Future prospects for contact factors as therapeutic targets

Gailani, David

doi:10.1182/asheducation-2014.1.52

Cited by 24 publications

(33 citation statements)

References 55 publications

(55 reference statements)

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“…[19][20][21] Support for a more prominent role of FXI over FXII in thrombosis comes from epidemiological studies (Table 1). Notably, congenital FXI deficiency is protective against venous thromboembolism (VTE), ischemic stroke, and myocardial infarction, whereas FXII deficiency not only is not protective but also may increase the risk.…”

Section: Why Target Fxi?mentioning

confidence: 99%

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: 99%

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Weitz

Fredenburgh

2018

ATVB

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“…22 These observations suggest that the contact pathway is a potential source of therapeutic targets for safer antithrombotic therapies. 23 Distinct from testing in animal models, testing inhibitors of FXIa and polyP in human blood under thrombotic flow conditions helps to prioritize and inform inhibitor development against these targets. Importantly, platelet concentrations in wallattached thrombi that form under flow are 50-to 200-fold greater than those found in whole blood, a complexity that distinguishes microfluidic flow studies from test tube studies.…”

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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“…These observations suggest that thrombosis is not a simple imbalance of hemostasis, the physiological process that prevents loss of blood from the vasculature, but rather, the result of alternative stimuli that exploit the hemostatic system. 27,28 Evolving treatment paradigms for arterial and venous thrombosis…”

Section: Role Of Thrombin In Thrombosismentioning

confidence: 99%

“…Interest in upstream targets FXII and FXI stems from basic and epidemiological studies that suggest these factors are important in thrombosis. 7,20,27 This makes them promising targets for the development of safer anticoagulants because they have little or no role in hemostasis.…”

Section: Fxii and Fxi As Targets For New Anticoagulantsmentioning

confidence: 99%

Emerging anticoagulant strategies

Fredenburgh

Gross

Weitz

2017

Blood

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Despite the introduction of direct oral anticoagulants (DOACs), the search for more effective and safer antithrombotic strategies continues. Better understanding of the pathogenesis of thrombosis has fostered 2 new approaches to achieving this goal. First, evidence that thrombin may be as important as platelets to thrombosis at sites of arterial injury and that platelets contribute to venous thrombosis has prompted trials comparing anticoagulants with aspirin for secondary prevention in arterial thrombosis and aspirin with anticoagulants for primary and secondary prevention of venous thrombosis. These studies will help identify novel treatment strategies. Second, emerging data that naturally occurring polyphosphates activate the contact system and that this system is critical for thrombus stabilization and growth have identified factor XII (FXII) and FXI as targets for new anticoagulants that may be even safer than the DOACs. Studies are needed to determine whether FXI or FXII is the better target and to compare the efficacy and safety of these new strategies with current standards of care for the prevention or treatment of thrombosis. Focusing on these advances, this article outlines how treatment strategies for thrombosis are evolving and describes the rationale and approaches to targeting FXII and FXI. These emerging anticoagulant strategies should address unmet needs and reduce the systemic underuse of anticoagulation because of the fear of bleeding.

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Future prospects for contact factors as therapeutic targets

Cited by 24 publications

References 55 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

Emerging anticoagulant strategies

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