Hemorrhage transformation (HT) is supposed as one kind of reperfusion injury, involving reperfusion-mediated injury with a biochemical cascade. As a result, HT will lead to secondary deterioration of ischemic brain tissue and neurological deficits [3].
The major pathophysiologic change of HT is the disturbance of vascular wall integrity, which is also known as “BBB disruption”. The permeability of BBB in infarct region increases during the first hour after reperfusion [6], reaches the two peaks after 3 and 48 h [7–9], then decreases gradually. The decrease pro- cess lasts for 4–5 weeks [10, 11]. There are several elements causing the destruction of BBB, for instance, oxygen stress and the neurovascular unit injury [12, 13].
1.1 Mechanisms
1.1.1 Oxidative Stress
The maintenance of the normal cerebral activation mainly depends on the abun- dant energy-supply of mitochondria in brain cells. While acute cerebral ischemia takes place, numerous mitochondrial enzymes such as cytochrome oxidase and manganese superoxide dismutase (MnSOD), will decrease their reactivities, then
Fig. 4.1 The mechanisms and clinical outcomes of reperfusion injury. MMP matrix metallopro- teinase, BBB blood-brain barrier, VCAM-1 vascular cell adhesion molecule-1, HT hemorrhagic transformation
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inhibit oxidative phosphorylation of complex IV and the final electron chain [14].
On one hand, due to lack of cytochrome oxidase (one of the final electron accep- tors), the remaining final electrons have to combine with proximal complexes, once cerebral blood perfusion is recovered. This process results in increasing reac- tive oxygen species (ROS). On the other hand, ischemic mitochondrial reperfusion easily makes complex I dysfunction, affects MnSOD expression, and reduces ROS clearance rate. A rapid increasing of the amount of ROS in the ischemic mitochon- dria causes changes in the cytoskeleton, and affects endothelial and epithelial cells—BBB permeability.
These processes have been found in several animal studies. During reperfu- sion after 2 h of ischemia, mitochondrial respiratory function recovers partially after the first hour. Whereas, after 2–4 h mitochondrial respiratory function will fall into secondary deterioration in the infarct tissues [14]. Folbergrova et al.
also found these similar changes of energy metabolism around the infarct area, suggesting that impaired mitochondrial function is the key to this metabolic response [15].
1.1.2 Neurovascular Unit Injury
Matrix metalloproteinase (MMP) is recognized as an important protease. It affects the permeability of BBB [8], by acting on the basement membrane of the cerebral capillaries. At early stage of reperfusion, up-regulation of MMP-2 and MMP-9 expression degrades tight junction proteins, claudin-5 and occludin, then damages the BBB. Thus, early permeability peak of blood-brain barrier usually develops at 3 h after reperfusion [8, 16]. The underlying second expression peak of important factors (such as MMP, IL-1, TNF-a) may affect the later brain-blood barrier reopening [17].
Postischemic hyperperfusion, such as hyperemia or “luxury perfusion”, has been defined as excess of blood flow or volume than what normal brain metabolic actually needs [18]. However, the underlying mechanisms of how it works and the function of postischemic hyperperfusion are still unclear. It is a double-edged sword, which largely depends on which time course it is [18]. The late postisch- emic reperfusion (12 h after onset), correlating with tissue necrosis, increases the hemorrhage transformation, infarct growth and edema [18]. The possible patho- logical mechanisms causing postischemic hyperperfusion may include the follow- ing two major aspects: (1) autoregulation dysfunction, that is, the accumulated ROS will cause delayed neuronal death and release vasoactive substances (such as lactic acid and adenosine), affecting vascular smooth muscles and leading to dila- tion of blood vessels [19, 20]; (2) BBB damage: If postischemic hyperperfusion starts immediately and persists for a long time, it often prompts malignant hyper- perfusion [21]. Animal experiments have found that when malignant hyperperfu- sion occurred, there were severe edema and serious necrosis of astrocyte foot and endothelial cells, resulting in significant damage of BBB [22].
