Activated partial thromboplastin time-protamine dose relation in the presence and absence of heparin

A protamine titration is one of the methods to determine the protamine dose necessary to neutralize heparin. The protamine dose response was studied with the activated partial thromboplastin time (APTT) in the presence of a known amount of heparin and in the absence of heparin, using freshly prepared human plasma. When heparin was present in the plasma, APTT values plateaued between a minimal neutralizing dose of protamine and a protamine dose five times greater. At doses above the APTT plateau, protamine exerted its own anticoagulant action as evidenced by an increase in APTT values. In the absence of heparin, APTT did not change until the protamine concentration reached 50 micrograms/mL. Then the APTT began to increase above this critical concentration. The increases in APTT values caused by an increase of 50 micrograms/mL of protamine were significantly greater without heparin than they were in the presence of heparin. These results suggest that protamine has a wide safety range when neutralizing heparin without exerting its own anticoagulant action. Although the mechanisms are under speculation, the heparin-protamine complex may inhibit the anticoagulant action of protamine in vitro.