Studies on a family with combined functional deficiencies of vitamin K-dependent coagulation factors.

Abstract

A B S T R A C T Two siblings with mild hemorrhagic symptoms had combined functional deficiencies of vitamin K-dependent clotting factors. Prothrombin (0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) were most severely affected. Antigenic amounts of affected coagulation factors were normal and normal generation of thrombin activity occurred in the patients' plasmas after treatment with nonophysiologic activators that do not require calcium for prothrombin activation. Hepatobilary disease, malabsorptive disorders, and plasma warfarin were not present. Both parents had normal levels of all coagulation factors. The patients' plasmas contained prothrombin that reacted both with antibody directed against des-y-carboxyprothrombin and native prothrombin. Crossed immunoelectrophoresis of patients' plasmas and studies of partially purified patient prothrombin suggested the presence of a relatively homogeneous species of dysfunctional prothrombin, distinct from the heterologous species found in the plasma of warfarin-treated persons. These studies are most consistent with a posttranslational defect in hepatic carboxylation of vitamin K-dependent factors. This kindred uniquely possesses an autosomal recessive disorder of vitamin K-dependent factor formation that causes production of an apparently homogeneous species of dysfunctional prothrombin; the functional deficiencies in clotting factors are totally corrected by oral or parenteral administration of vitamin KI.

Mechanism of Bone and Cartilage Maldevelopment in the Warfarin Embryopathy

“…An inborn error of vitamin K utilization was assumed and oral vitamin K therapy ini tiated which resulted in resolution of clinical symptoms and partial correction of vitamin K dependent clotting parameters. From these data it seems likely that this boy had a combined coagulopathy secondary to abnor malities of vitamin K. handling as has been previously reported in 6 other individuals [8][9][10][11][12],…”

Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K–dependent coagulation factor deficiency

“…[1][2][3][4][5][6][7][8] The inheritance of the disease is autosomal recessive and is due to mutations in the genes for either the ␥-carboxylase [9][10][11][12] or the vitamin K epoxide reductase (VKORC1). 13 The carboxylase converts clusters of Glus to ␥-carboxylated Glus (Glas) in the Gla domains of VKD proteins, which renders them active by generating a calcium-binding module that binds either to anionic phospholipids that become exposed on cell surfaces or to hydroxyapatite in the extracellular matrix.…”

Familial deficiency of vitamin K‐dependent clotting factors

“…In fact, massive parenteral doses of vitamin K do not always correct factor II, VII, IX and X activities, and there is clear biochemical evidence that the molecules are not fully carboxylated by such treatment [2,8]. Continued daily treatment with high-dose oral vitamin K is, however, successful in preventing some bleeding complications [2][3][4][5][7][8][9] and is generally recommended for these patients.…”

“…The probandÕs 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 haemorrhages. Additional VKCFD cases and pedigrees were reported over the years; bleeding has ranged from mild to severe [4][5][6][7][8][9][10][11].…”