Vitamin K–dependent clotting factor deficiency (VKCFD) is a rare autosomal recessive bleeding disorder that often presents with severe hemorrhage during infancy. The first case of VKCFD was reported in 1966 and described a 3-month-old girl with multiple bruises and hemorrhages [1
]. She had no evidence of malabsorption, liver disease, or warfarin poisoning. She was found to have a prothrombin time of 95 seconds and a partial thromboplastin time of 305 seconds. These times corrected on mixing 1:1 with normal plasma, indicating factor deficiency rather than inhibition of coagulation. Her plasma showed less than 3% activity of factors II, VII, IX, and X.
The proband was further studied at the age of 15 years and found to have immunologically recognizable coagulation factors II, VII, IX, and X that lacked γ-carboxyglutamic acid residues [2
]. Both parents of the children were found to have reduced levels of γ-carboxylated proteins in their urine, suggesting heterozygous defects in the vitamin K metabolic pathway (H.R. Roberts, personal communication). The roband’s obstetric care at the age of 34 years was also reported [3
]; management continued to involve high doses of oral vitamin K and plasma infusions for surgical procedures and significant hemorrhages. Additional VKCFD cases and pedigrees were reported over the years; bleeding has ranged from mild to severe [4
Subsequent characterization of anticoagulant proteins C, S, and Z in VKCFD cases showed defective γ-carboxylation of these proteins as well, and a modest propensity to thrombotic events has been suggested by a few cases [8
]. Skeletal defects have also been reported in some cases, likely due to defective γ-carboxylation of certain bone matrix proteins [7
] or from vitamin K interactions with other target genes in osteoblasts [11
The isolation and characterization of the human genes encoding the γ-glutamyl carboxylase (GGCX) in 1991 by forward genetics [12
] and the vitamin K epoxide reductase (VKOR) in 2004 by reverse genetics and expression cloning [14
] greatly advanced our understanding of VKCFD, as well as the metabolism of vitamin K and the biological roles of γ-carboxylation. Subsequent pedigree studies have looked at missense mutations in each gene, resulting in the subtype designations VKCFD1 and VKCFD2 [17
]. Common single nucleotide polymorphisms (SNPs) in these genes (particularly VKOR) and CYP2C9 (cytochrome p450 2C9) have been examined in large populations of various ethnic backgrounds in relation to warfarin dosing [reviewed in 19
]. Recent work has also focused on drug development and potential molecular therapeutics using the knowledge gained by VKCFD, making this rare coagulation disorder relevant in new ways.