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

From the Guidelines

Heparin works by binding to and activating antithrombin III, which then inhibits several clotting factors, primarily thrombin (factor IIa) and factor Xa. This mechanism of action is crucial in understanding how heparin prevents the formation of new clots and the extension of existing ones 1. The binding of heparin to antithrombin III causes a conformational change that accelerates its ability to inactivate coagulation enzymes.

Key Points about Heparin Mechanism of Action

• Unfractionated heparin (UFH) inhibits both thrombin and factor Xa equally, while low molecular weight heparin (LMWH) predominantly inhibits factor Xa.
• Heparin cannot break down clots that have already formed; it only prevents new clot formation.
• Heparin also has anti-inflammatory properties and can release tissue factor pathway inhibitor, which provides additional anticoagulant effects.
• The anticoagulant effect of heparin is immediate when administered intravenously, making it useful for acute situations requiring rapid anticoagulation, while subcutaneous administration takes 1-2 hours to reach therapeutic levels, as noted in the study by the American College of Chest Physicians 1.

Administration and Pharmacokinetics

• Heparin is not absorbed orally and must be administered parenterally, either by continuous IV infusion or subcutaneous injection.
• The dose of heparin should be higher when administered subcutaneously due to reduced bioavailability.
• Heparin binds to plasma proteins, endothelial cells, and macrophages, which can reduce its anticoagulant activity and contribute to variability in patient response. The complex kinetics of clearance, including a rapid saturable and a slower first-order mechanism, render the anticoagulant response to heparin nonlinear at therapeutic doses 1.

From the FDA Drug Label

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa) Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor

The mechanism of action of heparin is through its interaction with Antithrombin III, which enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Factor Xa and Factor IIa (thrombin) 2.

• Key points:
  • Heparin inhibits Factor Xa and thrombin (Factor IIa)
  • Heparin prevents the formation of a stable fibrin clot
  • Heparin does not have fibrinolytic activity and will not lyse existing clots

From the Research

Heparin Mechanism of Action

• Heparin works by binding to and increasing the activity of antithrombin III, which inhibits prothrombinase-mediated thrombin generation and direct thrombin generation by binding to factor Xa and thrombin factor IIa 3.
• The resulting complex inhibits the coagulation cascade, preventing the formation of blood clots.
• Heparin can be classified into two main types: unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs), such as enoxaparin.

Comparison of Heparin Types

• UFH has been shown to stimulate platelets, leading to both activation and aggregation, which may further promote clot formation 4.
• LMWHs, such as enoxaparin, have been shown to be superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction 4, 5.
• Enoxaparin has been shown to be at least as effective as UFH in reducing the frequency of venous thromboembolism in nonsurgical patients at increased risk for deep vein thrombosis and pulmonary embolism 3.

Clinical Applications

• Heparin is used as an anticoagulant to prevent and treat venous thromboembolism, including deep vein thrombosis and pulmonary embolism.
• Enoxaparin is used as prophylaxis in medically ill patients at increased risk for thromboembolism, and has shown significantly increased efficacy compared with placebo in reducing the incidence of deep vein thrombosis and pulmonary embolism 3.
• UFH and enoxaparin have been compared in various clinical trials, with enoxaparin showing a trend towards reduced mortality and major bleeding in some studies 6, 7.