Evolving Treatments for Arterial and Venous Thrombosis

Chan, Noel; Eikelboom, John W.; Weitz, Jeffrey I.

doi:10.1161/circresaha.116.306925

Cited by 102 publications

(72 citation statements)

References 135 publications

(141 reference statements)

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“…Driven by a quest for oral anticoagulants that were more convenient to administer than VKAs and enabled by advances in the structural characterization of thrombin and factor Xa, this generation of drugs includes dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, edoxaban, and betrixaban, which inhibit factor (F) Xa. 4 Known as direct oral anticoagulants (DOACs), these agents are at least as effective as VKAs but are associated with less bleeding, particularly less intracranial bleeding, and are easier to administer because they can be given in fixed doses without routine coagulation monitoring. Because of these attributes, current guidelines give preference to the DOACs over VKAs for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in patients without active cancer.…”

Section: See Insight Into Jeffrey I Weitz On Page 311mentioning

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: See Insight Into Jeffrey I Weitz On Page 311mentioning

confidence: 99%

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Weitz

Fredenburgh

2018

ATVB

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“…When compared with VKAs in more than 100 000 patients, the DOACs were at least as effective for stroke prevention in patients with nonvalvular atrial fibrillation and for prevention of recurrence in patients with VTE, but were associated with less bleeding, particularly less intracranial hemorrhage. 29 Therefore, many guidelines now give preference to the DOACs over VKAs for stroke prevention in most patients with nonvalvular atrial fibrillation or VTE treatment in patients without active cancer. 30,31 With a better understanding of the role of thrombin in arterial thrombosis and the contribution of platelets to venous thrombosis, treatment paradigms are changing.…”

Section: Role Of Thrombin In Thrombosismentioning

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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“…To date, only rivaroxaban has been licensed in Europe for secondary prevention in stabilised ACS patients who presented with elevated cardiac biomarkers, in combination with antiplatelet therapy. 7 DOACs have not been approved for patients with mechanical heart valves. Dabigatran was found to cause excess thromboembolic and bleeding events compared with warfarin in patients with mechanical valves, and the factor Xa inhibitors have not been studied in this setting.…”

Section: Stroke Prevention In Atrial Fibrillationmentioning

confidence: 99%