Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

Kraft, Peter; Schwarz, Tobias; Meijers, Joost C. M.; Stoll, Guido; Kleinschnitz, Christoph

doi:10.1371/journal.pone.0011658

Cited by 33 publications

(23 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13 Notwithstanding promising results, not all studies proclaim that inhibition of 1 antifibrinolytic constituent is sufficient to overcome thrombosis. 31,37,38 Because TAFI and PAI-1 have complementary roles that are localized at the fibrin surface, we hypothesized that simultaneous targeting of the 2 antifibrinolytics would amplify the profibrinolytic capacity in a fibrin-localized manner. Fibrinolysis is driven by enzymatic activation of plasminogen into active plasmin through …”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

• 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...

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…1 We here show that inhibition of PAI-1 and TAFI can protect mice from ischemia/ reperfusion injury by reducing cerebral fibrin(ogen) deposition and improving cerebral reperfusion. Remarkably, using the same model, Kraft et al 12 found that TAFI-deficient mice were unprotected. A plausible explanation could be the fact that MA-TCK26D6 specifically impairs the antifibrinolytic capacity of TAFI while preserving the anti-inflammatory potency of TAFI.…”

Section: September 2016mentioning

confidence: 92%

Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice

Denorme

Wyseure

Peeters

et al. 2016

Stroke

View full text Add to dashboard Cite

Background and Purpose-Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke. Methods-TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated. Results-Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant. Conclusions-Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy.

show abstract

“…Immunoreactivity for fibrin(ogen) (anti-Fibrinogen pAb 1:500; Acris Antibodies) 24 and occludin (antioccludin pAB 1:1000; Abcam) in the ischemic cortices and basal ganglia was detected and quantified by Western blot.…”

Section: Western Blotmentioning

confidence: 99%

C1-Inhibitor Protects From Brain Ischemia-Reperfusion Injury by Combined Antiinflammatory and Antithrombotic Mechanisms

Heydenreich

Nolte

Göb

et al. 2012

Stroke

Self Cite

View full text Add to dashboard Cite

Background and Purpose-Inflammation and thrombosis are pathophysiological hallmarks of ischemic stroke still unamenable to therapeutic interventions. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is involved in stroke development. C1-inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-inhibitor in models of ischemic stroke. Methods-Male and female C57Bl/6 mice and rats of different ages were subjected to middle cerebral artery occlusion and treated with C1-inhibitor after 1 hour or 6 hours. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, thrombus formation, and the local inflammatory response were determined poststroke. Results-Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by Ϸ60% and improved clinical scores in mice of either sex on day 1. This protective effect was preserved at later stages of infarction as well as in elderly mice and in another species, ie, rats. Delayed C1-inhibitor treatment still improved clinical outcome. Blood-brain barrier damage, edema formation, and inflammation were significantly lower compared with controls. Moreover, C1-inhibitor showed strong antithrombotic effects. Conclusions-C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings. (Stroke. 2012;43:2457-2467.)Key Words: blood-brain barrier Ⅲ C1-inhibitor Ⅲ inflammation Ⅲ kallikrein-kinin system Ⅲ middle cerebral artery occlusion Ⅲ thrombosis T he pathology of brain ischemia-reperfusion injury is complex and involves a myriad of distinct molecular and cellular pathways. Among these inflammation is one of the most relevant processes. 1,2 Activation of the cerebral endothelium early after the ischemic event triggers upregulation of cellular adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the circulation into the brain parenchyma. Those cells recruited from the periphery in concert with locally activated cell populations (endothelial cells, microglia, astrocytes) produce an array of highly active mediators such as cytokines and chemokines that perpetuate the inflammatory circuits, thereby causing direct or indirect tissue damage. Another characteristic of persisting ischemia is structural disintegration of the blood-brain barrier, which in consequence leads to the formation of brain edema. 3,4 Excessive edema can harm otherwise healthy brain regions by mechanical compression and is a frequent cause of worsening of neurological symptoms in stroke patients. Until now, convincing pharmacological strategies to combat inflammation or edema formation in acute ischemic stroke are lacking. 5 Current pathophysiological concepts also emphasize the importance of progressive thrombus formation...

show abstract

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

Cited by 33 publications

References 44 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

Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice

C1-Inhibitor Protects From Brain Ischemia-Reperfusion Injury by Combined Antiinflammatory and Antithrombotic Mechanisms

Contact Info

Product

Resources

About