Combined deficiencies of all clotting factors are rare and obviously one has first to exclude unequivocally the occurrence of vitamin K-deficiency or unsuspected intake of coumarins. Since the first suggestion of a defect in the carboxylase / reductase system, several other cases have been reported some of which also mentioned the occurrence of bone abnormalities comparable with those seen in warfarin-induced embryopathy. Such combined defects of bone development before birth and of the blood clotting system during childhood strongly suggest a decreased carboxylation of all Gla-proteins, and may be due to mutations in either the carboxylase or KO-reductase. After the carboxylase cDNA had been sequenced and cloned, some of these cases could indeed be associated with a mutation in the carboxylase gene.
Mutations in the clotting factor Pro-domain. These mutations may lead either to poor recognition of the precursor protein by carboxylase, or to impaired cleavage of the pro-peptide during protein maturation. Reported cases of impaired carboxylase recognition refer to factor IX and were discovered by the clinical symptoms (acquired hemophilia B) after mild coumarin treatment. Impaired pro-peptide cleavage leads to fully carboxylated clotting factors which lack procoagulant activity because the extension at their amino terminus strongly interferes with their binding to negatively charged phospholipid vesicles.Mutations in the clotting factor Gla-domain.
Besides frame-shift mutations and the introduction of stop codons, direct mutations in the Gla-domain may result in replacement of regular amino acids and of Gla-residues. Whereas all mutations may give rise to altered conformations, mutations leading to a decreased number of Gla-residues will inevitably decrease the protein's charge and calcium binding capacity. In case of the four vitamin K-dependent clotting factors this will result in decreased haemostatic capacity and increased risk of bleeding, in case of the coagulation inhibiting protein C and protein S the expected result is an increased thrombosis risk. Indeed several of such mutations have been reported during recent years, and the clinical symptoms matched the expectations. Whereas in the case of protein C and protein S mutations thrombosis risk can be successfully normalized by oral anticoagulant therapy. However, the symptoms of mutations in the clotting factors cannot be relieved by vitamin K.