Factor XI and factor XII as targets for new anticoagulants
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Published on: September 30, 2021
1Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada; Thrombosis and Atherosclerosis Research Institute, Hamilton, Canada.
Abstract:
Although the non-vitamin antagonist oral anticoagulants produce less intracranial bleeding than warfarin, serious bleeding still occurs. Therefore, the search for safer anticoagulants continues. Factor XII and factor XI have emerged as promising targets whose inhibition has the potential to prevent thrombosis with little or no disruption of hemostasis. Thus, thrombosis is attenuated in mice deficient in factor XII or factor XI and patients with congenital factor XII deficiency do not bleed and those with factor XI deficiency rarely have spontaneous bleeding. Strategies targeting factor XII and XI include antisense oligonucleotides to decrease their synthesis, inhibitory antibodies or aptamers, and small molecule inhibitors. These strategies attenuate thrombosis in various animal models and factor XI knockdown with an antisense oligonucleotide in patients undergoing knee replacement surgery reduced postoperative venous thromboembolism to a greater extent than enoxaparin without increasing bleeding. Therefore, current efforts are focused on evaluating the efficacy and safety of factor XII and factor XI directed anticoagulant strategies.
Insights
New anticoagulants targeting factor XII and factor XI show promise for preventing blood clots with reduced bleeding risk. Research is ongoing to evaluate their safety and effectiveness as alternatives to current therapies.
Area of Science:
- Cardiovascular research
- Hematology
- Pharmacology
Background:
- Current oral anticoagulants, while improved, still carry risks of serious bleeding, necessitating safer alternatives.
- Non-vitamin K antagonist oral anticoagulants (NOACs) have reduced intracranial bleeding compared to warfarin, but bleeding complications persist.
- Factor XII and Factor XI are identified as potential targets for novel anticoagulant therapies due to their role in thrombosis without significantly impacting hemostasis.
Purpose of the Study:
- To explore the potential of targeting Factor XII and Factor XI for developing safer anticoagulant strategies.
- To evaluate the efficacy of inhibiting Factor XII and XI in preventing thrombosis while minimizing bleeding risks.
- To summarize current research and ongoing efforts in developing Factor XII and XI directed anticoagulants.
Main Methods:
- Investigating the effects of Factor XII or XI deficiency on thrombosis in animal models.
- Developing and testing various inhibition strategies including antisense oligonucleotides, inhibitory antibodies, aptamers, and small molecule inhibitors.
- Conducting clinical studies, such as Factor XI knockdown with antisense oligonucleotides during knee replacement surgery.
Main Results:
- Thrombosis is attenuated in mice deficient in Factor XII or XI.
- Congenital Factor XII deficiency does not cause bleeding, and Factor XI deficiency rarely leads to spontaneous bleeding in patients.
- Factor XI knockdown significantly reduced postoperative venous thromboembolism compared to enoxaparin without increasing bleeding.
Conclusions:
- Inhibition of Factor XII and XI presents a promising approach for developing anticoagulants with a potentially improved safety profile.
- Current strategies targeting Factor XII and XI have demonstrated efficacy in preclinical models and early clinical investigations.
- Further evaluation of the efficacy and safety of Factor XII and XI directed anticoagulant strategies is warranted.
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