Background and Purpose-We investigated the relationship between the degree of thrombus resolution and the time from stroke onset or thrombus formation to intravenous tissue-type plasminogen activator (tPA) treatment. Methods-In patients with stroke, we measured thrombus volume on thin-section noncontrast brain computed tomographic scans taken at baseline and 1 hour after tPA administration. We determined the association between the time from symptom onset to tPA treatment and the degree of thrombus resolution. In a C57/BL6 mouse model of FeCl 3 -induced carotid artery thrombosis, we investigated the effect of tPA administered at different time intervals after thrombus formation, using Doppler-based blood flow measurement. Results-Of 249 patients enrolled, 171 showed thrombus on baseline computed tomography. Thrombus was resolved by ≥50% in 43 patients (25.1%, good volume reduction) and by <50% in 94 patients (55.0%, moderate volume reduction) 1 hour after tPA treatment. In 34 patients (19.9%, nonvolume reduction; either no change or thrombus volume increased), overall thrombus volume increased. The probability of thrombus resolution decreased as the time interval from symptom onset to treatment increased. On multivariate analysis, good volume reduction was independently related with shorter time intervals from symptom onset to tPA treatment (odds ratio, 0.986 per minute saved; 95% confidence interval, 0.974-0.999). In the mouse model, as the interval between thrombus formation and tPA treatment increased, the initiation of recanalization was delayed (P=0.006) and the frequency of final recanalization decreased (P for trends=0.006). Conclusions-Early administration of tPA after stroke onset is associated with better thrombus resolution.

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Microvascular integrity is lost during cerebral ischemia. Detachment of the microvascular basement membrane (BM) from the astrocyte, as well as degradation of the BM, is responsible for the loss of microvascular integrity. However, their ultrastructural and temporal changes during cerebral ischemia are not well known. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) for 1, 4, 8, 12, 16, 20, and 48 hr. By using transmission electron microscopy, the proportion of intact BM-astrocyte contacts and electron densities of the BM were measured from five randomly selected microvessels in the ischemic basal ganglia. Their temporal changes and associations with activities of the matrix metalloproteinases (MMPs) were investigated. The intact portion of the BM-astrocyte contacts was decreased significantly within 4 hr and was rarely observed at 48 hr after MCAO. Decreases in the electron density and degradation of the BM were significant 12 hr after MCAO. The intact BM-astrocyte contacts and the mean BM density showed a significant positive correlation (r = 0.784, P < 0.001). MMP-9 activity was correlated negatively with the intact BM-astrocyte contacts (r = −0.711, P < 0.001) and with the BM density (r = −0.538, P 5 0.0016). The increase in MMP-9 coincided temporally with the loss of the BMastrocyte contacts and a decrease in the BM density. Ultrastructural alterations occurring in the microvascular BM and its contacts with astrocyte endfeet were temporally associated in cerebral ischemia. Time courses of their alterations should be considered in the treatment targeted to the microvascular BM and its contact with astrocytes.Keywords cerebral ischemia; astrocytes; basement membrane; electron microscopy Brain edema and hemorrhagic transformation are major consequences of cerebral ischemic injury. Brain edema is the leading cause of death during the first week after cerebral infarction (Vahedi et al., 2007), and hemorrhagic transformation is a major obstacle of thrombolytic treatment, diminishing its efficacy. Both pathologic conditions are associated with damage to the cerebral microvessels. In addition, microvascular damage may contribute to cell death (Heo et al., 1999). In this regard, protection of the microvessels from ischemic injury could be a major target for specific treatments in acute stroke patients. The cerebral microvessels are a constituent of the blood-brain barrier (BBB), which is composed of microvascular endothelial cells, the basement membrane (BM), astrocyte endfeet, and pericytes (Ballabh et al., 2004). The BM attaches endothelial cells to one side and astrocyte endfeet to the other side. The astrocyte endfeet form an envelope around the blood vessels and are attached to the BM tightly by their adhesion molecules. The BM is composed of extracellular matrix (ECM) molecules such as type IV collagen, laminins, fibronectin, heparan sulfates, and proteoglycans. The integrity of the microvessels is maintained by the presence of an intact BM that provides stru...

Recent advances in endovascular thrombectomy have enabled the histopathologic analysis of fresh thrombi in patients with acute stroke. Histologic analysis has shown that the thrombus composition is very heterogeneous between patients. However, the distribution pattern of each thrombus component often differs between patients with cardiac thrombi and those with arterial thrombi, and the efficacy of endovascular thrombectomy is different according to the thrombus composition. Furthermore, the thrombus age is related to the efficacy of reperfusion therapy. Recent studies have shown that neutrophils and neutrophil extracellular traps contribute to thrombus formation and resistance to reperfusion therapy. Histologic features of thrombi in patients with stroke may provide some clues to stroke etiology, which is helpful for determining the strategy of stroke prevention. Research on thrombus may also be helpful for improving reperfusion therapy, including the development of new thrombolytic agents.