The "haemostatic balance" is maintained by activating and inhibiting coagulation factors. An important regulatory mechanism is the protein C system, which is necessary to bring an activated coagulation process to a stop and thereby preventing thrombosis. Protein C is activated to activated protein C (APC) by the thrombin/thrombomodulin complex on endothelial cells. In complex with phospholipids, calcium and the cofactor protein S, APC inactivates factors Va and VIIIa by proteolytic cleavage at specific sites. By APC resistance more than 90% of the cases are caused by a point mutation (G1691A) in exon 10 of the factor V. This mutation leads to an amino acid exchange from arginin to glutamin in one of the APC cleavage sites of factor V (position 506). The mutated factor Va thus becomes resistant to cleavage by APC, which strongly slows down its inactivation.
Hereditary APC resistance, which is due to the point mutation G1691A, is called the factor V Leiden or FV:Q506 mutation. In the Caucasian population the prevalence of the heterozygous form is 2-7%. In patients with familial thrombophilia, APC resistance is found in 30-50% of the cases, thus being by far the most frequent genetic factor for the disorder. The heterozygous mutation leads to a 7-fold increased thrombotic risk, the homozygous mutation to a 50 to 100-fold increased risk. The presence of further risk factors potentates the risk for thrombosis in patients with APC Resistance.
- Familial thrombophilia
- Occurrence of venous and/or arterial thrombosis before the age of 40
- Recurrent thrombosis
- Thrombosis in unusual sites
- Thrombosis during pregnancy
- Thrombosis during the use of oral contraceptives
- Risk estimation in situations, which carry an increased risk of thrombosis such as oral contraceptive use or elective surgery
- Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anti-coagulant response to activated potein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci 90, 1004-1008, 1993.
- Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 330, 517-522, 1994.
- Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dierven RJ, de Ronde H, Van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369, 64-67, 1994.
- De Visser M et al. A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis. Blood 93, 1271-1276, 1999.
- Rosen SB, Sturk A. Activated Protein C Resistance-A Major Risk Factor for Thrombosis. Eur J Clin Chem Biochem 35 (7), 501-516, 1997.
- Hall C et al. Evaluation of a modified APTT-based method for determination of APC resistance in plasma from patients on heparin or oral anticoagulant therapy. Thromb Res 89, 203-209, 1998.
- De Ronde, Bertina RM. Careful selection of sample dilution and factor V-deficient plasma makes the modified activated protein C resistance test highly specific for the factor V Leiden mutation. Blood Coag Fibrinol 10, 7-17, 1999.
- Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost. Mar 8(3), 2010.
- Van Cott EM, Khor B, Zehnder JL. Factor V Leiden. Am J Hematol. Jan 91(1), 46-9, 2016.