American Heart Association/American College of Cardiology
Foundation Guide to Warfarin Therapy
Jack Hirsh, MD, FRCP(C), FRACP, FRSC, DSc; Valentin Fuster, MD, PhD;
Jack Ansell, MD; Jonathan L. Halperin, MD
Pharmacology of Warfarin
Mechanism of Action of Coumarin
Anticoagulant Drugs
Warfarin, a coumarin derivative, produces an anticoagulant
effect by interfering with the cyclic interconversion of vita-
min K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is
a cofactor for the carboxylation of glutamate residues to
�-carboxyglutamates (Gla) on the N-terminal regions of
vitamin K–dependent proteins (Figure 1) (1–6). These pro-
teins, which include the coagulation factors II, VII, IX, and X,
require �-carboxylation by vitamin K for biological activity.
By inhibiting the vitamin K conversion cycle, warfarin
induces hepatic production of partially decarboxylated pro-
teins with reduced coagulant activity (7,8).
Carboxylation promotes binding of the vitamin K–depen-
dent coagulation factors to phospholipid surfaces, thereby
accelerating blood coagulation (9–11). �-Carboxylation re-
quires the reduced form of vitamin K (vitamin KH2). Cou-
marins block the formation of vitamin KH2 by inhibiting the
enzyme vitamin K epoxide reductase, thereby limiting the
�-carboxylation of the vitamin K–dependent coagulant pro-
teins. In addition, the vitamin K antagonists inhibit carboxy-
lation of the regulatory anticoagulant proteins C and S. The
anticoagulant effect of coumarins can be overcome by low
doses of vitamin K1 (phytonadione) because vitamin K1
bypasses vitamin K epoxide reductase (Figure 1). Patients
treated with large doses of vitamin K1 (usually �5 mg) can
become resistant to warfarin for up to a week because vitamin
K1 accumulating in the liver is available to bypass vitamin K
epoxide reductase.
Warfarin also interferes with the carboxylation of Gla
proteins synthesized in bone (12–15). Although these effects
contribute to fetal bone abnormalities when mothers are
treated with warfarin during pregnancy (16,17), there is no
evidence that warfarin directly affects bone metabolism when
administered to children or adults.
Pharmacokinetics and Pharmacodynamics
of Warfarin
Warfarin is a racemic mixture of 2 optically active isomers,
the R and S forms, in roughly equal proportion. It is rapidly
absorbed from the gastrointestinal tract, has high bioavail-
ability (18,19), and reaches maximal blood concentrations in
healthy volunteers 90 minutes after oral administration
(18,20). Racemic warfarin has a half-life of 36 to 42 hours
(21), circulates bound to plasma proteins (mainly albumin),
and accumulates in the liver, where the 2 isomers are
metabolically transformed by different pathways (21). The
relationship between the dose of warfarin and the response is
influenced by genetic and environmental factors, including
common mutations in the gene coding for cytochrome P450,
the hepatic enzyme responsible for oxidative metabolism of
the warfarin S-isomer (18,19). Several genetic polymor-
phisms in this enzyme have been described that are associated
with lower dose requirements and higher bleeding complica-
tion rates compared with the wild-type enzyme CYP2C9*
(22–24).
In addition to known and unknown genetic factors, drugs,
diet, and various disease states can interfere with the response
to warfarin.
The anticoagulant response to warfarin is influenced both
by pharmacokinetic factors, including drug interactions that
affect its absorption or metabolic clearance, and by pharma-
codynamic factors, which alter the hemostatic response to
given concentrations of the drug. Variability in anticoagulant
response also results from inaccuracies in laboratory testing,
patient noncompliance, and miscommunication between the
patient and physician. Other drugs may influence the phar-
macokinetics of warfarin by reducing gastrointestinal absorp-
tion or disrupting metabolic clearance. For example, the
anticoagulant effect of warfarin is reduced by cholestyramine,
which impairs its absorption, and is potentiated by drugs that
inhibit warfarin clearance through stereoselective or nonse-
lective pathways (25,26). Stereoselective interactions may
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(J Am Coll Cardiol 2003;41:1633–52.)
©2003 by the American Heart Association, Inc, and the American College of Cardiology Foundation.
doi: 10.1016/S0735-1097(03)00416-9
AHA/ACC Scientific Statement
affect oxidative metabolism of either the S- or R-isomer of
warfarin (25,26). Inhibition of S-warfarin metabolism is more
important clinically because this isomer is 5 times more
potent than the R-isomer as a vitamin K antagonist (25,26).
