Does a low Factor V (5) Leiden ratio indicate Factor V (5) Leiden mutation?

From the Guidelines

No, a low Factor V Leiden ratio does not necessarily indicate a Factor V Leiden mutation, as the mutation may account for 85-95% of patients with APC resistance, but not all cases 1.

Key Points

• The Factor V Leiden mutation is a single point mutation (G to A) at nucleotide 1691 of the factor V gene, resulting in substitution of a glutamine for arginine at residue 506 (R506Q) 1.
• This mutation is the most common hereditary thrombophilia and is found in roughly 11-20% of individuals presenting with their first episode of venous thrombosis 1.
• APC resistance is the most common recognized abnormality of coagulation among patients with venous thromboembolism, and the Factor V Leiden mutation may account for 85-95% of patients with APC resistance 1.
• However, APC-R with normal factor V R506 genotype is also a risk factor for venous thrombosis, indicating that a low Factor V Leiden ratio may not always indicate the presence of the mutation 1.
• The Factor V Leiden mutation is carried in heterozygous form by about 5% of the Caucasian population, and it is believed to produce a relative risk of venous thrombosis of about 7-fold in the heterozygous state and about 80-fold in the homozygous state 1.

Clinical Implications

• Testing for the Factor V Leiden mutation is possible by simple and inexpensive molecular genetic methods 1.
• A low Factor V Leiden ratio should be interpreted with caution, as it may not always indicate the presence of the mutation, and other risk factors for venous thrombosis should also be considered 1.

From the Research

Factor V Leiden Mutation and Low Factor V Leiden Ratio

• A low Factor V Leiden ratio does not necessarily indicate the presence of a Factor V Leiden mutation 2.
• The activated protein C (APC) resistance test is a sensitive screening assay for Factor V Leiden, but it has limitations in terms of specificity 2.
• A low APC resistance ratio can be caused by factors other than the Factor V Leiden mutation, and some individuals with a normal APC resistance ratio may still have the mutation 2.

Relationship Between Factor V Leiden Ratio and Thrombosis Risk

• The risk of venous thromboembolism (VTE) increases with increasing normalized APC sensitivity ratio (nAPCsr) in Factor V Leiden heterozygotes 3.
• Common F5 genetic variations can modulate the FV(Leiden)/normal FV ratio and affect VTE risk in Factor V Leiden heterozygotes 3.
• The clinical expression of Factor V Leiden is influenced by the number of Factor V Leiden alleles, coexisting genetic and acquired thrombophilic disorders, and circumstantial risk factors 4.

Diagnosis and Testing for Factor V Leiden

• Diagnosis of Factor V Leiden requires the activated Protein C resistance assay or DNA analysis of the F5 gene 4, 5.
• Testing for Factor V Leiden involves screening for APC resistance, followed by testing for the Factor V Leiden mutation if the screening test is positive 5.
• The presence of concomitant genetic risk factors, such as the prothrombin G20210A mutation or inherited deficiencies of antithrombin, protein C, or protein S, can increase the risk of VTE in individuals with Factor V Leiden 6.