• Tissue factor pathway inhibitor: inhibits tissue factor
• Protein C and protein S: Activated protein C and its cofactor protein S form the activated protein-C complex (APC complex), which inhibits factors Va and VIIIa.
  • Vitamin K-dependent synthesis in the liver
  • Shorter half-life than vitamin K-dependent coagulation factors (relevant for treatment with vitamin K antagonists, e.g., warfarin)
    • Clotting risk will increase during the initial administration of warfarin, because protein C and S will break down faster.
  • Clinical relevance
    • APC resistance
    • Factor V Leiden
      • Normally, activated protein C (APC) inactivates factor V in the clotting cascade → decreases the activation of thrombin.
      • A DNA point mutation substitutes guanine for adenine → corresponding mRNA codon forms glutamine in place of arginine on position 506 (Arg506Gln mutation) near the polypeptide cleavage site of factor V
      • In such patients, Gln506-Va is resistant to cleavage by APC → factor V remains active → activates prothrombin → increases thrombotic events (e.g., peripheral and cerebral vein thrombosis, recurrent pregnancy loss)
      • Risk of thromboembolism is several times higher in patients with homozygous mutations than in those with heterozygous mutations.
    • Protein C deficiency, protein S deficiency
• Antithrombin
  • Degrades thrombin and factors IXa and Xa
  • Activates tissue plasminogen activator (tPA)