Prothrombin And Abnormal (Des-_γ-Carboxy) Prothrombin: Assessment Of Plasma Levels By Ria In Disorders Of Hepatic Vitamin K-Dependent Carboxylation

The vitamin K-dependent blood coagulation zymogens contain γ-carboxyglutamic acid (Gla) in their amino terminal domains. The presence of these Gla residues is necessary for the physiologic activation of these zymogens to proteases. The Gla residues are synthesized from glutamic acids on precursor proteins in the liver by a vitamin K-dependent carboxylase. In treatment with vitamin K antagonists or in the presence of vitamin K-deficiency carboxylation is impaired and des-γ-carboxy forms circulate in the blood. We have developed specific RIAs for human prothrombin (NPT) and for des-γ-carboxy human prothrombin (APT) to evaluate the levels of these species in human plasma. These plasma assays measure only NPT despite the presence of APT or only APT despite the presence of NPT.

These results suggest that total prothrombin synthesis is decreased in patients treated with warfarin and in patients with intrinsic liver disease compared to normals or to vitamin K-deficient patients. APT is not a component of normal plasma (>0.03 g/ml). However APT is present in 90% of the patients with intrinsic liver disease. In ten patients with liver disease in whom samples were obtained before and after vitamin K administration APT persisted in the plasma. This indicates impaired vitamin-K-dependent car-boxylation in these disorders. We feel that the patterns of plasma NPT and APT in these disease states are characteristic and may prove useful in identifying and distinguishing liver disease from disorders of PT biosynthesis.