DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

864 inhibits platelet function. Elderly patients are more sensitive to oral
anticoagulants.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Resistance to Warfarin. Some patients require >20 mg/day of warfarin
to achieve a therapeutic INR. These patients often have excessive
vitamin K intake from the diet or parenteral supplementation.
Noncompliance and laboratory error are other causes of apparent
warfarin resistance. There have been reported a few patients with
hereditary warfarin resistance, in whom very high plasma concentrations
of warfarin are associated with minimal depression of vitamin
K-dependent coagulation factor biosynthesis; mutations in the
VKORC1 gene have been identified in some of these patients (Rost
et al., 2004).
Sensitivity to Warfarin. Approximately 10% of patients require
<1.5 mg/day of warfarin to achieve an INR of 2-3. As indicated earlier,
these patients often possess variant alleles of CYP2C9 or variant
VKORC1 haplotypes, which affect the pharmacokinetics or
pharmacodynamics of warfarin, respectively (Daly and King, 2003).
Toxicities
Bleeding. Bleeding is the major toxicity of warfarin
(Hirsh et al., 2003). The risk of bleeding increases with
the intensity and duration of anticoagulant therapy, the
use of other medications that interfere with hemostasis,
and the presence of a potential anatomical source of
bleeding. Especially serious episodes involve sites where
irreversible damage may result from compression of vital
structures (e.g., intracranial, pericardial, nerve sheath,
spinal cord) or from massive internal blood loss that may
not be diagnosed rapidly (e.g., gastrointestinal, intraperitoneal,
retroperitoneal).
Although the reported incidence of major bleeding episodes
varies considerably, it is generally <3% per year in patients treated
with a target INR of 2-3. The risk of intracranial hemorrhage
increases dramatically with an INR >4, especially in older patients.
In a large outpatient anticoagulation clinic, the most common factors
associated with a transient elevation of the INR to a value >6 were use
of a new medication known to potentiate warfarin (e.g., acetaminophen),
advanced malignancy, recent diarrheal illness, decreased oral
intake, and taking more warfarin than prescribed (Hylek et al., 1998).
Patients must be informed of the signs and symptoms of bleeding,
and laboratory monitoring should be done at frequent intervals during
intercurrent illnesses or any changes of medication or diet.
If the INR is above the therapeutic range but <5 and the
patient is not bleeding or in need of a surgical procedure, warfarin
can be discontinued temporarily and restarted at a lower dose once
the INR is within the therapeutic range (Hirsh et al., 2003). If the
INR is ≥5, vitamin K 1
(phytonadione, MEPHYTON, AQUAMEPHYTON)
can be given orally at a dose of 1-2.5 mg (for 5≤ INR ≤9) or 3-5 mg
(for INR >9). These doses of oral vitamin K 1
generally cause the
INR to fall substantially within 24-48 hours without rendering the
patient resistant to further warfarin therapy. Higher doses or parenteral
administration may be required if more rapid correction of the INR is
necessary. The effect of vitamin K 1
is delayed for at least several hours
because reversal of anticoagulation requires synthesis of fully carboxylated
coagulation factors. If immediate hemostatic competence is
necessary because of serious bleeding or profound warfarin overdosage
(INR >20), adequate concentrations of vitamin K-dependent
coagulation factors can be restored by transfusion of fresh
frozen plasma (10-20 mL/kg), supplemented with 10 mg of vitamin
K 1
, given by slow intravenous infusion. Transfusion of plasma
may need to be repeated because the transfused factors (particularly
factor VII) are cleared from the circulation more rapidly than the
residual oral anticoagulant. Concentrates containing three or four
of the vitamin K-dependent clotting factors are available in some
countries; these rapidly restore the INR to normal. Vitamin K 1
administered intravenously carries the risk of anaphylactoid reactions
and therefore should be used cautiously and administered
slowly. Patients who receive high doses of vitamin K 1
may become
unresponsive to warfarin for several days, but heparin can be used
if continued anticoagulation is required.
Birth Defects. Administration of warfarin during pregnancy causes
birth defects and abortion. A syndrome characterized by nasal
hypoplasia and stippled epiphyseal calcifications that resemble chondrodysplasia
punctata may result from maternal ingestion of warfarin
during the first trimester. Central nervous system abnormalities
have been reported following exposure during the second and third
trimesters. Fetal or neonatal hemorrhage and intrauterine death may
occur, even when maternal PT values are in the therapeutic range.
Vitamin K antagonists should not be used during pregnancy, but as
indicated in the previous section, heparin, LMWH, or fondaparinux
can be used safely in this circumstance.
Skin Necrosis. Warfarin-induced skin necrosis is a rare complication
characterized by the appearance of skin lesions 3-10 days after treatment
is initiated. The lesions typically are on the extremities, but adipose
tissue, the penis, and the female breast also may be involved.
Lesions are characterized by widespread thrombosis of the microvasculature
and can spread rapidly, sometimes becoming necrotic and
requiring disfiguring débridement or occasionally amputation. Because
protein C has a shorter t 1/2
than do the other vitamin K-dependent coagulation
factors (except factor VII), its functional activity falls more rapidly
in response to the initial dose of vitamin K antagonist. It has been
proposed that the dermal necrosis is a manifestation of a temporal
imbalance between the anticoagulant protein C and one or more of the
procoagulant factors and is exaggerated in patients who are partially
deficient in protein C or protein S. However, not all patients with heterozygous
deficiency of protein C or protein S develop skin necrosis
when treated with warfarin, and patients with normal activities of these
proteins also can be affected. Morphologically similar lesions can occur
in patients with vitamin K deficiency.
Other Toxicities. A reversible, sometimes painful, blue-tinged discoloration
of the plantar surfaces and sides of the toes that blanches
with pressure and fades with elevation of the legs (purple toe syndrome)
may develop 3-8 weeks after initiation of therapy with warfarin;
cholesterol emboli released from atheromatous plaques have
been implicated as the cause. Other infrequent reactions include
alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal
cramps, and anorexia.
Warfarin can precipitate the syndromes of venous limb gangrene
and multicentric skin necrosis when given to patients with
heparin-induced thrombocytopenia who are not receiving a parenteral
anticoagulant (Warkentin, 2003). Other anticoagulant agents,
such as lepirudin, argatroban, or fondaparinux should be continued