Treatment with tPA Predicts Better Outcome Even if MCA Occlusion Persists

Kablau, Micha; Alonso, Angelika; Hennerici, Michael G.; Fatar, Marc

doi:10.1111/j.1747-4949.2011.00750.x

Cited by 15 publications

(9 citation statements)

References 31 publications

(33 reference statements)

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“…9 Moreover, early alteplase treatment was also shown to predict better outcome despite persistence of large artery occlusion. 37 Our results provide mechanistic insights that could explain these clinical data. Indeed, unlike thrombo-embolic models, the monofilament model of tMCAO mimicks such clinical situations in which the causal occlusion and proximal recanalization are not affected by intravenous thrombolytic treatment.…”

Section: Strokementioning

confidence: 93%

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

Desilles

Loyau

Syvannarath

et al. 2015

Stroke

169

134

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Background and Purpose-Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model. Methods-Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion. Results-Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment.Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen. Conclusions-Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke. (Stroke. 2015;46:3241-3248.

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Section: Strokementioning

confidence: 93%

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

Desilles

Loyau

Syvannarath

et al. 2015

Stroke

169

134

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“…The beneficial effect of recanalization by r-tPA is undisputed; however, experimental stroke studies have also reported neurotoxic effects of r-tPA [14, 15]. It was previously reported that r-tPA leads to degranulation of neutrophils, thus increasing NE and MPO in serum [16], and that r-tPA reduces stroke lesion size or outcomes independent of successful recanalization [17, 18]. Potential off-target effects of r-tPA on innate bacterial defence mechanisms of granulocytes and monocytes have not yet been studied; they could, however, be relevant for patient outcomes.…”

Section: Introductionmentioning

confidence: 99%

Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function

Vogelgesang

Lange

Blümke

et al. 2017

J Neuroinflammation

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BackgroundStroke induces immune alterations such as impaired oxidative burst and reduced release of neutrophil extracellular traps (NETs). We hypothesised that key enzymes of these defence mechanisms may be altered in ischaemic stroke. Therefore, we analysed the intra- and extracellular amounts of myeloperoxidase (MPO) and neutrophil elastase (NE) in patient sera and granulocytes and monocytes. Because the autonomous nervous system is thought to mediate stroke-induced immune alterations, we also studied the influence of stress hormones and acetylcholine on MPO and NE.Rapid recanalization by recombinant tissue plasminogen activator (r-tPA) is the only available treatment for ischaemic stroke besides thrombectomy, and its influence on antibacterial defence mechanisms of granulocytes and monocytes were addressed here.MethodsEx vivo: Intracellular and serum MPO and NE were measured on days 0, 1, 3 and 5 post-stroke by either flow cytometry or enzyme-linked immunosorbent assay (ELISA) and compared to controls. In vitro: Blood from healthy donors was incubated with catecholamines, dexamethasone and acetylcholine, and the percentage of NET-producing cells and the area covered by NETs were quantified immunohistochemically. Intra- and extracellular MPO and NE were quantified by flow cytometry or ELISA. Blood samples from healthy donors were incubated with r-tPA, and oxidative burst, phagocytosis, NETosis, cytokine release, MPO and NE were quantified by flow cytometry, ELISA and microscopy.ResultsMPO was reduced in granulocytes but increased in sera obtained from stroke patients compared to controls. NE was not altered intracellularly but was elevated in patient sera. The percentage of NET-producing neutrophils was decreased by stress hormones and increased by acetylcholine. Neither intracellular MPO nor NE was altered by hormone treatment; however, adrenaline and acetylcholine induced NE release.r-tPA led to reduced phagocytosis and oxidative burst in granulocytes and monocytes in vitro. NETosis, MPO release and cytokines were not altered, whereas NE release was enhanced by r-tPA.ConclusionsIntracellular reduction of MPO might be responsible for reduced NETosis in stroke patients. The impact of enhanced MPO and NE serum levels in stroke patients should be addressed in future studies.r-tPA impaired antibacterial defence function in vitro. Therefore, patients who undergo unsuccessful recanalization therapy might be at higher risk for infection, which should be analysed in future investigations. Immune alterations due to r-tPA effects in stroke patients should also be investigated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0914-6) contains supplementary material, which is available to authorized users.

