REVERSAL OF HEPARIN ANTICOAGULATION BY RECOMBINANT PLATELET FACTOR-4 IN HUMANS

Background Protamine is used to reverse the anticoagulant effects of h eparin, but it can have important side effects. Platelet factor 4 (PF4 ) is a protein found in platelet alpha granules that binds to and ther eby neutralizes heparin. We evaluated the safety and effectiveness of intravenous recombinant PF4 to neutralize heparin anticoagulation afte r cardiac catheterization in a phase 1, open-label trial. Methods and Results The study group consisted of 18 patients having diagnostic car diac catheterization. Heparin (5000 U) was given after vascular access was obtained. In the first 12 patients, additional heparin was given at the conclusion of the procedure so that all patients had activated coagulation times >300 seconds before rPF4 was given. Three patients e ach received 0.5, 1.0, 2.5, or 5.0 mg/kg rPF4 over a period of 3 minut es at the conclusion of the catheterization procedure. In 6 additional patients, extra heparin was not given at the conclusion of the proced ure, and 1.0 mg/kg rPF4 was given. Hemodynamic measurements, cardiac o utput, and serial blood tests were performed 5, 10, 20, and 30 minutes after rPF4 and then into the next 24 hours. There were no serious sid e effects in any patient, despite transient rPF4 levels as high as 14 870 ng/mL in the patients receiving 5.0 mg/kg. One patient receiving 2 .5 mg/kg had a slight transient rise in liver enzymes possibly related to the rPF4. There were no important hemodynamic effects of rPF4 admi nistration at any dose used. Doses of 2.5 and 5.0 mg/kg were uniformly effective in reversing the anticoagulant effect of heparin. At lower doses, rPF4 neutralized the effects of heparin in most but not all pat ients. Pharmacokinetic analysis suggested a monophasic and one-compart ment clearance of the PF4-heparin complex. No neutralizing factors to rPF4 were detected in the samples collected 7 days after dosing. Concl usions rPF4, in doses ranging from 0.5 to 5.0 mg/kg over 3 minutes, ha d no serious side effects. Given in sufficient amounts, rPF4 can compl etely and rapidly reverse the anticoagulant effects of heparin.