What is the mechanism of action of heparin (unfractionated heparin)?

Mechanism of Action of Unfractionated Heparin

Unfractionated heparin primarily works by binding to antithrombin (AT), causing a conformational change that accelerates AT's ability to inactivate multiple coagulation factors, most importantly thrombin (Factor IIa) and Factor Xa. 1, 2

Primary Mechanism of Action

Heparin's anticoagulant effect occurs through a specific sequence of events:

1. Binding to Antithrombin (AT):

   • Heparin binds to positively charged lysine residues on AT through a unique pentasaccharide sequence 1
   • This binding induces a conformational change at AT's arginine reactive center 1
   • This transformation converts AT from a slow, progressive inhibitor to a very rapid inhibitor of serine proteases 1

2. Formation of Heparin-AT Complex:

   • Only approximately one-third of administered heparin molecules contain the high-affinity pentasaccharide required for AT binding 1
   • These molecules are responsible for most of heparin's anticoagulant effect 1

3. Inactivation of Coagulation Enzymes:

   • The heparin-AT complex inactivates multiple coagulation enzymes:
     • Thrombin (Factor IIa)
     • Factor Xa
     • Factor IXa
     • Factor XIa
     • Factor XIIa 1, 2
   • Thrombin and Factor Xa are the most responsive to inhibition 1
   • Thrombin is approximately 10-fold more sensitive to inhibition than Factor Xa 1

4. Mechanism of Enzyme Inhibition:

   • AT binds covalently to the active serine center of coagulation enzymes 1
   • This creates an irreversible complex that inhibits procoagulant activity 1
   • After enzyme inhibition, heparin dissociates from the complex and can be reused 1

Molecular Requirements for Activity

• For thrombin inhibition: Heparin must bind to both AT and thrombin simultaneously

  • Requires heparin molecules with at least 18 saccharide units 1
  • Smaller fragments cannot catalyze thrombin inhibition

• For Factor Xa inhibition: Binding to the enzyme is less important

  • Even very small heparin fragments containing the pentasaccharide sequence can catalyze Factor Xa inhibition 1

Secondary Mechanisms

1. Heparin Cofactor II Activation:

   • At higher concentrations, heparin can catalyze thrombin inhibition via heparin cofactor II 1
   • This effect requires high concentrations of heparin and occurs regardless of AT-binding affinity 1
   • Requires heparin chains with at least 24 saccharide units 1

2. Effects Beyond Anticoagulation:

   • Binds to platelets and can affect platelet function 1, 2
   • Increases vessel wall permeability 1
   • Suppresses vascular smooth muscle cell proliferation 1
   • Affects bone metabolism (suppresses osteoblast formation and activates osteoclasts) 1

Clinical Implications

• Heparin prevents fibrin formation and inhibits thrombin-induced activation of factors V and VIII 1
• Heparin does not have fibrinolytic activity and will not lyse existing clots 2
• The heterogeneity of heparin (molecular weight range 3,000-30,000 Da) contributes to its complex pharmacology 1, 3
• High-molecular-weight heparin fractions have greater effects on platelet function than low-molecular-weight fractions 1

Important Caveats

• The anticoagulant response to heparin is nonlinear at therapeutic doses due to its complex pharmacokinetics 1
• Only one-third of heparin molecules contain the high-affinity pentasaccharide required for anticoagulant activity 1
• Heparin binding to plasma proteins can reduce its anticoagulant activity at low concentrations, contributing to variability in anticoagulant response 1
• Heparin-induced bleeding may occur through mechanisms independent of its anticoagulant effect, such as interactions with platelets and endothelial cells 1

Understanding heparin's mechanism of action is essential for optimizing its clinical use and managing potential complications such as bleeding or heparin-induced thrombocytopenia.