Phenylbutazone (27), sulfinpyrazone (28), metronidazole
(29), and trimethoprim-sulfamethoxazole (30) inhibit clear-
ance of S-warfarin, and each potentiates the effect of warfarin
on the prothrombin time (PT). In contrast, drugs such as
cimetidine and omeprazole, which inhibit clearance of the
R-isomer, potentiate the PT only modestly in patients treated
with warfarin (26,29,31). Amiodarone inhibits the metabolic
clearance of both the S- and R-isomers and potentiates
warfarin anticoagulation (32). The anticoagulant effect is
inhibited by drugs like barbiturates, rifampicin, and carbam-
azepine, which increase hepatic clearance (31). Chronic
alcohol consumption has a similar potential to increase the
clearance of warfarin, but ingestion of even relatively large
amounts of wine has little influence on PT in subjects treated
with warfarin (33). For a more thorough discussion of the
effect of enzyme induction on warfarin therapy, the reader is
referred to a recent critical review (34).
Warfarin pharmacodynamics are subject to genetic and
environmental variability as well. Hereditary resistance to
warfarin occurs in rats as well as in human beings (35–37).
and patients with genetic warfarin resistance require doses 5-
to 20-fold higher than average to achieve an anticoagulant
effect. This disorder is attributed to reduced affinity of
warfarin for its hepatic receptor.
A mutation in the factor IX propeptide that causes bleeding
without excessive prolongation of PT also has been described
(38). The mutation occurs in �1.5% of the population.
Patients with this mutation experience a marked decrease in
factor IX during treatment with coumarin drugs, and levels of
other vitamin K–dependent coagulation factors decrease to
30% to 40%. The coagulopathy is not reflected in the PT, and
therefore, patients with this mutation are at risk of bleeding
during warfarin therapy (38–40). An exaggerated response to
warfarin among the elderly may reflect its reduced clearance
with age (41–43).
Subjects receiving long-term warfarin therapy are sensitive
to fluctuating levels of dietary vitamin K (44,45), which is
derived predominantly from phylloquinones in plant material
(45). The phylloquinone content of a wide range of foodstuffs
has been listed by Sadowski and associates (46). Phylloqui-
nones counteract the anticoagulant effect of warfarin because
they are reduced to vitamin KH2 through the warfarin-
insensitive pathway (47). Important fluctuations in vitamin K
intake occur in both healthy and sick subjects (48). Increased
intake of dietary vitamin K sufficient to reduce the anticoag-
ulant response to warfarin (44) occurs in patients consuming
green vegetables or vitamin K–containing supplements while
following weight-reduction diets and in patients treated with
intravenous vitamin K supplements. Reduced dietary vitamin
K1 intake potentiates the effect of warfarin in sick patients
treated with antibiotics and intravenous fluids without vita-
min K supplementation and in states of fat malabsorption.
Hepatic dysfunction potentiates the response to warfarin
through impaired synthesis of coagulation factors. Hypermet-
abolic states produced by fever or hyperthyroidism increase
warfarin responsiveness, probably by increasing the catabo-
lism of vitamin K–dependent coagulation factors (49,50).
Drugs may influence the pharmacodynamics of warfarin by
inhibiting synthesis or increasing clearance of vitamin K–de-
pendent coagulation factors or by interfering with other
pathways of hemostasis. The anticoagulant effect of warfarin
is augmented by the second- and third-generation cephalo-
sporins, which inhibit the cyclic interconversion of vitamin K
(51,52); by thyroxine, which increases the metabolism of
coagulation factors (50); and by clofibrate, through an un-
known mechanism (53). Doses of salicylates �1.5 g per day
(54) and acetaminophen (55) also augment the anticoagulant
effect of warfarin, possibly because these drugs have
warfarin-like activity (56). Heparin potentiates the anticoag-
ulant effect of warfarin but in therapeutic doses produces only
slight prolongation of the PT.
