Liver and Plasma Levels of Descarboxyprothrombin (PIVKA II) in Vitamin K Deficiency in Rats

Abstract

Abstract-Descarboxyprothrombin(PIVKA II) is a precursor of prothrombin without biological activity, and it increases with vitamin K deficiency.We studied the time course changes in liver and plasma levels of PIVKA II during the progress of vitamin K deficiency in rats. Good correlation was observed between liver PIVKA II and plasma PIVKA II and between liver or plasma PIVKA II and plasma prothrombin in experiments in which rats were fed a vitamin K-deficient diet. Feeding of a vitamin K-deficient diet or fasting caused marked increases in liver and plasma PIVKA II in male rats and a weaker response in female rats. Warfarin, a vitamin K antagonist, caused an abrupt increase in liver PIVKA II, but the increase in plasma PIVKA II was delayed about 3 hr. Plasma prothrombin decreased from about 30 min later. Factor VII decreased similarly to prothrombin, and changes in the prothrombin time and activated partial thromboplastin time were slower than the changes in these substances.Sex differences were not seen in these warfarin actions.These observations indicate that liver and plasma PIVKA II are sensitive markers of vitamin K deficiency in rats, and assay of PIVKA II can be useful for analyzing the action mechanism of drugs which influence blood coagulation.

Battery of Tests for Profiling Abnormalities of Vitamin K-Dependent Coagulation Factors in Drug-Toxicity Studies in Rats

“…We sometimes observe prolongation of the routine screening parameters, prothrombin time (PT) and activated partial thromboplastin time (APTT) in general toxicity studies in rats. One of the causes of this is decreased activity of vitamin K-dependent coagulation factors due to the generation of the inactive des-carboxyl form of coagulation factors, also known as "protein induced by vitamin K absence or antagonists (PIVKA)" [7,12]. Many chemicals are known to cause such abnormalities [8,20].…”

“…The abnormal vitamin K-dependent factors are detected in rats by measuring coagulation time using the Kurata, Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan thrombotest [4, 6, 14, 18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21].…”

“…One of the causes of this is decreased activity of vitamin K-dependent coagulation factors due to the generation of the inactive des-carboxyl form of coagulation factors, also known as "protein induced by vitamin K absence or antagonists (PIVKA)" [7,12]. Many chemicals are known to cause such abnormalities [8,20].The abnormal vitamin K-dependent factors are detected in rats by measuring coagulation time using the Kurata, Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan thrombotest [4, 6, 14, 18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21].…”

“…thrombotest [4,6,14,18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21].…”

“…PIVKA-II, if measured alone, is also insufficient due to the lack of information regarding other coagulation factors. In addition, the quantitative measurement of PIVKA-II involves extraction procedures and a manual assay [7,8], which are difficult to apply to routine toxicity studies. In this regard, a classical and simple method to detect PIVKA-II might be useful in routine toxicity studies; e.g., a method to compare factor II activity with its total activity using venom coagulation time [1][2][3]19].…”