New class of heparin derivatives with a potent antithrombotic effect and a very limited hemorrhagic activity

Eight heparin derivatives (HD1 to HD8) were prepared by mixing various doses of protamine with a fixed amount of heparin. After centrifugation and elimination of the formed complex, the supernatant was lyophilized and titrated. A dose of 5 mg (dry weight)/kg of these heparin derivatives was injected subcutaneously to rats in classical thrombosis model induced by stasis. Antithrombotic, hemorrhagic and anticoagulant activities are investigated and compared to those of Unfractionated Heparin (UFH) and LMWH (Enoxaparin). Seven rats in each group were studied. Significant antithrombic effect was exhibited by HD1, HD2, HD3, and HD4 which decreased progressively. Only HD1, HD2, and HD3 augmented hemorrhagic activity but to a lower degree than UFH and LMWH. No change was observed by coagulation assays; Activated Partial Thromboplastin Time (APTT) and Diluted Thrombin Time (dTT) and there was no effect on platelet aggregation except for UFH. These heparin derivatives might present advantages over UFH and LMWH in the treatment of thrombosis.