Evaluation of Recombinant Platelet Factor 4 and Protamine Sulfate for Heparin Neutralization: Clotting and Clearance Studies in Rat

Summary

Recombinant platelet factor 4 (rPF4) efficiently neutralized heparin anticoagulant activity in rats without the adverse effect of protamine sulfate (PS) (Circulation 1992; 85: 1102). This study confirmed that rPF4 and PS neutralized heparin in rats. In vitro addition of excess PS but not rPF4 to plasma prolonged the activated partial thromboplastin time. Injection of rPF4 or PS 2 min following injection of ³H-heparin augmented loss of radioactivity from the circulation over the first 2 min but did not affect the half life of ³H-heparin for the next 58 min. PS was coupled to 4-(p-Azidosalicylamido)butylamine (ASBA), radioiodina- ted and purified by means of heparin-agarose chromatography. Heparin prevented the rapid loss of ¹²⁵I-rPF4 from the circulation within the first 2 min but modestly increased loss of radioiodinated derivatized PS. Heparin extended the half-life of derivitized radioiodinated PS (measured between 2 and 60 min after injection) while modestly shortening that of ¹²⁵I-rPF4. Both radioiodinated heparin binding proteins accumulated predominantly in liver and kidney. A greater percentage of radioactivity was found in these organs with rPF4 than with PS but more PS was found in urine. A larger percentage of radioiodinated derivatized PS than ¹²⁵I-rPF4 was undetected. These results indicate that rPF4 and PS affect the kinetics of heparin clearance similarly but that organ deposition of the two agents may differ and offer an explanation of different physiological effects seen previously.

• References

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