Anticoagulants are a category of drugs that inhibit the coagulation cascade.
Anticoagulants are indicated in the treatment and prophylaxis of thrombotic events including:
- Venous thromboembolism (VTE)
- Arterial thrombosis
- Atrial fibrillation (AFib)
- After a heart valve replacement
There are several primary classes of anticoagulants:
- Unfractionated heparin
- Low-molecular-weight heparins (LMWHs)
- Vitamin K antagonists
- Direct thrombin inhibitors
- Factor Xa inhibitors:
- Direct factor Xa inhibitors
- Indirect factor Xa inhibitors
Physiology: Overview of the coagulation cascade
The coagulation cascade is a series of reactions that ultimately generates a strong, cross-linked fibrin clot. This cascade is also known as secondary hemostasis.
A number of coagulation factors undergo sequential activation down 1 of 2 pathways:
- Extrinsic pathway:
- Primarily responsible for initiation of the cascade
- Involves tissue factor and factor VII
- Assessed by the PT
- Intrinsic pathway:
- Primarily involved in amplification of the cascade
- Involves factors XII, XI, IX, and VIII
- Assessed by the aPTT
- The extrinsic and intrinsic pathways join together when factor X is activated to factor Xa at the beginning of the final common pathway.
- Involves factors X, V, II (prothrombin), and I (fibrinogen)
- Prothrombinase complex:
- A procoagulant, multi-component enzyme complex involving factor Xa (the protease), factor Va (the cofactor), and prothrombin (the substrate)
- Activation of prothrombin (factor II) → thrombin (factor IIa)
- Thrombin converts fibrinogen → fibrin, which is able to form a stable clot
Natural heparins are a group of large, endogenously produced polysaccharides of varying sizes that are not completely understood. Heparins have anticoagulant, anti-inflammatory, and possibly anti-angiogenic effects.
|Mechanism of action|| Binds to and potentiates antithrombin|
|Physiologic effects||Inactivation of Factor Xa and thrombin||Inactivation of Factor Xa and, to a much lesser extent, thrombin||Absorption|| Administered IV (rarely SC):|
|Distribution||Vd = ~ 35 mL/kg||Vd = 4.3 L|
|Reversal agent||Protamine sulfate||Protamine sulfate|
|Complications||Lower risks of HITT and osteoporosis than UFH|
LMWH: low-molecular-weight heparin
HITT: heparin-induced thrombocytopenia and thrombosis
Vitamin K-Dependent Antagonists: Warfarin
|Mechanism of action|
|Metabolism|| Metabolized in liver:|
|Reversal agent/antidote||Vitamin K (takes several hours for effect)|
|Interactions||Warfarin has numerous drug, herbal, and dietary interactions:|
|Specific contraindications||Pregnancy (warfarin is teratogenic)|
|Notes||Patients with CYP2C9 variants have ↓ enzyme activity → require ↓ dose|
Direct Thrombin Inhibitors
|Oral agents (DOAC)||Parenteral agents|
|Mechanism of action||Binds to and functionally inhibits thrombin in both serum and clots|
|Absorption||Onset of action: immediate<|
|Specific contraindications||None (beyond general contraindications listed above)|
|Notes||Often used as an alternative in patients with a history of HITT|
ACT: activated clotting time
HITT: heparin-induced thrombocytopenia and thrombosis
Factor Xa Inhibitors
|Direct factor Xa inhibitors (DOACs)||Indirect factor Xa inhibitors|
|Mechanism of action||Directly binds to and inhibits factor Xa|
|Distribution|| Rivaroxaban:||Metabolism||Primarily metabolized in the liver by CYP3A4||Eliminated unchanged|
|Antidote||Andexanet alfa||None||Specific contraindications||None (beyond general contraindications listed above)||Thrombocytopenia associated with a positive antiplatelet antibody test|
|Notes||A synthetic pentasaccharide with a functional site similar to heparin|
Reversal and Cessation of Anticoagulation
Factors to consider prior to reversing an anticoagulant:
- Indication for anticoagulation (assess risk of bleeding versus risk of thrombosis)
- Type of anticoagulant, dose, and timing of last dose
- Reasons for reversal:
- Accidental or intentional overdose
- Emergent versus elective procedure/surgery
- Acute bleeding event
Elective procedures and surgery
- Determine if cessation of the anticoagulant is required:
- Estimate bleeding and thromboembolic risks
- If possible, avoid reversing anticoagulation during the initial phases immediately after a thrombotic event.
