Factor V Leiden

Björn Dahlbäck, Lund University, Malmö, SE 20502 Malmö, Sweden

Published online: March 2011

DOI: 10.1002/9780470015902.a0005537.pub2

Full Article on Wiley Online Library

Factor V (FV) Leiden is the most common genetic risk factor for venous thrombosis in western societies. It is caused by a single point mutation in the coagulation factor V gene (F5), which results in the replacement of arginine at position 506 with a glutamine. Arginine 506 constitutes one of three cleavage sites in FV for the anticoagulant activated protein C (APC) and FV Leiden is resistant to APC cleavage at this site. This causes an imbalance between pro- and anticoagulant forces and as a result a lifelong hypercoagulable state that increases the risk of venous thrombosis. The FV Leiden mutation is the result of a single mutation event that is estimated to have occurred around 25000 years ago in a Caucasian ancestor. The prevalence of the mutation varies between zero and 15% in different ethnic populations.

Key Concepts:

Blood coagulation is controlled by anticoagulant pathways.
Venous thrombosis is a multifactorial disease.
Multiple genetic factors contributes to the risk of venous thrombosis.
Protein C, protein S, TFPI (tissue factor pathway inhibitor) and antithrombin are the main anticoagulant proteins in plasma.
Factor V is an important blood coagulation protein, which after its activation by thrombin functions as cofactor to factor Xa in the activation of prothrombin.
Factor V can be both pro- and anticoagulant.
APC resistance caused by a single factor V gene (f5) mutation is the most common genetic risk factor.
Factor V Leiden is the result of a single mutation event that took place around 20–25000 years ago.
Factor V Leiden is mainly present in Caucasians.
The Factor V Leiden mutation results in the replacement of Arg506 with a Gln.
One of the APC (activated protein C) cleavage sites in FV (at Arg506) is lost because of the Factor Leiden mutation.

Keywords: blood coagulation; trombosis; protein C; APC resistance; factor V

References
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Further Reading
	Bertina RM (2009) The role of procoagulants and anticoagulants in the development of venous thromboembolism. Thrombotic Research 123(suppl. 4): S41–S45.
	Dahlback B (2003) The discovery of activated protein C resistance. Journal of Thrombosis Haemostasis 1(1): 3–9.
	book Dahlbäck B and Stenflo J (2000) "The protein C anticoagulant system". In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM and Varmus H (eds) The Molecular Basis of Blood Diseases, pp. 614–656. WB Saunders: Philadelphia.
	Stenflo J (2006) From gamma-carboxy-glutamate to protein C. Journal of Thrombosis Haemostasis 4(12): 2521–2526.
Web Links
	ePath Coagulation factor II (prothrombin) (F2); Locus ID: 2147. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2147
	ePath Coagulation factor II (prothrombin) (F2); MIM number: 176930. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?176930
	ePath Coagulation factor V (proaccelerin, labile factor) (F5); Locus ID: 2153. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2153
	ePath Coagulation factor V (proaccelerin, labile factor) (F5); MIM number: 227400. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?227400

Article Title:	Factor V Leiden
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	Figure 1. Activation and propagation of blood coagulation. Tissue factor (TF) binds zymogen and activated forms of factor VII (factor VIIa) resulting in activation of factors IX and X. Factors IXa and Xa together with VIIIa and Va, respectively, form the tenase and prothrombinase complexes respectively. Thrombin has multiple functions, which are not shown, including conversion of fibrinogen to fibrin, activation of platelets and feedback activation of coagulation by activation of factors VIII and V.
	Figure 2. Molecular mechanisms of the protein C anticoagulant system. Thrombin (T) binds to thrombomodulin (TM) on the surface of endothelial cells. The T–TM complex activates protein C to activated protein C (APC). APC cleaves and inhibits factors VIIIa and Va. Protein S (PS) is a cofactor to APC in degradation of factor VIIIa and in the cleavage of Arg306 in factor Va. Factor V functions as a synergistic APC cofactor together with protein S in the degradation of factor VIIIa. VIIIi and Vi denote APC-inactivated VIII and V, respectively.
	Figure 3. Dual mechanisms yield the hypercoagulable state, which is associated with factor V (FV) Leiden. The multidomain character of FV (A1–A2–B–A3–C1–C2) is illustrated. Arrows pointing down to FV Leiden represent APC cleavage sites, whereas those pointing up are thrombin-sensitive sites. The B domain is released from FV during activation by thrombin and FVa is formed by A1–A2 bound to A3–C1–C2. APC cleaves several bonds (at positions 306, 506 and 679) in normal FV/Va. There are two biological consequences of the Arg506Gln mutation, which change the balance between pro- and anticoagulant forces in a procoagulant direction. One is impaired degradation of FVa due to loss of the Arg506 site and the other is decreased anticoagulant APC cofactor function of FV, which is important for inactivation of factor VIIIa. The poor APC cofactor activity of FV Leiden is caused by the loss of the APC cleavage site at position 506 because this APC cofactor activity is stimulated by the cleavage of Arg506 in normal FV.

Factor V Leiden

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