Neutralization of Unfractionated Heparin and Low Molecular Weight Heparin by Novel Salicylamide Derivatives

Abstract

Heparin (UFH) neutralization is critical post‐ bypass surgery to avoid excessive blood loss. Protamine use can be associated with severe side‐effects and less effectively neutralizes low molecular weight heparin (LMWH). We studied the ability of polycationic salicylamide derivatives (PolyMedix, Radnor, PA) to neutralize UFH and LMWH. Plasma was supplemented with UFH or enoxaparin (Sanofi‐Aventis, Paris, France) and protamine or one of six salicylamide derivatives and then analyzed using clotting (aPTT, Heptest, thrombin time) and amidolytic (anti‐Xa, anti‐IIa) assays. Protamine neutralized UFH in all assays. Two salicylamide derivatives produced a comparable effect, while three derivatives exhibited a stronger neutralization of UFH. While residual anti‐Xa and anti‐IIa activity (20% and 10%, respectively) was observed with a 5‐fold protamine excess, complete neutralization was observed with the salicylamide derivatives. Enoxaparin's anticoagulant activity was neutralized by 50% at a 5:1 protamine:enoxaparin ratio and completely by the salicylamide derivatives. 5 of 6 salicylamide derivatives inhibited anti‐Xa activity. The results show that salicylamide derivatives neutralize the anticoagulant and anti‐protease actions of UFH and may be more effective at neutralizing LMWHs. Future studies will characterize the compounds’ PK/PD profile in animal models of bleeding and thrombosis.