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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
UFH LMWH
Agents UFH
Enoxaparin (Lovenox®)
Dalteparin (Fragmin®)
Physiologic effects Inactivation of Factor Xa and thrombin Inactivation of Factor Xa and, to a much
lesser extent, thrombin
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
Monitoring
aPTT Factor Xa levels
Anti-factor Xa activity Note: aPTT is not reliable
Activated clotting time
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
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
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
Complications
Skin necrosis due to paradoxical local thrombosis (often related to protein C or S
deficiency)
Atheroemboli or cholesterol microemboli → purple toe syndrome
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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Normal Hemostasis Pharmacologic Anticoagulants
Direct Thrombin Inhibitors
Table: Direct thrombin inhibitors
Mechanism of action Binds to and functionally inhibits thrombin in both serum and clots
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
o Fecal excretion
o Half-life: approximately 45
minutes
8:16
Lepirudin, Bivalirudin & Warfarin (Coumadin)
Factor Xa Inhibitors
Table: Factor Xa inhibitors
Agents
Rivaroxaban (Xeralto®) Fondaparinux (Arixtra®)
Apixaban (Eliquis®) Note: Heparins can be considered
indirect factor Xa inhibitors.
Edoxaban (Lixiana®, Savaysa®)
Betrixaban (Bevyxxa®)
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%
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
Specific None (beyond general contraindications listed Thrombocytopenia associated with a positive
contraindications above) antiplatelet antibody test
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
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>
Warfarin
Vitamin K
PCC
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.