Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors

Bentounes, Nûn K.; Melicine, Sophie; Martin, Anne; Smadja, David; Gendron, Nicolas

doi:10.1016/j.jdmv.2023.04.002

Cited by 6 publications

(7 citation statements)

References 71 publications

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“…Patients with factor XI deficiency may suffer from epistaxis, hypermenorrhea, peripartum and periinterventional bleeding, whilst joint and muscle bleeds are uncommon. The low bleeding risk in patients with factor XI deficiency also promoted the development of factor XI pathway inhibitors (e. g., fesomersen, osocimab, abelacimab, milvexian, asundexian) for “safe anticoagulation”, the prophylaxis of thrombosis without inducing bleeding [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Two cases of Factor XI deficiency: Use of Thrombin Generation Assays (TGA) to detect a non-bleeding phenotype

Sucker,

Geisen,

Litmathe

2024

Arch Clin Cases

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Factor XI deficiency is a rare disorder of hemostasis. Previously also known as “hemophilia C”, this defect has been regarded as a risk factor for bleeding. However, it has been known for long that bleeding tendency and severity of bleeding are not related to the residual factor XI activity in symptomatic patients. Moreover, a large proportion of patients with even severe factor XI deficiency are clinically unremarkable and do not show any signs of abnormal bleeding. Here, we present two cases of factor XI deficiency with a non-bleeding phenotype. Adequate diagnostic work-up and evaluation of the bleeding risk are reported and discussed with focus on thrombin generation assays (TGA) for the prediction of bleeding in affected patients. This is of high relevance in affected patients, particularly in the context of surgery.

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Section: Discussionmentioning

confidence: 99%

Two cases of Factor XI deficiency: Use of Thrombin Generation Assays (TGA) to detect a non-bleeding phenotype

Sucker,

Geisen,

Litmathe

2024

Arch Clin Cases

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“…By way of reducing feedback activation of FXI or activity of FXIIa, FXI inhibitors have emerged as a promising strategy to reduce the propagation of thrombin generation and inflammation without compromising hemostasis [51 && ,52]. Based on the success of several small to medium phase 2 clinical studies [53], FXI inhibitors may represent a useful strategy for treatment of thromboinflammatory and neurocoagulant diseases, including multiple sclerosis.…”

Section: Thrombinmentioning

confidence: 99%

Factor XI as a therapeutic target in neuroinflammatory disease

Taskin,

Kohs,

Shatzel

et al. 2023

Current Opinion in Hematology

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Purpose of review This review summarizes the pathophysiology and potential therapeutic options for treatment of multiple sclerosis, a common neuronal demyelinating disorder affecting 2.2 million people worldwide. As an autoimmune disorder, multiple sclerosis is associated with neuroinflammation and increased permeability of the blood–brain barrier (BBB), although the cause linking multiple sclerosis with compromised barrier function remains ill-defined. It has been previously shown that coagulation factors, including thrombin and fibrin, exacerbate the inflammatory processes and permeability of the BBB. Recent findings Increased levels of the coagulation factor (F) XII have been found in patients presenting with relapsing–remitting multiple sclerosis, with a deleterious role for FXII being validated in murine model of multiple sclerosis, experimental autoimmune encephalitis (EAE). Recent work has uncovered a role for the major substrate activated by FXII and thrombin, FXI, in the disorder of EAE. The study found that pharmacological targeting of FXI decreased clinical symptoms, lymphocyte invasion, and white matter destruction in a multiple sclerosis model. Summary This review emphasizes the role of FXII and FXI in regulating barrier function and the immune response in neuroinflammation. These new findings broaden the potential for therapeutic utility of FXI inhibitors beyond thrombosis to include neuroinflammatory diseases associated with compromised BBB function, including multiple sclerosis.

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“…Importantly, all the conventional as well as the newer anticoagulants are associated with a significant risk of internal bleeding. − Certainly, the risk of major bleeding during DOAC therapy is approximately 2% per year, with a case fatality rate of major bleeding standing at 8% . Consequently, there has been a concerted effort in developing and deploying specific antidotes for DOACs, especially following the FDA approval of two antidotes: idarucizumab for dabigatran and andexanet alfa for anti-FXa DOACs.…”

Section: Introductionmentioning

confidence: 99%

“…These include frail patients (such as the elderly, those with low body weight, and individuals with renal impairment), patients with end-stage renal disease (ESRD) undergoing hemodialysis, and those with genitourinary and gastrointestinal cancers. Furthermore, DOACs may not be effective in certain clinical conditions, such as cases involving mechanical heart valves or antiphospholipid syndrome . Hence, a critical necessity exists for the advancement of new anticoagulants.…”

Section: Introductionmentioning

confidence: 99%

“… 10 − 15 Certainly, the risk of major bleeding during DOAC therapy is approximately 2% per year, with a case fatality rate of major bleeding standing at 8%. 16 Consequently, there has been a concerted effort in developing and deploying specific antidotes for DOACs, especially following the FDA approval of two antidotes: idarucizumab for dabigatran and andexanet alfa for anti-FXa DOACs. The latter, owing to its steep cost and debatable effectiveness and safety, is not widely adopted.…”

Section: Introductionmentioning

confidence: 99%

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New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants

Woodland,

Thompson,

Lipford

et al. 2024

ACS Omega

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Factor XIIa (FXIIa) functions as a plasma serine protease within the contact activation pathway. Various animal models have indicated a substantial role for FXIIa in thromboembolic diseases. Interestingly, individuals and animals with FXII deficiency seem to maintain normal hemostasis. Consequently, inhibiting FXIIa could potentially offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks associated with the existing anticoagulants. Despite the potential, only a limited number of small molecule inhibitors targeting human FXIIa have been documented. Thus, we combined a small library of 32 triazole and triazole-like molecules to be evaluated for FXIIa inhibition by using a chromogenic substrate hydrolysis assay under physiological conditions. Initial screening at 200 μM involved 18 small molecules, revealing that 4 molecules inhibited FXIIa more than 20%. In addition to being the most potent inhibitor identified in the first round, inhibitor 8 also exhibited a substantial margin of selectivity against related serine proteases, including factors XIa, Xa, and IXa. However, the molecule also inhibited thrombin with a similar potency. It also prolonged the clotting time of human plasma, as was determined in the activated partial thromboplastin time and prothrombin time assays. Subsequent structure−activity relationship studies led to the identification of several inhibitors with submicromolar activity, among which inhibitor 22 appears to demonstrate significant selectivity not only over factors IXa, Xa, and XIa, but also over thrombin. In summary, this study introduces novel triazole-based small molecules, specifically compounds 8 and 22, identified as potent and selective inhibitors of human FXIIa. The aim is to advance these inhibitors for further development as anticoagulants to provide a more effective and safer approach to preventing and/or treating thromboembolic diseases.

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Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors

Cited by 6 publications

References 71 publications

Two cases of Factor XI deficiency: Use of Thrombin Generation Assays (TGA) to detect a non-bleeding phenotype

Two cases of Factor XI deficiency: Use of Thrombin Generation Assays (TGA) to detect a non-bleeding phenotype

Factor XI as a therapeutic target in neuroinflammatory disease

New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants

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