The International

Normalized Ratio

Maimun Zulhaidah Arthamin

PDS Patologi Klinik cabang Malang
 Introduction
• International normalized ratio (INR) is the
preferred test of choice for patients
taking vitamin K antagonists (VKA).
• The dose of warfarin is adapted based on INR
scores so that it remains in the therapeutic
range to prevent thrombosis from
subtherapeutic INR or hemorrhagic
complications from supratherapeutic INR.
• Patients taking oral anticoagulants are required
to monitor INR to adjust the VKA doses
because these vary between patients.
• Warfarin treatment must be monitored
closely because the anticoagulant
response to fixed dosages varies among
individuals, and the efficacy and safety of
warfarin are highly dependent on
maintaining the anticoagulant effect
within a defined therapeutic range.
• The major reason why control of warfarin
therapy using the PT is problematic is
because thromboplastin reagents vary in
their responsiveness to warfarin-induced
reduction in clotting factors, a variability that
is dependent on their method of
preparation.
• The approach that is now recommended is
to standardize PT monitoring by using the
INR, a system that adjusts for the variable
sensitivities of the different thromboplastin
reagents.
The coagulation cascade
 International normalized ratio
• The International Normalized Ratio (INR)
was developed to standardize PT values via
the mathematical transformation:

• where PT is the prothrombin time, MNPT is

the mean normal PT, ISI is the International
Sensitivity Index of the thromboplastin,
and PTR is the prothrombin time ratio.
• The objective of the INR is to translate any
given PT value into the PTR that would be
obtained if the PT were performed by the
reference method, which consists of PT
testing using the tilt-tube method with an
international reference thromboplastin
preparation of the World Health
Organization (WHO).
• The MNPT is the geometric mean of PT
determinations from a set of reference subjects
(i.e., “normal” subjects) using the laboratory’s
analyzer and thromboplastin combination,
hereafter referred to as the working method.
• The ISI of a working method is determined by
split-sample PT testing against a reference
method.
• The College of American Pathologists
recommends that laboratories use
thromboplastins with an ISI ≤1.70 and the
Clinical and Laboratory Standards Institute
recommends an ISI ≤1.50
• The first step of the INR calculation is to
“normalize” the PT by comparing it to the
mean normal prothrombin time (MNPT),
the geometric mean of the prothrombin
times of the healthy adult population.
• In the second step, this ratio is raised to a
power designated the ISI, or international
sensitivity index. The ISI is a function of the
thromboplastin reagent.
• Two groups of data are used to derive
the ISI (i) normal healthy individuals and
(ii) patients stabilized on warfarin.
• Paired PT data are obtained from
multiple samples using both the
working thromboplastin reagent and the
international thromboplastin standard
• Optimizing the patient’s INR therapeutic
range can be challenging as narrow
therapeutic range had been seen in VKAs
and can be affected by patient's
characteristics, co-morbid conditions, diet,
and other drug interactions.
• Patients are monitored every 3–4 weeks
or less at the thrombosis centers (TC),
point-of-care (POC) clinics, or in the home
setting.
 Indication
The indications for obtaining an INR value are:
1.Bleeding diathesis in patients with coagulation
factors deficiency (fibrinogen and factors II, V, VII, or
X, or a combined deficiency) in the extrinsic
pathway
2.Disseminated intravascular coagulation (DIC)
3.Baseline sample collection before starting
anticoagulation
4.Monitoring the efficacy and safety while the
patients are on warfarin due to clinical conditions
with an increased risk of thrombosis
 Normal and Critical Findings
• For normal patients who are not on
anticoagulation, the INR is usually 1.0
regardless of the ISI or the particular
performing laboratory.
• For patients who are on anticoagulant
therapy, the therapeutic INR ranges
between 2.0 to 3.0. INR levels above 4.9 are
considered critical values and increase the
risk of bleeding.
• The therapeutic INR range differs in a
patient with prosthetic valve
 Interfering Factors

