Coagulation factor V (Factor V), also less commonly known asproaccelerin orlabile factor, is aprotein involved incoagulation, encoded, in humans, byF5gene.[5] In contrast to most other coagulation factors, it is not enzymatically active but functions as acofactor.[5] Factor V deficiency leads to predisposition forhemorrhage, while some mutations (most notablyfactor V Leiden) predispose forthrombosis.
Thegene for factor V is located on thefirst chromosome (1q24). It is genomically related to the family ofmulticopper oxidases, and is homologous tocoagulation factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.
Factor V protein consists of six domains: A1-A2-B-A3-C1-C2.
The A domains arehomologous to the A domains of the copper-binding proteinceruloplasmin, and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma.[6]
The C domains belong to thephospholipid-bindingdiscoidin domain family (unrelated toC2 domain), and the C2 domain mediates membrane binding. The B domainC-terminus acts as acofactor for theanticoagulantprotein C activation byprotein S.[7][8]
Activation of factor V to factor Va is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor Va.[7]
Factor V is produced bymegakaryocytes, which produce platelets and platelet-derived factor V, and hepatocytes, which produce plasma-derived factor V.[9] The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.[10]
Factor V is able to bind to activatedplatelets and is activated bythrombin. 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 bycalcium. The thereby activated factor V (now called FVa) is a cofactor of theprothrombinase complex: The activatedfactor X (FXa) enzyme requires calcium and activated factor V (FVa) to convert prothrombin tothrombin on the cell surface membrane.
Factor Va is degraded byactivated protein C, one of the principal physiological inhibitors of coagulation. In the presence ofthrombomodulin, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and action of protein C are important determinants in thenegative feedback loop through which thrombin limits its own activation.
Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form ofhemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in anautosomal recessive fashion.
There exists a bleeding tendency associated with the genetic up‐regulation of FV‐short, a minor splicing isoform of FV. This abnormal bleeding tendency occurs in east Texas bleeding disorder, Amsterdam bleeding disorder, and a third and more extreme example described in 2021 by Karen L. Zimowskiet al.[11]
Othermutations of factor V are associated withvenous thrombosis. They are the most common hereditary causes forthrombophilia (a tendency to formblood clots). The most common one of these,factor V Leiden, is due to the replacement of anarginine residue withglutamine 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.
Until the discovery of factor V, coagulation was regarded as a product of four factors:calcium (IV) and thrombokinase (III) together acting onprothrombin (II) to producefibrinogen (I); this model had been outlined byPaul Morawitz in 1905.[12]
The suggestion that an additional factor might exist was made byPaul Owren [no] (1905–1990), aNorwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered fromnosebleeds andmenorrhagia (excessive menstrual blood loss) for most her life, and was found to have a prolongedprothrombin time, suggesting eithervitamin K deficiency orchronic 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 theSecond 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 inThe Lancet in 1947.[12][13]
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.[12]
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.[12]
The complete amino acid sequence of the protein was published in 1987.[14] In 1994factor V Leiden, resistant to inactivation byprotein C, was described; this abnormality is the most common genetic cause forthrombosis.[15]
Factor V has been shown tointeract withProtein S.[16][17]
