Abstract 310: Do Biologic Variations in Plasminogen Levels Affect Endogenous Fibrinolysis and Outcomes in Acute Thrombotic Disease Such as Ischemic Stroke?

Abstract

Introduction: After activation of plasminogen (Pg), plasmin is the key enzyme that acutely dissolves thrombi. Yet, despite significant biologic variation in Pg levels between humans, there is no clear link between Pg levels (or Pg deficiency) and the development or resolution of acute thrombotic vascular diseases such as stroke. Hypothesis: We tested the hypothesis that plasma levels of Pg affect endogenous fibrinolysis, brain injury, hemorrhage and swelling after thromboembolic stroke. Methods and results: We examined male and female Pg +/+ ([Pg] =84±4.8 μg/ml), Pg +/- ([Pg] =37±5.2 μg/ml) and Pg -/- ([Pg] =1.3±3 μg/ml) mice, n= 10-13 per group. Ischemic stroke was induced by endovascular placement of an autologous 125 I-fibrin plasma clot at the origin of middle cerebral artery (MCA) that reduced hemispheric blood flow by ≥80%. After 6 hours of stroke, the dissolution of the culprit MCA thrombus was determined and the effects on brain injury were assessed. Data was analyzed by a two-way ANOVA with Neumann-Keul’s correction. There was a dose-dependent relationship between Pg levels and endogenous dissolution of the MCA thrombus (p=0.0019) with Pg +/+ mice showing greater lysis (20.7±6.6%) than Pg +/- mice (19.0±3.8%) and Pg -/- mice (12.6±6.4%). There was a significant, inverse dose-response effect on brain infarction with higher Pg levels associated with less severe infarction: Pg +/+ (24.8±4.3%) <Pg +/- (27.3±9.4%) <Pg -/- (37.4±8.9%) mice. No significant sex based differences were found in fibrinolysis and brain injury. Brain swelling showed a significant, but non-linear dose-dependence on Pg levels (p<0.01) which was affected by sex (p<0.01). There was no significant association between brain hemorrhage and Pg levels. Conclusions: In vivo, Pg levels have concentration-dependent effects on endogenous fibrinolysis, brain infarction and swelling after thromboembolic stroke. Further studies should be done to assess how Pg levels may affect outcomes in human thrombotic diseases.