Abstract 14779: Relative Roles of Endogenous Thrombolytic and Anti-Thrombotic Axes in Cardiac Allograft Vasculopathy
Introduction: Nonimmune mechanisms of vascular injury contribute to cardiac allograft vasculopathy (CAV) pathogenesis. To analyze antigen-independent mechanisms contributing to CAV, we hypothesized that creation of a fibrin stroma by thrombosis (or inhibiting fibrinolysis) drives development of an occluding neointima. To test this, we considered the roles of the major fibrinolytic serine protease, tissue plasminogen activator (tPA), its main circulating inhibitor, plasminogen activator inhibitor-1 (PAI-1), and Factor V Leiden (FVL), a major endogenous regulator of thrombosis.
Methods: A fully-vascularized heterotopic (abdominal) murine heart transplant model was used with a full allo-mismatch strain combination of C57BL/6J and B10A. Gene mutant mice (all on C57BL/6J background) were either homozygous PAI-1 or tPA null, or FV mutant, a strain into which the human ortholog of FVL was placed making them thrombophilic by resisting protein C activation. FVL mice were either hetero- or homozygous FVL. Grafts were harvested 8 wks after transplantation and CAV (% luminal occlusion) measured by histomorphometry.
Results: CAV was significantly exacerbated in tPA null donor grafts (60% versus 41% mean neointimal occlusion, tPA null vs WT, n=10, p<0.05), but reduced in PAI-1 deficient recipients (37% versus 49%, PAI-1 null vs WT, n=11, p<0.05). Although there were more perioperative deaths in the homozygote (but not heterozygote) FVL recipients (56%, 20% 12% for FVL homo, FVL hetero, & WT respectively, n=9, 10 & 17, p<0.001 for homo versus others), rates of CAV did not differ between FVL and control groups regardless of whether the donor or recipient mice were mutant in one or both FVL alleles (45% FVL homo, 46% FVL hetero, & 49% WT, respectively, P=NS).
Conclusions: Thrombophilia based on FVL mutation contributes to perioperative mortality, but it does not contribute to CAV in an experimental murine model. Endogenous fibrinolytic mechanisms on the other hand do strongly regulate development of occluding neointima with increased local fibrinolysis being protective. These data suggest that inhibiting circulating PAI-1 could be a therapeutic strategy to protect against CAV.
- © 2010 by American Heart Association, Inc.