Histidine-rich glycoprotein plus zinc to neutralize heparin

Histidine-rich glycoprotein (HRG) binds heparin and neutralizes its anticoagulant effect. Because zinc greatly enhances this interaction, it is possible that the combination of HRG and zinc could be used as an antidote for heparin. We have determined the plasma concentrations of HRG and zinc necessary to neutralize clinically relevant concentrations of heparin. Using a thrombin-time assay, we found that HRG plus zinc can neutralize 0.2 to 4.5 units/mL heparin, although the maximal effect requires an HRG plasma concentration about six times normal and a zinc concentration about 10 times normal. In a system using purified proteins and a thrombin-specific chromogenic substrate, we found that both the concentration of HRG and the molar ratio of HRG to zinc are important in determining the potency of the anti-heparin activity. Whether HRG and zinc can be administered as an antidote for heparin will depend on whether the requisite doses can be achieved without toxicity.