598 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
namic instability, severe deep venous thrombosis such as the
superior vena caval syndrome, and ascending thrombophle-
bitis of the iliofemoral vein with severe lower extremity ede-
ma. These drugs are also given intra-arterially, especially for
peripheral vascular disease.
Thrombolytic therapy in the management of acute myo-
cardial infarction requires careful patient selection, the use of
a specific thrombolytic agent, and the benefit of adjuvant
therapy. Streptokinase is administered by intravenous infu-
sion of a loading dose of 250,000 units, followed by 100,000
units/h for 24–72 hours. Patients with antistreptococcal anti-
bodies can develop fever, allergic reactions, and therapeutic
resistance. Urokinase requires a loading dose of 300,000 units
given over 10 minutes and a maintenance dose of 300,000
units/h for 12 hours. Alteplase (t-PA) is given by intravenous
infusion of 60 mg over the first hour and then 40 mg at a rate
of 20 mg/h. Reteplase is given as two intravenous bolus injec-
BASIC PHARMACOLOGY OF ANTIPLATELET AGENTS
Platelet function is regulated by three categories of substances.
The first group consists of agents generated outside the platelet
that interact with platelet membrane receptors, eg, catechol-
amines, collagen, thrombin, and prostacyclin. The second cate-
gory contains agents generated within the platelet that interact
with membrane receptors, eg, ADP, prostaglandin D2, prosta-
glandin E2, and serotonin. The third group comprises agents
generated within the platelet that act within the platelet, eg,
prostaglandin endoperoxides and thromboxane A2, the cyclic
nucleotides cAMP and cGMP, and calcium ion. From this list of
agents, several targets for platelet inhibitory drugs have been
identified (Figure 34–1): inhibition of prostaglandin synthesis
(aspirin), inhibition of ADP-induced platelet aggregation (clo-
pidogrel, ticlopidine), and blockade of glycoprotein IIb/IIIa re-
ceptors on platelets (abciximab, tirofiban, and eptifibatide).
Dipyridamole and cilostazol are additional antiplatelet drugs.
ASPIRIN
The prostaglandin thromboxane A2 is an arachidonate prod-
uct that causes platelets to change shape, release their gran-
ules, and aggregate (see Chapter 18). Drugs that antagonize
this pathway interfere with platelet aggregation in vitro and
prolong the bleeding time in vivo. Aspirin is the prototype of
this class of drugs.
As described in Chapter 18, aspirin inhibits the synthesis of
thromboxane A2 by irreversible acetylation of the enzyme
cyclooxygenase. Other salicylates and nonsteroidal anti-inflam-
matory drugs also inhibit cyclooxygenase but have a shorter
duration of inhibitory action because they cannot acetylate
cyclooxygenase; that is, their action is reversible.
The FDA has approved the use of 325 mg/d for primary
prophylaxis of myocardial infarction but urges caution in this
tions of 10 units each, separated by 30 minutes. Tenecteplase
is given as a single intravenous bolus of 0.5 mg/kg. Anistre-
plase (where available) is given as a single intravenous injec-
tion of 30 units over 3–5 minutes. A single course of
fibrinolytic drugs is expensive: hundreds of dollars for strep-
tokinase and thousands for urokinase and t-PA.
Recombinant t-PA has also been approved for use in acute
ischemic stroke within 3 hours of symptom onset. In patients
without hemorrhagic infarct or other contraindications,
this therapy has been demonstrated to provide better out-
comes in several randomized clinical trials. The recom-
mended dose is 0.9 mg/kg, not to exceed 90 mg, with 10%
given as a bolus and the remainder during a 1 hour infu-
sion. Streptokinase has been associated with increased
bleeding risk in acute ischemic stroke when given at a dose
of 1.5 million units, and its use is not recommended in this
setting.
use of aspirin by the general population except when pre-
scribed as an adjunct to risk factor management by smoking
cessation and lowering of blood cholesterol and blood pres-
sure. Meta-analysis of many published trials of aspirin and
other antiplatelet agents confirms the value of this interven-
tion in the secondary prevention of vascular events among
patients with a history of vascular events.
CLOPIDOGREL & TICLOPIDINE
Clopidogrel and ticlopidine reduce platelet aggregation by in-
hibiting the ADP pathway of platelets. These drugs are thienopy-
ridine derivatives that achieve their antiplatelet effects by
irreversibly blocking the ADP receptor on platelets. Unlike as-
pirin, these drugs have no effect on prostaglandin metabolism.
Randomized clinical trials with both drugs report efficacy in
the prevention of vascular events among patients with tran-
sient ischemic attacks, completed strokes, and unstable angina
pectoris. Use of clopidogrel or ticlopidine to prevent throm-
bosis is now considered standard practice in patients under-
going placement of a coronary stent.
Adverse effects of ticlopidine include nausea, dyspepsia,
and diarrhea in up to 20% of patients, hemorrhage in 5%, and,
most seriously, leukopenia in 1%. The leukopenia is detected
by regular monitoring of the white blood cell count during the
first 3 months of treatment. Development of thrombotic
thrombocytopenic purpura has also been associated with the
ingestion of ticlopidine. The dosage of ticlopidine is 250 mg
twice daily. It is particularly useful in patients who cannot tol-
erate aspirin. Doses of ticlopidine less than 500 mg/d may be
efficacious with fewer adverse effects.
