What is the mechanism of action of heparin?

Mechanism of Action of Heparin

The mechanism of action of heparin is potentiation of antithrombin III action (option d), as heparin binds to antithrombin through a specific pentasaccharide sequence, causing a conformational change that dramatically enhances antithrombin's ability to inhibit multiple coagulation enzymes, particularly thrombin (Factor IIa) and Factor Xa. 1, 2, 3

Primary Mechanism: Antithrombin III Potentiation

Heparin works primarily through its interaction with antithrombin (formerly called antithrombin III or AT-III). This interaction occurs through the following steps:

1. Heparin binds to lysine sites on antithrombin through a unique pentasaccharide sequence 1
2. This binding induces a conformational change in antithrombin's structure 2
3. The conformational change converts antithrombin from a slow, progressive inhibitor to a very rapid inhibitor of serine proteases 1, 3
4. The heparin-antithrombin complex then inactivates multiple coagulation enzymes 1
5. After antithrombin binds covalently to the active serine center of coagulation enzymes, heparin dissociates from the complex and can be reused 1, 2

Target Coagulation Factors

The heparin-antithrombin complex inhibits several coagulation enzymes, with varying degrees of sensitivity:

• Thrombin (Factor IIa) - most sensitive, approximately 10-fold more sensitive than Factor Xa 1
• Factor Xa - second most sensitive 1
• Factors IXa, XIa, and XIIa - also inhibited but to a lesser extent 1, 2

Important Structural Requirements

The molecular structure of heparin is critical to its function:

• Only approximately one-third of administered heparin contains the high-affinity pentasaccharide sequence required for binding to antithrombin 1, 2
• For thrombin inhibition, heparin molecules must have at least 18 saccharides to bind simultaneously to both thrombin and antithrombin 1
• Smaller heparin fragments containing the pentasaccharide sequence can still catalyze inhibition of Factor Xa but cannot inhibit thrombin 1

Secondary Mechanisms

At higher concentrations, heparin exhibits additional mechanisms:

• Activation of heparin cofactor II, which specifically inhibits thrombin 1, 2
• Binding to platelets, which can affect platelet function 1
• Prevention of fibrin clot formation by inhibiting the activation of fibrin stabilizing factor 3

Why Other Options Are Incorrect

• (a) Direct inhibition of thrombin - Incorrect because heparin does not directly inhibit thrombin but rather potentiates antithrombin's inhibitory action 1, 3
• (b) Prevention of factor II synthesis - Incorrect because heparin does not affect the synthesis of coagulation factors (this is the mechanism of vitamin K antagonists like warfarin) 3
• (c) Inhibition of cyclo-oxygenase - Incorrect because this is the mechanism of action for aspirin and other non-steroidal anti-inflammatory drugs, not heparin 3

Heparin's heterogeneity (molecular weight range 3,000-30,000 Da) contributes to its complex pharmacology and variable anticoagulant response in clinical practice 1, 2.