Factor XI and factor XII as targets for new anticoagulants

Thromb Res. 2016 May;141 Suppl 2:S40-5. doi: 10.1016/S0049-3848(16)30363-2.

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.

Keywords: Anticoagulants; contact system; factor XI; factor XII; intrinsic pathway; thrombosis.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Antibodies / therapeutic use
  • Anticoagulants / pharmacology
  • Anticoagulants / therapeutic use*
  • Aptamers, Nucleotide / pharmacology
  • Aptamers, Nucleotide / therapeutic use
  • Blood Coagulation / drug effects
  • Drug Discovery* / methods
  • Factor XI / antagonists & inhibitors*
  • Factor XI / metabolism
  • Factor XII / antagonists & inhibitors*
  • Factor XII / metabolism
  • Humans
  • Molecular Targeted Therapy* / methods
  • Oligonucleotides, Antisense / pharmacology
  • Oligonucleotides, Antisense / therapeutic use
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use
  • Thrombosis / blood
  • Thrombosis / drug therapy*
  • Thrombosis / metabolism

Substances

  • Antibodies
  • Anticoagulants
  • Aptamers, Nucleotide
  • Oligonucleotides, Antisense
  • Small Molecule Libraries
  • Factor XII
  • Factor XI