Article
Cardiac & Cardiovascular Systems
Antonio Greco, Claudio Laudani, Marco Spagnolo, Federica Agnello, Denise Cristiana Faro, Simone Finocchiaro, Marco Legnazzi, Maria Sara Mauro, Placido Maria Mazzone, Giovanni Occhipinti, Carla Rochira, Lorenzo Scalia, Davide Capodanno
Summary: Therapeutic anticoagulation is used to prevent or treat blood clots, but it can increase the risk of bleeding. Inhibitors of Factor XI (FXI) show promise in reducing the adverse events of anticoagulation. Large-scale phase 3 clinical trials are needed to confirm the role of FXI inhibitors and determine their clinical indications.
Review
Cardiac & Cardiovascular Systems
Charles Hsu, Edward Hutt, Daniel M. Bloomfield, David Gailani, Jeffrey I. Weitz
Summary: Hemostasis and thrombosis are closely linked, with factor XI inhibitors potentially providing a safer alternative to current anticoagulants. Clinical studies are ongoing to determine the efficacy of factor XI inhibitors in attenuating thrombosis without disrupting hemostasis.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2021)
Review
Hematology
James C. Fredenburgh, Jeffrey I. Weitz
Summary: Oral anticoagulants are widely used for preventing and treating thrombosis. Direct oral anticoagulants (DOACs) such as dabigatran and apixaban have replaced traditional anticoagulants. New DOACs like asundexian and milvexian, targeting FXIa, offer potential advantages over existing ones.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Ophira Salomon, David Gailani
Summary: Therapeutic inhibitors targeting FXI(a) are being evaluated as potential treatments for preventing thrombosis, with the expectation of having a smaller impact on hemostasis than current anticoagulants targeting thrombin or factor Xa. However, some patients on these inhibitors may still experience abnormal bleeding or require emergent surgery, necessitating the development of strategies to address these situations. Treatment with antifibrinolytic agents and low doses of recombinant factor VIIa has been effective in preventing abnormal bleeding in FXI-deficient patients, suggesting a potential strategy for patients on therapeutic FXI(a) inhibitors experiencing bleeding or requiring invasive procedures.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Hematology
Ruiqi Yin, Vishal Patel, Rida A. Malik, James C. Fredenburgh, Jeffrey I. Weitz
Summary: Polyphosphate (polyP) serves as a template to promote feedback activation of factor XI by thrombin. This study determines the contribution of thrombin exosites 1 and 2 to polyP-induced potentiation of FXI activation. The results show that polyP accelerates FXI activation by thrombin and exosite 2 ligands attenuate this activation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Dirk Thomas, Friederike Kanefendt, Stephan Schwers, Sigrun Unger, Ashraf Yassen, Stefanie Boxnick
Summary: This study evaluated the safety, pharmacokinetic, and pharmacodynamic properties of the orally administered small molecule targeting FXIa in healthy men. The results showed that BAY 2433334 demonstrated favorable safety and tolerability, exhibited dose-dependent inhibition of FXIa activity, and is considered a promising oral anticoagulant drug candidate.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Review
Cardiac & Cardiovascular Systems
Martha M. S. Sim, Semekidus Shiferawe, Jeremy P. Wood
Summary: Antithrombotic therapy requires balancing the benefits of preventing thrombotic events with the risks of major bleeds. Traditional approaches involve carefully dosing and monitoring antiplatelet and anticoagulant medications, all of which carry bleeding risk. Recent advancements have identified new targets to mitigate bleeding risk. This review discusses the current state of antithrombotic therapy and explores new generation drugs and strategies to reverse anticoagulants, moving closer to a treatment that prevents clots without bleeding risk.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2023)
Review
Hematology
James C. Fredenburgh, Jeffrey Weitz
Summary: The article discusses the rationale for developing factor XI inhibitors, identifies the most advanced stage agents, describes the results of completed clinical trials and ongoing trials, highlighting opportunities and challenges for this new generation of anticoagulants.
