Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

Vercauteren, Ellen; Emmerechts, Jan; Peeters, Miet; Hoylaerts, Marc; Declerck, Paul; Gils, Ann

doi:10.1182/blood-2010-08-303677

Cited by 38 publications

(49 citation statements)

References 33 publications

(45 reference statements)

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“…In a model of thromboplastin-induced thromboembolism, which is well established for the evaluation of profibrinolytic agents, 17,18,23,32 the diabody was tested to determine an effective dose. Because of the extremely low baseline levels of PAI-1 in mice, endotoxemic mice were used in this type of acute model to obtain a potential contributing effect of PAI-1 inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Thromboplastin-induced thromboembolism was performed as described previously, 17 with slight modifications. Endotoxemia was induced in overnightfasted nonanesthetized mice by intraperitoneal injection of lipopolysaccharide (0.5mg/kg) from Escherichia coli serotype 026:B6 (Sigma-Aldrich, St Louis, MO) 3 hours prior to the start of the experiment.…”

Section: Venous Thromboembolism Modelmentioning

confidence: 99%

“…17 Interestingly this antibody also prevents the specific interaction of TAFIa on fibrin, but not on the other small proinflammatory substrates The online version of this article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] MA-TCK26D6 modulates TAFI/TAFIa by impairing activation mediated by thrombin and plasmin; however, it does not block the stronger activator, thrombin/thrombomodulin. 17 Interestingly this antibody also prevents the specific interaction of TAFIa on fibrin, but not on the other small proinflammatory substrates The online version of this article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

“…The thromboprophylactic capacity of the diabody was evaluated in a well-established mouse model of venous thromboembolism. 17,18,23,24 In addition, the effect of the diabody on brain ischemia/reperfusion injury was assessed in a mechanical transient middle cerebral artery occlusion (tMCAo) model in which brain lesion and neurologic/motor outcome were measured. Furthermore, the profibrinolytic capacity was evaluated in 2 stroke models in which in situ clots are induced in the vascular lumen of the middle cerebral artery (MCA) via a thrombin-and a ferric chloride (FeCl 3 )-induced MCA occlusion (MCAo) model.…”

mentioning

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: Resultsmentioning

confidence: 99%

Section: Venous Thromboembolism Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

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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Platelets and Fibrinolysis

Colucci

Semeraro

2017

Platelets in Thrombotic and Non-Thrombotic Disorders

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When I joined Marc Verstraete's laboratory as a medical student in 1959, the emphasis was on hemophilia, vitamin K antagonists as oral anticoagulants, and the development of thrombolysis. Platelet studies were limited to platelet count, bleeding time, and clot retraction. When an otherwise healthy patient with a bleeding disorder had a normal coagulation profile, a normal platelet count, a prolonged bleeding time, and an absent clot retraction, we diagnosed Glanzmann's thrombasthenia; if, however, in the same setting the clot retraction was normal, we considered von Willebrand's disease. How times have changed! In the 1960s, aggregometry allowed the first functional platelet studies; the inhibitory effect of some anti-inflammatory agents, in particular aspirin, was discovered, and the first speculations made about a possible antithrombotic potential of these agents. In the 1970s, there was in scientific meetings a strict divide between "clotters" (studying coagulation) and "clumpers" (studying platelet aggregation); fortunately, this gap gradually narrowed when it became obvious that platelets are closely involved in physiological coagulation and that coagulation induces platelet activation. The 1980s saw confirmation of aspirin as antithrombotic agent; it became a mainstay for the prevention and treatment of arterial vascular disease. At the same time, new developments in cell biology were being applied to megakaryocytes and platelets. Since then, new pathways and receptors have been continuously discovered; the molecular bases of numerous congenital thrombocytopenias have been defined; new platelet inhibitors have been developed and evaluated in clinical studies; platelet inhibition remains crucial despite the continuing progress with vascular stents to combat arterial disease. Platelets are now recognized to play an important role in inflammation, angiogenesis, cancer, etc.So why, in this Internet age, a new book on platelets? Platelet studies are a typical area where cell biology and clinical practice meet. A book is an ideal site to bring these two separate worlds together. Cell biologists are interested in the potential clinical application of their findings; clinicians are interested in the biological basis of their treatments; this book provides all the answers in one place. It now has become impossible to possess the total knowledge on platelets; even experts will benefit from a book like this. For students entering the field, it provides them with a daunting but comprehensive "state of the art," to which they can hope to add new findings.The first edition of this book dates from 2002. When comparing the Tables of Contents, I find, besides an update of previously covered topics, many new entries such as the platelet proteome and transcriptome, CLEC, a new emphasis on neutrophil-platelet interactions, platelets as carriers of genetic material for cell delivery, or platelets in regenerative medicine, among several others.The book now contains 97 chapters. To identify and convince top scientists to contribu...

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Thrombomodulin and its role in inflammation

2011

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The goal is to provide an extensive review of the physiologic role of thrombomodulin (TM) in maintaining vascular homeostasis, with a focus on its anti-inflammatory properties. Data were collected from published research. TM is a transmembrane glycoprotein expressed on the surface of all vascular endothelial cells. Expression of TM is tightly regulated to maintain homeostasis and to ensure a rapid and localized hemostatic and inflammatory response to injury. By virtue of its strategic location, its multidomain structure and complex interactions with thrombin, protein C (PC), thrombin activatable fibrinolysis inhibitor (TAFI), complement components, the Lewis Y antigen, and the cytokine HMGB1, TM exhibits a range of physiologically important anti-inflammatory, anti-coagulant, and anti-fibrinolytic properties. TM is an essential cofactor that impacts on multiple biologic processes. Alterations in expression of TM and its partner proteins may be manifest by inflammatory and thrombotic disorders. Administration of soluble forms of TM holds promise as effective therapies for inflammatory diseases, and infections and malignancies that are complicated by disseminated intravascular coagulation.

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Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

Cited by 38 publications

References 33 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

Platelets and Fibrinolysis

Thrombomodulin and its role in inflammation

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