What is the mechanism of action of heparin (unfractionated heparin) in patients with a history of deep vein thrombosis, pulmonary embolism, or atrial fibrillation?

Mechanism of Action of Heparin

Heparin exerts its anticoagulant effect primarily by binding to antithrombin (AT) through a specific pentasaccharide sequence, which accelerates AT's ability to inactivate thrombin (factor IIa) and factor Xa by approximately 1000-fold. 1, 2

Primary Anticoagulant Mechanism

The fundamental mechanism involves a conformational change in antithrombin:

• Heparin binds to lysine sites on antithrombin through a unique pentasaccharide sequence, converting AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor 1, 2
• Only approximately one-third of administered heparin molecules contain this high-affinity pentasaccharide sequence required for anticoagulant activity 1, 2
• After the heparin-AT complex binds covalently to the active serine center of coagulation enzymes, heparin dissociates and can be reutilized 1

Differential Effects on Coagulation Factors

The heparin-AT complex demonstrates varying potency against different coagulation factors:

• Thrombin (factor IIa) is approximately 10-fold more sensitive to inhibition than factor Xa by the heparin-AT complex 1, 2
• The complex also inactivates factors IXa, XIa, and XIIa, though these are less clinically significant 1, 2
• By inactivating thrombin, heparin prevents fibrin formation and inhibits thrombin-induced activation of factors V and VIII 1, 2

Molecular Size Requirements

Critical structural considerations determine heparin's anticoagulant activity:

• For thrombin inhibition, heparin molecules must contain at least 18 saccharides to bind simultaneously to both thrombin and AT 1, 2
• Smaller heparin fragments containing the pentasaccharide sequence can still catalyze factor Xa inhibition by AT, even without binding to the enzyme itself 1
• Unfractionated heparin has a mean molecular weight of 15,000 Da, ranging from 3,000 to 30,000 Da 1

Secondary Mechanisms at Higher Concentrations

At supratherapeutic concentrations, additional mechanisms contribute:

• Heparin can catalyze the action of heparin cofactor II, a second plasma protein that also inhibits thrombin 1, 2
• This effect requires high concentrations and occurs equally with both high- and low-affinity heparin 1

Non-Anticoagulant Effects Contributing to Bleeding

Important caveat: Heparin's hemorrhagic effects extend beyond anticoagulation:

• Heparin binds to platelets and can inhibit platelet function, contributing to bleeding risk through a mechanism independent of its anticoagulant effect 1, 2
• High-molecular-weight heparin fractions have greater effects on platelet function than low-molecular-weight fractions 1
• Binding to von Willebrand factor inhibits von Willebrand factor-dependent platelet function 1, 3
• Heparin prolongs bleeding time and enhances blood loss from the microvasculature 1

Pharmacokinetic Complexity

Protein binding significantly affects heparin's clinical behavior:

• After entering the bloodstream, heparin binds extensively to plasma proteins, endothelial cells, and macrophages, which reduces its anticoagulant activity at low concentrations 1, 3
• This extensive protein binding contributes to the variable anticoagulant response among patients and the phenomenon of "heparin resistance" 1, 3, 4
• The two-thirds of heparin molecules without the pentasaccharide sequence bind to other proteins and have minimal anticoagulant activity at therapeutic concentrations 1