Injury mechanisms in acute intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is the most common hemorrhagic stroke subtype, and rates are increasing with an aging population. Despite an increase in research and trials of therapies for ICH, mortality remains high and no interventional therapy has been demonstrated to improve outcomes. We review known mechanisms of injury, recent clinical trial results, and newly discovered signaling pathways involved in hematoma clearance. Enthusiasm remains high for methods of minimally invasive clot removal as well as pharmacologic strategies to improve recovery after ICH, both of which are currently being evaluated in clinical trials. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

Keywords: Brain edema; Hematoma; Hypertension; Intracerebral hemorrhage; Iron; Thrombin.

Fig. 1

Axial computerized tomography (CT) scan showing spontaneous cerebellar intracerebral hemorrhage with intraventricular extension causing compression of the 4^th ventricle and brainstem.

Fig. 2

Deferoxamine (DFX) reduces reddish zone around hematoma at days 3 and 7 in a piglet autologous blood injection intracerebral hemorrhage model. Values are mean ± standard deviation, n = 4, cross-hatch (#) denotes p < 0.01 vs. vehicle. Reproduced with permission of Wolters Kluwer Health, Inc. (Gu et al., 2009).

Fig. 3

A schematic of potential methods for reducing the harmful effects of clot-derived neurotoxins in intracerebral hemorrhage. The hematoma contains constituents (e.g., hemoglobin and iron) that can damage perihematomal neural cells directly or indirectly (e.g., by inducing neuroinflammation) – red arrow. These damaging effects might be reduced by several approaches: (1) preventing hematoma expansion after ictus (limiting the size of the hemorrhage), (2) evacuating the hematoma (although as yet there is no definitive evidence for surgical evacuation), (3) accelerating hematoma resolution (e.g., using PPARγ agonists, CD47 blockade), (4) preventing the release of the neurotoxins from the hematoma (e.g., by promoting phagocytosis of erythrocytes over red blood cell lysis, detoxifying neurotoxin while within the hematoma), (5) preventing the uptake of the neurotoxin into perihematomal cells (e.g., potentially CD163 inhibition), (6) preventing cellular toxicity (depends on the individual neurotoxin but includes inhibiting cell injury pathways, ‘neuroprotection’, and inducing protective pathways in the cell).

Fig. 4

(A) Erythrophagocytosis (arrows) at days 3 and 7 in a piglet autologous blood injection model of intracerebral hemorrhage, with hemosiderin deposition (arrowhead) noted at day 7. Scale bar, 10 µm. (B) Time course of CD47 levels in the hematoma. Values are mean ± standard deviation, asterisk (*) and cross-hatch (#) denote p < 0.05 and p < 0.01, respectively, vs. 4-h. Reproduced with permission of Wolters Kluwer Health, Inc. (Cao et al., 2016).