Anticoagulants

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.

Definition
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
o MI
o Stroke 
 Atrial fibrillation (AFib)
 After a heart valve replacement
 Thrombophilias

Classification
There are several primary classes of anticoagulants:
 Heparins:
o Unfractionated heparin
o Low-molecular-weight heparins (LMWHs)
 Vitamin K antagonists
 Direct thrombin inhibitors
 Factor Xa inhibitors:
 o Direct factor Xa inhibitors
o 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: 
o Primarily responsible for initiation of the cascade
o Involves tissue factor and factor VII
o Assessed by the PT
 Intrinsic pathway: 
o Primarily involved in amplification of the cascade
o Involves factors XII, XI, IX, and VIII
o 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: 
o A procoagulant, multi-component enzyme complex involving factor Xa
(the protease), factor Va (the cofactor), and prothrombin (the substrate)
o Activation of prothrombin (factor II) → thrombin (factor IIa)
 Thrombin converts fibrinogen → fib

rin, which is able to form a stable clot

Table: Heparins

UFH LMWH

Agents UFH
 Enoxaparin (Lovenox®)
 Dalteparin (Fragmin®)

Mechanism of Binds to and potentiates antithrombin

action
 Heparin induces a conformational change in antithrombin, which ↑ its activity 1,000‒
4,000 fold
 Antithrombin inactivates:
o Factor Xa
o 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):

 Administered SC
 IV absorption is immediate
 Peak activity at 3‒5 hours
 SC absorption is variable: peak activity at
 ↑ Bioavailability compared to
2‒4 hours
UFH

Distribution Vd = ~ 35 mL/kg Vd = 4.3 L

Metabolism Liver
 Liver
 Reticuloendothelial system

Elimination
 Renally excreted  Renally excreted
 Renal function does not impact elimination  Elimination may be ↓ in
except at extremely high doses. patients with kidney disease
 Half-life is short and dose dependent (mean  Longer half-life than UFH:
Table: Heparins

UFH LMWH

1‒2 hours). Enoxaparin: 4.5‒7 hours

Monitoring
 aPTT  Factor Xa levels
 Anti-factor Xa activity  Note: aPTT is not reliable
 Activated clotting time

Reversal agent Protamine sulfate Protamine sulfate

Complications Lower risks of HITT and osteoporosis

 Transient thrombocytopenia than UFH
 HITT
 Osteoporosis with chronic use

Specific
contraindications  Allergy to bovine or porcine components
 History of HITT

Notes
 Highly acidic → will be neutralized by a  Very predictable effects →
base (e.g., protamine sulfate) monitoring is rarely needed
 A mixture of large molecules with varying  Derived from UFH
sizes
 Isolated from porcine or bovine intestines
 Unlike direct thrombin inhibitors, does not
affect thrombin already within clots

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:
o Procoagulant factors II, VII, IX, X
o 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.
o Patients typically require coadministration of an additional anticoagulant until a
therapeutic INR is achieved.

Absorption
 Completely absorbed orally
 Peak activity approximately 4 hours

Metabolism Metabolized in liver:

 Primarily via CYP2C9
 Minor pathways via CYP2C8, 2C18, 2C19, 1A2, and 3A4

Distribution
 Vd = 0.14 L/kg
 Protein binding: 99%

Elimination
 Renally excreted as metabolites
 Half-life: 20‒60 hours (highly variable)

Monitoring
 Therapeutic window is narrow and levels are easily affected
 Patients should be monitored weekly based on:
o PT
o INR
 ↑ INR → ↑ risk of hemorrhage
 ↓ INR → ↑ risk of thrombosis

Reversal Vitamin K (takes several hours for effect)

agent/antidote
Interactions Warfarin 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 Pregnancy (warfarin is teratogenic)

contraindications

Complications
 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

10:32
Anticoagulants

Heparins
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.
UFH: unfractionated heparin
LMWH: low-molecular-weight heparin
HITT: heparin-induced thrombocytopenia and thrombosis

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Hematology: Pharmacology

Vitamin K-Dependent Antagonists: Warfarin

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10:04
Normal Hemostasis Pharmacologic Anticoagulants
 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

