Mechanisms of action of anticoagulant drugs: Heparin, Low-Molecular-Weight Heparin (LMWH), Warfarin (Vitamin K Antagonist – VKAs), and Direct Oral Anticoagulants (DOAs).
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Anticoagulants are drugs used to reduce blood clotting, or coagulation.
Coagulation is critical for the control of bleeding, which has 4 stages:
– Stage 1: formation of platelet plugs.
– Stage 2: formation of blood clots. Coagulation cascade produces thrombin and fibrin.
– Stage 3: termination of clot formation. Antithrombin binds to thrombin, as well as several other clotting factors, and inhibits their function.
– Stage 4: dissolution of blood clots.
Medications that prevent formation of platelet plugs are antiplatelets. Medications that interfere with the function or synthesis of clotting factors are anticoagulants. Anticoagulants and antiplatelets are the 2 classes of antithrombotic drugs.
Heparin binds to antithrombin and increases its affinity for thrombin and other clotting factors, thereby enhancing antithrombin’s inhibitory effect on coagulation, typically up to thousand-fold.
Low-molecular-weight heparin is produced by chemically splitting heparin into pieces of about one-third of its original size. The smaller size reduces its non-specific binding to plasma proteins and blood components, resulting in fewer side effects, longer half-life, and a more predictable dose-dependent response, so monitoring is not usually required. However, the shorter chain length also reduces its ability to bridge between antithrombin and thrombin, producing a reduced inhibitory effect on thrombin. Its anticoagulation effect relies on inhibition of factor 10a, for which a specific five-saccharide motif is sufficient.
Fondaparinux is a synthetic drug based on this five-saccharide sequence. It has a longer half-life and is associated with less bleeding complication than low-molecular-weight heparin in some studies.
Vitamin K Antagonists, such as warfarin, act by inhibiting the enzyme required for activation of vitamin K. Vitamin K is an essential cofactor for the synthesis of many clotting factors.
Direct oral anticoagulants are a new class of synthetic drugs that includes direct thrombin inhibitors and direct factor 10a inhibitors.
The major adverse effect of all anticoagulants is uncontrolled bleeding. Reversal of anticoagulation: hemodialysis, red blood cells transfusion, platelet transfusion, activated charcoal to prevent absorption of the last dose of an oral anticoagulant. Certain anticoagulants have specific reversal agents that can counteract their effect. Heparin’s action can be reversed with protamine. Vitamin K, given orally or intravenously, can counteract warfarin. There are also specific antidotes for direct oral anticoagulants.