What is the primary mechanism of action of Heparin (anticoagulant medication)?

Mechanism of Action of Heparin

Heparin primarily works by potentiating the action of antithrombin III (AT-III), which is the correct answer (d) to the question. 1, 2

Primary Mechanism of Action

• Heparin binds to antithrombin III (AT-III) through a unique pentasaccharide sequence, inducing a conformational change in AT-III that converts it from a slow to a very rapid inhibitor of coagulation enzymes 1
• This heparin-AT-III complex then inactivates multiple coagulation enzymes, most importantly thrombin (factor IIa) and factors Xa, IXa, XIa, and XIIa 1, 2
• After binding to the coagulation enzyme, AT-III forms a covalent bond with the active serine center of the enzyme, while heparin dissociates from the complex and can be reused 1

Molecular Requirements for Anticoagulant Activity

• Only approximately one-third of administered heparin contains the specific high-affinity pentasaccharide sequence required to bind to AT-III 1
• For thrombin inhibition, heparin molecules must contain at least 18 saccharides to bind simultaneously to both thrombin and AT-III 1
• Smaller heparin fragments containing only the pentasaccharide sequence can still catalyze inhibition of factor Xa but cannot inhibit thrombin 1

Effects on Different Coagulation Factors

• Thrombin (factor IIa) is approximately 10 times more sensitive to inhibition by the heparin-AT-III complex than factor Xa 1
• By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of factors V and VIII 1

Additional Mechanisms and Effects

• At higher concentrations, heparin can also catalyze the action of a second plasma protein, heparin cofactor II, which also inhibits thrombin 1
• Heparin does bind to platelets and can inhibit platelet function, which contributes to its hemorrhagic effects, but this is not its primary anticoagulant mechanism 1
• Heparin does not prevent factor VII synthesis (option b is incorrect) 1, 2
• Heparin is not a cyclo-oxygenase inhibitor (option c is incorrect) 1, 2
• Heparin does not have fibrinolytic activity and therefore will not lyse existing clots 2

Clinical Implications

• The anticoagulant effect of heparin is heterogeneous due to its variable molecular weight (ranging from 3,000 to 30,000 Da) 1
• Higher molecular weight heparin fractions have greater effects on platelet function than lower molecular weight fractions 1
• Heparin's pharmacokinetics follow a biphasic clearance pattern: a rapid saturable clearance followed by slower first-order elimination 2
• The plasma half-life of heparin is dose-dependent, ranging from 0.5 to 2 hours 2

In summary, the primary mechanism of action of heparin is through potentiation of antithrombin III activity, which then inhibits multiple coagulation factors, particularly thrombin and factor Xa.