Emerging applications of aptamers for anticoagulation and hemostasis

Chabata, Charlene V.; Frederiksen, James W.; Sullenger, Bruce A.; Gunaratne, Ruwan

doi:10.1097/moh.0000000000000452

Cited by 32 publications

(20 citation statements)

References 59 publications

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“…Ir-CPI attenuated arterial and venous thrombosis in murine models, 20 prolonged the time to catheter occlusion in rabbits, and reduced clotting on an extracorporeal circuit in sheep to the same extent as heparin. 21 Although a phase 1 study of Ir-CPI in healthy volunteers is underway (clinicaltrials.gov; NCT04653766), neither Fasxiator nor FXI-directed aptamers 22 have been evaluated in humans.…”

Section: Inhibitors Of Fximentioning

confidence: 99%

Factor XI as a Target for New Anticoagulants

Fredenburgh

Weitz

2021

Hamostaseologie

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Despite advances in anticoagulant therapy, thrombosis remains the leading cause of morbidity and mortality worldwide. Heparin and vitamin K antagonists (VKAs), the first anticoagulants to be used successfully for the prevention and treatment of thrombosis, are associated with a risk of bleeding. These agents target multiple coagulation factors. Thus, by activating antithrombin, heparin mainly inhibits factor Xa and thrombin, whereas VKAs lower the levels of the vitamin K–dependent clotting factors. Direct oral anticoagulants, which have replaced VKAs for many indications, inhibit only factor Xa or thrombin. Although the direct oral anticoagulants are associated with less bleeding than VKAs, bleeding remains their major side effect. Epidemiological and animal studies have identified factor XI as a target for potentially safer anticoagulant drugs because factor XI deficiency or inhibition protects against thrombosis and is associated with little or no bleeding. Several factor XI–directed strategies are currently under investigation. This article (1) reviews the rationale for the development of factor XI inhibitors, (2) identifies the agents in most advanced stages of development, (3) describes the results of completed clinical trials and provides a summary of those underway, and (4) highlights the opportunities and challenges for this next generation of anticoagulants.

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Section: Inhibitors Of Fximentioning

confidence: 99%

Factor XI as a Target for New Anticoagulants

Fredenburgh

Weitz

2021

Hamostaseologie

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“…They bind to their target with high affinity, in the low nanomolar to high picomolar region, similar to monoclonal antibodies. [14][15][16][17][18] They can be chemically modified to customize their bioavailability, chemically synthesized in large scale, and, most pertinent to our application, they can be rapidly reversed. [19][20][21][22] Previous studies by our group demonstrated that antidote-controlled aptamer inhibition of coagulation factor IXa (FIXa) is an effective rapid-onset yet rapidly reversible anticoagulant in patients presenting with acute coronary syndrome.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels

et al. 2019

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Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifested in these diseases, is the leading cause of disability and death in the western world. Current parenteral antithrombotic and thrombolytic agents used to treat these conditions are limited by a short therapeutic window, irreversibility, and major risk of hemorrhage. To overcome these limitations, we developed a novel anti-vWF aptamer, called DTRI-031, that selectively binds and inhibits vWF-mediated platelet adhesion and arterial thrombosis while enabling rapid reversal of this antiplatelet activity by an antidote oligonucleotide (AO). Aptamer DTRI-031 exerts dose-dependent inhibition of platelet aggregation and thrombosis in whole blood and mice, respectively. Moreover, DTRI-031 can achieve potent vascular recanalization of platelet-rich thrombotic occlusions in murine and canine carotid arteries. Finally, DTRI-031 activity is rapidly (<5 min) and completely reversed by AO administration in a murine saphenous vein hemorrhage model, and murine toxicology studies indicate the aptamer is well tolerated. These findings suggest that targeting vWF with an antidote-controllable aptamer potentially represents an effective and safer treatment for thrombosis patients having plateletrich arterial occlusions in the brain, heart, or periphery.

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“…Preclinical studies based on other natural or synthetic direct FXa inhibitors have been completed with promising results, 63,64 thus paving the way to planning randomized clinical trials for testing their efficacy and safety profiles in vivo. Notably, although most of these new compounds act as direct FXa inhibitors, encouraging evidence is also emerging on some antithrombotic molecules and aptamers targeting intrinsic pathway factors (i.e., FIXa, FXIa, and FXIIa), as recently reviewed elsewhere, [65][66][67] while no additional direct thrombin inhibitors seem to be in the pipeline of the pharmacological industry to the best of our knowledge. Some explanation can be proposed, including the hypothesis that the inhibition of FXa, which is in an upstream position in the coagulation cascade, may not directly interfere with preexisting thrombin activity, thus enabling a more effective balance between the risk of bleeding and thrombosis.…”

Section: Resultsmentioning

confidence: 99%

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

Lippi

Gosselin

Favaloro

2019

Semin Thromb Hemost

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Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59–7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

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Emerging applications of aptamers for anticoagulation and hemostasis

Abstract: Overall, these recent findings exemplify the versatility of aptamers to modulate a variety of procoagulant and anticoagulant factors, along with their capacity to be used complementarily with other aptamers or drugs for wide-ranging applications.

Cited by 32 publications

References 59 publications

Factor XI as a Target for New Anticoagulants

Factor XI as a Target for New Anticoagulants

Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

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