The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy

Wheeler, Allison P.; Gailani, David

doi:10.1016/j.hoc.2016.05.007

Cited by 65 publications

(38 citation statements)

References 94 publications

(141 reference statements)

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“…In recent history, our understanding of the contribution of the intrinsic coagulation pathway to thrombosis has significantly advanced . Studies indicate that patients with a hereditary deficiency of FXII, prekallikrein, or HK do not exhibit bleeding problems.…”

Section: The Coagulation Process and Current Anticoagulantsmentioning

confidence: 99%

“…13 In recent history, our understanding of the contribution of the intrinsic coagulation pathway to thrombosis has significantly advanced. [14][15][16][17][18] Studies indicate that patients with a hereditary deficiency of FXII, 19 prekallikrein, 20 or HK 21,22 do not exhibit bleeding problems. Likewise, hemophilia C patients who suffer from FXI deficiency generally have no bleeding problems.…”

Section: The Coagulation Process and Current Anticoagulantsmentioning

confidence: 99%

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Recent advances in the discovery and development of factor XI/XIa inhibitors

Al‐Horani

Afosah

2018

Medicinal Research Reviews

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Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding. Several inhibitors of FXI/FXIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. Antisense oligonucleotides (ASOs), which ultimately reduce the hepatic biosynthesis of FXI, have also been introduced. A phase II study, which included patients undergoing elective primary unilateral total knee arthroplasty, revealed that a specific FXI ASO effectively protects patients against venous thrombosis with a relatively limited risk of bleeding. Initial findings have also demonstrated the potential of FXI/FXIa inhibitors in sepsis, listeriosis, and arterial hypertension. This review highlights various chemical, biochemical, and pharmacological aspects of FXI/FXIa inhibitors with the goal of advancing their development toward clinical use.

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Section: The Coagulation Process and Current Anticoagulantsmentioning

confidence: 99%

Section: The Coagulation Process and Current Anticoagulantsmentioning

confidence: 99%

Recent advances in the discovery and development of factor XI/XIa inhibitors

Al‐Horani

Afosah

2018

Medicinal Research Reviews

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“…Thus, patients with congenital FXI deficiency are protected from venous thromboembolism (VTE) and ischemic stroke, subjects with higher levels of FXI are at greater risk for VTE and ischemic stroke than those with lower levels, and the levels of FXI correlate with stroke risk in women taking oral contraceptives ( 19 , 20 ). The role of FXI in myocardial infarction is less clear; some studies suggest that it is important while others do not ( 21 , 22 ). This discrepancy may reflect differences in study design or the contribution of FXI to thrombosis in the coronary circulation may be distinct from that in other vascular beds.…”

Section: Role Of the Contact System In Thrombosismentioning

confidence: 99%

Factors XI and XII as Targets for New Anticoagulants

Weitz

Fredenburgh

2017

Front. Med.

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Compared with vitamin K antagonists, the direct oral anticoagulants (DOACs) are simpler to administer and are associated with less intracranial bleeding. Nonetheless, even with the DOACs, bleeding still occurs and many patients with atrial fibrillation fail to receive anticoagulant thromboprophylaxis because of the fear of bleeding. Therefore, there is an urgent need for safer anticoagulants. Recent investigations into the biochemistry of hemostasis and thrombosis have identified new targets for development of novel anticoagulants. Using data from complementary sources, including epidemiological studies and investigations in various animal models, the contact pathway has emerged as a potential mediator of thrombosis that plays a minor part in hemostasis. Consequently, factor (F) XII of the contact system and FXI in the intrinsic pathway have been identified as potentially safer targets of anticoagulation than thrombin or FXa. However, further studies are needed to identify which is the better target for the appropriate indication. This review highlights the evidence for focusing on FXI and FXII and examines the novel approaches directed at these new targets. These emerging strategies should address current unmet medical needs and provide new avenues by which to improve anticoagulant therapy by reducing the risk of bleeding.

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“…While physiological hemostasis depends primarily on the TF-factor pathway, the intrinsic pathway is not considered to be essential for hemostasis in vivo, even though its components appear to be involved in the pathogenesis of thrombosis (Doggen, Rosendaal, & Meijers, 2006;Meijers, Tekelenburg, Bouma, Bertina, & Rosendaal, 2000;Minnema, et al, 2000;Wheeler & Gailani, 2016). Epidemiologic data suggest that individuals with congenital factor XI deficiency while largely being protected against venous and arterial thrombosis (Rosen, Gailani, & Castellino, 2002;Salomon, Steinberg, Koren-Morag, Tanne, & Seligsohn, 2008;Salomon, et al, 2011;Tucker, et al, 2009), generally do not exhibit spontaneous bleeding (Duga & Salomon, 2013;James, Salomon, Mikovic, & Peyvandi, 2014).…”

Section: Contact System As Novel Target For Anticoagulation Therapymentioning

confidence: 99%

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

Nourse

Danckwardt

2018

Preprint

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The treatment and prevention of thrombosis is currently under a period of rapid change with the replacement of traditional anticoagulant vitamin K antagonists with direct oral anticoagulants (DOACs), which specifically target factors FXa or FIIa.Nevertheless therapeutic targeting of blood coagulation is an inherently difficult task as it interferes with the delicate balance of pro-and anticoagulant activities. Although anticoagulants are employed in millions of thrombophilic patients worldwide each year, for a growing population with comorbidities who exhibit an increased risk of bleeding with DOAC treatment satisfying therapeutic options are still lacking and the quest for novel therapeutics continues.Recently the targeting of factors FXI and FXII have emerged as new therapeutic strategies. As these factors play an important roles in thrombosis, however are more or less functionally dispensable for hemostasis, they may potentially overcoming the functional obstacle of treating or preventing thrombosis without affecting hemostasis.A key question in following up this approach is which of these two factors is likely to be the more reliable target? Here we present and discuss a hitherto unrecognized rationale for the therapeutic targeting of FXI. This is based on mimicking endogenous FXI gene expression control by therapeutic delivery of miRNA mimics.Studies are urgently needed to test this therapeutic principle in a clinical setting. This is particularly applicable in hemostaseology where monitoring of therapeutic effects remains a daily routine and thus assessment of the efficacy and safety of such therapeutic components could be simply implemented ushering in a novel therapeutic era with broad applicability.

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The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy

Cited by 65 publications

References 94 publications

Recent advances in the discovery and development of factor XI/XIa inhibitors

Recent advances in the discovery and development of factor XI/XIa inhibitors

Factors XI and XII as Targets for New Anticoagulants

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

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