Elsevier

The Lancet Neurology

Volume 12, Issue 7, July 2013, Pages 689-705
The Lancet Neurology

Review
Factors influencing haemorrhagic transformation in ischaemic stroke

https://doi.org/10.1016/S1474-4422(13)70055-3Get rights and content

Summary

Haemorrhagic transformation (HT) of ischaemic infarction occurs when an area of brain infarction is stained with blood products, mainly red blood cells. An abnormally permeable blood–brain barrier resulting from ischaemia of the capillary endothelium allows this extravasation of blood products. HT is part of the natural history of some forms of ischaemic infarction, especially cerebral embolism, but it can be precipitated or enhanced by therapeutic interventions used in the acute phase of ischaemic stroke. The old view of HT after cerebral embolism as a generally asymptomatic change in a tissue that is already necrotic has been challenged by observations from therapeutic thrombolysis that suggest that HT can have a negative effect on patients' outcomes. Understanding of the risk factors for and the underlying mechanisms and clinical variability of HT in the context of acute therapeutic interventions in ischaemic stroke could help in the early detection of this complication, in determining the safety of recanalisation approaches, and in setting the stage for future research into the prevention or treatment of HT in patients with acute ischaemic stroke.

Introduction

Haemorrhagic transformation (HT) is a frequent, often asymptomatic event that occurs after acute ischaemic stroke and is detected by routine CT or MRI. The incidence of HT is difficult to estimate accurately because of inter-study differences in the definition of HT, in the techniques used for brain imaging, and in the timing of assessment from stroke onset. However, it is known to occur as part of the natural history of cerebral infarction, and its frequency and severity are increased by the use of anticoagulants, thrombolytics, and endovascular manipulations.

HT occurs when an initially so-called pale area of brain infarction becomes blood-stained owing to the extravasation of blood products, especially red blood cells, into the infarcted brain tissue.1 Abnormal permeability of the blood–brain barrier resulting from ischaemic endothelial dysfunction of capillaries within an area of infarction underlies both brain oedema and HT of ischaemic brain tissue.2, 3 The process of HT tends to occur in areas of grey matter such as the deep grey nuclei and the cerebral cortex because the density of capillaries is greater in grey matter than in white matter. Because HT occurs in brain tissue that is already necrotic, often no clinical changes that signal the development of HT are seen. However, the severity of HT varies from small, asymptomatic petechial staining of necrotic brain tissue to the extreme of severe, confluent, and symptomatic HT caused by whole-blood extravasation through the severely disrupted ischaemic endothelium. Because HT can cause clinical deterioration with associated poor outcomes by contributing to an increase in brain tissue damage, establishment of whether HT, either symptomatic or asymptomatic, can be precipitated or exacerbated by therapeutic interventions in the acute phase of ischaemic brain infarction is important. This question has become more relevant as therapies that alter blood coagulation and fibrinolysis, such as antithrombotic and thrombolytic drugs, have increasingly been used, often in combination with recanalisation of the initially occluded cerebral arteries by various interventions.

In this Review, we focus on the clinical, imaging, and laboratory factors that most consistently predict the frequency and severity of HT, with the aim of helping clinicians to assess the risks associated with recanalisation techniques available for the management of patients with acute ischaemic stroke. We hope that knowledge of these data will stimulate research into measures that could reduce the frequency, severity, and clinical consequences of HT in patients with acute ischaemic stroke.

Section snippets

Pathophysiology

Several mechanisms have been suggested to underlie HT of brain infarction. Fragmentation and distal migration of an embolus, with reperfusion of an ischaemic vascular bed, leads to HT close to the initial site of occlusion,1 as exemplified by HT in the basal ganglia region after initial embolic occlusion of the middle cerebral artery stem (figure 1). An alternative anatomical pattern of HT occurs along the most distal portions of an ischaemic arterial territory by reperfusion of ischaemic

Classification

The classification of HT after acute ischaemic stroke has varied across studies as different authors have attempted to define HT by degree of severity and, to a lesser extent, by clinical consequences. Pessin and colleagues17 were among the first authors to delineate the anatomical varieties of HT, and their observations formed the basis of definitions that were used subsequently in clinical trials and clinical series of post-thrombolysis HT. The following distinctions are based on the clinical

Risk factors for and predictors of HT

Several factors are associated with or predict HT. Although the usefulness of some of these markers in clinical practice might be limited, the development of imaging techniques and the identification of predictive biomarkers might help in the selection of patients at increased risk of HT as a group of particular interest when fibrinolytic or antithrombotic therapy are being considered in the setting of acute ischaemic stroke.

Implications for management of patients

The predictive value of the various factors that we have discussed, and their potential for interaction, need to be considered in the context of the clinical management of patients with acute ischaemic stroke. For the clinician at the bedside who is trying to estimate the risk of HT, especially parenchymal haemorrhage, in a patient who is a candidate for thrombolysis or other revascularisation therapies, the combination of clinical and imaging data from the neurological examination and early CT

Prevention strategies and future research

Strong evidence exists to suggest that matrix metalloproteinases, especially matrix metalloproteinase 9, have a central role in the pathogenesis of the abnormal permeability of the blood–brain barrier that underlies HT. The use of drugs that block the release of matrix metalloproteinase 9 is promising; the preventive effect of the phosphodiesterase-III inhibitor cilostazol for HT after alteplase treatment has been shown in a mouse model of focal ischaemia.170 Cilostazol prevented the

Search strategy and selection criteria

We searched PubMed for articles published in English between 2000 and November, 2012, using the search terms “haemorrhagic transformation”, “ischaemic stroke”, and “thrombolysis.” We manually searched the reference lists of published articles and our personal files for further articles. We included papers published before 2000 if they were considered relevant to the scope of this Review, especially those dealing with the pathophysiology of HT and the use of intravenous alteplase in acute

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