Drugs such as aspirin (57), nonsteroidal antiinflammatory
drugs (58), penicillins (in high doses) (59,60), and moxolac-
tam (52) increase the risk of warfarin-associated bleeding by
inhibiting platelet function. Of these, aspirin is the most
important because of its widespread use and prolonged effect
(61). Aspirin and nonsteroidal antiinflammatory drugs also
can produce gastric erosions that increase the risk of upper
gastrointestinal bleeding. The risk of clinically important
bleeding is heightened when high doses of aspirin are taken
Figure 1. The vitamin K cycle and its link to carboxylation of
glutamic acid residues on vitamin K–dependent coagulation
proteins. Vitamin K1 obtained from food sources is reduced to
vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin
KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction
that is coupled to carboxylation of glutamic acid residues on
coagulation factors. This carboxylation step renders the coagu-
lation factors II, VII, IX, and X and the anticoagulant factors pro-
tein C and protein S functionally active. Vit KO is then reduced
to Vit K1 in a reaction catalyzed by vitamin KO reductase. By
inhibiting vitamin KO reductase, warfarin blocks the formation of
vitamin K1 and vitamin KH2, thereby removing the substrate
(vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1,
either given therapeutically or derived from food sources,
can overcome the effect of warfarin by bypassing the warfarin-
sensitive vitamin KO reductase step in the formation of
vitamin KH2.
1634 Hirsh et al. JACC Vol. 41, No. 9, 2003
Guide to Warfarin Therapy May 7, 2003:1633–52
during high-intensity warfarin therapy (international normal-
ized ratio [INR] 3.0 to 4.5) (57,62). In 2 studies, one
involving patients with prosthetic heart valves (63) and the
other involving asymptomatic individuals at high risk of
coronary artery disease (64), low doses of aspirin (100 mg
and 75 mg daily, combined with moderate- and low-intensity
warfarin anticoagulation, respectively) also were associated
with increased rates of minor bleeding.
The mechanisms by which erythromycin (65) and some
anabolic steroids (66) potentiate the anticoagulant effect of
warfarin are unknown. Sulfonamides and several broad-
spectrum antibiotic compounds may augment the anticoagu-
lant effect of warfarin in patients consuming diets deficient in
vitamin K by eliminating bacterial flora and aggravating
vitamin K deficiency (67).
Wells et al (68) critically analyzed reports of possible
interactions between drugs or foods and warfarin. Interactions
were categorized as highly probable, probable, possible, or
doubtful. There was strong evidence of interaction in 39 of
the 81 different drugs and foods appraised; 17 potentiate
warfarin effect and 10 inhibit it, but 12 produce no effect.
Many other drugs have been reported to either interact with
oral anticoagulants or alter the PT response to warfarin
(69,70). A recent review highlighted the importance of
postmarketing surveillance with newer drugs, such as cele-
coxib, a drug that showed no interactions in Phase 2 studies
but was subsequently suspected of potentiating the effect of
warfarin in several case reports (71). This review also drew
attention to potential interactions with less well-regulated
herbal medicines. For these reasons, the INR should be
measured more frequently when virtually any drug or herbal
medicine is added or withdrawn from the regimen of a patient
treated with warfarin.
The Antithrombotic Effect of Warfarin
The antithrombotic effect of warfarin conventionally has
been attributed to its anticoagulant effect, which in turn is
mediated by the reduction of 4 vitamin K–dependent coag-
ulation factors. More recent evidence, however, suggests that
the anticoagulant and antithrombotic effects can be dissoci-
ated and that reduction of prothrombin and possibly factor X
are more important than reduction of factors VII and IX for
the antithrombotic effect. This evidence is indirect and
derived from the following observations: First, the experi-
ments of Wessler and Gitel (72) more than 40 years ago,
which used a stasis model of thrombosis in rabbits, showed
TABLE 1. Capillary Whole Blood (Point-of-Care) PT Instruments
Instrument
Clot Detection
Methodology
Type of
Sample
Home Use
Approval
Protime Monitor 1000
Coumatrak*
Ciba Corning 512 Coagulation Monitor*
CoaguChek Plus*
CoaguChek Pro*
CoaguChek Pro/DM*
Clot initiation: Thromboplastin
Clot detection: Cessation of blood flow through
capillary channel
Capillary WB
Venous WB
No
CoaguChek
CoaguChek S
Thrombolytic Assessment System
Rapidpoint Coag
Clot initiation: Thromboplastin
Clot detection: Cessation of movement of iron
particles
Capillary WB
Venous WB Plasma
Yes†
(CoaguChek
only)
ProTIME Monitor
Hemochron Jr‡
GEM PCL‡
Clot initiation: Thromboplastin
Clot detection: Cessation of blood flow through
capillary channel
Capillary WB
Venous WB
Yes
Avosure Pro�§
Avosure Pro§
Avosure PT§
Clot initiation: Thromboplastin
Clot detection: Thrombin generations detected
by fluorescent thrombin probe
Capillary WB
Venous WB Plasma
Yes
Harmony Clot initiation: Thromboplastin
Clot detection: Cessation of blood flow through
capillary channel
Capillary WB
Venous WB
Yes
INRatio� Clot initiation: Thromboplastin
Clot detection: Change in impedance in sample
Capillary WB
Venous WB
Yes
WB indicates whole blood.
