Laboratory Monitoring of Warfarin Therapy - Pathology

Warfarin Monitoring
Crystalline warfarin sodium (Coumadin,
Panwarfin, Sofarin, Coufarin, Athrombin-K) is
the most widely used oral anticoagulant in
the world. Warfarin interferes with the hepatic
synthesis of the vitamin-K dependent
coagulation factors by interfering with the
vitamin K cycle. Laboratory monitoring of
warfarin therapy is mandatory, since the
agent has a relatively narrow therapeutic
range. The therapeutic efficacy is of warfarin
is reduced with an inadequate dose, while there
is a serious risk of bleeding with an excess
amount of the drug. In addition, the pharmacokinetics
of warfarin are significantly influenced
by the diet, other medications, and
many other factors. During the past two decades,
several developments in laboratory science
have helped the clinician to ensure a
proper dosage intensity that decreases the
risk of bleeding while maintaining therapeutic
efficacy. These developments include improved
laboratory reagents and instrumentation,
as well as a standardized method for reporting
the prothrombin time (i.e., International
Normalized Ratio, INR). However, a comprehensive
system of quality assurance is still
necessary for optimal patient care.
It is imparative that physicians monitoring
warfarinized patients must understand the biological
effect and pharmacokinetics of warfarin,
its interaction with other medications, and the
factors affecting the prothrombin time/INR assay,
including the recently discovered impact of
the CYP2C9 and VKORC1 genetic polymorphisms.
The physician must also work with
other members of the patient care team to ensure
that patient identification procedures are
followed and the proper type and amount of
specimen is submitted for laboratory testing.
Warfarin is a synthetic derivative of the
naturally occurring anti-coagulant dicumarol.
The anti-coagulant properties of dicumarol
were first observed in cattle that suffered a
hemorrhagic disorder after being fed spoiled
sweet clover hay during the 1920s. Karl Link
identified the causative agent by 1939 and
later developed warfarin as a rat poison before
it was used in humans in the 1950s. However
the anticoagulant mechanism of warfarin
was not elucidated until twenty years
later.
Warfarin is a specific inhibitor of the vitamin
K epoxide reductase necessary for the
regeneration of vitamin K from vitamin K
2,3-epoxide in vivo (Fig. 1). Vitamin K acts as
a cofactor for !-glutamyl carboxylase, which
carboxylates specific glutamic acid residues
in vitamin K dependent proteins. The vitamin
K dependent proteins include coagulation
factors V, VII, IX, and X as well as protein C
and protein S. This post-translational modification
forms !-carboxyglutamic acid residues
that chelate metal ions and allow the proteins
to bind specific cofactors on phospholipid
surfaces necessary for normal coagulation.
The carboxylation reaction generates vitamin
K 2,3-epoxide, which must be converted back
to vitamin K by an epoxide reductase to
maintain stores. Inhibition of vitamin K epoxide
reductase reduces the availability of vitamin
K, which leads to a decrease in the active
forms of vitamin K dependent coagulation
factors and ultimately anti-coagulation.
Warfarin is currently the only FDA approved
orally available anti-coagulant medication.
It is rapidly absorbed from the gastrointestinal
tract, reaching maximum concentration
90 minutes after administration, with
a half-life of 36 to 42 hours. However, the
pharmacokinetics of warfarin can by highly
variable. It circulates bound to albumin and is
metabolized in the liver. Genetic variation in
a cytochrome P450 enzyme alters the dose-
Warfarin Structure, Metabolism, Pharmacokinetics 2