Thrombophilia – APC resistance

Venous thromboembolism is the principal clinical manifestation. Deep vein thrombosis of the legs and pulmonary embolism predominate; upper-extremity, cerebral, and superficial venous thromboses also occur. The relative risk of a first venous thromboembolism is increased approximately three- to eightfold in individuals with a single factor V Leiden variant allele, while the overall annual incidence remains low at around 0.5%. Those carrying two variant alleles face a substantially higher thrombotic burden, reportedly nine- to 80-fold above baseline, and tend to present at a younger age. Pregnancy markedly modifies risk: women with one variant allele have a five- to eightfold greater risk of pregnancy-related venous thromboembolism, with the highest risk occurring during the first six weeks post-partum. Onset is typically in young to middle adulthood, and clinical expression is highly variable; many affected individuals never develop thrombosis, whereas combined oral contraceptives, surgery, immobilisation, malignancy, or co-inheritance of the prothrombin G20210A polymorphism markedly amplify risk.

The estimated prevalence of the factor V Leiden variant in European and U.S. populations is 3-8% (approximately 1/12 to 1/33); approximately 1/5,000 individuals carry the variant on both alleles, and the highest rates are reported in southern Sweden and Greece (10-15%).

The vast majority of hereditary cases (~95%) are caused by a single molecular variant (c.1601G>A p.Arg534Gln) in the F5 gene, known as the factor V Leiden variant. The substitution replaces an arginine at the APC cleavage site of coagulation factor V with glutamine. As a result, factor Va is inactivated by APC approximately tenfold more slowly, persists longer in the circulation, and drives increased thrombin generation, producing a mild hypercoagulable state. In addition to the factor V Leiden variant, a number of other, extremely rare F5 variants have also been shown to be associated with APC resistance.

Thrombophilia due to APC resistance is inherited in an autosomal dominant manner. Each child of a parent carrying the F5 c.1601G>A variant has a 50% chance of inheriting it; if both parents carry the variant, offspring have a 25% risk of inheriting two variant alleles, which is associated with a substantially higher thrombotic burden. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established primarily by molecular genetic testing. A qualitative or quantitative activated protein C (APC) resistance assay typically demonstrates a low APC sensitivity ratio and provides the principal suggestive laboratory finding; definitive confirmation requires identification of the factor V Leiden variant on one or both alleles.

• The prothrombin G20210A polymorphism occurs with comparable frequency and is associated with a risk of thrombosis that is on the same order of magnitude as that of the Factor V Leiden variant.
• Furthermore, thrombophilia can also be caused by a hereditary deficiency of , , or antithrombin III. While these conditions are significantly less common, they are associated with a substantially elevated risk of thrombosis.
• Of note, homozygosity/compound heterozygosity for F5 variants other than factor V Leiden results in factor V deficiency, which manifests as a bleeding tendency rather than thrombosis.

• Establishing the diagnosis ends diagnostic uncertainty and provides molecular confirmation of the clinical impression, supporting informed clinical decision-making for the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing can be offered to at-risk relatives following genetic counselling, enabling them to clarify their personal risk status.

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• Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. PMID: .