IN VIVO EFFECTS OF MURINE AND HUMAN APC
Abstract number: O-T-094
Furlan Freguia1 C., Schuettrumpf1 J., Zou1 J., Schlachterman1 A., Downey1 H.D., Baila1 S., Zhou1 S., Arruda1 V.R.
1Pediatrics, The Childrens Hospital of Philadelphia, Philadelphia, United States
How-to-cite Furlan Freguia C, Schuettrumpf J, Zou J, Schlachterman A, Downey HD, Baila S, Zhou S, Arruda VR. IN VIVO EFFECTS OF MURINE AND HUMAN APC. J Thromb Haemost 2007; 5 Supplement 2: O-T-094
Introduction: Because APC as anticoagulant and/or anti-inflammatory drug may have several clinical applications, we sought to create models for continuous expression of stable levels of APC to facilitate the assessment of APC's effects in vivo.
Methods: Eight dose-cohorts of mice (n=5-10/group) were injected with adeno-associated viral vectors to direct liver-expression of human (h) or murine (m) APC or zymogen hPC or mPC. APC levels were measured by specie-specific ELISA capture assays and aPTT. Thrombosis models included the laser-induced damage to cremaster arteriole (microcirculation) and FeCl3-carotid artery injury (macrocirculation).
Results: We determine a dose-dependent increase in APC levels, ranging from 25-260ng/ml or 10-83ng/ml of hAPC and mAPC, respectively. PC-treated mice failed to increase APC levels. These data agree with prolongation of the aPTTs. At comparable levels mAPC is superior to hAPC (~80ng/ml) in terms of prolonging clotting times (36.4 vs. 31.8sec) and by 2-fold higher blood-loss after tail-cut (p<0.05). Both APC forms reduce the rates of thrombus formation at the microcirculation. Notably, mAPC levels required to prevent >90% of thrombi are 3-fold lower than those of hAPC, whereas zymogens provide no anticoagulant effect. However, prevention rates of thrombosis at macrocirculation were similar for hAPC and mAPC groups (100% vs. 75%, respectively). The minimum levels of hAPC or mAPC to achieve sustained anticoagulation at both thrombosis models without increased risk of bleeding were 160 and 20ng/ml, respectively. Upon induction of LPS-mediated sepsis, hAPC (260 ng/ml) decreased mortality rates compared to controls (91% vs. 61%, p<0.03) at LD-50. Surprisingly, mAPC at the highest tested levels was of modest benefit. These findings raise concerns on the safety of prolonged periods of APC infusion.
Conclusions: APC's anticoagulant and anti-inflammatory properties in vivo are clearly independent. This strategy provides a valid tool to assess APC's role in complex disease models.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
||XXIst ISTH Congress
| Back to top