Ali Saad, MD

Lemarchand E, Gauberti M, Martinez de Lizarrondo S, Villain H, Repessé Y, et al. Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis: Role of the Hepatic Clearance of Tissue-Type Plasminogen Activator. Stroke. 2015

The authors put 10% alcohol in mice’s drinking water and allowed them to drink as much as they’d like for 6 weeks. the volume of consumed liquid was similar to the control group who got regular water. They then injected the mice with thombin directly into their MCAs followed by tPA 20 minutes later. Both groups were randomized to either tPA or saline injections (placebo) resulting in 4 treatment groups. finally they got MRIs on them at 2h30min and 24 hours from thrombin administration.

Mice who had been drinking alcohol had 115% larger DWI volumes on MRI compared to control mice who just drank water (p<0.05) when scanned at 2h30min. However, there was no significant difference in DWI volumes at this early time point between the mice who got tPA and those who got saline.

At 24 hours, the DWI volume on MRI remained significantly larger in the alcohol drinking mice compared to control at +78%, p<0.05. Control mice who got tPA had -61.3% DWI volume reduction compared to those who got saline, but this difference disappeared in the alcohol exposed mice. Moreover, the alcohol exposed mice had a 7.6 fold increase in the DWI volume between the 2h30min and 24 hour scans.

The authors did control for perfusion differences between alcohol and normal water mice and found that alcohol did not alter perfusion to the brain. There were no differences in brain swelling/bleeding between the 2 groups. What did change was that alcohol exposed mice had higher factor VII levels and lower PT, factor V, and platelet counts. Low density lipoprotein receptor-related protein 1 (LRP1), which is involved in tPA metabolism, was also down in the alcohol exposed mice. They also found that tPA remained enzymatically active and in the bloodstream significantly longer in the alcohol exposed mice and the penetration into brain tissue was also greater than control by 6 fold. The authors suggest that the neurotoxic effects of tPA is increased in alcohol exposed mice due to BBB leakage thereby leading to worse strokes.

Limitations of this study include: it is a murine model, strokes were induced artificially, and the longer term effects of alcohol on the liver and the clotting cascade are not assessed with this model. The authors mention specific changes to the clotting cascade, but state that there were no differences in the endogenous/exogenous fibrinolytic activity of the 2 groups, which seems contradictory.

Implications of the study would be if this were duplicated in human models, a history of alcoholism or low LRP1 might preclude someone from receiving tPA.

How does this literature change my practice? I might be less optimistic about the beneficial effects of tPA in patients with alcohol abuse. However, i would not withhold treatment. the BBB leakage of tPA leading to direct neuro-toxicity reinforces my belief that the decision to give tPA for stroke mimics is usually OK unless the differential includes RPLS or status epilepticus where there is likely breakdown of the blood brain barrier and increased risk of neuro-toxicity, stroke, or ICH.