期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 13, 期 8, 页码 1383-1395出版社
WILEY
DOI: 10.1111/jth.13005
关键词
anticoagulant; factor XI; factor XII; thrombosis; venous thrombosis
资金
- NCATS NIH HHS [UL1 TR000128, UL1TR000128] Funding Source: Medline
- NCRR NIH HHS [RR000163, K01 RR000163, P51 RR000163] Funding Source: Medline
- NHLBI NIH HHS [R01 HL058837, HL58837, R01 HL101972, R01 HL081326, HL81326, HL101972] Funding Source: Medline
- NIAID NIH HHS [R44 AI088937, AI088937, R43 AI088937] Funding Source: Medline
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000128] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [P51RR000163] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL101972, R01HL081326, R01HL058837] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R43AI088937, R44AI088937] Funding Source: NIH RePORTER
The most commonly used anticoagulants produce therapeutic antithrombotic effects either by inhibiting thrombin or factor Xa (FXa) or by lowering the plasma levels of the precursors of these key enzymes, prothrombin and FX. These drugs do not distinguish between thrombin generation contributing to thrombosis from thrombin generation required for hemostasis. Thus, anticoagulants increase bleeding risk, and many patients who would benefit from therapy go untreated because of comorbidities that place them at unacceptable risk for hemorrhage. Studies in animals demonstrate that components of the plasma contact activation system contribute to experimentally induced thrombosis, despite playing little or no role in hemostasis. Attention has focused on FXII, the zymogen of a protease (FXIIa) that initiates contact activation when blood is exposed to foreign surfaces, and FXI, the zymogen of the protease FXIa, which links contact activation to the thrombin generation mechanism. In the case of FXI, epidemiologic data indicate this protein contributes to stroke and venous thromboembolism, and perhaps myocardial infarction, in humans. A phase 2 trial showing that reduction of FXI may be more effective than low molecular weight heparin at preventing venous thrombosis during knee replacement surgery provides proof of concept for the premise that an antithrombotic effect can be uncoupled from an anticoagulant effect in humans by targeting components of contact activation. Here, we review data on the role of FXI and FXII in thrombosis and results of preclinical and human trials for therapies targeting these proteins.
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