Hemorrhagic Transformation After Ischemic Stroke: Mechanisms and Management

Abstract

Symptomatic hemorrhagic transformation (HT) is one of the complications most likely to lead to death in patients with acute ischemic stroke. HT after acute ischemic stroke is diagnosed when certain areas of cerebral infarction appear as cerebral hemorrhage on radiological images. Its mechanisms are usually explained by disruption of the blood-brain barrier and reperfusion injury that causes leakage of peripheral blood cells. In ischemic infarction, HT may be a natural progression of acute ischemic stroke and can be facilitated or enhanced by reperfusion therapy. Therefore, to balance risks and benefits, HT occurrence in acute stroke settings is an important factor to be considered by physicians to determine whether recanalization therapy should be performed. This review aims to illustrate the pathophysiological mechanisms of HT, outline most HT-related factors after reperfusion therapy, and describe prevention strategies for the occurrence and enlargement of HT, such as blood pressure control. Finally, we propose a promising therapeutic approach based on biological research studies that would help clinicians treat such catastrophic complications.

Keywords: acute; cerebral hemorrhage; hemorrhagic transformation (HT); reperfusion; risk factors; stroke.

Figure 1

Illustration showing correlation between HT and reperfusion time after ischemic stroke. Under the risk factors commonly associated with HT; (A) no HT (no bleeding regardless of reperfusion); (B) early HT (definite bleeding usually 6–24 h after stroke); (C) delayed HT (definite bleeding usually more than 24 h after ischemic stroke). HT, hemorrhagic transformation; ROS, reactive oxygen species.

Figure 2

Possible mechanisms in early and delayed HT. The disruption of the BBB is a common pathway in HT formation following acute ischemic stroke. Various molecules from neutrophils and peripheral blood in possible processes in early HT are mainly associated with HT after ischemic stroke. Exogenous tPA can also increase MMP-9 levels by activating neutrophils and increasing MMP-2 levels. Conversely, in possible processes for delayed HT, the brain tissue is a major source of MMP-9 within the first 18–24 h following stroke, and endogenous tPA can act on endothelial cells to increase MMP-2 release from astrocytes as well as MMP-9 release from microglia. HT, hemorrhagic transformation; NVU, neurovascular unit; MMP, matrix-metalloproteinase; ROS, reactive oxygen species; tPA, tissue plasminogen activator; BBB, blood-brain barrier; VEGF, vascular endothelial growth factor.

Figure 3

Sequential BP changes, cerebral autoregulation, and HT (91). (A) Patient with BP deviation from autoregulatory limits: Relative hyperperfusion above the upper limit of autoregulation may lead to HT and unfavorable outcomes. The yellow arrowhead points out the radiological HT after cerebral ischemic stroke. (B) Patient with acceptable BP fluctuations: Strictly controlled blood pressure within personalized limits of autoregulation can prevent secondary brain injury by protecting against HT after stroke. BP, blood pressure; ULA, upper limit of autoregulation; MAP, mean arterial pressure; LLA, lower limit of autoregulation.

Figure 4

Treatment algorithm for appropriate medical and surgical approaches to HT after ischemic stroke (115). NIHSS, National Institutes of Health Stroke Scale; CT, computed tomography; MRI, magnetic resonance imaging; ICU, intensive care unit; LMWH, low molecular weight heparin; UFH, unfractionated heparin; SBP, systolic blood pressure; IV, intravenous; PCC, prothrombin complex concentrates; FFP, fresh frozen plasma; INR, international normalized ratio; DOAC, direct oral anticoagulants; EVD, external ventricular drainage; ICP, intracranial pressure.