Anticoagulant activity of heparin increased by interaction with terbium ions and complexation with ADP, arginine, glycine, and proline: comparative analysis

Abstract

A comparative analysis of blood plasma coagulation with the participation of terbium ions (Tb 3+ ) and complexes of high-molecular-weight heparin with endogenous ligands (adenosine triphosphate, arginine, glycine, and proline) has been performed using published data on the computer simulations of chemical equilibria, results of biochemical experiments in vitro with blood plasma of laboratory rats, and the modern enzymatic theory of blood clotting. The participation of Tb 3+ was investigated by computer simulation of chemical equilibria based on pH-metric data for the calcium chloride—terbium nitrate—unfractionated heparin system in physiological solution and by biochemical experiments in vivo with intraperitoneal injections of terbium heparinate and terbium chloride into laboratory rats. It is established that terbium heparinate at a concentration equivalent to 50 IU heparin and terbium chloride in the concentration range 1.5 10 –5 – 1.5 10 –2 act as coagulants. The hypothetical mechanism of competitive complexation of Tb 3+ and Ca 2+ with blood clotting factors is not confirmed by the results of biochemical experiments that are consistent with the modern enzymatic theory of blood clotting and the blood plasma component composition. Heparin complexes with blood plasma ligands were constructed by computer simulation of chemical equilibria based on pH-metric data for heparin-L and MCl2—heparin L (M = Ca 2+ and Mg 2+ ; L = ATP, Arg, Gly, Pro) systems in physiological solution and by biochemical experiments in vitro and in vivo with blood plasma of laboratory rats. Complexes of heparin with ATP, Arg, Gly, and Pro are non-toxic, contain organic cations of ligands bound to heparin sulfonates, and do not disrupt the enzymatic blood coagulation process. These complexes regulate the blood coagulation process by decreasing the equilibrium concentration of Ca 2+ (through the formation of stable complexes) and produce a two- to three-fold increase in heparin activity.