Absorption Onset of action: immediate<

 Administered as an etexilate
prodrug
 Hydrolyzed to active state
 Bioavilability: 3‒7%
 Peak activity at 1‒2 hours

Distribution Bivalirudin:
 Vd = 50‒70 L
 Vd = 240 mL/kg
 Protein binding: 35%
 Protein binding 0%
Argatroban:
 Vd = 174 mL/kg
 Protein binding: 54%

Metabolism Liver
 Bivalirudin: kidney, liver, and other sites
(proteolytic cleavage)
 Argatroban: liver

Elimination
 Renally excreted  Bivalirudin:
 Half-life: 12‒17 hours o Renally excreted
o Half-life: 25 minutes
 Argatroban:
Table: Direct thrombin inhibitors

Oral agents (DOAC) Parenteral agents

o Fecal excretion
o Half-life: approximately 45
minutes

Monitoring aPTT ACT

Antidote Idarucizumab (Praxbind®) None

Specific None (beyond general contraindications listed above)

contraindications

Notes Often used as an alternative in patients

with a history of HITT

8:16
Lepirudin, Bivalirudin & Warfarin (Coumadin)

Factor Xa Inhibitors
Table: Factor Xa inhibitors

Direct factor Xa inhibitors (DOACs) Indirect factor Xa inhibitors

Agents
 Rivaroxaban (Xeralto®)  Fondaparinux (Arixtra®)
 Apixaban (Eliquis®)  Note: Heparins can be considered
indirect factor Xa inhibitors.
 Edoxaban (Lixiana®, Savaysa®)
 Betrixaban (Bevyxxa®)

Mechanism of Directly binds to and inhibits factor Xa

action  Binds to antithrombin (similar to
heparin) → inactivates factor Xa →
inhibits thrombin formation
 Does not inhibit thrombin (too small)
Table: Factor Xa inhibitors

Direct factor Xa inhibitors (DOACs) Indirect factor Xa inhibitors

Absorption
 Oral  SC
 Rapidly absorbed  Bioavailability approximately 100%
 Time to peak: 2‒3 hours

Distribution Rivaroxaban:
 Vd = 7‒11 L
 Vd = ~ 50 L
 Protein binding: ~ 95% (to
 Protein binding: ~ 95% antithrombin)
Apixaban:
 Vc = ~ 21 L
 Protein binding: ~ 87%

Metabolism Primarily metabolized in the liver by CYP3A4 Eliminated unchanged

Elimination
 Renal and fecal/bile excretion  Renally excreted
 Half-life:  Half-life: 17‒21 hours, prolonged in
renal impairment
o Rivaroxaban: 5‒9 hours
o Apixaban: approximately 12
hours

Monitoring
 Generally not required  Generally not required
 Anti-Xa activity calibrated specifically  Anti-Xa activity calibrated
for the medication specifically for fondaparinux

Antidote Andexanet alfa None

Specific None (beyond general contraindications listed Thrombocytopenia associated with a positive
contraindications above) antiplatelet antibody test

Notes A synthetic pentasaccharide with a functional

site similar to heparin
DOAC: direct oral anticoagulant

Reversal and Cessation of Anticoagulation

Considerations
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:
o Accidental or intentional overdose
o Emergent versus elective procedure/surgery
o Acute bleeding event

Elective procedures and surgery

 Determine if cessation of the anticoagulant is required:
o Estimate bleeding and thromboembolic risks
o If possible, avoid reversing anticoagulation during the initial phases
immediately after a thrombotic event.
o Can the procedure be delayed if the thromboembolic risk is transient?
 Determine the appropriate timing of anticoagulation interruption:
o When to discontinue the anticoagulant?
o How long should it be held?
o 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:
o Anticoagulant
o Procedure
 o Thrombotic risk to the patient

Table: General guidelines for stopping anticoagulation therapy prior to invasive procedures

Medication Time prior to the procedure for which the medication should b
stopped

Warfarin 5 days

Heparin 4 hours

LMWH
 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

Medication Reversal agent

Warfarin
 Vitamin K
 PCC

Heparin and LMWHs Protamine sulfate

 Table: Reversal agents

Medication Reversal agent

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.