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Response to Letter Regarding Article, “Smoking-Thrombolysis Paradox: Recanalization and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischemic Stroke”

Originally published 2013;44:e59


We thank Plas et al1 for their interest in our article and for sharing their results about the smoking–thrombolysis paradox in ischemic stroke. A meta-analysis is an important further step to clarify the much debated and often conflicting results on this topic. Plas et al1 performed an analysis of 7 studies including 7494 patients receiving thrombolysis, which revealed an odds ratio of 1.38 (95% confidence interval, 1.24–1.53; P=0.02) for smoking in favor of a good functional outcome (modified Rankin Scale score ≤2) 3 months after stroke. The authors pointed out that the lack of adjustment for age and sex is a limitation of their analysis. This is an essential point, because smokers tend to be significantly younger and more often are men. Age is a strong predictor for outcome and studies have shown gender-specific differences in vascular risk factors and functional recovery.2 Nonetheless, the meta-analysis is reassuring that our observation is not a mere result of chance. An appropriately adjusted meta-analysis is without a doubt still necessary to determine the concrete effects of smoking on ischemic stroke.

Two recent studies have shed light on possible pathophysiological mechanisms underlying this peculiar phenomenon. One suggests smoking to have early protective effects and the other suggests an enhanced treatment efficacy in patients with this risk factor. Lisi et al3 provide evidence suggesting that short-term exposure to reactive oxygen species caused by smoking triggers ischemic preconditioning, reducing endothelial susceptibility to ischemia and reperfusion damage. Nielsen et al4 propose that smoking alters the nature of plasmin–antiplasmin–carbon monoxide interactions in blood plasma, consequently modifying fibrin clot kinetics. Earlier studies have demonstrated that smoking decreases endogenous tissue-type plasminogen activator release, causing an increase in fibrinogen levels and more fibrin-rich thrombi, thereby increasing susceptibility to exogenous tissue-type plasminogen activator treatment.5

Smoking remains a proven risk factor for stroke and has detrimental effects on the cardiovascular system. Whether smoking leads to increased tissue-type plasminogen activator efficacy deserves further studies. Either way, we continue to believe that no stroke is always better than a recanalized stroke.

Anna Kufner, MScChristian H. Nolte, MDMartin Ebinger, MDKlinik und Hochschulambulanz für NeurologieCharité—Universitätsmedizin BerlinBerlin, Germany


Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited. Include a completed copyright transfer agreement form (available online at and


  • 1. Plas GJJ, Uyttenboogaart M, Luijckx G-J. Letter regarding article, ‘smoking-thrombolysis paradox: recanalization and reperfusion rates after intravenous tissue plasminogen activator in smokers with ischemic stroke.’2013; 44: e58.Google Scholar
  • 2. De Silva DA, Ebinger M, Davis SM. Gender issues in acute stroke thrombolysis.J Clin Neurosci. 2009; 16:501–504.CrossrefMedlineGoogle Scholar
  • 3. Lisi M, Dragoni S, Leone MC, Munzel T, Parker JD, Gori T. Acute (but not chronic) smoking paradoxically protects the endothelium from ischemia and reperfusion: insight into the “smoking paradox.”Clin Res Cardiol. 2013(Epub ahead of print).CrossrefMedlineGoogle Scholar
  • 4. Nielsen VG, Hafner DT, Steinbrenner EB. Can divergent plasmin-antiplasmin-carbon monoxide interactions in young, healthy tobacco smokers explain the ‘smoker’s paradox’?Blood Coagul Fibrinolysis. 2013(Epub ahead of print).CrossrefGoogle Scholar
  • 5. Newby DE, McLeod AL, Uren NG, Flint L, Ludlam CA, Webb DJ, et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.Circulation. 2001; 103:1936–1941.LinkGoogle Scholar


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