Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants are used in the treatment and prevention of thrombotic and embolic diseases including cardioembolic ischemic stroke, acute coronary syndrome, and venous thromboembolism, among other conditions. Patients with atrial fibrillation or thrombophilias may require indefinite or lifelong anticoagulation. Accordingly, the route of administration, drug interactions, pharmacokinetics, and availability of reversal factors should be considered while selecting the anticoagulant therapy.

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Anticoagulants are a category of drugs that inhibit the coagulation cascade.

General indications

Anticoagulants are indicated in the treatment and prophylaxis of thrombotic events including:

  • Venous thromboembolism (VTE)
  • Arterial thrombosis
    • MI
    • Stroke 
  • Atrial fibrillation (AFib)
  • After a heart valve replacement
  • Thrombophilias


There are several primary classes of anticoagulants:

  • Heparins:
    • 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.

Coagulation factors:

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

Common pathway:

  • 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
Overview of the coagulation cascade

Overview of the coagulation cascade
a: activated form
PF3: platelet factor 3 (phospholipids)

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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.

Table: Heparins
Agents UFH
  • Enoxaparin (Lovenox®)
  • Dalteparin (Fragmin®)
Mechanism of action Binds to and potentiates antithrombin
  • Heparin induces a conformational change in antithrombin, which ↑ its activity 1,000‒4,000 fold
  • Antithrombin inactivates:
    • Factor Xa
    • Thrombin (Factor IIa)
  • Inactivation of thrombin requires larger heparin molecules → UFH has ↑↑ thrombin-inactivation effects compared to LMWHs
Physiologic effects Inactivation of Factor Xa and thrombin Inactivation of Factor Xa and, to a much lesser extent, thrombin
Absorption Administered IV (rarely SC):
  • IV absorption is immediate
  • SC absorption is variable: peak activity at 2‒4 hours
  • Administered SC
  • Peak activity at 3‒5 hours
  • ↑ Bioavailability compared to UFH
Distribution Vd = ~ 35 mL/kg Vd = 4.3 L
  • Liver
  • Reticuloendothelial system
  • Renally excreted
  • Renal function does not impact elimination except at extremely high doses.
  • Half-life is short and dose dependent (mean 1‒2 hours).
  • Renally excreted
  • Elimination may be ↓ in patients with kidney disease
  • Longer half-life than UFH: Enoxaparin: 4.5‒7 hours
  • aPTT
  • Anti-factor Xa activity
  • Activated clotting time
  • Factor Xa levels
  • Note: aPTT is not reliable
Reversal agent Protamine sulfate Protamine sulfate
  • Transient thrombocytopenia
  • HITT
  • Osteoporosis with chronic use
Lower risks of HITT and osteoporosis than UFH
Specific contraindications
  • Allergy to bovine or porcine components
  • History of HITT
  • Highly acidic → will be neutralized by a base (e.g., protamine sulfate)
  • A mixture of large molecules with varying sizes
  • Isolated from porcine or bovine intestines
  • Unlike direct thrombin inhibitors, does not affect thrombin already within clots
  • Very predictable effects → monitoring is rarely needed
  • Derived from UFH
UFH: unfractionated heparin
LMWH: low-molecular-weight heparin
HITT: heparin-induced thrombocytopenia and thrombosis

Vitamin K-Dependent Antagonists: Warfarin

Table: Vitamin K-dependant antagonists: Warfarin (Coumadin®)
Mechanism of action
  • Competitively inhibits vitamin K epoxide reductase → depletes “active” vitamin K reserves required for the formation of vitamin K-dependent factors:
    • Procoagulant factors II, VII, IX, X
    • Anticoagulant proteins C and S
  • Note: Because Proteins C and S have a shorter half-life than the procoagulant factors, patients develop a transient hypercoagulable state for several days after warfarin therapy.
    • Patients typically require coadministration of an additional anticoagulant until a therapeutic INR is achieved.
  • Completely absorbed orally
  • Peak activity approximately 4 hours
Metabolism Metabolized in liver:
  • Primarily via CYP2C9
  • Minor pathways via CYP2C8, 2C18, 2C19, 1A2, and 3A4
  • Vd = 0.14 L/kg
  • Protein binding: 99%
  • Renally excreted as metabolites
  • Half-life: 20‒60 hours (highly variable)
  • Therapeutic window is narrow and levels are easily affected
  • Patients should be monitored weekly based on:
    • PT
    • INR
      • ↑ INR → ↑ risk of hemorrhage
      • ↓ INR → ↑ risk of thrombosis
Reversal agent/antidote Vitamin K (takes several hours for effect)
InteractionsWarfarin has numerous drug, herbal, and dietary interactions:
  • CYP450 inducers (e.g., carbamazepine, phenytoin, barbiturates, rifampin) → ↑ clearance → ↓ INR
  • CYP450 inhibitors (e.g., amiodarone, selective-seratonin reuptake inhibitors) → ↓ clearance → ↑ INR
  • Broad-spectrum antibiotics: kill normal gut flora that biosynthesize vitamin K → vitamin K deficiency → ↑ INR
Specific contraindications Pregnancy (warfarin is teratogenic)
  • Skin necrosis due to paradoxical local thrombosis (often related to protein C or S deficiency)
  • Atheroemboli or cholesterol microemboli → purple toe syndrome
Notes Patients with CYP2C9 variants have enzyme activity → require dose

