title: Restoration of the normal coagulation process: advances in therapies to antagonize heparin.
abstract: A number of naturally occurring anticoagulants exist that preserve normal blood fluidity and limit blood clot formation to vascular injury sites, thus acting as regulators of hemostasis. The protein C/protein S pathway is one system that acts to modulate thrombin formation. The activation of protein C by thrombin is accelerated more than 1,000-fold at the endothelial surface by thrombomodulin localized on the endothelial cell. Activated protein C then binds to its co-factor, protein S, and the protein C/protein S complex exerts its antithrombotic function by inactivating the coagulation factors Va and VIIIa. Patients deficient in protein C and protein S may be particularly vulnerable to thrombotic events after cardiac surgery. In addition, several studies suggest that reductions in protein C and protein S concentrations, as well as thrombomodulin, occur during cardiopulmonary bypass (CPB). The possibility of a low anticoagulant potential when heparinization is reversed may be an important factor in the subsequent morbidity associated with thrombotic complications. Aprotinin is a serine protease inhibitor that in vitro binds competitively with the serine protease-activated protein C. However, aprotinin in the clinical setting has not been reported to alter levels of protein C in patients undergoing CPB. Reversal of the heparinization needed for CPB is almost universally performed with protamine. However, protamine has many deleterious effects. Recombinant platelet factor 4 (rPF4) has been proposed as an alternative to protamine. We investigated the effective heparin neutralization dose of rPF4 vs. the standard agent protamine in human blood activated through exposure to the CPB circuit. Activated clotting time (ACT) measurements suggested a 2:1 (w/w) reversal ratio for rPF4 and protamine. The first human open-label phase 1 trial of rPF4 reported no serious side effects and no important hemodynamic effects. Doses of 2.5 and 5.0 mg/kg were uniformly effective in reversing the anticoagulant effect of heparin and reducing the ACT to <200 s by 5 min after administration. Repeated monitoring of the ACT did not detect a rebound effect of heparin.
authors.affiliation: Cardiac Anesthesia Group, Massachusetts General Hospital, Boston, USA.
authors.forename: M
authors.initials: M
authors.lastname: D'Ambra
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D006493:Heparin / Q000627:therapeutic use; D006494:Heparin Antagonists / Q000627:therapeutic use*; D006801:Humans; D010978:Platelet Factor 4 / Q000627:therapeutic use
chemical_list: D006494:Heparin Antagonists; D010978:Platelet Factor 4; D006493:Heparin