Normal APC-resistance phenotype in a case of FV Leiden mutation along with F5-deficiency due to c.5017C>T genotype

Introduction: Activated protein C (APC) resistance, commonly associated to factor V Leiden mutation (FVL), is a risk factor for venous thromboembolism. We report a case of normal APC resistant phenotype in the presence of heterozygous FVL mutation along with FV-deficiency due to c.5017C>T genotype.

Method: A 19-year-old woman presented with two triggered thromboembolic events. In August 2023 she developed bilateral pulmonary embolism following surgical intervention (thoracic wall abscess drainage). Shortly thereafter, in March 2024, she experienced a second thrombotic event following a period of prolonged immobilisation (distal right-leg deep vein thrombosis). Laboratory analysis performed in two independent samples revealed heterozygous FVL mutation (G1691A) along with normal APC-resistant phenotype combined with reduced factor V levels to 50% or normal. The finding of normal APC resistance was unexpected, as the FVL mutation typically reduces APC inactivation of Factor Va, leading to reduced APC resistance ratios. The discrepancy between the genetic result and the functional assay prompted in sequencing of the F5 gene. Sequencing confirmed the presence of both the heterozygous FVL mutation and a heterozygous c.5017C>T variant in exon 15 in the F5 gene, not listed in clinical databases (ClinVar, GnomAD) so far, therefore classified as a variant of uncertain significance.

Results: In literature, “pseudo-wild-type” FVL has been documented, wherein a mutation in F5 leading to reduced FV levels results in a normal APC ratio despite the presence of a heterozygous FVL mutation, hypothesizing that the co-inheritance of the heterozygous FVL mutation along with a heterozygous F5 mutation on the same allele facilitates the exclusive expression of the non-FVL protein. The latter yields to a normal APC resistant phenotype. Of note, most reported cases of concomitant FVL mutation and FV deficiency are associated with APC resistance ratios typical for homozygous FVL mutation [1]. In our case it is most likely that the two mutations reside on the same allele, which would explain the normal APC ratio.

Conclusion: We identified a F5 (c.5017C>T) mutation which leads to FV deficiency causing “pseudo-wild-type” FVL. To elucidate the prothrombotic effect in this woman presenting with two thrombotic events at a young age, carrying the FVL mutation along with a concomitant mutation in the F5 gene, further genetic testing in the core family is discussed.

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2025

• References

• 1 Prüller F., Raggam R.B., Mangge H., Truschnig-Wilders M., Matzhold E.-M., Weiss E.-C., Hasiba B., Summers K.L., Renner W., Siegert G., Kostka H.. 2013; A novel factor V mutation causes a normal activated protein C ratio despite the presence of a heterozygous F5 R506Q (factor V Leiden) mutation. British Journal of Haematology