Key result
Recombinant neorudin cuts thrombus weight ~51% with less bleeding than equimolar hirudin in rabbits.
Why the study?
The low-bleeding antithrombotic effects of recombinant neorudin were evaluated in experimental thrombosis models to provide a test basis for clinical trials.
Does recombinant neorudin (EH) prevent thrombus formation with reduced bleeding risk compared to hirudin and LMWH in animal models?
Does recombinant neorudin (EH) prevent thrombus formation with reduced bleeding risk compared to hirudin and LMWH in animal models?
Effect estimate: 51.1% reduction
p-value: p=<0.001
Recombinant neorudin (EH) effectively inhibits thrombus formation while reducing the risk of bleeding compared to hirudin and LMWH in preclinical animal models.
Recombinant neorudin merits further preclinical optimization; leaves open translation to human antithrombotic use with lower bleeding risk.
Introduction: Recombinant neorudin (EPR-hirudin, EH) was developed through the addition of an EPR (Glu-Pro-Arg) peptide to the amino terminus of hirudin, which can be recognized and cut by coagulation factors XIa (FXIa) and/or Xa (FXa). In this study, the low-bleeding antithrombotic effects of EH were evaluated utilizing experimental models of thrombosis in rabbits and rats to provide a test basis for clinical trials. Methods: The bleeding risks of EH and hirudin were first compared in mice by the tail-clipping method, and then the antithrombotic activity of EH was investigated in a rabbit model of arteriovenous bypass thrombosis and a rat model of thrombotic cerebral infarction. Results: In mice, intravenous administration of EH at 1.5 mg/kg and 3 mg/kg did not affect the bleeding time compared with normal saline, while the administration of hirudin at 1.5 mg/kg prolonged the bleeding time by over 3 times the administration of normal saline. Furthermore, intravenous administration of EH had a significant dose-dependent inhibitory effect on the formation and development of arteriovenous bypass thrombosis and thrombotic cerebral infarction. Compared with an equimolar dose of hirudin, the antithrombotic effect of EH was similar, while the bleeding side effects were significantly attenuated. Moreover, when the antithrombotic effects were similar, EH had a shorter bleeding time and was associated with less bleeding than low molecular weight heparin (LMWH). EH had a therapeutic effect on thrombotic cerebral infarction without increasing the occurrence of cerebral hemorrhage. Conclusion: The findings from the preclinical animal models used in this study showed that EH could not only effectively inhibit thrombus formation but also reduce the risk of bleeding.
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Liu et al. (2022) studied Thrombosis and cerebral infarction (n=180). Recombinant neorudin (EH) vs. Normal saline, hirudin, low molecular weight heparin (LMWH), and argatroban was evaluated on Wet weight of arteriovenous bypass thrombus in rabbits (51.1% reduction, p=<0.001). Recombinant neorudin at 10 mg/kg significantly reduced the wet weight of arteriovenous thrombi by 51.1% in rabbits and displayed a lower bleeding risk profile compared to equimolar hirudin.
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