Novel or expanding current targets in fibrinolysis

Wyseure, Tine; Declerck, Paul

doi:10.1016/j.drudis.2014.05.025

Cited by 26 publications

(24 citation statements)

References 59 publications

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“…7,8,10,11 Antifibrinolytic proteins, such as TAFI and PAI-1, have been extensively studied as drug targets in thrombosis-related pathologies. 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.…”

Section: Discussionmentioning

confidence: 99%

“…6 Accordingly, elevated plasma levels of TAFI, PAI-1, or both inhibitors instigate an increased risk for thrombotic disorders (eg, venous thromboembolism, 7 acute ischemic stroke, 8 and acute myocardial infarction 9,10 ) and cause thrombolytic failure. 11,12 A considerable number of studies using animal thrombosis models have demonstrated a beneficial effect of TAFI and PAI-1 as drug targets, 13 but no study has yet shown thrombolytic superiority over plasminogen activators. 14,15 We postulate that single targeting of the antifibrinolytic system does not suffice for robust thrombolysis.…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Inhibition of TAFI was considered as a therapeutic strategy in thrombotic disorders but only a limited number of drug candidates have made it to clinical trials, which were then discontinued (reviewed elsewhere [147, 148]). More recent work has investigated the TAFI-inhibitory ability of TAFI-derived peptides on the protein’s activation and activity.…”

Section: Current Approaches To Reduce Hypofibrinolysis In Diabetesmentioning

confidence: 99%

“…There have been numerous attempts at inhibiting PAI-1 with antibodies, reviewed elsewhere [148, 156] but none have been taken forward to the clinical arena. Recent work in mouse models of thrombotic stroke have shown that simultaneous inhibition of PAI-1 and TAFI with a bispecific antibody results in a significant enhancement of fibrinolysis in mice, without increased bleeding [157].…”

Section: Current Approaches To Reduce Hypofibrinolysis In Diabetesmentioning

confidence: 99%

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Kearney

Tomlinson

Smith

et al. 2017

Cardiovasc Diabetol

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An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition.

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“…Secondary fibrinolysis is caused by fibrin generation. This phenomenon keeps the blood vessels patent by resolving redundant clot [13]. Hyperfibrinolysis occurs when the fibrinolytic (anticoagulation) pathway is activated more than fibrin generation, and causes excessive bleeding which can occur after a variety of major surgical procedures [6,12,14,15].…”

Section: Discussionmentioning

confidence: 99%

Utility of rotational thromboelastometry for the diagnosis of asymptomatic hyperfibrinolysis secondary to anaphylaxis

Koami

Sakamoto²,

Furukawa³

et al. 2016

Blood Coagulation &Amp; Fibrinolysis

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We present a case of hyperfibrinolysis induced by oxaliplatin-derived anaphylactic shock, which was diagnosed with rotational thromboelastometry (ROTEM). A 57-year-old male patient underwent a second course of oxaliplatin (126 mg/m/course)-based chemotherapy for stage IV metastatic rectal cancer. Two minutes after the infusion of oxaliplatin, the patient lost consciousness and developed generalized urticarial lesions, followed by hemodynamic instability and respiratory insufficiency. He was diagnosed anaphylactic shock and transported to emergency department (ED) after intramuscular injection of 0.2 mg of adrenaline, an intravenous injection of 100 mg of hydrocortisone, and 500 mg of methylprednisolone. After arriving in the ED, the patient remained in shock and early resuscitation with administration of 5 mg of D-chlorpheniramine maleate and 20 mg of famotidine was performed. He recovered from his state of shock 30 min after the resuscitation. ROTEM findings showed fulminant hyperfibrinolysis with minimal changes in standard coagulation tests (SCTs) and no remarkable coagulopathy. Seven hours after the attack, he became asymptomatic and follow-up ROTEM revealed values within normal limits with the exception of sustained slight abnormalities of SCTs. He was discharged the next day without any signs of spontaneous bleeding and has continued his outpatient chemotherapy uneventfully. A review of the literature on anaphylaxis-induced hyperfibrinolysis and a discussion of the mechanism between anaphylactic shock and hyperfibrinolysis were performed. Although administration of tissue-type plasminogen activator can play a vital role in anaphylactic shock-induced hyperfibrinolysis, early effective resuscitation is imperative to prevent severe hemorrhagic complications. Therefore, ROTEM is a useful tool that can detect these dynamic changes faster and more accurately than SCTs.

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Novel or expanding current targets in fibrinolysis

Cited by 26 publications

References 59 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

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Utility of rotational thromboelastometry for the diagnosis of asymptomatic hyperfibrinolysis secondary to anaphylaxis

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