title: Platelet factor 4 efficiently reverses heparin anticoagulation in the rat without adverse effects of heparin-protamine complexes.
abstract: BACKGROUND
  It has been observed that the reversal of heparin anticoagulation in humans by protamine sulfate (PS) results in various adverse reactions including leukopenia, thrombocytopenia, activation of complement, increased vascular permeability, systemic hypotension, pulmonary vasoconstriction, and pulmonary edema. The purpose of this study was to compare the efficacy and effects of native platelet factor 4 (PF4) and recombinant platelet factor 4 (rPF4) with those of PS in heparin neutralization in vivo, using a rat model.
  
  
  RESULTS
  Sprague-Dawley rats were anesthetized with sodium pentobarbital, and the right femoral vein and carotid artery were cannulated. For determination of activated partial thromboplastin time, platelet count, white blood cell count, and complement titer, arterial blood samples were taken before and immediately after heparin (10 units/100 g) infusion and at several time points after the infusion of the neutralizing agent (PS, 0.1 mg/100 g; PF4, 0.5 mg/100 g). In separate groups of animals, mean arterial blood pressure was monitored throughout identical protocols and the lungs were prepared for histological examination. The anticoagulant activity of heparin was effectively reversed by all of the neutralizing agents (PS, PF4, and rPF4). Platelet count (48% of initial), white blood cell count (52% of initial), complement titer (60% of initial), and mean arterial pressure (20% decrease) decreased significantly in heparinized animals receiving PS but not in those receiving PF4 or rPF4. Lung interstitium appeared normal when heparin was followed by PF4; however, interstitial edema and hemorrhage were observed with heparin-PS.
  
  
  CONCLUSIONS
  These results suggest that PF4 efficiently reverses heparin anticoagulation in the rat without the adverse effects of heparin-protamine complexes. Therefore, rPF4 may be an appropriate substitute for PS in patients undergoing cardiovascular surgery and other procedures that require heparin anticoagulation.
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: J J
authors.initials: JJ
authors.lastname: Cook
authors.forename: S
authors.initials: S
authors.lastname: Niewiarowski
authors.forename: Z
authors.initials: Z
authors.lastname: Yan
authors.forename: L
authors.initials: L
authors.lastname: Schaffer
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.forename: G J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: D M
authors.initials: DM
authors.lastname: Mosser
authors.forename: J A
authors.initials: JA
authors.lastname: Myers
authors.forename: T E
authors.initials: TE
authors.lastname: Maione
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006494:Heparin Antagonists / Q000494:pharmacology*; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced; D010978:Platelet Factor 4 / Q000494:pharmacology*; D011479:Protamines / Q000009:adverse effects*; D011654:Pulmonary Edema / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D006494:Heparin Antagonists; D011479:Protamines; D011994:Recombinant Proteins; D010978:Platelet Factor 4