Which serine protease is not bound and inhibited by antithrombin (a protein that inactivates several enzymes of the coagulation system)?

Serine Proteases Not Inhibited by Antithrombin

Factor VIIa (D) is the only serine protease listed that is not effectively bound and inhibited by antithrombin. While antithrombin inhibits multiple coagulation factors, its inhibitory effect on factor VIIa is significantly weaker compared to other serine proteases in the coagulation cascade.

Antithrombin's Inhibitory Activity on Serine Proteases

Antithrombin is a critical serine protease inhibitor (SERPIN) that plays a major role in regulating the coagulation cascade. It functions by:

• Acting as a pseudosubstrate that irreversibly inhibits target enzymes by covalently binding to their active sites 1
• Forming stable enzyme-inhibitor complexes that remove active proteases from circulation
• Having its inhibitory activity significantly enhanced by glycosaminoglycans (particularly heparin)

Serine Proteases Effectively Inhibited by Antithrombin

Antithrombin effectively inhibits the following serine proteases:

1. Factor XIa (A) - Antithrombin directly inhibits factor XIa 1
2. Factor Xa (B) - One of antithrombin's primary targets, inhibited through the pentasaccharide binding mechanism 1, 2
3. Factor IXa (C) - Effectively inhibited by antithrombin 1
4. Thrombin (Factor IIa) - Antithrombin's most sensitive target (approximately 10-fold more sensitive to inhibition than Factor Xa) 2
5. Factor XIIa - Also inhibited by antithrombin 1

Why Factor VIIa is Different

Factor VIIa is minimally inhibited by antithrombin for several reasons:

• The inhibition of factor VIIa by antithrombin is significantly slower and less efficient compared to other coagulation factors 1
• Factor VIIa is primarily inhibited by tissue factor pathway inhibitor (TFPI) rather than antithrombin 1
• When factor VIIa forms a complex with tissue factor, antithrombin's inhibitory effect is even further reduced 2

Clinical Significance

Understanding which coagulation factors are effectively inhibited by antithrombin has important implications:

• Heparin therapy works primarily by enhancing antithrombin's inhibitory activity against factors IIa, Xa, IXa, and XIa
• The relatively poor inhibition of factor VIIa by antithrombin explains why direct factor Xa inhibitors or direct thrombin inhibitors may have advantages in certain clinical scenarios
• Hereditary or acquired antithrombin deficiencies lead to hypercoagulable states due to insufficient inhibition of these key serine proteases 3, 4

This differential inhibition pattern helps explain why the extrinsic pathway (initiated by tissue factor and factor VIIa) can still activate coagulation even in the presence of therapeutic anticoagulation with heparin.