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

Abstract

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

Session Details

Date:	01/08/2007
Time:	00:00-00:00
Session name:	XXIst ISTH Congress
Subject:
Location:	Oxford, UK
Presentation type:
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