Page 2442 - Hematology_ Basic Principles and Practice ( PDFDrive )

2180 Part XII Hemostasis and Thrombosis

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Ca 2+ factor VII, and factor X. The test is performed by adding throm-
Ca 2+ boplastin, a reagent that contains tissue factor, phospholipid, and
YYYY calcium, to citrated plasma and determining the time to clot forma-
Glu Gla tion. Thromboplastins vary in their sensitivity to reductions in the
Precursor O 2 γ-carboxylated levels of the vitamin K–dependent clotting factors. Consequently, less
clotting factor sensitive thromboplastins will prompt the administration of higher
Vitamin K- doses of warfarin to achieve a target prothrombin time. This is
dependent problematic because higher doses of warfarin increase the risk of
carboxylase bleeding.
Vitamin K Vitamin K The INR was developed to circumvent many of the problems
hydroquinone epoxide associated with the prothrombin time assay. To calculate the INR,
the patient’s prothrombin time is divided by the mean normal pro-
thrombin time, and this ratio is then multiplied by the international
Warfarin Warfarin sensitivity index (ISI), an index of the sensitivity of the thromboplas-
tin used for prothrombin time determination to reductions in the
Vitamin K Vitamin K levels of the vitamin K–dependent clotting factors. Highly sensitive
thromboplastins have an ISI of 1.0. Most current thromboplastins
epoxide
reductase Vitamin K reductase have ISI values that range from 1.0 to 1.4.
Although the INR has helped to standardize anticoagulant prac-
Fig. 149.7 THE VITAMIN K CYCLE AND ITS INHIBITION BY tice, problems persist. The precision of INR determination varies
WARFARIN. Dietary vitamin K is reduced by vitamin K reductase to gener- depending on reagent–coagulometer combinations. This leads to
ate vitamin K hydroquinone. Vitamin K hydroquinone serves as a cofactor variability in the INR results. Also complicating INR determination
for the vitamin K–dependent carboxylase that converts glutamic acid residues is unreliable reporting of the ISI by thromboplastin manufacturers.
at the N-termini of the vitamin K–dependent precursors to γ-carboxyglutamic Furthermore, every laboratory must establish the mean normal pro-
acid residues, thereby creating the so-called Gla domain. By binding calcium, thrombin time with each new batch of thromboplastin reagent. To
the Gla domain is critical for the interaction of the vitamin K–dependent accomplish this, the prothrombin time must be measured in fresh
clotting factors with negatively charged phospholipid membranes. During plasma samples from at least 20 healthy volunteers using the same
vitamin K–dependent carboxylation, vitamin K is oxidized to vitamin K coagulometer that is used for patient samples.
epoxide. Vitamin K epoxide is then converted to vitamin K by vitamin K For most indications, warfarin is administered in doses that
epoxide reductase. Vitamin K antagonists, such as warfarin, interfere with produce a target INR of 2.0 to 3.0. An exception is patients with
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this cycle by inhibiting vitamin K epoxide reductase and vitamin K reductase. mechanical heart valves in the mitral position, where a target INR of
Of these two enzymes, vitamin K antagonists more readily block vitamin K 2.5 to 3.5 is recommended. Vitamin K antagonists have a narrow
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epoxide reductase than vitamin K reductase. Consequently, supplemental therapeutic window. Thus studies in atrial fibrillation demonstrate an
vitamin K can overcome the inhibitory effects of vitamin K antagonists.
increased risk of cardioembolic stroke when the INR falls below 1.7
and an increase in bleeding with INR values over 4.5. Likewise, a
Pharmacology study with patients receiving long-term warfarin therapy for unpro-
voked venous thromboembolism demonstrated a higher rate of
Warfarin is a racemic mixture of R and S isomers; of these, the S recurrent venous thromboembolism when the warfarin dose was
isomer is more active. Warfarin is rapidly and almost completely adjusted to achieve a target INR of 1.5 to 1.9 than with a target INR
absorbed from the gastrointestinal tract. Levels of warfarin in the of 2.0 to 3.0. Rates of major bleeding were similar.
blood peak about 90 minutes after drug administration. Racemic
warfarin has a plasma half-life of 36 to 42 hours, and over 97% of
circulating warfarin is bound to albumin. Only unbound warfarin is Dosing
biologically active.
Warfarin accumulates in the liver, where the two isomers are Warfarin is usually started at a dose of 5 to 10 mg. The dose is then
metabolized via distinct pathways. Oxidative metabolism of the more titrated to achieve the desired target INR. Because of its delayed onset
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active S isomer is effected by CYP2C9. Two relatively common of action, patients with established thrombosis or those at high risk
variants, CYP2C9*2 and CYP2C9*3, have reduced activity. Patients for thrombosis are given concomitant treatment with a rapidly acting
with these variants require a lower maintenance dose of warfarin. The parenteral anticoagulant, such as heparin, LMWH, or fondaparinux.
target of warfarin is VKOR. Polymorphisms in the C1 subunit of this Initial prolongation of the INR reflects reduction in the functional
enzyme (VKORC1) also can render patients less or more responsive levels of factor VII. Consequently, concomitant treatment with the
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to the anticoagulant effects of warfarin. These findings have parenteral anticoagulant should be continued until the INR has been
prompted a recommendation that patients starting on warfarin therapeutic for at least 2 consecutive days. A minimum 5-day course
should be tested for these polymorphisms and that this information of parenteral anticoagulation is recommended to ensure that the
should be incorporated into their warfarin-dosing algorithms. levels of prothrombin have been reduced into the therapeutic range
Whether this approach will increase the efficacy and/or safety of with warfarin.
warfarin therapy is uncertain. Because warfarin has a narrow therapeutic window, frequent
In addition to genetic factors, diet, drugs, and various disease coagulation monitoring is essential to ensure that a therapeutic
states influence the anticoagulant effect of warfarin. Fluctuations in anticoagulant response is obtained. Even patients with stable warfarin
dietary vitamin K intake affect the activity of warfarin. A wide variety dose requirements should have their INR determined every 2 to 4
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of drugs can alter absorption, clearance, or metabolism of warfarin. weeks. More frequent monitoring is necessary when new medica-
Because of the variability in the anticoagulant response to warfarin, tions are introduced because many drugs enhance or reduce the
coagulation monitoring is essential to ensure that a therapeutic anticoagulant effects of warfarin.
response is obtained.
Side Effects
Monitoring
Like all anticoagulants, the major side effect of warfarin is bleed-
Warfarin therapy is most often monitored using the prothrombin ing. A rare complication is skin necrosis. Warfarin crosses the
time, a test that is sensitive to reductions in the levels of prothrombin, placenta and can cause fetal abnormalities. Consequently, warfarin