Hemorrhagic Transformation of Ischemic Strokes

Abstract

Ischemic stroke, resulting from insufficient blood supply to the brain, is among the leading causes of death and disability worldwide. A potentially severe complication of the disease itself or its treatment aiming to restore optimal blood flow is hemorrhagic transformation (HT) increasing morbidity and mortality. Detailed summaries can be found in the literature on the pathophysiological background of hemorrhagic transformation, the potential clinical risk factors increasing its chance, and the different biomarkers expected to help in its prediction and clinical outcome. Clinicopathological studies also contribute to the improvement in our knowledge of hemorrhagic transformation. We summarized the clinical risk factors of the hemorrhagic transformation of ischemic strokes in terms of risk reduction and collected the most promising biomarkers in the field. Also, auxiliary treatment options in reperfusion therapies have been reviewed and collected. We highlighted that the optimal timing of revascularization treatment for carefully selected patients and the individualized management of underlying diseases and comorbidities are pivotal. Another important conclusion is that a more intense clinical follow-up including serial cranial CTs for selected patients can be recommended, as clinicopathological investigations have shown HT to be much more common than clinically suspected.

Keywords: antithrombotic treatment; biomarkers; clinical risk factors; clinicopathological studies; hemorrhagic transformation; ischemic stroke; pathophysiology.

Figure 1

Schematic representation of the (a) healthy neurovascular unit (NVU) and blood–brain barrier (BBB) and (b) their disruption due to acute ischemic damage. The NVU is composed of endothelial cells, pericytes, the extracellular matrix (ECM) surrounding them, astrocytes, and neurons. The main components of the BBB are the endothelial cells, the different junctions between them, and the basement membrane. Endothelial cells, pericytes, and the surrounding ECM ensure a regulated trans- and paracellular transport required for the maintenance of the homeostasis in the brain parenchyma under healthy conditions. Mechanical occlusion of a vessel by a thrombus or an embolus, as shown on the right side of the figure, brings about a cascade of events including endothelial swelling, detachment and dysfunction of pericytes and astrocytes. The trans- and paracellular transport changes (represented by blue stars and red dots, respectively), leading to a sequel of pathophysiological processes including cytotoxic edema. Neutrophil cells are recruited to the damaged area; their extravasation, activation, and degranulation contribute to the neuroinflammatory processes mediated by the activated microglia and several soluble factors. Induction of proteases like matrix metalloproteases (MMPs) further enhance ECM degradation and disruption of the BBB.