Clopidogrel has fewer adverse effects than ticlopidine and is
rarely associated with neutropenia. Thrombotic thrombocyto-

penic purpura associated with clopidogrel has been reported.
Because of its superior side effect profile and dosing require-
ments, clopidogrel is preferred over ticlopidine. The antithrom-
botic effects of clopidogrel are dose-dependent; within 5 hours
after an oral loading dose of 300 mg, 80% of platelet activity will
be inhibited. The maintenance dose of clopidogrel is 75 mg/d,
which achieves maximum platelet inhibition. The duration of
the antiplatelet effect is 7–10 days.
Aspirin & Clopidogrel Resistance
The reported incidence of resistance to these drugs varies
greatly, from less than 5% to 75%. In part this tremendous
variation in incidence reflects the definition of resistance
(recurrent thrombosis while on antiplatelet therapy vs in
vitro testing), methods by which drug response is mea-
sured, and patient compliance. Several methods for testing
aspirin and clopidogrel resistance in vitro are now FDA-
approved; however, their utility outside of clinical trials re-
mains controversial.
BLOCKADE OF PLATELET
GLYCOPROTEIN IIB/IIIA RECEPTORS
The glycoprotein IIb/IIIa inhibitors are used in patients with
acute coronary syndromes. These drugs target the platelet IIb/
IIIa receptor complex (Figure 34–1). The IIb/IIIa complex
functions as a receptor mainly for fibrinogen and vitronectin
but also for fibronectin and von Willebrand factor. Activation
of this receptor complex is the “final common pathway” for
platelet aggregation. There are approximately 50,000 copies of
this complex on the surface of each platelet. Persons lacking
CLINICAL PHARMACOLOGY OF DRUGS USED
TO PREVENT CLOTTING
VENOUS THROMBOSIS
Risk Factors
A. Inherited Disorders
The inherited disorders characterized by a tendency to form
thrombi (thrombophilia) derive from either quantitative or
qualitative abnormalities of the natural anticoagulant system.
Deficiencies (loss of function mutations) in the natural antico-
agulants antithrombin, protein C, and protein S account for ap-
proximately 15% of selected patients with juvenile or recurrent
thrombosis and 5–10% of unselected cases of acute venous
thrombosis. Additional causes of thrombophilia include gain of
function mutations such as the factor V Leiden mutation and
the prothrombin 20210 mutation, elevated clotting factor and
cofactor levels, and hyperhomocysteinemia that together ac-
CHAPTER 34 Drugs Used in Disorders of Coagulation 599
this receptor have a bleeding disorder called Glanzmann’s
thrombasthenia.
Abciximab, a chimeric monoclonal antibody directed
against the IIb/IIIa complex including the vitronectin recep-
tor, was the first agent approved in this class of drugs. It has
been approved for use in percutaneous coronary intervention
and in acute coronary syndromes. Eptifibatide is an analog of
the sequence at the extreme carboxyl terminal of the delta
chain of fibrinogen, which mediates the binding of fibrinogen
to the receptor. Tirofiban is a smaller molecule with similar
properties. Eptifibatide and tirofiban inhibit ligand binding to
the IIb/IIIa receptor by their occupancy of the receptor but do
not block the vitronectin receptor.
The three agents described above are administered parenter-
ally. Oral formulations of IIb/IIIa antagonists are in various
stages of development.
ADDITIONAL ANTIPLATELET-
DIRECTED DRUGS
Dipyridamole is a vasodilator that inhibits platelet function by
inhibiting adenosine uptake and cGMP phosphodiesterase activ-
ity. Dipyridamole by itself has little or no beneficial effect. There-
fore, therapeutic use of this agent is primarily in combination
with aspirin to prevent cerebrovascular ischemia. It may also be
used in combination with warfarin for primary prophylaxis of
thromboemboli in patients with prosthetic heart valves. A com-
bination of dipyridamole complexed with 25 mg of aspirin is now
available for secondary prophylaxis of cerebrovascular disease.
Cilostazol is a newer phosphodiesterase inhibitor that pro-
motes vasodilation and inhibition of platelet aggregation. Cil-
ostazol is used primarily to treat intermittent claudication.
count for the greater number of hypercoagulable patients. Al-
though the loss of function mutations is less common, they are
associated with the greatest thrombosis risk. Some patients have
multiple inherited risk factors or combinations of inherited and
acquired risk factors as discussed below. These individuals are
at higher risk for recurrent thrombotic events and are often
considered candidates for lifelong therapy.
B. Acquired Disease
The increased risk of thromboembolism associated with atrial
fibrillation and with the placement of mechanical heart valves
has long been recognized. Similarly, prolonged bed rest, high-
risk surgical procedures, and the presence of cancer are clearly
associated with an increased incidence of deep venous throm-
bosis and embolism. Antiphospholipid antibody syndrome is
another important acquired risk factor. Drugs may function as