Current Understandings on Biological Characteristics of Thrombolytics in Acute Ischemic Stroke

Acute ischemic stroke leads to rapid and progressive neuronal losses. Early revascularization with thrombolytics and/or endovascular thrombectomy plays an important role in salvaging brain infarction. Currently, alteplase and tenecteplase are approved thrombolytics for the treatment of acute ischemic stroke, whereas favorable outcomes of reteplase have recently been reported in a phase 3 clinical trial. These thrombolytics share common and distinct pharmacological characteristics, which contribute to their efficacy and safety in patients. In this review, biological profiles of alteplase, tenecteplase, and reteplase, including their advantages versus disadvantages in acute ischemic stroke, are discussed. Tenecteplase has high fibrin specificity, increased resistance to plasminogen activator inhibitor-1 (PAI-1), wider concentration-response curve, and less off-target activities, which support its efficacy with low incidence of symptomatic intracranial hemorrhage (sICH). Reteplase greatly penetrates into the clot with prolonged retention, generating durable clot lysis. This activity might be associated with its excellent clinical outcomes in patients, although reteplase is sensitive to PAI-1. Notably, reteplase and alteplase produce off-target activities by inducing hypofibrinogenemia and hypoplasminogenemia, which may increase risk of hemorrhagic transformation. Moreover, orolingual angioedema is a life-threatening complication of all thrombolytics. Mechanistically, an increase in plasmin by thrombolytics leads to bradykinin generation. In addition, plasmin activates mast cell degranulation (e.g., histamine release). Together, these biopharmacological data of thrombolytics promote insights into their clinical outcomes, and might provide comprehensive bases for future research.