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1.2 Predictive Imaging Markers
1.2.1 Brain-Blood Barrier Permeability
Hyperintense acute reperfusion marker (HARM), a novel marker of early BBB dis- ruption, can be detected on delayed gadolinium enhancement of cerebrospinal fluid space on fluid-attenuated inversion recovery (FLAIR) [5]. Steven et al. found that among all of the acute ischemic stroke patients, 33% (47/144) of them had the HARM signal, which suggested the presence of early BBB damage. Early reperfu- sion is the strongest predictor of BBB damage (OR = 4.09, 95% CI = 1.28–13.1, p = 0.018). Comparing to those without intravenous thrombolysis, patients treated with intravenous thrombolysis showed significantly higher early BBB damage and rate of hemorrhagic transformation (55% vs. 25%, 31% vs. 14%). Besides, patients with hemorrhagic transformation (73% vs. 25%) was more prone to have early BBB destruction and achieved a poor prognosis (63% vs. 25%).
As for postischemic BBB permeability, there are several quantitative evaluation, including Patlak algorithm. Analysis of dynamic contrast-enhanced magnetic reso- nance imaging (DCE-MRI) using Patlak plots model can provide a quantitative approach to calculate the degree of BBB leakage damage [10, 23]. Parameters esti- mated in the Patlak method model include transfer constant (Ki) of Gd-DTPA and the distribution volume (Vp) of the mobile protons [24]. Abo-Ramadan et al.
observed dynamic changes of parameters (Ki and Vp) from hyper-acute phase to chronic stage of ischemic stroke rat models and found that brain-blood barrier once opened at early stage and then closed, followed with secondary reopening [10].
With these parameters, it becomes possible to predictively depict the vulnerable regions in acute ischemic tissues where is destined for HT.
Lupo et al. pointed out that parameters like relative recirculation (rR) and recovery percentage (%R) can be used to estimate the degree of BBB tight con- nectivity on T2* images [25]. Thornhill et al. also analyzed the dynamic T2* imag- ing of 18 patients with acute cerebral ischemic stroke, among them 8 cases presented with HT. The average rR of those 8 patients with HT were apparently higher than patients without HT (0.22 ± 0.06 vs. 0.14 ± 0.06, p = 0.006), accom- panied by a deceased trend between %R and HT (76 ± 6 versus 82 ± 11%, p = 0.092), suggesting that both rR and %R were potential estimators for BBB leakage and HT identification [26].
1.2.2 Postischemic Hyperperfusion
Postischemic hyperperfusion is a common phenomenon after recanalization, which can be observed in perfusion images such as CT perfusion (CTP), magnetic resonance perfusion-weighted imaging (MRP), arterial spin labeling (ASL), and even earlier positron emission tomography (PET) [27, 28]. By means of cerebral blood flow (CBF) maps, which can be obtained from the above perfusion
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imagings, hyperperfusion is usually identified as visually perceivable regions with patchy increased CBF when compared with the homologous contralateral hemi- sphere [28] (Fig. 4.2).
Yu et al. studied 221 acute ischemic stroke patients due to middle cerebral artery occlusion, with a total of 361 ASL scans and found that postischemic hyperperfu- sion was more likely to appear in the patients who received reperfusion therapies, and was more prone to become HT [28]. Approximately 48% of patients who treated with reperfusion therapy had significant higher blood flow velocity (1.7 times on average) within or around the ischemic core areas than the contralateral side. During follow-up period, a correlation between HT and postischemic hyperperfusion was observed (OR = 3.5, 95% CI = 2.0–6.3, p < 0.001). About 47.6% of patients devel- oped postischemic hyperperfusion and hemorrhagic transformation that occurred at the same time point. Late HT in hyperperfusion areas occurred in 35.7% of patients.
The later time of hyperperfusion was related with the risk of higher grade of HT (Spearman’s rank correlation of 0.44, p = 0.003).