Targeting factor XI and factor XIa to prevent thrombosis

被引:12
作者
Gailani, David [1 ,3 ]
Gruber, Andras [2 ]
机构
[1] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA
[2] Aronora Inc, 1818 SW Ave,Suite 102, Portland, OR 97201 USA
[3] Vanderbilt Univ, Med Ctr, Vanderbilt Clin, Pathol Microbiol & Immunol, Room 4918,1301 Med Ctr Dr, Nashville, TN 37232 USA
基金
美国国家卫生研究院;
关键词
VITAMIN-K ANTAGONISTS; COAGULATION-FACTOR-XI; DIRECT ORAL ANTICOAGULANTS; VENOUS THROMBOEMBOLISM; BLEEDING TENDENCY; ISCHEMIC-STROKE; TISSUE FACTOR; FACTOR-IX; PROVIDES PROTECTION; MEDIATED ACTIVATION;
D O I
10.1182/blood.2023020722
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Direct oral anticoagulants (DOACs) that inhibit the coagulation proteases thrombin or factor Xa (FXa) have replaced warfarin and other vitamin K antagonists (VKAs) for most indications requiring long-term anticoagulation. In many clinical situations, DOACs are as effective as VKAs, cause less bleeding, and do not require laboratory monitoring. However, because DOACs target proteases that are required for hemostasis, their use increases the risk of serious bleeding. Concerns over therapy-related bleeding undoubtedly contribute to undertreatment of many patients who would bene fi t from anticoagulation therapy. There is considerable interest in the plasma zymogen factor XI (FXI) and its protease form factor XIa (FXIa) as drug targets for treating and preventing thrombosis. Laboratory and epidemiologic studies support the conclusion that FXI contributes to venous and arterial thrombosis. Based on 70 years of clinical observations of patients lacking FXI, it is anticipated that drugs targeting this protein will cause less severe bleeding than warfarin or DOACs. In phase 2 studies, drugs that inhibit FXI or FXIa prevent venous thromboembolism after total knee arthroplasty as well as, or better than, low molecular weight heparin. Patients with heart disease on FXI or FXIa inhibitors experienced less bleeding than patients taking DOACs. Based on these early results, phase 3 trials have been initiated that compare drugs targeting FXI and FXIa to standard treatments or placebo. Here, we review the contributions of FXI to normal and abnormal coagulation and discuss results from preclinical, nonclinical, and clinical studies of FXI and FXIa inhibitors.
引用
收藏
页码:1465 / 1475
页数:11
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