Familial deficiency of vitamin K‐dependent clotting factors

Abstract

Summary. Combined deficiency of vitamin K‐dependent clotting factors II, VII, IX and X (and proteins C, S, and Z) is usually an acquired clinical problem, often resulting from liver disease, malabsorption, or warfarin overdose. A rare inherited form of defective γ‐carboxylation resulting in early onset of bleeding was first described by McMillan and Roberts in 1966 and subsequently has been termed ‘vitamin K‐dependent clotting factor deficiency’ (VKCFD). Biochemical and molecular studies identify two variants of this autosomal recessive disorder: VKCFD1, which is associated with point mutations in the γ‐glutamylcarboxylase gene (GGCX), and VKCFD2, which results from point mutations in the vitamin K epoxide reductase gene (VKOR). Bleeding ranges in severity from mild to severe. Therapy includes high oral doses of vitamin K for prophylaxis, usually resulting in partial correction of factor deficiency, and episodic use of plasma infusions or prothrombin complex concentrate. Recent molecular studies have the potential to further our understanding of vitamin K metabolism, γ‐carboxylation, and the functional role this post‐translational modification has for other proteins. The results may also provide potential targets for molecular therapeutics and pharmacogenetics.

Rare Bleeding Disorders in Children: Identification and Primary Care Management

“…19,25,26 The least common RBDs are FII and FXIII deficiencies, with a prevalence of ∼1 per 2 million each, 25,26 and vitamin K-dependent clotting factor deficiency (VKCFD), of which ,30 cases were reported as of 2008. 31 …”

“…For example, umbilical cord bleeding may occur in conditions other than FX and FXIII deficiencies, including HA, HB, and other RBDs. 22,25,35,36,43,44 Likewise, ICH has been described in the neonatal period in severe deficiencies of FII, FV, and FVII and in VKCFD, 31,42,45,46 although ICH is especially common in FX and FXIII deficiencies; ICH has been reported in as many as 20% of individuals with FX deficiency 44,47,48 and as many as 30% of those with FXIII deficiency, [49][50][51] in which ICH is the main cause of death and disability. 23,49 Other life-and limb-threatening bleeding events, such as ovulatory hemoperitoneum and hemarthroses, have been reported, most frequently in FII, FX, and FXIII deficiencies.…”

“…60 In contrast, VKCFD is often associated with significant bleeding. 31 VKCFD results from inherited defects in activation (g-carboxylation) of the vitamin K-dependent factors (FII, FVII, FIX, and FX). 31 Affected children often present in infancy or in early childhood with serious bleeding events, including ICH.…”

“…31 VKCFD results from inherited defects in activation (g-carboxylation) of the vitamin K-dependent factors (FII, FVII, FIX, and FX). 31 Affected children often present in infancy or in early childhood with serious bleeding events, including ICH. Skeletal abnormalities have also been reported, possibly due to defective gcarboxylation of bone matrix proteins.…”

VKORC1 and CYP2C9 genotypic data-based dose prediction alone does not accurately predict warfarin dose requirements in some Malaysian patients

“…low (27)(28)(29). Future investigation of the role of VKORC1 polymorphisms on the activity of VKD clotting factors may provide a better understanding of the association of individual VKD clotting factor activities with VKORC1 polymorphisms.…”