- Can the procedure be delayed if the thromboembolic risk is transient?
- Determine the appropriate timing of anticoagulation interruption:
- When to discontinue the anticoagulant?
- How long should it be held?
- Determine whether bridging therapy is required either before or after the procedure:
- Example: High-risk patients on warfarin may be started on LMWH while off warfarin, because LMWH can be stopped closer to the procedure.
- Consider placement of an inferior vena cava filter.
- Various guidelines and protocols exist based on the specific:
- Thrombotic risk to the patient
|Medication||Time prior to the procedure for which the medication should be stopped|
|DOACs: Dabigatran, rivaroxaban, apixaban, edoxaban|
LMWH: low-molecular-weight heparin
Bleeding while on anticoagulants
- Stop the anticoagulant.
- Supportive treatment including blood components and local hemostasis measures
- Hemodialysis is of little use in anticoagulant reversal.
- Use reversal agents to allow clotting to occur.
|Heparin and LMWHs||Protamine sulfate|
|Apixaban, rivaroxaban||Andexanet alfa|
|Fondaparinux||None, consider recombinant activated factor VII|
PCC: prothrombin complex concentrate
Some of the most common therapeutic uses of anticoagulants include:
- Deep vein thrombosis (DVT): a clot that has formed in the deep veins, most commonly in the calf. Patients with DVT may present with pain, redness, and swelling distal to the thrombus. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Ultrasound can be used to visualize the thrombus. Anticoagulation is the primary mode of treatment.
- Thrombotic PE: a potentially fatal condition that occurs as a result of vascular obstruction of the main pulmonary artery or its branches due to a thrombus. Thrombotic PEs commonly arise from a DVT in the leg; thus, patients may present with unilateral lower extremity edema and/or calf pain, in addition to dyspnea and/or chest pain. The diagnosis is usually made based on a chest CT. Management is aimed at stabilizing unstable patients. Anticoagulation is indicated in patients with a thrombotic PE.
- Atrial fibrillation: a supraventricular tachyarrhythmia and the most common kind of arrhythmia. Atrial fibrillation is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Diagnosis is confirmed based on an ECG that will show an “irregularly irregular” heartbeat without distinct P waves and with narrow QRS complexes. Atrial fibrillation increases the risk of thromboembolic events and anticoagulation is often indicated. Treatment is primarily based on ventricular rate and rhythm control, which can be achieved through drug therapy and/or cardioversion.
- Myocardial infarction: ischemia of the myocardial tissue due to a complete obstruction or drastic constriction of the coronary artery. Myocardial infarction is usually accompanied by an increase in cardiac enzymes, typical ECG changes, and chest pain. Treatment depends on the timing of presentation and available resources, but most patients initially receive anticoagulation therapy, antiplatelet therapy, and medications that decrease the oxygen demand of the heart.
- Thromboembolic ischemic stroke: ischemia of the brain due to a thrombotic or embolic obstruction of blood flow. Thrombotic strokes are caused by clots within the large or small vessels in the brain. Embolic strokes are due to clots that break off from elsewhere and ultimately become lodged in the brain; these clots often arise from cardiac or carotid sources. Patients present with neurologic deficits, and the diagnosis is made using a CT scan. Management is complex, but the initial treatment often involves the use of anticoagulants.
- Thrombophilias/hypercoagulable states: a group of hematological diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. There are both inherited and acquired causes of thrombophilias, with factor V Leiden being the most common inherited cause. Clinically, hypercoagulable states present with thrombotic events, which can cause vessel occlusion and lead to organ damage. Thrombotic disorders can be fatal if not treated. Management usually involves anticoagulants.
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