What mechanism does heparin (unfractionated heparin) use to break a clot?

From the Guidelines

Heparin does not actually break existing clots, but rather prevents new clot formation and allows the body's natural fibrinolytic system to gradually dissolve existing clots. Heparin works by binding to and activating antithrombin III (also called antithrombin), which then inhibits several clotting factors, particularly thrombin (factor IIa) and factor Xa, as described in the study by 1. This inhibition prevents the conversion of fibrinogen to fibrin and blocks the amplification of the coagulation cascade. Unfractionated heparin requires antithrombin to exert its anticoagulant effect and has no direct fibrinolytic (clot-dissolving) activity.

The mechanism of heparin is further supported by a more recent study from 1, which highlights the limitations of unfractionated heparin, including its inability to bind clot-bound thrombin and its variable patient responses. However, the study also acknowledges the extensive use of heparin in primary PCI for STEMI.

When administered for treatment of thrombosis, heparin is typically given as an intravenous bolus followed by a continuous infusion, with dose adjustments based on activated partial thromboplastin time (aPTT) monitoring, as described in 1. The therapeutic goal is to maintain the aPTT at 1.5-2.5 times the control value. While heparin prevents clot propagation, the body's endogenous tissue plasminogen activator (tPA) system is responsible for the actual breakdown of the clot through conversion of plasminogen to plasmin, which degrades fibrin. For active clot dissolution, fibrinolytic agents like alteplase would be required.

Key points to consider when using heparin include:

• Heparin does not break existing clots, but prevents new clot formation
• Heparin works by binding to and activating antithrombin III
• Heparin has no direct fibrinolytic activity
• Heparin is typically given as an intravenous bolus followed by a continuous infusion
• The therapeutic goal is to maintain the aPTT at 1.5-2.5 times the control value
• Heparin has limitations, including its inability to bind clot-bound thrombin and its variable patient responses.

From the FDA Drug Label

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

Heparin does not break a clot by lysing it, as it does not have fibrinolytic activity. Instead, it prevents the formation of new clots and inhibits further coagulation by:

• Inactivating activated Factor X
• Inhibiting the conversion of prothrombin to thrombin
• Inactivating thrombin
• Preventing the conversion of fibrinogen to fibrin
• Inhibiting the activation of the fibrin stabilizing factor 2

From the Research

Mechanism of Heparin in Breaking a Clot

• Heparin works by binding to and enhancing the inhibitory activity of antithrombin, a plasma protein that inhibits several serine proteases of the coagulation system, including factors IIa (thrombin), Xa, and IXa 3.
• The binding of heparin to antithrombin causes conformational changes that increase its inhibitory activity, allowing it to bind directly to the enzyme target 3.
• Heparin can also act through other serine protease inhibitors, such as heparin co-factor II, protein C inhibitor, and tissue factor plasminogen inhibitor 3.
• However, heparin is less effective at inhibiting thrombin bound to fibrin, as the heparin binding site on thrombin may be inaccessible when the enzyme is bound to fibrin 4.
• Clot-bound thrombin is relatively protected from inhibition by heparin-antithrombin III, but is susceptible to inactivation by antithrombin III-independent inhibitors 4.

Role of Antithrombin in Heparin's Mechanism

• Antithrombin is a key inhibitor of thrombin and other coagulation factors, and its activity is enhanced by heparin 5, 6.
• Antithrombin can inhibit thrombin generated by factor Xa-associated clot, but its effect is not enhanced by low molecular weight heparin or unfractionated heparin 6.
• The inhibitory ability of antithrombin is significantly increased in the presence of heparin, allowing it to more effectively inhibit thrombin and other coagulation factors 5.

Clinical Implications of Heparin's Mechanism

• Heparin is an effective treatment for preventing thrombus propagation, but it has minimal therapeutic effect in dissolving preexisting venous thrombus 7.
• The use of heparin in combination with other therapies, such as mechanical thrombectomy, may be necessary to effectively treat deep venous thrombosis 7.
• Antithrombin III-independent inhibitors may be more effective than heparin in certain clinical settings, such as in the treatment of clot-bound thrombin 4.