The role of thrombin activatable fibrinolysis inhibitor in arterial thrombosis at a young age: the ATTAC study

Bruijne, E.L.E. de; Gils, Ann; Guimarães, Ana H.C.; Dippel, Diederik W.J.; Deckers, Jaap W.; Meiracker, Anton H. van den; Poldermans, Don; Rijken, D.C.; Declerck, Paul; Maat, Moniek P.M. de; Leebeek, Frank W.G.

doi:10.1111/j.1538-7836.2009.03350.x

Cited by 63 publications

(53 citation statements)

References 34 publications

(58 reference statements)

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“…In line with this observation, TAFI and PAI-1 levels are increased in patients suffering from ischemic stroke, often correlating with stroke severity, suggesting a negative impact of these antifibrinolytic molecules in stroke development. 8,[44][45][46][47][48][49][50] Interestingly, whereas the diabody ameliorated the outcome in this model, tPA has a controversial effect, potentially through aggravating neuronal damage after focal cerebral ischemia. 51 As a control, an in vitro neurotoxicity assay was performed with or without N-methyl-D-aspartate and demonstrated the absence of any neurotoxicity associated with the diabody (supplemental Figure 4).…”

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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• 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%

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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“…Even though the CPB2 1040T allele had a protective effect on RA, it is also associated with an increased risk of certain thrombotic diseases (44)(45)(46)(47), which demonstrates the diverse role of CPB in inflammation and coagulation. Although erosive changes were reduced in patients carrying the CPB2 1040T allele, we observed no differences in other disease activity indices, including DAS28, health assessment questionnaire score, tender joint count, and CRP, between CPB2 1040T allele carriers and 1040C homozygotes.…”

Section: Tablementioning

confidence: 99%

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

Song¹,

Hwang²,

Cho³

et al. 2011

J. Clin. Invest.

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The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

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“…15 Male patients aged 18 to 45 years and female patients aged 18 to 55 years, who experienced a first acute ischemic complication in either the heart or the brain, were eligible for inclusion. The patients had coronary heart disease (CHD), including acute myocardial The online version of this article contains a data supplement.…”

Section: Study Populationmentioning

confidence: 99%

Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease

Schie¹,

Maat²,

Isaacs

et al. 2011

Blood

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High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (

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The role of thrombin activatable fibrinolysis inhibitor in arterial thrombosis at a young age: the ATTAC study

Cited by 63 publications

References 34 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

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease

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