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

From the Guidelines

Heparin works as an anticoagulant by binding to and enhancing the activity of antithrombin III, a natural protein in the blood that inhibits several clotting factors, as supported by the most recent evidence 1. The mechanism of action of heparin involves binding to antithrombin III, causing a conformational change that accelerates antithrombin's ability to inactivate thrombin (factor IIa) and factor Xa by approximately 1000-fold, preventing the conversion of fibrinogen to fibrin, which is essential for clot formation.

• Unfractionated heparin affects multiple points in the coagulation cascade,
• while low molecular weight heparins (like enoxaparin) primarily target factor Xa. Heparin requires antithrombin III to function and cannot break down existing clots but prevents new clot formation.

Key Points

• Dosing varies by indication, with unfractionated heparin typically administered intravenously with dose adjustments based on aPTT monitoring,
• while low molecular weight heparins are given subcutaneously at weight-based doses, as seen in studies such as 1 and 1.
• The anticoagulant effect of heparin can be reversed with protamine sulfate in emergency situations, making it useful for procedures requiring temporary anticoagulation, as noted in 1. The most recent and highest quality study 1 provides the best evidence for the mechanism of action of heparin, and its findings support the use of heparin as an effective anticoagulant.

Administration and Monitoring

• Heparin is not absorbed orally and must be administered parenterally, either by continuous IV infusion or subcutaneous injection, as stated in 1.
• The dose of heparin should be higher when administered subcutaneously due to reduced bioavailability, and an initial subcutaneous dose can be accompanied by an IV bolus for immediate anticoagulant effect, as seen in 1 and 1. Overall, heparin is a crucial anticoagulant that works by enhancing the activity of antithrombin III, and its use requires careful consideration of dosing, administration, and monitoring to ensure effective and safe anticoagulation, as supported by the evidence from 1, 1, and 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 anticoagulants like 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 Xa and IIa.

• Key points:
  • Inhibition of Factor Xa and thrombin (Factor IIa)
  • Prevention of stable fibrin clot formation
  • No fibrinolytic activity, will not lyse existing clots 2

From the Research

Mechanism of Anticoagulants like Heparin

• The anticoagulant agent heparin inhibits thrombosis by interacting with antithrombin III 3.
• Heparin has three distinct chemical elements: Mucopolysaccharides, amino acids, and sugars, and three unique domains of activity based on its functional interaction with antithrombin III 3.
• The molecular basis for the anticoagulant action of heparin lies in its ability to bind to and enhance the inhibitory activity of antithrombin against several serine proteases of the coagulation system, most importantly factors IIa (thrombin), Xa and IXa 4.
• Two major mechanisms underlie heparin's potentiation of antithrombin: conformational changes induced by heparin binding, and a template mechanism in which both inhibitor and enzyme bind to the same heparin molecule 4.

Anticoagulant and Antithrombotic Mechanisms

• Heparin can act through other serine protease inhibitors such as heparin co-factor II, protein C inhibitor and tissue factor plasminogen inhibitor 4.
• The antithrombotic action of heparin in vivo is dominated by anticoagulant mechanisms, but interactions with other plasma proteins and cells play significant roles in the living vasculature 4.
• Fondaparinux, a synthetic pentasaccharide, inhibits thrombin formation by inhibiting Factor Xa, which is located at the crossing of both the intrinsic and extrinsic pathways 5.

Comparison of Anticoagulants

• Fondaparinux has similar effectiveness and safety as argatroban and danaparoid in patients with suspected heparin-induced thrombocytopenia (HIT) 6, 7.
• Argatroban and fondaparinux were similarly effective in resolving thrombocytopenia, preventing further thromboembolic events, and maintaining safety in patients with confirmed HIT 7.