Although hemorrhagic transformation occurs frequently after ischemic stroke, it is often asymptomatic, part of the natural course of ischemic infarction, and may not alter the clinical outcome beyond what is to be expected based on the intrinsic characteristics of the ischemic infarct. Only symptomatic hemorrhagic transformation has clinical relevance. Different stroke trials have varying definitions of what constitutes symptomatic hemorrhagic transformation. In order to clarify this confusion, Berger et al. analyzed data from patients previously enrolled in the European Cooperative Acute Stroke Study (ECASS II) trial and found that clinically significant hemorrhagic transformation occurred mainly if greater than 30% of the infarcted area had dense homogenous-appearing hemorrhage with mass effect. In this case, patients had significantly increased risk of early neurologic deterioration and worse long-term outcome. In patients with smaller (<30%) homogenous hemorrhagic transformation with minimal mass effect, a worse short-term outcome was observed, but no effect on long-term clinical outcome was seen. In contrast, patients with small heterogeneous petechial hemorrhages did not have worse early or long-term outcome.

The mechanisms for hemorrhagic transformation vary depending on the clinical scenario; however, one of the essential requirements is breakdown of the blood–brain barrier (BBB). Certain factors at baseline may predict a higher rate of hemorrhagic transformation. These factors include hyperglycemia, increased patient age, embolic stroke
mechanism, increased infarct size, edema formation, excessive hypertension, increased severity of stroke symptoms, and receiving anticoagulant or tissue-type plasminogen activator (tPA). Patients receiving tPA had about a 6.4% rate of symptomatic hemorrhagic transformation, as seen in the National Institute of Neurological Disorders and Stroke (NINDS) trial. One group of investigators found that tPA use facilitated dysregulation of extracellular proteolysis, resulting in BBB breakdown.