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

or protamine zinc insulin), but untoward reactions are not limited to
this group. A less common reaction consisting of pulmonary vasoconstriction,
right ventricular dysfunction, systemic hypotension,
and transient neutropenia also may occur after protamine administration.
Protamine only binds long heparin molecules. Therefore, protamine
only partially reverses the anticoagulant activity of LMWHs
and has no effect on that of fondaparinux. Because the long heparin
molecules account for the anti-factor IIa activity of LMWH, protamine
completely reverses this activity. In contrast, protamine only
partially reverses the anti-factor Xa activity of LMWH, which is
mediated by shorter heparin molecules. The very short molecules of
fondaparinux do not bind protamine. Therefore, fondaparinux lacks
a specific antidote.
Heparin-Induced Thrombocytopenia. Heparin-induced
thrombocytopenia (platelet count <150,000/mL or a
50% decrease from the pretreatment value) occurs in
~0.5% of medical patients 5-10 days after initiation of
therapy with heparin (Warkentin, 2007). Although the
incidence may be lower, thrombocytopenia also occurs
with LMWHs and fondaparinux, and platelet counts
should be monitored. Thrombotic complications that
can be life-threatening or lead to amputation occur in
about one-half of the affected heparin-treated patients
and may precede the onset of thrombocytopenia. The
incidence of heparin-induced thrombocytopenia and
thrombosis is higher in surgical patients than in medical
patients. Women are twice as likely as men to develop
this condition.
Venous thromboembolism occurs most commonly, but arterial
thromboses causing limb ischemia, myocardial infarction, and
stroke also occur. Bilateral adrenal hemorrhage, skin lesions at the
site of subcutaneous heparin injection, and a variety of systemic
reactions may accompany heparin-induced thrombocytopenia.
The development of IgG antibodies against complexes of heparin
with platelet factor 4 (or, rarely, other chemokines) appears to cause
all of these reactions. These complexes activate platelets by binding
to FcγIIa receptors, which results in platelet aggregation, release of
more platelet factor 4, and thrombin generation. The antibodies also
may trigger vascular injury by binding to platelet factor 4 attached
to endogenous heparan sulfate on the endothelium.
Heparin, LMWH, and fondaparinux should be discontinued
immediately if unexplained thrombocytopenia or any of the clinical
manifestations mentioned above occur 5 or more days after beginning
therapy, regardless of the dose or route of administration. The
onset of heparin-induced thrombocytopenia may occur earlier in
patients who have received heparin within the previous 3-4 months
and have residual circulating antibodies. The diagnosis of heparininduced
thrombocytopenia can be confirmed by a heparin-dependent
platelet activation assay or an assay for antibodies that react with
heparin/platelet factor 4 complexes. Because thrombotic complications
may occur after cessation of therapy, an alternative anticoagulant
such as lepirudin, argatroban (see the next section), or
fondaparinux should be administered to patients with heparin-induced
thrombocytopenia. LMWH preparations should be avoided, because
these drugs often cross-react with heparin in heparin-dependent antibody
assays. In contrast, fondaparinux does not cross-react with
these heparin-dependent antibodies, and, although large clinical
trials are lacking, fondaparinux has been used successfully in
patients with heparin-induced thrombocytopenia. Warfarin may precipitate
venous limb gangrene or multicentric skin necrosis in
patients with heparin-induced thrombocytopenia and should not be
used until the thrombocytopenia has resolved and the patient is adequately
anticoagulated with another agent.
Other Toxicities. Abnormalities of hepatic function tests occur frequently
in patients who are receiving heparin or LMWHs. Mild elevations
of the activities of hepatic transaminases in plasma occur
without an increase in bilirubin levels or alkaline phosphatase activity.
Osteoporosis resulting in spontaneous vertebral fractures can
occur, albeit infrequently, in patients who have received full therapeutic
doses of heparin (>20,000 units/day) for extended periods
(e.g., 3-6 months). The risk of osteoporosis is lower with LMWHs
or fondaparinux than it is with heparin. Heparin can inhibit the synthesis
of aldosterone by the adrenal glands and occasionally causes
hyperkalemia, even when low doses are given. Allergic reactions to
heparin (other than thrombocytopenia) are rare.
Other Parenteral Anticoagulants
Lepirudin. Lepirudin (REFLUDAN) is a recombinant
derivative (Leu 1 -Thr 2 -63-desulfohirudin) of hirudin, a
direct thrombin inhibitor present in the salivary glands
of the medicinal leech. Lepirudin is a 65–amino acid
polypeptide that binds tightly to both the catalytic site
and the extended substrate recognition site (exosite I) of
thrombin. It is approved in the U.S. for treatment of
patients with heparin-induced thrombocytopenia.
Lepirudin is administered intravenously at a dose adjusted to
maintain the aPTT at 1.5-2.5 times the median of the laboratory’s
normal range for aPTT. The drug is excreted by the kidneys and has
a t 1/2
of ~1.3 hours. Lepirudin should be used cautiously in patients
with renal failure because it can accumulate and cause bleeding in
these patients. Patients may develop antibodies against hirudin that
occasionally prolong the t 1/2
and cause a paradoxical increase in the
aPTT; therefore, daily monitoring of the aPTT is recommended.
There is no antidote for lepirudin.
Desirudin. Desirudin (IPRIVASK) is a recombinant derivative
of hirudin that differs only by the lack of a sulfate
group on Tyr 63 .
Desirudin is indicated for the prophylaxis of DVT in patients
undergoing elective hip replacement surgery. The recommended dose
is 15 mg every 12 hours by subcutaneous injection. It is eliminated
by the kidney; the t 1/2
is ~2 hours following subcutaneous administration.
Similar to lepirudin, the drug should be used cautiously in
patients with decreased renal function, and serum creatinine and
aPTT should be monitored daily.
Bivalirudin. Bivalirudin (ANGIOMAX) is a synthetic,
20–amino acid polypeptide that directly inhibits
thrombin by a mechanism similar to that of lepirudin.
859
CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS