Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

Desilles, Jean‐Philippe; Loyau, Stéphane; Syvannarath, Varouna; Gonzalez‐Valcarcel, Jaime; Cantier, Marie; Louedec, Liliane; Lapergue, Bertrand; Amarenco, Pierre; Ajzenberg, Nadine; Jandrot‐Perrus, Martine; Michel, Jean‐Baptiste; Ho‐Tin‐Noé, Benoît; Mazighi, Mikaël

doi:10.1161/strokeaha.115.010721

Cited by 174 publications

(150 citation statements)

References 49 publications

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“…These data strengthen our previous 17 and current intravital observations showing that the thromboinflammatory response to tMCAO is an early event that is initiated before recanalization. From a clinical perspective, it suggests that therapeutical strategies aiming at dampening AIS-associated DMT might require to be administered as early as possible after stroke onset and before recanalization to be efficient whether in NG or HG patients.…”

Section: Discussionsupporting

confidence: 91%

“…One of the characteristic features of petechial bleeding is that it develops at sites of neutrophil extravasation in postcapillary venules. 20 It is worth noting that, confirming our previous results, 17 tMCAO-induced leukocyte recruitment took place almost exclusively in the venous compartment. One could then hypothesize that the exacerbated downstream neutrophil influx from cortical postcapillary venules of HG rats contributes to their higher propensity to develop HT.…”

Section: Discussionsupporting

confidence: 87%

“…17 ELISA-based methods for rat hemoglobin (Abcam; Hemoglobin rat ELISA kit) and rat IgG (Abcam; IgG rat ELISA kit) were used to quantitatively measure HT and BBB disruption in brain homogenates.…”

Section: Determination Of Infarct Size Brain Swelling Neurological mentioning

confidence: 99%

“…17 Therefore, we investigated the impact of preexisting hyperglycemia on tMCAO-induced DMT. Observation of pial surface vessels by intravital microscopy through a partial dura-sparing craniotomy revealed that HG rats presented an abnormal leukocyte rolling and firm adhesion in cortical veins at baseline.…”

Section: Hyperglycemia Exacerbates Dmtmentioning

confidence: 99%

“…15,16 In addition, we have shown that neutrophils were central actors of proximal occlusion-induced downstream microvascular thromboinflammation (DMT), which participates to neurovascular damage in AIS. 17 Neutrophils and DMT might, therefore, contribute to the deleterious impact of preexisting hyperglycemia on AIS. Here we investigated this possibility using a rat model of transient cerebral ischemia caused by proximal cerebral arterial occlusion.…”

mentioning

confidence: 99%

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Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Desilles

Syvannarath

Ollivier

et al. 2017

Stroke

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123

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A cute ischemic stroke (AIS) remains a leading cause of disability, cognitive impairment, and mortality worldwide, despite the development of revascularization therapies. Besides recanalization status, other prognostic factors in AIS patients are associated with clinical outcome. Among them, hyperglycemia has been found to be associated with hemorrhagic transformation (HT) and worsened neurological outcomes. 1,2 Given that 40% to 50% of AIS patients present with hyperglycemia, 3 understanding and reducing hyperglycemia-induced neurovascular injury constitute an important clinical stake. Experimental studies have investigated extensively the relationship between hyperglycemia and poor outcome after AIS. [4][5][6] Notably, these studies have shown that preexisting hyperglycemia, whether acute or prolonged, was an important determinant of brain injury in AIS. In contrast, hyperglycemia induced after the period of ischemia had no effect on experimental stroke outcome.5 Hyperglycemia was further shown to increase cerebral ischemia-reperfusion-induced blood-brain Background and Purpose-Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. Methods-Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. Results-Hyperglycemic rats had an increased infarct volume with an increased blood-brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. Conclusions-We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion-induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood-brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a po...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

Section: Determination Of Infarct Size Brain Swelling Neurological mentioning

confidence: 99%

Section: Hyperglycemia Exacerbates Dmtmentioning

confidence: 99%

mentioning

confidence: 99%

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Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Desilles

Syvannarath

Ollivier

et al. 2017

Stroke

Self Cite

123

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Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke

Zi¹,

Qiu²,

Li³

et al. 2021

JAMA

403

426

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IMPORTANCEFor patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. OBJECTIVE To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020).INTERVENTIONS A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. MAIN OUTCOMES AND MEASURESThe primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was −10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. RESULTSThe trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, −5.1% to ϱ)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, −0.8%; 95% CI, −7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, −0.5%; 95% CI, −10.3% to 9.2%).CONCLUSIONS AND RELEVANCE Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold.

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Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke

Renú

Millán

Román

et al. 2022

JAMA

195

105

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Key PointsQuestionDoes the use of adjunct intra-arterial thrombolysis following an angiographically successful thrombectomy improve functional outcomes in patients with large vessel occlusion acute ischemic stroke?FindingsIn this randomized clinical trial that included 121 adults, treatment with intra-arterial alteplase compared with placebo resulted in a modified Rankin Scale score of 0 or 1 in 59.0% vs 40.4% of patients at 90 days. This difference was statistically significant.MeaningAmong patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days; however, the findings should be considered preliminary until replicated.

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Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

Cited by 174 publications

References 49 publications

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke

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