F5 – Thrombophilia due to activated protein C resistance

Factor V Leiden, caused by a recurrent missense variant in F5, leads to hereditary resistance to activated protein C and predisposes to both venous and arterial thrombosis. The condition is characterized by impaired proteolytic inactivation of factor Va, resulting in a hypercoagulable state. Although most reports focus on venous thromboembolism, arterial events such as digital necrosis have been documented in extravasation injuries (PMID:9718155).

Autosomal dominant inheritance underlies thrombophilia due to activated protein C resistance. Heterozygotes exhibit partial APC resistance, while compound heterozygotes or homozygotes of the same locus present with more severe phenotypes. A single nucleotide change c.1691G>A (p.Arg506Gln) abolishes a key APC cleavage site in the F5 protein and is detected by both functional assays and molecular tests (PMID:7493138).

Genetic evidence includes screening of 113 unrelated protein C–deficient patients, identifying 15 carriers of c.1691G>A (14%) compared to 1/104 controls (PMID:7795227). In a general thrombophilia cohort of 303 individuals, 30 were heterozygous for the same variant (PMID:9785636). Case series from multiple populations have confirmed the founder effect and high allele frequency (2–7%) in Europeans.

Familial segregation has been observed in at least three kindreds: a pseudo-homozygous APC-resistant family with compound defects showing complete cosegregation (PMID:9375735), and two unrelated pedigrees demonstrating dominant transmission of the Leiden allele with thrombotic events in first-degree relatives. Affected_relatives: 3.

The variant spectrum is dominated by the canonical c.1691G>A (p.Arg506Gln) founder allele. Rare functional variants such as F5 Hong Kong (Arg306Gly) and Cambridge (Arg306Thr) also alter APC sensitivity but confer a milder risk profile. No truncating or deep-intronic variants have been implicated in APC-resistance phenotypes to date.

Functional studies show that p.Arg506Gln impairs APC-mediated cleavage of factor Va, prolongs clotting times in prediluted plasma, and increases thrombin generation in tissue-factor-driven assays (PMID:12091344). Recombinant analyses confirm intermediate resistance patterns in Arg306 variants and complete resistance in R506Q, with protein S modulating cleavage at secondary sites.

No significant conflicting reports have challenged the causal role of c.1691G>A in APC resistance. The evidence base exceeds ClinGen maximum scoring and supports routine use of both functional aPC-resistance assays and targeted DNA tests for clinical diagnosis. Key take-home: F5 c.1691G>A (p.Arg506Gln) is a definitive, autosomal dominant risk factor for activated protein C resistance with direct clinical utility in thrombophilia screening and management.

References

• Annals of Plastic Surgery • 1998 • Progressive gangrene of the hand following extravasation of antibiotics associated with hereditary resistance to activated protein C. PMID:9718155
• Blood • 1995 • Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. PMID:7795227
• Diagnostic Molecular Pathology • 1995 • Molecular detection of a common mutation in coagulation factor V causing thrombosis via hereditary resistance to activated protein C. PMID:7493138
• British Journal of Haematology • 1997 • Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for Arg506Gln (factor V Leiden) and His1299Arg substitutions in factor V. PMID:9375735
• Blood • 2002 • Functional characterization of recombinant FV Hong Kong and FV Cambridge. PMID:12091344

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