F10 – Congenital Factor X Deficiency

Congenital factor X deficiency is a rare autosomal recessive bleeding disorder characterized by low plasma FX activity and antigen levels, leading to variable bleeding manifestations from mild bruising and epistaxis to life-threatening hemorrhage. Diagnosis relies on prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) combined with FX:C and FX:Ag assays. Genetic testing confirms pathogenic F10 variants and guides family counseling and management.

Multiple case reports and series describe over 90 unrelated probands from more than 20 families worldwide, demonstrating autosomal recessive inheritance with homozygous and compound heterozygous F10 mutations. Variants include missense changes (e.g., c.214G>C (p.Glu72Gln))([PMID:9622212]), splice-region deletions, nonsense and frameshift mutations. Genotype–phenotype correlations show that null alleles or severe catalytic‐domain substitutions produce severe deficiency (<1% FX:C; severe bleeding), whereas hypomorphic alleles or heterozygotes often have mild phenotypes.

Functional studies corroborate a loss-of-function mechanism via diverse processes: defective splice-site recognition within intron D reduces FX synthesis([PMID:9734641]), Gla-domain substitutions impair Ca²⁺ binding and conformational activation([PMID:1973167]), and signal peptide mutations block secretion([PMID:8449937]). A viable mouse model carrying the human Pro343→Ser (Friuli) variant shows that ≥1–3% residual FX activity suffices for survival but not hemostatic normality, underscoring haploinsufficiency and minimal activity thresholds.

Clinical heterogeneity is notable: patients with FX activity 10% may still experience severe events such as intraperitoneal hemorrhage([PMID:25810617]). Regular prophylactic replacement with plasma-derived FX concentrate or prothrombin complex concentrates effectively reduces bleeding episodes and supports surgical interventions.

The association between F10 and congenital factor X deficiency is hereby classified as Definitive. Robust genetic evidence (numerous unrelated probands, consistent autosomal recessive segregation) and strong functional data (in vitro, in vivo models) underpin clinical validity. KEY TAKE-HOME: F10 gene analysis is integral for definitive diagnosis, carrier detection, and tailored replacement therapy in congenital FX deficiency.

References

• British journal of haematology • 1998 • Molecular abnormality observed in a patient with coagulation factor X (FX) deficiency: a novel three-base-pair (CTT) deletion within the polypyrimidine tract of the FX intron D. PMID:9734641
• Blood coagulation & fibrinolysis • 1998 • Factor X Frankfurt I: molecular and functional characterization of a hereditary factor X deficiency (Gla+25 to Lys). PMID:9622212
• British journal of haematology • 1999 • A family with hereditary factor X deficiency with a point mutation Gla32 to Gln in the Gla domain (factor X Tokyo). PMID:10468877
• Indian journal of pathology & microbiology • 2004 • Factor X deficiency--a rare disorder. PMID:16295475
• Indian journal of critical care medicine • 2015 • Near fatal spontaneous intraperitoneal bleeding: A rare manifestation in a congenital factor X deficiency carrier. PMID:25810617

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