Anticoagulants are medications that reduce blood clotting, or coagulation.
They are used to treat and prevent unwanted blood clot formation in conditions such as
atrial fibrillation, deep vein thrombosis, acute coronary syndrome, and in patients with
a prosthetic heart valve.
Anticoagulants are also used to prevent excess coagulation during surgery and dialysis.
Coagulation is critical for the control of bleeding, which has 4 stages:
- Stage 1: formation of platelet plugs.
- Stage 2: formation of blood clots, which are essentially platelet plugs reinforced
with strands of fibrin.
Fibrin is the final product of the coagulation cascade - a multi-step chain reaction where
one clotting factor activates the next.
The 2 activation pathways, extrinsic and intrinsic, converge to produce thrombin and ultimately
fibrin.
Thrombin has a central role: it cleaves fibrinogen to generate fibrin, it further activates platelets,
and initiates a positive feedback loop that is essential for clot propagation.
- Stage 3: termination of clot formation.
Antithrombin is among a number of mechanisms designed to control the extent 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, commonly produced from pig intestine, is a sulfated polysaccharide.
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.
Heparin is fast-acting, has a short half-life, and is usually administered intravenously
for immediate therapeutic effect.
It can also be injected subcutaneously for prevention purposes, in which case, the onset
of action is within a couple of hours.
Heparin is not absorbed through the gastrointestinal tract and therefore cannot be taken orally.
The major disadvantage of heparin is that it produces highly variable effects in different
patients, thus requiring monitoring with special blood tests and meticulous dosing.
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.
Depletion of active vitamin K leads to reduced production of these factors.
Warfarin is administered orally.
It takes days to be effective because the existing pool of active clotting factors needs
some time to be cleared.
The effectiveness of warfarin is highly variable among patients and depends on a large number
of patient-specific factors.
Use of warfarin therefore requires frequent assessment and monitoring.
Direct oral anticoagulants are a new class of synthetic drugs that includes direct thrombin
inhibitors and direct factor 10a inhibitors.
These products have a rapid onset, fewer drug and dietary interactions, and a more predictable
dose-dependent response that eliminates the need for monitoring.
The major adverse effect of all anticoagulants is uncontrolled bleeding.
When this happens, anticoagulants are discontinued.
Hemodialysis, red blood cells transfusion, and platelet transfusion may be performed.
Activated charcoal may be administered to prevent absorption of the last dose of an
oral anticoagulant.
In addition, 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.