Factor V Leiden


Factor V (FV) circulates in plasma as a procofactor with little procoagulant activity. It is activated by thrombin to FVa, which is a highly efficient cofactor to factor Xa in the activation of prothrombin. FVa is regulated by activated protein C (APC) together with its cofactor protein S. A single point mutation in the FV gene (F5), FV Leiden, is a common genetic risk factor for venous thrombosis. It results in the replacement of arginine506 with a glutamine. Arginine506 constitutes one of the three APC‐cleavage sites in FVa. The resulting APC resistance causes an imbalance between pro‐ and anticoagulant forces and a lifelong hypercoagulable state that increases the risk of venous thrombosis approximately three‐ to sevenfold. The FV Leiden mutation is the result of a single mutation event that is estimated to have occurred around 20–25 000 years ago in a Caucasian ancestor, which explains why the mutation is highly prevalent (up to 15%) in Caucasian and rare in other ethnic groups.

Key Concepts

  • 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 to thrombin.
  • Blood coagulation is controlled by several anticoagulant pathways.
  • Protein C, protein S, TFPI (tissue factor pathway inhibitor) and antithrombin are the main anticoagulant proteins in plasma.
  • Activated protein C (APC) together with its cofactor protein S regulates coagulation by cleaving and inactivating factor Va and factor VIIIa.
  • Venous thrombosis is a multifactorial disease.
  • Multiple genetic and circumstantial risk factors contribute to the risk of venous thrombosis.
  • The APC resistance phenotype is the most common inherited risk factor for venous thrombosis. It is caused by a single factor V gene (F5) mutation (Factor V Leiden) that results in the loss of one of the APC cleavage sites as Arg506 is replaced with a Gln.
  • Factor V Leiden is the result of a single mutation event that took place around 20–25 000 years ago.
  • Factor V Leiden is mainly present in Caucasians.
  • Heterozygous carriers of the FV Leiden mutation have a lifelong three‐ to sevenfold increased risk of thrombosis.

Keywords: blood coagulation; thrombosis; protein C; APC resistance; factor V; thrombophilia; prothrombin; protein S; venous thrombosis

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.


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Further Reading

Bertina RM (2009) The role of procoagulants and anticoagulants in the development of venous thromboembolism. Thrombosis Research 123 (suppl. 4): S41–S45.

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.

Dahlbäck B (2003) The discovery of activated protein C resistance. Journal of Thrombosis and Haemostasis 1 (1): 3–9.

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Esmon CT (2003) Inflammation and thrombosis. Journal of Thrombosis and Haemostasis 1 (7): 1343–1348.

Esmon CT (2009) Basic mechanisms and pathogenesis of venous thrombosis. Blood Reviews 23 (5): 225–229.

Martinelli I, De Stefano V and Mannucci PM (2014) Inherited risk factors for venous thromboembolism. Nature Reviews. Cardiology 11 (3): 140–156.

Stenflo J (2006) From gamma‐carboxy‐glutamate to protein C. Journal of Thrombosis and Haemostasis 4 (12): 2521–2526.

Van Cott EM, Khor B and Zehnder JL (2016) Factor V Leiden. American Journal of Hematology 91 (1): 46–49.

Web Links

Coagulation factor V (F5); OMIM number: 612309. OMIM: http://www.ncbi.nlm.nih.gov/Omim/612309

Coagulation factor II (prothrombin) (F2); OMIM number: 176930. OMIM: http://www.ncbi.nlm.nih.gov/OMIM/176930

Thrombophilia due to activated protein C resistnce; THPH2; Factor V Leiden included; OMIN number 188055. OMIM: http://www.ncbi.nlm.nih.gov/OMIM/188055

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Dahlbäck, Björn(Sep 2016) Factor V Leiden. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005537.pub3]