Review
Cardiac & Cardiovascular Systems
Stephan Nopp, Daniel Kraemmer, Cihan Ay
Summary: While anticoagulation therapy has made progress, thrombosis remains a leading cause of death worldwide. Direct oral anticoagulants dominate clinical practice, but bleeding risk is still significant. Therefore, research focuses on developing safer anticoagulants, with factor XI (FXI) inhibition as a promising target.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Hematology
Maria Selvadurai, Moeen Riaz, Sophia Xie, Andrew M. Tonkin, John J. McNeil, Paul Lacaze, Justin R. Hamilton
Summary: This article examines the association between the single-nucleotide polymorphism rs773902 and cardiovascular events and aspirin use. The results indicate that rs773902 is not significantly associated with thrombotic or bleeding events.
THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Hematology
Debora Bertaggia Calderara, Maxime G. Zermatten, Alessandro Aliotta, Ana P. Batista Mesquita Sauvage, Vanessa Carle, Christian Heinis, Lorenzo Alberio
Summary: In this study, the correlation of TF-dependent and -independent coagulation parameters with the clinical phenotype of FXI deficiency and their ability to assess hemostasis after FXI replacement were investigated. The results indicated that TF-independent coagulation parameters could help identify the clinical phenotype in FXI-deficient patients and monitor FXI replacement therapy.
THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Hematology
Alisa S. Wolberg, Yaqiu Sang
Summary: This article discusses the pathogenesis of venous thromboembolism and focuses on the role of fibrinogen and factor XIII in thrombus formation and resolution, providing insights for the development of new anticoagulant strategies.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2022)
Review
Cardiac & Cardiovascular Systems
Raffaele De Caterina, Domenico Prisco, John W. Eikelboom
Summary: This paper reviews the potential of drugs targeting factor XI in anticoagulant therapy, along with ongoing clinical trials and future research directions.
EUROPEAN HEART JOURNAL
(2023)
Review
Cardiac & Cardiovascular Systems
Hugo ten Cate, Tomasz J. Guzik, John Eikelboom, Henri M. H. Spronk
Summary: Atherosclerosis is a chronic inflammatory disease that leads to cardiovascular morbidity and mortality. Endothelial dysfunction, vascular smooth muscle cell activation, and vascular inflammation play essential roles in the development of acute cardiovascular events. The effects of the coagulation system on vascular biology extend beyond thrombosis.
CARDIOVASCULAR RESEARCH
(2021)
Article
Hematology
Anja Maag, Priyanka Sharma, Tim J. Schuijt, Wil F. Kopatz, Danielle Kruijswijk, J. Arnoud Marquart, Tom van Der Poll, Tilman M. Hackeng, Gerry A. F. Nicolaes, Joost C. M. Meijers, Mettine H. A. Bos, Cornelis van 't Veer
Summary: TIX-5 is a unique anticoagulant tick protein that inhibits the FXa-mediated activation of FV. It contains a single rod structure formed by multiple beta sheets wrapped around a central C-terminal alpha helix, and has three essential interaction sites for its anticoagulant properties: one for phospholipid binding, one for FV interaction, and one potentially acting as a pseudosubstrate of FXa. The elucidation of its mechanism of action will help understand the initiation phase of blood coagulation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Review
Hematology
James C. Fredenburgh, Jeffrey I. Weitz
Summary: Anticoagulants have been used for over 80 years, with advancements in basic science leading to the development of new compounds targeting single coagulation enzymes. More recent research focuses on drugs that target the contact system, believed to be crucial for thrombosis.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Editorial Material
Cardiac & Cardiovascular Systems
Noel C. Chan, Jeffrey Weitz
EUROPEAN HEART JOURNAL
(2022)
Article
Hematology
Tammy K. Truong, Rida A. Malik, Xintong Yao, James C. Fredenburgh, Alan R. Stafford, Hasam M. Madarati, Colin A. Kretz, Jeffrey Weitz
Summary: The histidine-rich glycoprotein (HRG) interacts with FXIIa and polyP through its histidine-rich region (HRR), thereby downregulating the contact pathway and contributing to the regulation of coagulation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Editorial Material
Hematology
Jeffrey I. Weitz, Flora Peyvandi
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Rheumatology
Jeffrey Weitz, Zoltan Szekanecz, Christina Charles-Schoeman, Ivana Vranic, Burak Sahin, Sara A. Paciga, Zhenyu Wang, Craig Hyde, David A. Martin
Summary: This exploratory post hoc analysis did not identify biomarkers that explained the increased VTE risk for tofacitinib versus TNFi. However, month 12 D-dimer levels were positively associated with risk of a subsequent VTE within the tofacitinib treatment arms.