1. Adherence to the VKAs

VKAs are commonly associated with
monitoring, and dose adjustments
along with food and drug interactions
make the adherence difficult in clinical
practice.
2. Drug Interactions
Following are the drugs that cause prolongation of
INR:
Antibiotics: especially cotrimoxazole, macrolides,
metronidazole, and fluoroquinolones
Antifungals: azoles (fluconazole)
Chemotherapeutics: imatinib, Fluorouracil (5-FU)
Amiodarone
Allopurinol
Serotonin reuptake inhibitors (fluoxetine,
sertraline)
Several medications may decrease INR value, for
example:
Antibiotics: Dicloxacillin, nafcillin
Azathioprine
Antiepileptics (Carbamazepine, phenobarbital,
phenytoin)
Saint John's Wort
Vitamin K

3. Comorbidities
Chronic liver disease may interfere with warfarin
dosage, INR value, and coagulation homeostasis.
Acute illness such as infections and
gastrointestinal illnesses may impact the INR
control.
 Evaluation of Discrepant INRs
• Warfarin patients generally receive INR testing
over an extended period of time and often from
more than one laboratory.
• The laboratory director usually receive inquiries
about INR values that appear discrepant, either
between two laboratories or from one
laboratory at different times.
• Some discrepancies are caused by the
laboratory, some are caused by patients, and
some reflect inherent limitations of the INR
schema.
• When evaluating an INR discrepancy, the
laboratory director should encourage the
patient’s physician to increase the
thoroughness of the dietary and
medication history.
Table. Causes of discrepant INRs
 Rationale for Laboratory Monitoring
of Warfarin
• First, warfarin has a relatively narrow
therapeutic window. Under-anticoagulation
greatly reduces warfarin’s therapeutic efficacy,
while over-anticoagulation greatly increases the
risk of bleeding.
• Second, the dose-response between individuals
is highly variable and may be quite variable in
the same individual over time.
• Third, warfarin’s effect may be either
potentiated or inhibited by a large number of
medications.
• Fourth, warfarin’s effect is influenced by
fluctuations in dietary vitamin K intake. The
half-life of vitamin K is only about 1 1⁄2 days, so
continual intake is required, and changes in
vitamin K intake affect the anticoagulant activity
of warfarin within days.
• Fifth, coexisting diseases or illnesses may affect
the absorption and metabolism of warfarin and
vitamin K and the synthesis of clotting factors.
• Sixth, as with many medications, patient
compliance is an issue with warfarin and affects
the stability of the anticoagulant effect.
VII, IX, X, PC, PS, PZ Precursor VII, IX, X, PC, PS, PZ

