Franklin A. Bontempo, M.D.,
Medical Director, Coagulation Laboratory
Drugs that inhibit platelet function have
assumed increasing importance in the care of patients with cardiovascular
and cerebrovascular disease, which are leading causes of death in the U.S.
They also have uses in other settings to a lesser extent.
Aspirin - Aspirin, or
acetylsalicylic acid (ASA), remains the most studied, most clinically
effective, most widely used, and least expensive antiplatelet agent
currently available. ASA exerts its antiplatelet effect by acetylating
the endoperoxide cyclo-oxygenase irreversibly within minutes of the
ingestion of a low dose of the drug. Thus for the life of the
platelet, normally 10 days, platelet function will be inhibited.
Bleeding times may be prolonged for at least 3-5 days after ASA
ingestion. Clinically, the ASA anti-platelet effect is more important
in preventing arterial thrombi, where platelets are more involved in the
formation of clot, than in venous thrombi. Numerous trials have shown
ASA beneficial for:
prevention of primary myocardial
infarction(MI),particularly in males but also in females
reduction of the risk of MI and death
in the setting of unstable angina
prevention of recurrent MI after
prevention of new or recurrent stroke
and death after transient ischemic attacks (TIAs)
or minor stroke
prevention of coronary artery bypass
graft and stent closure.
In addition, one major study reported the
addition of ASA to warfarin decreases the thrombotic risk without increasing
the bleeding risk in patients with prosthetic cardiac valves.
Major side effects of ASA include
increased risk of bleeding in general, GI irritation, and bleeding from
ulceration of gastric mucosa in particular. There is a slight increase
in risk of hemorrhagic stroke in patients taking ASA. Ototoxicity with
tinnitus can occur; this as well as the other side
effects of ASA are seen less often at low doses.
Dosing recommendations for ASA vary
widely, but a dose of 325 mg/day (one standard ASA tablet) is a reasonable
dose that may minimize side effects for all of the above indications except
for ASA use with warfarin in cardiac valve patients where 100 mg/day is
recommended (slightly more than one baby aspirin which is 81 mg).
Clopidogrel (Plavix) - Clopidogrel
is an oral thienopyridine platelet antagonist that has been associated with
fewer side effects to date than its structurally related predecessor,
ticlopidine (Ticlid). Clopidogrel exerts its antiplatelet action for
the life of the platelet, i.e. 10 days, and may cause prolongation of the
bleeding time. For optimal reduction in bleeding risk, it should be
stopped 10-14 days prior to surgery. The mechanism of action of
clopidogrel is unclear, but seems to be by inhibition of ADP-induced
platelet aggregation but does not interfere with in vitro platelet function
studies commonly done in the laboratory.
The indications for use of clopidogrel are
evolving, but a large randomized study and other reports have shown it to
superior to ASA for prevention of
stroke, myocardial infarction, and peripheral
vascular disease in patients with atherosclerotic
superior to ticlopidine when used in
conjunction with ASA for prevention of coronary
artery stent closure.
probably superior for stroke
prevention in combination with ASA than either
useful for true ASA allergic patients
Side effects include increased risk of GI
bleeding at an incidence not higher than that for other antiplatelet agents.
Dosing is 75 mg once daily with or without food. For
coronary artery stents, dosing is recommended for 30 days along with ASA.
Ticlopidine (Ticlid) - Ticlopidine
is an oral platelet antagonist found to be useful in patients with unstable
angina and prevention of stroke in patients with transient ischemic
attacks. It is also of benefit in patients with coronary artery stents
when used in conjunction with ASA. Its higher toxicity profile
relative to clopidogrel, has made it currently more difficult to recommend.
Side effects of ticlopidine include
cholestatic jaundice, nausea, diarrhea, neutropenia and skin rash. The
latter may require its discontinuance. Monitoring white blood counts
every 2 weeks during the first three months of therapy is necessary.
Recent reports have clearly indicated that ticlopidine is also associated
with thrombotic thrombocytopenic purpura (TTP).
The standard dose is 250 mg PO q12h.
Overdosage has not been a clinical problem, but prolonged bleeding times
with ticlopidine may be normalized with methylprednisolone at a dose of 20
Abciximab (ReoPro) - Abciximab is a
human-mouse monoclonal antibody for intravenous infusion, binding to the
glycoprotein IIb/IIIa receptor on human platelets, and inhibiting platelet
aggregation. It may markedly prolong the bleeding time, and while it
has a half-life of only 10 minutes, low levels of glycoprotein IIb/IIIa
receptor blockade may be present for up to 10 days after infusion. The
major indication for abciximab is as adjunctive therapy with heparin and
aspirin for prevention of abrupt coronary vessel closure after
angioplasty. The major side effects are bleeding and thrombocytopenia
(»5%) and caution must be taken in patients with any predisposing bleeding
risks. The dose is 0.25 mg/kg IV given as a bolus 10-60 minutes prior
to the start of angioplasty followed by an infusion of 10 microgram (.01
mg)/min IV for 12 hours.
Tirofiban (Aggrastat) - Tirofiban
is a synthetic glycoprotein IIb/IIIa inhibitor for intravenous use indicated
for unstable angina as an adjunct to heparin and aspirin therapy in coronary
angioplasty and atherectomy. For most patients, dosing is 0.4
microgram/kg/min for 30 min. followed by 0.1 microgram/kg/min.
Patients with creatinine clearance of < 30mL/min should have a dose rate
reduction of 50%.
Eptifibatide (Integrelin) -
Eptifibatide is a reversible inhibitor of platelet aggregation that prevents
binding of fibrinogen, von Willebrand's factor, and other ligands to the
glycoprotein IIb/IIIa receptor. Safety and efficacy studies for
eptifibatide have been done in-patients who received concomitant heparin and
ASA. Eptifibatide has been shown to be effective in patients with
acute coronary syndromes and those undergoing percutaneous balloon
angioplasty or atherectomy. Dosing recommendations vary depending on
Dipyridamole (Persantine) - The
indications for dipyridamole have narrowed in recent years with the
introduction of other platelet inhibitors. It retains an indication as
an adjunct to warfarin for the prevention of postoperative thromboembolic
complications of prosthetic cardiac valve replacement. While several
biochemical effects of dipyridamole are known, the exact manner in which it
causes platelet inhibition is unclear. The dose for patients with
recent prosthetic valve surgery is 75-100 mg p.o. qid. When
dipyridamle is used as an adjunct with warfarin, ASA should not be
Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)
- NSAIDS have weaker antiplatelet activity than other antiplatelet agents
and are not indicated for prevention of thrombosis. NSAIDS are classified as
cyclo-oxygenase-1 (COX-1) or cyclo-oxygenase-2 (COX-2) inhibitors with only
the COX-1 inhibitors having antiplatelet activity. This is of clinical
importance when choosing an NSAID for analgesia in a patient with a bleeding
history where a COX-2 inhibitor may be preferable. In general most of the
older NSAIDS have significant antiplatelet COX-1 activity except for choline
magnesium trisalicylate (Trilisate) and nabumetone (Relafen). The newer
NSAIDS celecoxib (Celebrex) and rofecoxib (Vioxx) are also COX-2 inhibitors
and may be safer in patients with a bleeding history.
Miscellaneous - Other substances
have been shown to be associated with acquired platelet dysfunction to the
point of causing bleeding in some situations. These include garlic,
ginger, cumin, onions, turmeric, Chinese black tree fungus, and vitamins C
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