Coagulation factor XI as a novel target for antithrombotic treatment.
Coagulation factor (F)XI was first described as a member of the contact pathway of coagulation. However, the 'classic' theory of the extrinsic and intrinsic pathway has been revised and FXI was found to be activated by thrombin and to play a role in sustained thrombin generation and fibrinolysis inhibition. Recent studies have pointed to a disproportionate role of FXI in thrombosis and hemostasis. The observations that human congenital FXI deficiency is generally accompanied by mild and injury-related bleeding, and that experimental, provoked bleeding in animals is unaffected by FXI deficiency or FXI inhibition, suggest that the FXI amplification pathway is less important for normal hemostasis in vivo. In contrast, elevated plasma levels of FXI may contribute to human thromboembolic disease and the antithrombotic efficacy of FXI inhibition has been demonstrated in numerous animal models of arterial, venous and cerebral thrombosis. Whether severe FXI deficiency in humans protects against thromboembolic events remains unclear, although some evidence exists that the occurrence of ischemic stroke or venous thrombosis is low in severely FXI-deficient patients. Because of its distinctive function in thrombosis and hemostasis, FXI is an attractive target for the treatment and prevention of thromboembolism. A novel strategy for FXI inhibition is the use of antisense technology which has been studied in various thrombosis and bleeding animal models. The results are promising and support the concept that targeting FXI might serve as a new, effective and potentially safer alternative for the treatment of thromboembolic disease in humans.
Löwenberg
E C
EC
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. e.c.lowenberg@amc.uva.nl
Meijers
J C M
JC
Monia
B P
BP
Levi
M
M
D000818:Animals; D001777:Blood Coagulation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005172:Factor XI / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005173:Factor XI Deficiency / Q000628:therapy*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006487:Hemostasis; D006801:Humans; D051379:Mice; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015427:Reperfusion Injury; D013923:Thromboembolism / Q000517:prevention & control / Q000628:therapy; D013927:Thrombosis / Q000188:drug therapy*; D014859:Warfarin / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D016376:Oligonucleotides, Antisense; D014859:Warfarin; D005172:Factor XI