Figure. Vitamin
K1 is reduced to
vitamin KH2. The
major warfarin-
sensitive enzyme
in this reaction is
the vitamin K
oxide reductase
mainly inhibited
by the S-
enantiomer of
warfarin. S-
warfarin is
metabolized by
the p450
cytochrome
enzyme, CYP2C9.
 Warfarin Therapeutic Monitoring
• The recommended test for monitoring
warfarin therapy is the INR. Use of any
other test should be discouraged.
• Although several target ranges were
widely used in the past, recent studies
have led to the recommendation of a
single target range of 2.0– 3.0 for virtually
all indications.
Therapeutic
Anticoagulant
monitoring:
Hemostasis
disorders can be
regulated by a
broad panel of
anti-thrombotic or
anti-hemorrhagic
treatments.
• Additional points about warfarin therapeutic
monitoring: First, the PT assay is sensitive to
changes in factor VII levels. Because factor
VII has a short half-life, the PT/INR may begin
to be prolonged within hours of a warfarin
dose.
• Some non-compliant patients have admitted
to taking warfarin only the day prior to
testing to make it appear to the physician
that the patient is compliant with the
prescribed therapy.
• In cases where patient compliance is
doubtful but the INR indicates a warfarin
effect, specific factor assays showing
decreased factor VII levels with normal or
nearly normal factor II levels suggest that
warfarin has been taken only recently.
• During long-term therapy at steady state,
factor II and factor VII levels should be
roughly equally decreased.
• Second, heparin in therapeutic doses
does not significantly affect the PT/INR
with most working methods, since most
thromboplastin reagents contain
heparin neutralizers.
• For patients on both heparin and
warfarin, the INR reflects only the
warfarin effect.
• Direct thrombin inhibitors (DTIs) and
factor Xa inhibitors affect clot-based
assays that involve thrombin or factor X,
including the PT.
• In patients being treated with warfarin and
a DTI or factor Xa inhibitor, the INR reflects
the effects of both warfarin and the other
antithrombotic medication.
• During the conversion from a DTI or factor
Xa inhibitor to warfarin, the INR therapeutic
target should be increased or the dose of
DTI should be decreased.
• Third, patients with significantly
supratherapeutic INRs are frequently
treated with oral vitamin K to partially
reverse the warfarin effect.
• Many physicians believe the reversal will
occur within a few hours, but significant
lowering of the INR may take 24 h or
longer due to the relatively long half-life
of warfarin.
 Improper Use of International
Normalized Ratio Test
• The INR is a test with a singular purpose: a
standardized calibration for the measurement of the
anticoagulant activity of warfarin.
• It has no other reason for existence, yet it is
frequently ordered as part of routine screening for
previously undiagnosed coagulopathy.
• The INR and PT are elevated only in: vitamin K–
dependent factor deficiency, presence of factor VII
inhibitor, DIC, or massive transfusion. A mild
elevation of INR or PT is typically of no clinical
significance nor is it associated with increased
bleeding risk.
• The prime example of this
misunderstanding and misuse of the INR is
in approach to patients with cirrhosis or
end-stage liver disease (ESLD).
• As a result of their chronic liver injury,
these patients have impaired intrahepatic
synthesis of a number of important
elements of hemostasis.
The INR does not accurately reflect underlying
coagulopathy.
•Patients with impaired hepatic synthetic
dysfunction do suffer from a diminished
hemostatic reserve. These deficiencies are
counterbalanced by pro-hemostatic features
(elevated levels of von Willenbrand factor,
elevated factor VIII, & low levels of protein C & S).
•The PT & INR only narrowly reflect one portion
of the coagulation cascade, do not reflect a
holistic view of the ability to clot, and do not
accurately represent bleeding risk.
• This leads to a second important conclusion
regarding the approach to patients with
ESLD: FFP should not routinely be used as
procedural prophylaxis or treatment for the
bleeding cirrhotic with an elevated INR.
• The typical dose required to “correct” an
elevated INR of 4 units of FFP in patients with
cirrhosis and upper gastrointestinal bleeding
(UGIB) adds approximately a liter of high-
osmotic intravascular volume.
• The issue by misinterpreting these tests in
the setting of ESLD, whose “rebalanced”
hemostasis is best reflected only in the
newer clot-formation assays, such as
thromboelastometry (ROTEM) or
thromboelastography (TEG).
• The INR for the routine screening and
treatment of coagulopathy and bleeding is
harming patients and wasting limited
resources.
 Conclusion
• International normalized ratio is the
preferred test of choice for patients
taking VKA.
• The purpose of the INR is to transform PT
values into the PT ratio that would have
been obtained had the specimen been
tested by a reference method.
• The dose of warfarin is based on INR scores
so that it remains in the therapeutic range
to prevent thrombosis or hemorrhagic
complications
• Timely INR monitoring and patient-centered
education on INR management is an integral
part of patient care.
• INR management in the therapeutic range
remains a challenge, and hopefully, providers
will be able to achieve optimal outcomes for
their patients through clinical practice
guidelines.
• The PT and INR only narrowly reflect one
portion of the coagulation cascade, do not
reflect a holistic view of the ability to clot, and
do not accurately represent bleeding risk.