Intracranial Bleeding after Reperfusion Therapy in Acute Ischemic Stroke

The use of reperfusion therapy with intravenous (iv) thrombolytic agents (alteplase and tenecteplase) and /or endovascular treatment in ischemic stroke patients is now a standard of care. Intracranial bleeding, however, is the most feared complication of reperfusion therapy. The bleeding can occur either within the infarcted brain tissue (referred to as hemorrhagic transformation (HT)) or in the tissue remote from the cerebral ischemia (referred to as remote parenchymal hemorrhage (rPH)). HT occurs spontaneously during the evolution of the cerebral infarct, and risk is further increased with reperfusion therapy. In the positive iv alteplase trials (NINDS and ECASS III), the risk from iv alteplase in an approved time window (<3h and 3-4.5h respectively) was increased; however, it did not translate into excess mortality. This argument is now commonly used in support of iv alteplase. The EXTEND-IA tenecteplase trial showed symptomatic hemorrhage risk which was similar between the iv alteplase and iv tenecteplase arms of the trial. In the late time window, the HERMES trialists noted that the rate of symptomatic intracranial bleeding was similar in patients treated with endovascular therapy and those with iv alteplase.

Whereas these clinical data have been reassuring, our goal should be to mitigate the risk of intracranial bleeding also at an individual patient level. Various approaches can be adopted towards this goal. For example, by identifying patients with imaging profiles linked to increased bleeding risk (e.g. very low cerebral blood volume, prolonged Tmax delay, poor or absent collateral flow, an elevated hypoperfusion intensity ratio, and disrupted blood brain barrier), one can exclude them from receiving reperfusion therapy; use this information to discuss risk with patient and family, and nevertheless go ahead and treat these patients; weigh in the risks associated with reperfusion therapy and adopt neuroprotective measures to prevent worse outcome; and design studies to test the role of novel interventions (e.g. neuroprotectants; sonothrombolysis) in reperfusion therapy and use these imaging approaches to stratify patient population and add to the robustness of the trials. Thrombolytic agents like desmoteplase and tenecteplase appear to have better safety and efficacy profiles compared to iv alteplase but need further investigation, particularly with respect to bleeding risk and efficacy profile within the approved time window. Antithrombotic agents like argatroban and abciximab need continued investigation to assess whether greater recanalization rates are associated with increased bleeding risk in acute ischemic stroke patients. There is therefore a critical need to develop a better understanding of the pathomechanism linked to intracranial bleeding in these patients treated with various reperfusion strategies.

We therefore welcome reports on human studies for this Research Topic. We aim to educate our readership about the contemporary knowledge on the pathomechanism of intracranial bleeding in ischemic stroke patients who receive reperfusion therapy, and about research methodology that can be adopted to reduce this risk. For this Research Topic we welcome articles relevant to the following topics:

• History of intracranial bleeding after reperfusion therapy;
• Pathomechanisms of intracranial bleeding following iv alteplase;
• Pathomechanisms of intracranial bleeding following endovascular therapy;
• Safety and efficacy of Desmoteplase, Tenecteplase and Urokinase;
• Patterns and implications of blood brain barrier disruption;
• Neuroimaging predictors of hemorrhagic transformation;
• Hemorrhagic transformation in patients treated with Sonothrombolysis;
• Management of Intracranial Hemorrhage following reperfusion therapy;
• Intracranial hemorrhage in patients with milder strokes;
• Intracranial hemorrhage in patients with ischemic stroke linked to small vessel disease;
• Clinical trials and future directions in preventing the risk of intracranial bleeding following reperfusion therapy.