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.

Tumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

The efficacy of mesenchymal stem cell (MSC) transplantation in ischemic stroke might depend on the timing of administration. We investigated the optimal time point of MSC transplantation. After MSC treatment, we also investigated the expression of matrix metalloproteinases (MMPs), which play a role in vascular and tissue remodeling. Human bone marrow-derived MSCs (2 × 10⁶, passage 5) were administrated intravenously after permanent middle cerebral artery occlusion (MCAO) was induced in male Sprague-Dawley rats. First, we determined the time point of MSC transplantation that led to maximal neurological recovery at 1 h, 1 day, and 3 days after MCAO. Next, we measured activity of MMP-2 and MMP-9, neurological recovery, infarction volume, and vascular density after transplanting MSCs at the time that led to maximal neurological recovery. Among the MSC-transplanted rats, those of the MSC 1-hour group showed maximal recovery in the rotarod test (P = 0.023) and the Longa score (P = 0.018). MMP-2 activity at 1 day after MCAO in the MSC 1-hour group was significantly higher than that in the control group (P = 0.002), but MMP-9 activity was not distinct. The MSC 1-hour group also showed smaller infarction volume and higher vascular density than did the control group. In a permanent model of rodent MCAO, very early transplantation of human MSCs (1 h after MCAO) produced greater neurological recovery and decreased infraction volume. The elevation of MMP-2 activity and the increase in vascular density after MSC treatment suggest that MSCs might help promote angiogenesis and lead to neurological improvement during the recovery phase after ischemic stroke.

Shim Y, et al. Yonsei Med J. 2021 Nov;62(11):1032-1041. https://doi.org/10.3349/ymj.2021.62.11.1032

BACKGROUND: Cancer is associated with an increased risk of stroke. Tumor cells activate platelets, induce a coagulation cascade, and generate thrombin. The composition of thrombi may reflect the mechanism of thrombosis, aiding the determination of the treatment strategy. Here, we investigated the composition and expression of coagulation factors in the thrombi of patients with cancer-associated stroke. METHODS: Patients with stroke who underwent endovascular thrombectomy between September 2014 and June 2020 and whose cerebral thrombi were obtained were divided into those with cancer-associated stroke (cancer group) and propensity score–matched patients without cancer (control group), using 1:1 matching based on age and sex. Immunohistochemistry was performed of the thrombi, and the composition and expression of coagulation factors were compared between groups. RESULTS: Among the 320 patients who underwent endovascular thrombectomy and who had thrombi obtained, this study included 23 patients with cancer and 23 matched controls. In both groups, the median age was 65 years, and 12 patients (52.2%) were men. Platelet composition was significantly higher in the cancer group than in the control group (median [interquartile range], 51.3% [28.0%–61.4%] versus 9.5% [4.8%–14.0%]; P <0.001). Among coagulation factors, thrombin (26.2% [16.2%–52.7%] versus 4.5% [1.3%–7.2%]; P <0.001) and tissue factors (0.60% [0.34%–2.06%] versus 0.37% [0.22%–0.60%]; P =0.024) were higher and factor X was lower (1.25% [0.39%–3.60%] versus 2.33% [1.67%–4.48%]; P =0.034) in the cancer group. There was a positive correlation between thrombin and platelets in the cancer group (r=0.666; P =0.001) but not in the control group (r=−0.167; P =0.627). CONCLUSIONS: Cerebral thrombi in patients with cancer-associated stroke showed higher proportions of platelets, thrombin, and tissue factors, suggesting their key roles in arterial thrombosis in cancer and providing a therapeutic perspective for preventing stroke in patients with cancer-associated stroke.