Relative Pharmacological Properties
Bleeding risk. Bleeding risk has been the main problem in the application of anticoagulants. Herein, the effect of dHG-5 on bleeding was assessed by the mice tail bleeding model. At 10 times anti-thrombosis ED50 doses, dHG-5 did not significantly increase the blood loss compared with control group (Figure 6C).
f.XII and platelets activation. Native FG had the undesired activation on f.XII and platelets (J. Z. Li, Bao et al. , 1985), which may result in proinflammation or thrombocytopenia, respectively. Therefore, the activation of dHG-5 and its containing oligosaccharides (oHG-8, oHG-14 and oHG-29) on f.XII and platelets were analyzed.
The results showed that dHG-5 and its containing oligosaccharides had no obvious activation on f.XII at the concentrations up to 10 µM (Figure 7A). At the peak concentrations of the bleeding tolerance doses (Figure S28) dHG-5, oHG-8, oHG-14 and oHG-29 showed no obvious activation on platelets, either in human PRP or rat WP, whereas FG could induce platelet aggregation (Figure 7B-C).
Preliminary pharmacodynamics. After administrating subcutaneously to mice, the effect of dHG-5 on plasma APTT was determined (Figure 8). And the pharmacodynamic parameters were calculated according to noncompartmental procedure model (Table S3). The the maximum APTT-prolonging effect (Emax) and AUC0-8h (the area under the time-effect curve within 8 h) increased in a dose-proportional manner, while the half-life (T1/2) did not obviously change (Figure 8 and Table S3).