Page 2183 - Hematology_ Basic Principles and Practice ( PDFDrive )

1936 Part XII Hemostasis and Thrombosis

aggregation returns to normal in approximately 4 hours, with the PDE5 Inhibitors
bleeding time normalizing within 1 hour. 55
Dipyridamole has several biologic effects, including PDE inhibition,
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targeting the PDE5 isoform that degrades cGMP. It also enhances
Tirofiban the release and prevents the breakdown of prostaglandin I 2 (prosta-
cyclin). 61,67 Primarily used for prevention of stroke, its usefulness was
Tirofiban (Aggrastat) is a peptidomimetic agent based on the RGD demonstrated by a metaanalysis of randomized trials showing that
sequence, with a pharmacokinetic profile similar to that of eptifiba- the combination of dipyridamole (particularly the modified release
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tide. Tirofiban antagonizes α IIb β 3 and does not cross-react with form) and low-dose aspirin was more effective than aspirin alone in
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α V β 3. As with eptifibatide, the maximum antiplatelet effect is seen secondary prevention of vascular events after transient ischemic attack
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at concentrations that leave a high concentration of unbound drug or stroke. Dipyridamole has been associated with a significantly
in the plasma. Therefore platelet transfusions are not often effective increased risk of GI bleeding when used either as a single agent or in
in reversing tirofiban’s antiplatelet effect. However, its half-life is even combination with aspirin. 69
shorter than that of eptifibatide (≈2 hours), and its antiplatelet effect Recently, inhibitors of PDE5 have become popular in the treat-
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diminishes rapidly after discontinuation of infusion. ment of erectile dysfunction. PDE5 is expressed in platelets, and
The major adverse effects of α IIbβ 3 inhibitors are thrombocytope- its inhibition results in increases in the level of platelet cGMP, an
nia and bleeding complications. Up to 5% of patients receiving effect similar to the effect of the well-known inhibitor of platelet
abciximab may experience mild thrombocytopenia (<100,000/µL), function, nitric oxide. One study examined the activation response of
and 1% may develop profound thrombocytopenia (platelet count platelets drawn from patients taking sildenafil (Viagra) when stimu-
<20,000/µL). 57,58 The incidence of severe thrombocytopenia is lower lated with either ADP or low-dose thrombin. The results showed
with tirofiban and eptifibatide, being approximately 0.2%. 58,59 A significantly reduced activation in response to ADP in sildenafil-
decrease in the platelet count is appreciable within the first hours after treated platelets, suggesting that the drug impairs selected pathways
administration. It is therefore essential that a platelet count be of platelet function in vivo. Several reports of sildenafil-associated
obtained 2–4 hours after initiating treatment. Most patients with bleeding have appeared, including epistaxis, 71,72 hemorrhoidal bleed-
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severe thrombocytopenia respond well to platelet transfusions and ing, spontaneous intracranial hemorrhage, and acute variceal
their platelet counts usually recover within 5 days, although they may bleeding. 75
take more than 1 week to do so.
Bleeding complications with α IIb β 3 inhibitors are quite common,
especially in the inguinal area when the femoral artery has been Adenyl Cyclase Stimulators or
breached during procedures. Rates of major bleeding vary between Prostacyclin Analogues
0.7% and 5.2% in different randomized controlled studies. 59,60 Intra-
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cranial bleeding is very rare (0.09%). Bleeding risk increases in Epoprostenol (the synthetic salt of prostacyclin), prostacyclin (ilo-
patients older than 65 years of age; in patients weighing less than prost), and an orally active stable analogue (beraprost) are prostacyclin-
50 kg; in patients taking anticoagulant, antiplatelet, or thrombolytic like agents in clinical use. Despite the potent inhibition of platelet
therapies; and in patients with inherited or acquired bleeding disor- aggregation by prostacyclin in vitro, the effects on the bleeding time
ders such as hemophilia and uremia, respectively. 59,60 are minimal and inconsistent. These drugs are used for pulmonary
arterial hypertension and peripheral artery disease. 76

Phosphodiesterase Inhibitors
Other Drugs That Adversely Affect Platelet Function
Elevation of cAMP or cyclic guanosine monophosphate (cGMP)
inhibits many pathways involving platelet activation, including shape Nonsteroidal Antiinflammatory Drugs
change, α IIb β 3 activation, and degranulation. Phosphodiesterases
(PDEs) catalyze degradation of cAMP and cGMP, thus preventing In addition to aspirin, many other drugs used for their antiinflam-
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platelet inhibition. Eleven PDE isoforms have been described, and matory and analgesic properties can impair platelet function. As
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three are expressed in platelets: PDE2, PDE3, and PDE5. Many with aspirin, their mechanism of action appears to be the inhibition
PDE inhibitors have antiplatelet effects. of COX-1; but in contrast to aspirin, these agents only temporarily
affect COX-1 function, inhibiting the enzyme only as long as the
active drug circulates. Among these agents, therefore, only drugs such
Nonselective Phosphodiesterase Inhibitors as piroxicam, which has a plasma half-life of more than 2 days, affect
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platelets for more than a few hours. Like with aspirin, the most sensi-
These include the methylxanthines caffeine (1,3,7-trimethylxan- tive indicator of impaired platelet function is the inhibition of in vitro
thine), theophylline (1,3-dimethylxanthine), and pentoxifylline platelet aggregation and secretion. These agents induce little or no
(3,7-dimethyl-1-(5-oxohexyl)xanthine). Caffeine, at a dosage of prolongation of the bleeding time, consistent with the bleeding time
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250 mg orally three times a day for 1 week, was demonstrated to being a less sensitive measure of the aspirin-induced defect. PFA-100
reduce platelet aggregation in healthy subjects. 62 may detect the defect, manifested as a prolonged closure time with
PDE3 inhibitors are anagrelide, cilostazol, and milrinone. the collagen/epinephrine cartridge. 79
Although anagrelide inhibits platelet aggregation in vitro, it surpris- Reports of bleeding correlate with the effects of these agents on
ingly also inhibits megakaryocyte maturation and proliferation, and platelet function, suggesting that they increase the risk for excessive
causes thrombocytopenia in humans by a mechanism that is poorly bleeding less than aspirin. As with aspirin, they may increase the
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understood. Anagrelide is used to treat essential thrombocytemia. 64 bleeding times in patients with severe hemophilia, but in two studies,
Cilostazol is a cyclic nucleotide PDE inhibitor with both platelet therapeutic doses of ibuprofen had no effect on the bleeding time in
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inhibitory and vasodilatory effects; its current clinical use for periph- 19 of 20 patients with hemophilia. Therefore, the clinical approach
eral artery disease in the United States was preceded by its use in to patients taking any drug that can inhibit COX-1 should be similar,
Japan and other Asian countries. In addition to selectively inhibiting but the reversibility of the effect of NSAIDs provides an added
PDE, cilostazol also inhibits adenine nucleotide uptake, a property margin of safety when these agents are used. Because of the increased
not shared with other PDE inhibitors that further enhances its bleeding risk, these drugs should be stopped before surgery. The
antiplatelet activity. 65 timing for cessation of NSAIDs is based on the half-lives of the
Milrinone inhibits platelet aggregation and shape change. The individual drug. Indomethacin, ibuprofen, ketoprofen, and diclofe-
drug is used for congestive heart failure. nac all have short half-lives (2–6 hours), and discontinuing these