title: Reversal of heparin anticoagulation by recombinant platelet factor 4 in humans.
abstract: BACKGROUND
  Protamine is used to reverse the anticoagulant effects of heparin, but it can have important side effects. Platelet factor 4 (PF4) is a protein found in platelet alpha granules that binds to and thereby neutralizes heparin. We evaluated the safety and effectiveness of intravenous recombinant PF4 to neutralize heparin anticoagulation after cardiac catheterization in a phase 1, open-label trial.
  
  
  RESULTS
  The study group consisted of 18 patients having diagnostic cardiac 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 each received 0.5, 1.0, 2.5, or 5.0 mg/kg rPF4 over a period of 3 minutes at the conclusion of the catheterization procedure. In 6 additional patients, extra heparin was not given at the conclusion of the procedure, and 1.0 mg/kg rPF4 was given. Hemodynamic measurements, cardiac output, 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 side 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 administration 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 patients. Pharmacokinetic analysis suggested a monophasic and one-compartment clearance of the PF4-heparin complex. No neutralizing factors to rPF4 were detected in the samples collected 7 days after dosing.
  
  
  CONCLUSIONS
  rPF4, in doses ranging from 0.5 to 5.0 mg/kg over 3 minutes, had no serious side effects. Given in sufficient amounts, rPF4 can completely and rapidly reverse the anticoagulant effects of heparin.
authors.affiliation: C.V. Richardson Cardiac Catheterization Laboratory, University of North Carolina Hospital, Chapel Hill 27514, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Dehmer
authors.forename: M
authors.initials: M
authors.lastname: Fisher
authors.forename: D A
authors.initials: DA
authors.lastname: Tate
authors.forename: S
authors.initials: S
authors.lastname: Teo
authors.forename: E M
authors.initials: EM
authors.lastname: Bonnem
mesh_terms: D006328:Cardiac Catheterization; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000627:therapeutic use; D006494:Heparin Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010978:Platelet Factor 4 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011479:Protamines / Q000009:adverse effects / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014914:Whole Blood Coagulation Time
chemical_list: D006494:Heparin Antagonists; D011479:Protamines; D011994:Recombinant Proteins; D010978:Platelet Factor 4; D006493:Heparin