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“…In more recent case reports, tissue plasminogen activator (tPA), a potent fibrinolytic agent, has shown promise in ameliorating cast burden in plastic bronchitis of non-SM causes (7-10), but only anecdotally. tPA is currently used as firstline therapy in several clot-associated diseases, such as stroke (35,36) and myocardial infarction (37), and can improve survival with these life-threatening entities. In regard to plastic bronchitis, no placebo-controlled clinical trials have been done to evaluate the effects of tPA.…”

Section: Clinical Relevancementioning

confidence: 99%

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Veress

Hendry‐Hofer²,

Loader³

et al. 2013

Am J Respir Cell Mol Biol

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Sulfur mustard (SM) inhalation causes the rare but life-threatening disorder of plastic bronchitis, characterized by bronchial cast formation, resulting in severe airway obstruction that can lead to respiratory failure and death. Mortality in those requiring intubation is greater than 80%. To date, no antidote exists for SM toxicity. In addition, therapies for plastic bronchitis are solely anecdotal, due to lack of systematic research available to assess drug efficacy in improving mortality and/or morbidity. Adult rats exposed to SM analog were treated with intratracheal tissue plasminogen activator (tPA) (0.15-0.7 mg/kg, 5.5 and 6.5 h), compared with controls (no treatment, isoflurane, and placebo). Respiratory distress and pulse oximetry were assessed (for 12 or 48 h), and arterial blood gases were obtained at study termination (12 h). Microdissection of fixed lungs was done to assess airway obstruction by casts. Optimal intratracheal tPA treatment (0.7 mg/kg) completely eliminated mortality (0% at 48 h), and greatly improved morbidity in this nearly uniformly fatal disease model (90-100% mortality at 48 h). tPA normalized plastic bronchitis-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress (i.e., clinical scores) while decreasing airway fibrin casts. Intratracheal tPA diminished airwayobstructive fibrin-containing casts while improving clinical respiratory distress, pulmonary gas exchange, tissue oxygenation, and oxygen utilization in our model of severe chemically induced plastic bronchitis. Most importantly, mortality, which was associated with hypoxemia and clinical respiratory distress, was eliminated.Keywords: plastic bronchitis; tissue plasminogen activator; airway obstruction; sulfur mustard; fibrin Sulfur mustard (bis(2-chloroethyl)sulfide; SM) is a vesicant and chemical weapon used in warfare during much of the twentieth century, and which remains in the stockpiles of multiple nations today (Syria, Iran, North Korea, Libya, the United States, and possibly others). SM exposure affects the eyes, skin, upper airways, and lungs. After a brief latent period, respiratory failure and death can develop within 12 to 48 hours. Despite a century of study, the mechanisms responsible for SM's toxic effects remain unsolved, and clinically effective rescue therapies or antidotes are not available.Initial reports of human SM inhalation toxicity in the early 1900s described the presence of airway-obstructive necrotic debris/ mucosa, or "pseudomembranes," in the large airways of victims, and these were more recently confirmed in the victims of the IranIraq war (1, 2). Such severe lesions have been reported to lead to respiratory compromise, with need for artificial ventilation, and death in 80% of those needing intubation (2). Furthermore, chronic conducting airway lesions, such as bronchiolitis obliterans, tracheal/bronchial stenosis, and chronic bronchitis, are commonly found in survivors of SM inhalation months to years after exposure (2, 3), whereas chronic alveolar or paren...

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Treatment with tPA Predicts Better Outcome Even if MCA Occlusion Persists

Cited by 15 publications

References 31 publications

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

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

Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

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