Next-generation antithrombotics in ischemic stroke: preclinical perspective on ‘bleeding-free antithrombosis’
Therapies Friday, August 10th, 2012Journal of Cerebral Blood Flow & Metabolism: 7/18/12
Recombinant tissue plasminogen activator (tPA) is the only approved medication in acute ischemic stroke. However, <20% of all stroke patients receive tPA (Weimar et al, 2006), a situation mainly owed to the narrow treatment time window of 4.5 hours. Another significant limitation of tPA is bleeding-related adverse events. Moreover, as time increases between symptom onset and treatment, the efficacy of tPA decreases (Lees et al, 2010). In the case of stroke prevention, the situation is not different. Platelet inhibitors (PIs) and anticoagulants are commonly used in (early) secondary prophylaxis, but often with limited efficacy (CAST, 1997; IST, 1997).
It is known for many years that during ischemic stroke platelets become locally activated and adhere to the cerebral endothelium, thereby promoting thrombus formation and subsequent thrombus growth (del Zoppo, 1998; Okada et al, 1994). Consequently, in some of the early experimental studies, the prototype of PIs, acetylsalicylic acid (ASA), was used in an attempt to salvage brain tissue by counteracting detrimental microvascular thrombosis. In rats, ASA was effective only after temporary, but not permanent, occlusion of the MCA (Berger et al, 2007). In mice, multiple applications of very high doses (6 × 40 mg/kg, which corresponds to roughly 19 g for humans) were needed to significantly reduce infarct volumes (Berger et al, 2004). Even then, no amelioration of functional deficits could be observed, whereas lower doses of ASA remained inefficient. Read more
