Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

Yau, Jonathan W.; Liao, Peng; Fredenburgh, James C.; Stafford, Alan R.; Revenko, Alexey S.; Monia, Brett P.; Weitz, Jeffrey I.

doi:10.1182/blood-2013-12-540872

Cited by 149 publications

(153 citation statements)

References 45 publications

(45 reference statements)

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“…31 Thus, catheters coated with corn trypsin inhibitor, which inhibits FXIIa, remain patent longer than control catheters when inserted in the jugular veins of rabbits. 32 Likewise, in the same rabbit model, FXII knockdown prolongs the catheter-induced occlusion time by >2-fold, 33 and a FXIIa-directed antibody is as effective as heparin at preventing clotting in an extracorporeal membrane oxygenation circuit in rabbits but produces less bleeding. 34 Therefore, these studies suggest that contact activation of FXII initiates clotting on artificial surfaces.…”

Section: Why Target Fxi?mentioning

confidence: 94%

“…Strategies to inhibit FXI are illustrated in Table 2 and include (1) ASOs that reduce hepatic synthesis of the clotting protein 27,33,44 ; (2) monoclonal antibodies that block FXI activation, FXIa activity, or both 25,45,46 ; (3) aptamers that block FXI activation or activity 47,48 ; and (4) small molecules that block the active site of FXIa [49][50][51] or induce allosteric modulation.…”

Section: Strategies To Inhibit Fximentioning

confidence: 99%

“…Up to a month of ASO treatment is required to lower FXI levels into the therapeutic range, which limits their use for initial treatment of thrombosis or for immediate thromboprophylaxis. 27,33,44 In contrast, small-molecule inhibitors and antibodies typically achieve therapeutic levels within minutes or hours of administration. The prolonged half-life of FXI-directed antibodies or ASOs could be problematic if there is bleeding with trauma or surgery.…”

Section: 53mentioning

confidence: 99%

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2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Weitz

Fredenburgh

2018

ATVB

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Abstract-The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI-deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development. Visual Overview-An online visual overview is available for this article. (Arterioscler Thromb Vasc Biol. 2018;38: 304-310.

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Section: Why Target Fxi?mentioning

confidence: 94%

Section: Strategies To Inhibit Fximentioning

confidence: 99%

Section: 53mentioning

confidence: 99%

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2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Weitz

Fredenburgh

2018

ATVB

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“…4 The prothrombotic function of FXII and FXI has been demonstrated in several animal vessel injury models. [5][6][7][8][9][10][11][12][13][14][15] Additionally, platelet-derived polyphosphate (polyP; ;60-70mer) has recently been identified as a weak FXII activator 16 that also promotes the feedback activation of FXI by thrombin 17 and factor V (FV) activation by FXIa, factor Xa (FXa), or thrombin 18,19 and enhances fibrin physical structure. 20,21 Cationic inhibitors of polyP also reduce venous and arterial thrombosis in animal injury models.…”

Section: Introductionmentioning

confidence: 99%

FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

Zhu

Travers

Morrissey

et al. 2015

Blood

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“…De igual forma, la reducción de la expression del FXII y FXI en conejos redujo la incidencia de thrombosis venosa de catéter central (32) .…”

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Tema 17-2014: La Vía De Contacto: ¿el Futuro De Los Anticoagulantes?

López¹

2014

RC_UCR-HSJD

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RESUMENDurante décadas el desarrollo de nuevos anticoagulantes se ha basado en la modificación de fármacos o moléculas previamente disponibles. La poca oferta ha ocasionado que actualmente sea aceptado no administrar anticoagulantes cuando existe una indicación clara de anticoagulación, incrementando así el riesgo de extensión del fenómeno trombótico, el síndrome postrombótico, la discapacidad a largo plazo y las recurrencias, que en conjunto causan más morbilidad y mortalidad que el sangrado secundario a sobreanticoagulación. Los nuevos anticoagulantes orales han ampliado la cantidad de pacientes potenciales, sin embargo existen más opciones viables a mediano plazo que pueden cambiar la anticoagulación tal y como la conocemos hoy en día. Se resume la evidencia disponible en cuanto a la utilización del Sistema de Contacto de la coagulación como modelo para el desarrollo de futuras opciones terapéuticas y sus implicaciones futuras. PALABRAS CLAVEAnticoagulación. Sistema de Contacto. Factor XII. ABSTRACTFor years, the development of new anticoagulant drugs has been based on modifications of previously available compounds. Currently, it is widely accepted to withhold the administration of anticoagulants even in the presence of an indication of anticoagulation, increasing the morbidity, long-term disability and relapses, which together account for more mortality than bleeding as a secondary effect. The novel oral anticoagulants have broadened the number of potential candidates; however, more options are foreseen in the future that can change clinical anticoagulation as it is prescribed today. We will summarize current knowledge on the coagulation Contact System and future therapeutic options.

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Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

Abstract: Key Points Antisense oligonucleotides reduce levels of target hepatic mRNA and protein and decrease clotting activity in rabbits. Selective depletion of factors XI and XII in rabbits attenuates catheter thrombosis, whereas factor VII depletion does not.

Cited by 149 publications

References 45 publications

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

Tema 17-2014: La Vía De Contacto: ¿el Futuro De Los Anticoagulantes?

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