been outlined by is_associated_with::Paul Morawitz in 1905.

The suggestion that an additional factor might exist was made by Dr Paul Owren (1905–1990), a Norwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from nosebleeds and is_associated_with::menorrhagia (excessive menstrual blood loss) for most her life, and was found to have a prolonged is_associated_with::prothrombin time, suggesting either is_associated_with::vitamin K deficiency or is_associated_with::chronic liver disease leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I-IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during the Second World War, and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in is_associated_with::The Lancet in 1947.

The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later.

Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V.

The complete amino acid sequence of the protein was published in 1987. In 1994 is_associated_with::factor V Leiden, resistant to inactivation by is_associated_with::protein C, was described; this abnormality is the most common genetic cause for is_associated_with::thrombosis.

Interactions
Factor V has been shown to interact with is_associated_with::Protein S.