Fibrinolysis: strategies to enhance the treatment of acute ischemic stroke

Stroke is a major cause of disability worldwide, and is the second leading cause of death after ischemic heart disease. Until recently, tissue-type plasminogen activator (t-PA) was the only treatment for acute ischemic stroke. If administered within 4.5 h of symptom onset, t-PA improves the outcome in stroke patients. Mechanical thrombectomy is now the preferred treatment for patients with acute ischemic stroke resulting from a large-artery occlusion in the anterior circulation. However, the widespread use of mechanical thrombectomy is limited by two factors. First, only ⁓ 10% of patients with acute ischemic stroke have a proximal large-artery occlusion in the anterior circulation and present early enough to undergo mechanical thrombectomy within 6 h; an additional 9-10% of patients presenting within the 6-24-h time window may also qualify for the procedure. Second, not all stroke centers have the resources or expertise to perform mechanical thrombectomy. Nonetheless, patients who present to hospitals where thrombectomy is not an option can receive intravenous t-PA, and those with qualifying anterior circulation strokes can then be transferred to tertiary stroke centers where thrombectomy is available. Therefore, despite the advances afforded by mechanical thrombectomy, there remains a need for treatments that improve the efficacy and safety of thrombolytic therapy. In this review, we discuss: (i) current treatment options for acute ischemic stroke; (ii) the mechanism of action of fibrinolytic agents; and (iii) potential strategies to manipulate the fibrinolytic system to promote endogenous fibrinolysis or to enhance the efficacy of fibrinolytic therapy.