Editorial Material
Cardiac & Cardiovascular Systems
Jeffrey I. Weitz, John W. Eikelboom
Editorial Material
Hematology
John W. Eikelboom, Jeffrey I. Weitz
THROMBOSIS AND HAEMOSTASIS
(2023)
Review
Cardiac & Cardiovascular Systems
Nick van Es, Raffaele De Caterina, Jeffrey Weitz
Summary: In the past 20 years, there has been a transition from vitamin K antagonists to direct oral anticoagulants (DOACs). DOACs include dabigatran, apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding, reversal agents may be needed in cases of serious bleeding or urgent surgery/intervention. This paper provides insight into reversing the effects of DOACs, discusses new reversal agents, and outlines a strategic framework for reversing factor XI inhibitors in clinical trials.
EUROPEAN HEART JOURNAL
(2023)
Article
Hematology
Rida A. Malik, Peng Liao, Ji Zhou, Rawaa Hussain, James C. Fredenburgh, Lisa Hettrick, Alexey S. Revenko, Jeffrey I. Weitz
Summary: FXII knockdown prolongs catheter occlusion time, while HRG knockdown shortens it. HRG supplementation may prevent catheter thrombosis.
Review
Hematology
Noel C. Chan, Jeffrey I. Weitz
Summary: This review discusses the role of FXI and FXII in the pathogenesis of venous thromboembolism, explains why FXI is a better target, and describes the potential advantages of FXI inhibitors over currently available anticoagulants. It also provides an overview of the FXI inhibitors under development and their potential in addressing unmet needs in venous thromboembolism management.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Hematology
Samuel K. Lee, Rida A. Malik, Ji Zhou, Wei Wang, Peter L. Gross, Jeffrey I. Weitz, Rithwik Ramachandran, Bernardo L. Trigatti
Summary: This study investigated the effects of PAR4 inhibitory pepducin (RAG8) on coronary artery disease in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet. The results showed that RAG8 reduced coronary artery atherosclerosis and myocardial fibrosis, as well as platelet and leukocyte accumulation in atherosclerotic coronary arteries.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Review
Hematology
James C. Fredenburgh, Jeffrey I. Weitz
Summary: Oral anticoagulants are widely used for preventing and treating thrombosis. Direct oral anticoagulants (DOACs) such as dabigatran and apixaban have replaced traditional anticoagulants. New DOACs like asundexian and milvexian, targeting FXIa, offer potential advantages over existing ones.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Ruiqi Yin, Vishal Patel, Rida A. Malik, James C. Fredenburgh, Jeffrey I. Weitz
Summary: Polyphosphate (polyP) serves as a template to promote feedback activation of factor XI by thrombin. This study determines the contribution of thrombin exosites 1 and 2 to polyP-induced potentiation of FXI activation. The results show that polyP accelerates FXI activation by thrombin and exosite 2 ligands attenuate this activation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Zeyu Guan, Roxanna Wang, Rawaa H. Hussain, James C. Fredenburgh, Iqbal H. Jaffer, Jeffrey I. Weitz
Summary: This study compared the effects of apixaban, rivaroxaban, and enoxaparin on the prevention of catheter-induced clotting in vitro. The results showed that apixaban and rivaroxaban were significantly less potent than enoxaparin in preventing catheter-induced clotting and thrombin generation. Clinical trials are needed to compare the efficacy of low-molecular-weight heparin with that of direct oral anticoagulants for both prevention and treatment of catheter thrombosis.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
John W. Eikelboom, Jeffrey I. Weitz
Summary: Although DOACs are preferred over VKAs for stroke prevention in most patients with AF, they are not recommended for those with rheumatic heart disease or mechanical heart valves. Results from the INVICTUS and PROACT Xa trials support the use of VKAs for these specific indications. This paper reviews the findings from these trials, provides insights into why VKAs were superior to DOACs, and discusses future directions for anticoagulation in these disorders.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)