Impact of Tissue Plasminogen Activator on the Neurovascular Unit: From Clinical Data to Experimental Evidence

Vivien, Denis; Gauberti, Maxime; Montagne, Axel; Defer, Gilles; Touzé, Emmanuel

doi:10.1038/jcbfm.2011.127

Cited by 96 publications

(79 citation statements)

References 147 publications

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“…The presence of resistant platelet-rich clots contributes to the failure of thrombolytic therapy in the majority of patients. 52,53 Thus, in this model, tPA does not reduce the lesion volume nor does it improve recanalization, even when administered early (ie, at 20 minutes postocclusion). 29 In clinical practice, cerebral blood flow (CBF) is often measured during and early after tPA administration to evaluate the success of tPA-mediated thrombolysis.…”

Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paimentioning

confidence: 99%

“…2,3 This reluctance against thrombolysis stems from life-threatening side effects (hemorrhagic transformation and possible neurotoxicity of tPA) and a thrombus-resolving efficiency that is rather low. 52,53 Unexpectedly, neuroprotective agents, which block molecular elaboration of ischemic insult on brain cells, have shown no clinical benefit in patients despite their preclinical efficacy. 54 Because recanalization of the occluded vessel is in essence associated with improved clinical outcome, 1 it makes sense to target proteins such as TAFI and PAI-1 that inhibit thrombolysis.…”

Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paimentioning

confidence: 99%

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Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Wyseure

Rubio

Denorme

et al. 2015

Blood

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• Early thrombolytic treatment with a bispecific inhibitor against TAFI and PAI-1 is effective without exogenous tPA.• Even at the highest dose tested, the bispecific inhibitor against TAFI and PAI-1 does not prolong bleeding time.Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissuetype plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding. (Blood. 2015;125(8):1325-1332 IntroductionPlasminogen activators are the only thrombolytic agents approved to rapidly revascularize a thrombosed vessel. Reperfusion of the ischemiaaffected organ leads to an improved outcome in patients when applied within the first hours after ischemic onset.1 Despite this evidence-based beneficial effect, current thrombolytic agents remain widely underutilized due to life-threatening side effects such as cerebral hemorrhages and possible neurotoxicity.2,3 For acute ischemic stroke, in particular, the only licensed treatment option consists of a high systemic dose of recombinant tissue-type plasminogen activator (tPA), which is actually given to ,10% of the patients. Therefore, there is an unmet clinical need to explore novel therapeutic avenues to enhance fibrinolysis without plasminogen activator-associated adverse effects. Endogenous intravascular fibrinolysis is driven on the release of tPA from the endothelium, which in turn enzymatically activates plasminogen into the fibrin-degrading enzyme, plasmin.4 This activation step is attenuated by circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1). Activated TAFI (TAFIa; encoded by the CPB2 gene) eliminates C-terminal Lys exposed on partially degraded fibrin, which ultimately leads to a diminished efficiency and localizati...

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Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paimentioning

confidence: 99%

Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paimentioning

confidence: 99%

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Wyseure

Rubio

Denorme

et al. 2015

Blood

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“…10 Moreover, to the best of our knowledge, the effects of rtPA on chemokine expression in animal models of stroke have not yet been investigated. In the current study, we analyzed cellular adhesion molecule, chemokine and cytokine expressions as well as inflammatory cell recruitment, brain injury, and mortality up to 72 hours after stroke in mice treated with rtPA or saline.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

Lenglet

Montecucco

Coutts

et al. 2014

J Cereb Blood Flow Metab

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The effect of recombinant human tissue plasminogen activator (rtPA) on neuroinflammation after stroke remains largely unknown. Here, we tested the effect of rtPA on expression of cellular adhesion molecules, chemokines, and cytokines, and compared those with levels of inflammatory cell recruitment, brain injury, and mortality over 3 days after transient middle cerebral artery occlusion (MCAO) in mice. Mortality was dramatically increased after rtPA treatment compared with saline treatment during the first day of reperfusion. Among the animals that survived, rtPA significantly increased CCL3 expression, microglia recruitment, and cerebral infarction 6 hours after MCAO. In contrast, the extent of neutrophils and macrophages infiltration in the brain was similar in both saline-and rtPA-treated animals. Recombinant human tissue plasminogen activator induced Il1b and Tnf expression, 6 and 72 hours after MCAO, respectively, and dramatically reduced interleukin 6 (IL-6) level 24 hours after reperfusion. A dose response study confirmed the effect of rtPA on CCL3 and Il1b expressions. The effect was similar at the doses of 1 and 10 mg/kg. In conclusion, we report for the first time that rtPA amplified microglia recruitment early after stroke in association with a rapid CCL3 production. This early response may take part in the higher susceptibility of rtPA-treated animals to reperfusion injury.

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“…To override this limiting effect, intravenous tPA is administered. tPA can also increase the permeability of the blood-brain barrier from activation of latent platelet-derived growth factor-CC (PDGF-CC) [14,15], and an increase in matrix metalloproteinases [16]. Furthermore, tPA enhances the excitotoxic effect of glutamatergic (NMDA) receptors [17].…”

Section: Actions Of Tpamentioning

confidence: 99%

Minocycline: A Novel Stroke Therapy

Møller¹

2015

JNSK

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Impact of Tissue Plasminogen Activator on the Neurovascular Unit: From Clinical Data to Experimental Evidence

Cited by 96 publications

References 147 publications

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

Minocycline: A Novel Stroke Therapy

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