Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys

Younis, Husam S.; Crosby, Jeff; Huh, Jung-Im; Lee, Hong Soo; Rime, Soyub; Monia, Brett P.; Henry, Scott P.

doi:10.1182/blood-2011-10-387134

Cited by 79 publications

(80 citation statements)

References 29 publications

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“…[18][19][20][21] Because ASOs are species specific, we developed ASOs that target rabbit coagulation factors. Consistent with previous investigations in other species, fXI-and fXII-directed ASO treatment reduced mRNA, protein expression, and procoagulant activity in a targeted fashion.…”

Section: Discussionmentioning

confidence: 99%

Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

Yau

Liao

Fredenburgh

et al. 2014

Blood

149

140

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Section: Discussionmentioning

confidence: 99%

Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

Yau

Liao

Fredenburgh

et al. 2014

Blood

149

140

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“…In recent decades, anticoagulants that have emerged as alternatives to heparin-like drugs primarily target FIIa and FXa in the common pathway of the coagulation cascade but still exhibit adverse effects, particularly the risk of serious bleeding (5,6,(36)(37)(38). A series of studies has demonstrated that inhibitors of the activated coagulation factors in the intrinsic pathway, such as factors FIXa, FXIa, and FXIIa, should effectively prevent thrombus formation with negligible bleeding risk (8,10,11,39). The intrinsic tenase is the final and rate-limiting enzyme complex in the intrinsic pathway.…”

Section: Compounds 5-8 Exhibit Strong Anticoagulant Activities By Selmentioning

confidence: 99%

“…The development of new anticoagulant agents that inhibit components of the intrinsic pathway and that have a lower risk of causing bleeding has thus become a research focus (9)(10)(11). Factor IXa (FIXa), a serine protease, and factor VIIIa (FVIIIa), a protein cofactor, form a Ca 2+ -and phospholipid surface-dependent complex referred to as the intrinsic tenase complex, which efficiently converts zymogen factor X (FX) to FXa (1,12,13).…”

mentioning

confidence: 99%

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Zhao

Xiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

152

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Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylationdeaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant.T hrombotic disease is seriously harmful to human health and is one of the major causes of death in modern society (1). Despite their long-term and widespread use as anticoagulants, heparin, low-molecular-weight heparin (LMWH), and coumarins still have a major unresolved issue: the risk of serious bleeding during therapy (1-3). It is generally recognized that the risk of bleeding associated with these agents is related to the nonselectivity of their anticoagulant activity. Therefore, selective inhibitors of human factor Xa (FXa) and thrombin (FIIa), such as dabigatran, rivaroxaban, and apixaban, which have predictable pharmacokinetics, have recently been developed; however, these agents have not effectively reduced the risk of bleeding in clinical applications (4-7).Components of the intrinsic coagulation pathway are promising targets for antithrombotic therapy because they are important for thrombosis but are not required for hemostasis (1,8). The development of new anticoagulant agents that inhibit components of the intrinsic pathway and that have a lower risk of causing bleeding has thus become a research focus (9-11). Factor IXa (FIXa), a serine protease, and factor VIIIa (FVIIIa), a protein cofactor, form a Ca 2+ -and phospholipid surface-dependent complex referred to as the intrinsic tenase complex, which efficiently converts zymogen factor X (FX) to FXa (1,12,13). Because the intrinsic tenase is the final and rate-limiting enzyme complex in the intrinsic pathway, the development of inhibitors of this enzyme complex is important for meeting clinical demands (1). However, limited progress has been achieved due to the unavailability of selective inhibitors with welldefined structures.Fucosylated glycosaminoglycan (FG; 1 in Fig. 1), which is a complex acidic polysaccharide isolated from sea cucumber, has recently attracted considerable attention because of its various bioactivities (14). Notably, FG has potent anticoagula...

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“…6 Thus, mice deficient in FXII or FXI exhibit attenuated thrombosis at sites of arterial or venous injury, [7][8][9] and depletion of FXII or FXI with antisense oligonucleotides (ASOs), or inhibition of FXIIa or FXIa with antibodies or inhibitors, reduces thrombosis in animal models. [10][11][12][13][14] With increasing evidence that they contribute to thrombosis, but have little role in hemostasis, FXII and FXI have emerged as attractive targets for new anticoagulants. 6,15 The intrinsic pathway is initiated when FXII is activated on polyanionic surfaces, a process enhanced by PK and HK.…”

Section: Introductionmentioning

confidence: 99%

Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein

Zhou

Leslie

et al. 2015

Blood

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Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys

Cited by 79 publications

References 29 publications

Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein

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