Summary
The purpose of this study was to design and evaluate hirudin (HIR) derivatives with
low bleeding risk. In these derivatives, the factor (F) XIa, FXa, and thrombin recognition
peptides (EPR, GVYAR, and LGPR, respectively) were linked to the N-terminus of HIR.
The intact derivatives have no anticoagulant activity because of the extension of
the N-terminus of HIR. After cleavage by the corresponding coagulation factor that
occurs on the activation of the coagulation system and in the presence of the thrombus,
its activity is released. This limited the anticoagulant activity of these derivatives
to the vicinity of the thrombus, and as a result, systemic bleeding complications
were avoided. The definite antithrombotic effect and low bleeding parameters of these
derivatives were investigated in rat carotid artery and inferior vena cava thrombosis
models. In both models, the three derivatives showed significant antithrombotic effects,
indicating that anticoagulant activity could be successfully released in vivo. Moreover, the bleeding parameters of these derivatives were lower than that of HIR
as indicated by the values of activated partial thromboplastin time (APTT) and thrombin
time (TT). To further assess the safety of these derivatives, bleeding time was measured
in a mouse tail-cut model. Although the derivatives had obvious effects on bleeding
at a dose of 6 mg/kg, the effect of these derivatives on bleeding was significantly
weaker than that of HIR at a dose of 1.5 mg/kg. Thus, the benefit-to-risk profiles
of the derivatives were superior to that of HIR.
Keywords
Hirudin - derivative - blood coagulation factors - bleeding