*All instruments in this category are based on the original Biotrack model (Protime Monitor 1000) and licensed under different
names. The latest version available is the CoaguChek Pro and Pro/DM (as models evolved, they acquired added capabilities); earlier
models are no longer available.
†CoaguChek not actively marketed for home use at the time of this writing. Thrombolytic Assessment System not available for home
use.
‡Hemochron Jr and GEM PCL are simplified versions of the ProTIME Monitor.
§Avosure instruments removed from market when manufacturer (Avocet, Inc) ceased operations (2001). Technology has since been
purchased by Beckman Coulter.
�INRange system manufactured by Hemosense, Inc, is currently in development.
1635JACC Vol. 41, No. 9, 2003 Hirsh et al.
May 7, 2003:1633–52 Guide to Warfarin Therapy
that the antithrombotic effect of warfarin requires 6 days of
treatment, whereas an anticoagulant effect develops in 2. The
antithrombotic effect of warfarin requires reduction of pro-
thrombin (factor II), which has a relatively long half-life of
�60 to 72 hours, compared with 6 to 24 hours for other
K-dependent factors responsible for the more rapid anticoag-
ulant effect. Second, in a rabbit model of tissue factor–
induced intravascular coagulation, the protective effect of
warfarin is mainly a result of lowering prothrombin levels
(73). Third, Patel and associates (74) demonstrated that clots
formed from umbilical cord plasma (containing about half the
prothrombin concentration of adult control plasma) generated
significantly less fibrinopeptide A, reflecting less thrombin
activity, than clots formed from maternal plasma. The view
that warfarin exerts its antithrombotic effect by reducing
prothrombin levels is consistent with observations that clot-
bound thrombin is an important mediator of clot growth (75)
and that reduction in prothrombin levels decreases the
amount of thrombin generated and bound to fibrin, reducing
thrombogenicity (74).
The suggestion that the antithrombotic effect of warfarin is
reflected in lower levels of prothrombin forms the basis for
overlapping heparin with warfarin until the PT (INR) is
prolonged into the therapeutic range during treatment of
patients with thrombosis. Because the half-life of prothrom-
bin is �60 to 72 hours, �4 days’ overlap is necessary.
Furthermore, the levels of native prothrombin antigen during
warfarin therapy more closely reflect antithrombotic activity
than the PT (76). These considerations support administering
a maintenance dose of warfarin (�5 mg daily) rather than a
loading dose when initiating therapy. The rate of lowering
prothrombin levels was similar with either a 5- or a 10-mg
initial warfarin dose (77), but the anticoagulant protein C was
reduced more rapidly and more patients were excessively
anticoagulated (INR �3.0) with a 10-mg loading dose.
Management of Oral Anticoagulant Therapy
Monitoring Anticoagulation Intensity
The PT is the most common test used to monitor oral
anticoagulant therapy (78). The PT responds to reduction of 3
of the 4 vitamin K–dependent procoagulant clotting factors
(II, VII, and X) that are reduced by warfarin at a rate
proportionate to their respective half-lives. Thus, during the
first few days of warfarin therapy, the PT reflects mainly
reduction of factor VII, the half-life of which is �6 hours.
Subsequently, reduction of factors X and II contributes to
prolongation of the PT. The PT assay is performed by adding
calcium and thromboplastin to citrated plasma. The tradi-
tional term “thromboplastin” refers to a phospholipid-protein
extract of tissue (usually lung, brain, or placenta) that
contains both the tissue factor and phospholipid necessary to
promote activation of factor X by factor VII. Thromboplas-
tins vary in responsiveness to the anticoagulant effects of
warfarin according to their source, phospholipid content, and
preparation (79–81). The responsiveness of a given throm-
boplastin to warfarin-induced changes in clotting factors
reflects the intensity of activation of factor X by the factor
VIIa/tissue factor complex. An unresponsive thromboplastin
produces less prolongation of the PT for a given reduction in
vitamin K–dependent clotting factors than a responsive one.
The responsiveness of a thromboplastin can be measured by
assessing its International Sensitivity Index (ISI) (see below).
PT monitoring of warfarin treatment is very imprecise
when expressed as a PT ratio (calculated as a simple ratio of
the patient’s plasma value over that of norma