Factor V ProteinEditFactor V (FV) is a single-chain polypeptide involved in blood coagulation. It is synthesized (mostly) in the liver and circulates through the bloodstream in an inactive form. FV is activated to FVa by thrombin, which cleaves the protein into two chains which non-covalently interact via a calcium ion. It has no enzymativ activity, but acts as a cofactor of the prothrombinase complex. FVa has three arginine residues which act as cleavage sites for activated protein C (APC, a serine protease). Sequential cleavage at these sites inactivates FVa. (Wikipedia, Wintrobe Clinical Hematology, 12th Edition)
Blood CoagulationEditThe process of haemostasis is crucial to stemming blood loss following vascular injury. It involves a complex balance of pro- and anti-coagulant activiites by a multitude of enzymes and cofactors that ultimately lead to a fibrin clot followed by attenuation of the coagulation response to restore normal blood flow. In short, the serine protease thrombin can be thought of as the star player: thrombin cleaves fibrinogen to fibrin (forming the clot) and also activates a trans-glutaminase (Factor XIII) which will create cross-links in the clot to enhance it's tensile strength. Furthermore, upon the formation of the clot thrombin also activates protein C as part of a negative feedback loop, which in turn degrades various cofactors (including FVa) and ultimately shuts down the coagulation response. (PMID: 16500122)
One of the key cofactors involved in this process is activated Factor V (FVa), which binds with activated Factor X (FXa) on a phospholipid membrane (usually a platelet, but also endothelial cells and monocytes) to form the prothrombinase complex. The prothrombinase complex is responsible for generating the vast majority of active thrombin during coagulation. The enzymatic FXa is capable of activating prothrombin to thrombin on its own, but when bound by FVa a rate enhancement of 3x10^5-fold is observed.(PMID 500617) This rate enhancement is critical for a balanced coagulation response.
The Factor V GeneEdit
The gene encoding FV is located on chromosome 1. It spans approximately 80 thousand bases and consists of 24 introns and 25 exons. The pattern of intron-exon within the gene is very similar to that of another coagulation factor, factor VIII (found on the X chromosome), and it is believed that they evolved from a common ancestor. (Wintrobe Clinical Hematology, 12th Edition) It is also believed that all jawed vertebrates share this common blood coagulation cascade, including FV. (PMID:12624623) The FV gene has 53 homologs and 4 notable paralogs. It also contains over 1600 SNPs. (EMBL-EBI)
Click here for a link to map the chromosome on which the F5 gene is located, along with more detail on the specific region as well as the gene itself. (Link doesn't load the sequence; click link next to "Location" on top left of page)
Click here to view a CLUSTAL alignment of the F5 gene with that of F8, or factor VIII. These genes share approximately 26% identity. (Link doesn't load the sequence; click "Alignment cDNA" under the first paralogue listed)
Factor V LeidenEdit
Factor V Leiden is a variant of FV caused by a missense mutation of G --> A at nucleotide position 1691, which resides in exon 10 of the gene. This mutation causes an amino acid switch in the final protein from arginine to glutamine at position 605. This location is involved in the regulation of FVa, as it is a cleavage site for APC. APC has greatly reduced activity for cleaving the FVa-Leiden, which allows FVa to retain it's ability to act as a cofactor in the prothrombinase complex and continue producing more thrombin. This results in a phenotype with an increased risk of thrombosis (estimated to be a 7-fold increase in heterozygotes, 80-fold for homozygotes) due to sustained thrombin generation far past the physiological norm. FV-leiden is of great interest in clinical research, as it represents the most common pro-thrombotic risk factor. (Wintrobe Clinical Hematology, 12th Edition)
Interestingly, due to it's high prevalence in the human population (estimated at up to 15%), it has been suggested that the FV Leiden mutation may confer an evolutionary advantage to afflicted individuals. Some possible methods discussed are an increased survivability during sepsis, and improved hemoglobin status in women. (PMID: 18537629)
Diagnosis of FV Leiden is not performed regularly unless an individual has had several thrombotic episodes in their past. Should these events occur, doctors will administer what is called an APC resistance assay, which essentially measures the ability of clotting blood to resist inactivation via the APC pathway. Should results indicate that an individual is indeed resistant, genetic testing is done to identify if the mutation within the FV gene has occured.
Children and teens are not regularly tested, as clotting events in younger populations are very rare and highly unusual. The exception to this is if a family has a history of clotting disorders including FV Leiden. Mayo Foundation for Medical Education and Research (MFMER).
The symptoms of FV Leiden are treated by various blood-thinners such as warfarin (Coumadin) and/or heparin. Due to the bleeding risks caused by these medications however, they are usually only administered if an individual is determined to be high risk. A high-risk person would be someone who has had at least one thrombotic event, or is being hospitalized due to injury.
Many lifestyle changes are reccommended to patients with FV Leiden to reduce their risk of a blood clot. These can be everything from avoiding contact sports and dangerous work environments to using a softer toothbrush and quitting smoking.
Pregnant women with FV Leiden are at an inreased risk for developing a blood clot. This poses a challenge for clinicians, as the risks involved with blood thinning therapies greatly outweighs the potential benefits for pregnant women. Mayo Foundation for Medical Education and Research (MFMER).
"Coagulation Factor V (proaccelerin, Labile Factor)." Gene & Protein Summary. EMBL-EBI, July 2012. Web. <http://www.ebi.ac.uk/s4/summary/molecular?ter m=HUMAN+f5 &clas sification=9606& tid=nameOrgENSG00000198734>.Edit
Davidson CJ, Hirt RP, Lal K, Snell P, Elgar G, Tuddenham EG, et al. Molecular evolution of the vertebrate blood coagulation network. Thromb Haemost. 2003;89(3):420-8.Edit
"Factor V." Wikipedia. Wikimedia Foundation, 25 July 2012. Web. <http://en.wikipedia.org/wiki/Factor_V>. Edit
"Factor V Leiden." Mayo Clinic. Mayo Foundation for Medical Education and Research, 06 Sept. 2012. Web. <http://www.mayoclinic.com/health/factor-v-leiden/DS0 1083/DSE CTION =tests-and-diagnosis>.Edit
Lindqvist PG, Dahlback B. Carriership of Factor V Leiden and evolutionary selection advantage. Curr Med Chem. 2008;15(15):1541-4.Edit
Mann KG, Brummel-Ziedins K, Orfeo T, Butenas S. Models of blood coagulation. Blood Cells Mol Dis. 2006;36(2):108-17.Edit
Nesheim ME, Taswell JB, Mann KG. The contribution of bovine Factor V and Factor Va to the activity of prothrombinase. J Biol Chem. 1979;254(21):10952-62.Edit
Wintrobe, Maxwell M., and John P. Greer. Wintrobe's Clinical Hematology. 12th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009. Print. Edit