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

until the heparin-induced thrombocytopenia has resolved (see
“Heparin toxicities,” earlier in the chapter).
Clinical Use. Vitamin K antagonists are used to prevent
the progression or recurrence of acute DVT or pulmonary
embolism following an initial course of heparin. They
also are effective in preventing venous thromboembolism
in patients undergoing orthopedic or gynecological surgery,
recurrent coronary ischemia in patients with acute
myocardial infarction, and systemic embolization in
patients with prosthetic heart valves or chronic atrial fibrillation.
Specific recommendations for oral anticoagulant
use for these and other indications have been
reviewed (Geerts et al., 2008).
Prior to initiation of therapy, laboratory tests are used in conjunction
with the history and physical examination to uncover
hemostatic defects that might make the use of vitamin K antagonists
more dangerous (e.g., congenital coagulation factor deficiency,
thrombocytopenia, hepatic or renal insufficiency, vascular abnormalities).
Thereafter, the INR calculated from the patient’s PT is
used to monitor the extent of anticoagulation and compliance.
Therapeutic INR ranges for various clinical indications have been
established empirically and reflect dosages that reduce the morbidity
from thromboembolic disease while minimally increasing the
risk of serious hemorrhage. For most indications, the target INR is
2-3. A higher target INR (e.g., 2.5-3.5) generally is recommended
for patients with high-risk mechanical prosthetic heart valves (Hirsh
et al., 2003).
For treatment of acute venous thromboembolism, heparin,
LMWH, or fondaparinux usually is continued for at least 5 days after
warfarin therapy is begun and until the INR is in the therapeutic
range on 2 consecutive days. This overlap allows for adequate depletion
of the vitamin K-dependent coagulation factors with long t 1/2
,
especially factor II. Frequent INR measurements are indicated at the
onset of therapy to guard against excessive anticoagulation in the
unusually sensitive patient. The testing interval can be lengthened
gradually to weekly and then monthly for patients on long-term therapy
whose test results have been stable.
Monitoring Anticoagulant Therapy: The INR (International Normalized
Ratio). To monitor therapy, a blood sample is obtained, and the PT is
determined along with that of a sample of normal pooled plasma.
Formerly, the results were reported as a simple ratio of the two PT
values. However, this ratio can vary widely depending on the
thromboplastin reagent and the instrument used to initiate and detect
clot formation. The PT is prolonged when the functional levels of
fibrinogen, factor V, or the vitamin K-dependent factors II, VII, or X
are decreased. Reduced levels of factor IX or proteins C or S have no
effect on the PT. PT measurements are converted to INR measurements
by the following equation:
ISI
pt ⎞
⎟
ref
PT
INR = ⎛ ⎝ ⎜ PT ⎠
where INR = international normalized ratio
ISI = international sensitivity index
The ISI value, supplied by the manufacturer of the test regent,
indicates the relative sensitivity of the PT (determined from a given
batch of thromboplastin) to decreases in the vitamin K-dependent
coagulation factors in comparison with a World Health Organization
human thromboplastin standard. Reagents with lower ISI values are
more sensitive to the effects of vitamin K antagonists (i.e., the PT is
prolonged to a greater extent in comparison with that obtained with
a less-sensitive reagent having a higher ISI). Ideally, the ISI value of
each batch of thromboplastin should be confirmed in each clinical
laboratory using a set of reference plasmas to control for local variables
of sample handling and instrumentation.
The INR does not provide a reliable indication of the degree
of anticoagulation in patients with the lupus anticoagulant, in whom
the PT and other phospholipid-dependent coagulation tests are prolonged
at baseline. In these patients, a chromogenic factor X assay
or the prothrombin-proconvertin time assay may be used to monitor
therapy (Moll and Ortel, 1997).
Other Vitamin K Antagonists
Phenprocoumon and Acenocoumarol. These agents
generally are not available in the U.S. but are prescribed
in the E.U. and elsewhere.
Phenprocoumon (MARCUMAR) has a longer plasma t 1/2
(5 days)
than warfarin, as well as a somewhat slower onset of action and a
longer duration of action (7-14 days). It is administered in daily
maintenance doses of 0.75-6 mg. By contrast, acenocoumarol
(SINTHROME) has a shorter t 1/2
(10-24 hours), a more rapid effect on
the PT, and a shorter duration of action (2 days). The maintenance
dose is 1-8 mg daily.
Indandione Derivatives. Anisindione (MIRADON) is available for clinical
use in some countries. It is similar to warfarin in its kinetics of
action but offers no clear advantages and may have a higher frequency
of untoward effects. Phenindione (DINDEVAN) still is available in some
countries. Serious hypersensitivity reactions, occasionally fatal, can
occur within a few weeks of starting therapy with this drug, and its
use can no longer be recommended.
Rodenticides. Bromadiolone, brodifacoum, diphenadione, chlorophacinone,
and pindone are long-acting agents (prolongation of the PT
may persist for weeks). They are of interest because they sometimes
are agents of accidental or intentional poisoning. In this setting, reversal
of the coagulopathy can require very large doses of vitamin K (i.e.,
>100 mg/day) for weeks or months.
NEW ORAL ANTICOAGULANTS
Dabigatran Etexilate (PRADAXA, PRADAX). A novel oral
anticoagulant, dabigatran etexilate is a prodrug that is
rapidly converted to dabigatran, which reversibly blocks
the active site of thrombin.
The drug has oral bioavailability of ~6%, a peak onset of
action in 2 hours, and a plasma t 1/2
of 12-14 hours. When given in
fixed doses, dabigatran etexilate produces such a predictable anticoagulant
response that routine coagulation monitoring is unnecessary.
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CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS