Developing a Highly Active Blood Anticoagulant—a Heparin Complex with Glutamic Acid—by Simulating Chemical Equilibria Based on pH-Metric Data

Abstract

The anticoagulant activity of high-molecular-weight heparin is increased by developing a new highly active heparin complex with glutamate using the thermodynamic model of chemical equilibria based on pH-metric data. The anticoagulant activity of the developed complexes is estimated in the pH range of blood plasma according to the drop in the calculated equilibrium Ca2+ concentration associated with the formation of mixed ligand complexes of Ca2+ ions, heparin (Na4hep), and glutamate (H2Glu). A thermodynamic model is calculated by mathematically modelling chemical equilibria in the CaCl2–Na4hep–H2Glu–H2O–NaCl system in the pH range of 2.30 ≤ pH ≤ 10.50 in diluted saline that acts as a background electrolyte (0.154 М NaCl) at 37°C and initial concentrations of the main components of ν × 10−3 M, where n ≤ 4. The thermodynamic model is used to determine the main complex of the monomeric unit of heparin with glutamate (HhepGlu5–) and the most stable mixed ligand complex of Ca2+ with heparin and glutamate (Ca2hepGlu2–) in the pH range of blood plasma (6.80 ≤ рН ≤ 7.40). It is concluded that the Ca2hepGlu2– complex reduces the Ca2+ concentration 107 times more than the Ca2+ complex with pure heparin. The anticoagulant effect of the developed HhepGlu5– complex is confirmed in vitro and in vivo via coagulation tests on the blood plasma of laboratory rats. Additional antithrombotic properties of the developed complex are identified. The new highly active anticoagulant, HhepGlu5– complex with additional antithrombotic properties, is patented.