What coagulation factors do antithrombin, protein C, and protein S inhibit?

Inhibitory Functions of Antithrombin, Protein C, and Protein S in Coagulation

Antithrombin inhibits thrombin (Factor IIa), Factor IXa, Factor Xa, Factor XIa, and the Factor VIIa-Tissue Factor complex, while Protein C (when activated) inhibits Factors Va and VIIIa, and Protein S serves as a cofactor for activated Protein C. 1

Antithrombin (AT III)

• Antithrombin is a serine protease inhibitor (SERPIN) that acts as a pseudosubstrate to irreversibly inhibit multiple coagulation factors 1
• It primarily inhibits thrombin (Factor IIa), Factor IXa, Factor Xa, Factor XIa, and the Factor VIIa-Tissue Factor complex 1
• Antithrombin's inhibitory action is dramatically enhanced by heparin, which increases the rate of thrombin inhibition markedly 1, 2
• Heparin interacts with antithrombin to induce a conformational change that enhances its serine protease inhibitory activity 2
• Small amounts of heparin primarily inhibit Factor Xa, while larger amounts are needed to inhibit thrombin (Factor IIa) 2

Protein C

• Protein C is a vitamin K-dependent zymogen that must be activated to become activated protein C (APC) 1
• Activation occurs via the thrombin-thrombomodulin complex on endothelial cell surfaces 1
• Activated Protein C functions as a natural anticoagulant by proteolytically inactivating procoagulant Factors Va and VIIIa 1, 3
• This inhibitory action requires the presence of Protein S as a cofactor 3
• The inactivation of Factors Va and VIIIa by APC is a critical control point in regulating thrombin generation 1

Protein S

• Protein S serves as an essential cofactor for activated Protein C 1, 3
• It facilitates the binding of activated Protein C to cell surfaces where the anticoagulant complex can form 3
• Protein S enhances the ability of activated Protein C to inactivate Factors Va and VIIIa 1
• Only free Protein S (not bound to C4b-binding protein) functions in the anticoagulant pathway 3
• Protein S works in concert with Protein C as part of a natural anticoagulant system 3

Clinical Significance

• Deficiencies of antithrombin, Protein C, or Protein S are associated with increased risk of venous thromboembolism 1, 4
• These natural anticoagulants function to confine normal hemostatic plugs to the site of vessel wall injury and prevent pathologic thrombus formation 1
• The anticoagulant system is activated in parallel with the procoagulant system to maintain hemostatic balance 1
• Measurement of these factors is important in the evaluation of patients with recurrent thrombosis 5
• In nearly 50% of patients with recurrent deep venous thrombosis, a decrease in at least one of these natural anticoagulants (AT III, Protein C, Protein S) can be observed 5

Developmental Considerations

• Normal physiological differences in these inhibitors exist throughout development (developmental hemostasis) 1
• Infants and children have decreased levels of antithrombin, Protein C, and Protein S compared to adults 1
• These levels gradually approach adult values later in childhood or at puberty 1
• Normal newborns have physiologically lower antithrombin III levels (20-80% of adult values) that approach adult values by 6 months of age 6