Direct Thrombin Inhibitors

Table: Direct thrombin inhibitors
Oral agents (DOAC)Parenteral agents
Agents Dabigatran (Pradaxa®)
  • Bivalirudin (Angiomax®)
  • Argatroban (Argatra®)
  • Lepirudin (discontinued)
Mechanism of action Binds to and functionally inhibits thrombin in both serum and clots
  • Administered as an etexilate prodrug
  • Hydrolyzed to active state
  • Bioavilability: 3‒7%
  • Peak activity at 1‒2 hours
Onset of action: immediate<
  • Vd = 50‒70 L
  • Protein binding: 35%
  • Vd = 240 mL/kg
  • Protein binding 0%
  • Vd = 174 mL/kg
  • Protein binding: 54%
Metabolism Liver
  • Bivalirudin: kidney, liver, and other sites (proteolytic cleavage)
  • Argatroban: liver
  • Renally excreted
  • Half-life: 12‒17 hours
  • Bivalirudin:
    • Renally excreted
    • Half-life: 25 minutes
  • Argatroban:
    • Fecal excretion
    • Half-life: approximately 45 minutes
Monitoring aPTT ACT
Antidote Idarucizumab (Praxbind®) None
Specific contraindications None (beyond general contraindications listed above)
Notes Often used as an alternative in patients with a history of HITT
DOAC: direct oral anticoagulant
ACT: activated clotting time
HITT: heparin-induced thrombocytopenia and thrombosis

Factor Xa Inhibitors

Table: Factor Xa inhibitors
Direct factor Xa inhibitors (DOACs)Indirect factor Xa inhibitors
  • Rivaroxaban (Xeralto®)
  • Apixaban (Eliquis®)
  • Edoxaban (Lixiana®, Savaysa®)
  • Betrixaban (Bevyxxa®)
  • Fondaparinux (Arixtra®)
  • Note: Heparins can be considered indirect factor Xa inhibitors.
Mechanism of action Directly binds to and inhibits factor Xa
  • Binds to antithrombin (similar to heparin) → inactivates factor Xa → inhibits thrombin formation
  • Does not inhibit thrombin (too small)
  • Oral
  • Rapidly absorbed
  • SC
  • Bioavailability approximately 100%
  • Time to peak: 2‒3 hours
Distribution Rivaroxaban:
  • Vd = ~ 50 L
  • Protein binding: ~ 95%
  • Vc = ~ 21 L
  • Protein binding: ~ 87%
  • Vd = 7‒11 L
  • Protein binding: ~ 95% (to antithrombin)
Metabolism Primarily metabolized in the liver by CYP3A4 Eliminated unchanged
  • Renal and fecal/bile excretion
  • Half-life:
    • Rivaroxaban: 5‒9 hours
    • Apixaban: approximately 12 hours
  • Renally excreted
  • Half-life: 17‒21 hours, prolonged in renal impairment
  • Generally not required
  • Anti-Xa activity calibrated specifically for the medication
  • Generally not required
  • Anti-Xa activity calibrated specifically for fondaparinux
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
DOAC: direct oral anticoagulant

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:
    • Anticoagulant
    • Procedure
    • Thrombotic risk to the patient
Table: General guidelines for stopping anticoagulation therapy prior to invasive procedures
MedicationTime prior to the procedure for which the medication should be stopped
Warfarin 5 days
Heparin 4 hours
  • 12 hours for prophylactic dosing
  • 24 hours for therapeutic dosing>/li>
DOACs: Dabigatran, rivaroxaban, apixaban, edoxaban
  • 24 hours for patients at low risk
  • 48 hours for patients at high risk
DOAC: direct oral anticoagulant
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.
Table: Reversal agents
MedicationReversal agent
  • Vitamin K
  • PCC
Heparin and LMWHs Protamine sulfate
Dabigatran Idarucizumab (Praxbind®)
Argatroban, bivalirudin None
Apixaban, rivaroxaban Andexanet alfa
Fondaparinux None, consider recombinant activated factor VII
LMWH: low-molecular-weight heparin
PCC: prothrombin complex concentrate

Clinical Relevance

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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