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2078 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2079

inhibitor has been approved in the United States for the treatment of ANTICOAGULANTS, FIBRINOLYTIC AGENTS,
peripheral vascular disease and may have utility in the prevention of ANTIFIBRINOLYTIC AGENTS
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cardiac stent occlusion. Nitric oxide (NO) and organic nitrates such
as nitroglycerin inhibit platelet function in vitro, probably by activat- Heparin predisposes to bleeding primarily through its anticoagulant
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ing guanylyl cyclase, thereby increasing cGMP. Their effect on in vivo effect, but it may also impair platelet function. For example, a bolus
platelet function is uncertain. High concentrations of caffeine and the- injection of heparin (100 U/kg) can cause a significant prolongation of
ophylline also inhibit platelet phosphodiesterases in vitro. the bleeding time in normal subjects and in patients prior to cardio-
pulmonary bypass, suggesting that therapeutic doses of heparin may
impair platelet function. Heparin likely impairs platelet function
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ANTIBIOTICS by inhibiting the generation and action of the potent platelet agonist
Penicillins contain a β-lactam ring and a unique side chain. Most cause thrombin. On the other hand, in vitro studies suggest that heparin can
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a dose-dependent prolongation of the bleeding time in normal vol- enhance platelet aggregation induced by other platelet agonists. Hep-
unteers. Because they reduce platelet aggregation and secretion, as arin binds to a single class of high-affinity binding sites on resting plate-
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well as ristocetin-induced platelet agglutination, they may affect both lets and to an additional class of lower-affinity binding sites on fully
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platelet adhesion and platelet activation. Tests of platelet aggregation activated platelets. High heparin doses also impair VWF-dependent
are abnormal in 50 to 75 percent of individuals receiving large doses platelet function, possibly by binding to the heparin-binding domain
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(at least several grams per day) of carbenicillin, penicillin G, ticarcillin, of VWF. The contributions of these effects on platelet function to the
ampicillin, nafcillin, and azlocillin and in 25 to 50 percent of patients bleeding complications of heparin therapy are uncertain.
taking piperacillin, azlocillin, or mezlocillin. 127–129 Differences in the Bleeding during fibrinolytic therapy is predominantly a result
antiplatelet effects of these antibiotics probably relate to differences in of the combined effects of structural lesions in blood vessels and the
blood levels and drug potency. Their effect on platelets is maximal after fibrin(ogen)olytic activity of the agent used. However, pharmacologic
1 to 3 days of administration and may remain for several days after the doses of streptokinase, urokinase, and tissue plasminogen activator
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antibiotic has been stopped, suggesting that the effect of these antibiot- (t-PA) can affect platelet function. High concentrations of plasmin
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ics on platelets in vivo is irreversible. ex vivo cause platelet aggregation. Moreover, marked increases in the
Penicillins can impair the interaction of agonists and von Wille- urinary excretion of the TXA metabolite 2,3-dinor-TXB have been
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brand factor (VWF) with the platelet membrane. Indeed, when many detected in patients receiving streptokinase or t-PA for coronary throm-
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penicillins are incubated with washed platelets, albeit at concentra- bolysis, suggesting that in vivo platelet activation had occurred during
tions higher than those attained in vivo, they inhibit the interaction of infusion of the drug. 146,147 Nevertheless, several in vitro studies indicate
VWF and agonists, such as ADP and epinephrine, with their platelet that plasmin generation has an inhibitory effect on platelet function.
receptors. The relative in vitro antiplatelet potency of the penicil- First, very high levels of fibrin(ogen) degradation products, coupled
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lins correlates well with their lipid solubility and with the inhibitory with very low levels of fibrinogen, may impair platelet aggregation.
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potency of the isolated side chains. Moreover, the inhibitory effect Second, plasminogen can bind to platelets and after its conversion to
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of penicillin G on platelet function in vitro is potentiated by the pres- plasmin, enzymatically degrade platelet glycoprotein (GP) Ib, impairing
ence of probenecid. When platelet function was tested after intrave- the interaction of platelets with VWF. 150,151 Third, plasmin can inhibit
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nous administration of penicillin, oxacillin or mezlocillin for 3 to 17 platelet arachidonic acid metabolism. Fourth, t-PA promotes the
days to patients or normal volunteers, irreversible inhibition of ago- disaggregation of platelet aggregates, presumably by inducing lysis of
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nist-induced aggregation was noted, along with a 40 percent reduction the fibrinogen that mediates aggregate formation. Finally, after initial
in low-affinity TXA receptors. Thus, penicillins probably inhibit activation, platelets incubated with plasmin and recombinant t-PA in
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platelet function by binding to one or more membrane components vitro become refractory to activation by other agonists. Whether any
necessary for adhesive interactions with the vessel wall or for stimu- of these in vitro and ex vivo observations apply to the in vivo situation
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lus-response coupling. and are clinically significant remains uncertain. The antifibrinolytic
Although clinically significant bleeding is associated with the use drug, ε-aminocaproic acid, can increase the bleeding time when admin-
of carbenicillin, penicillin G, ticarcillin, and nafcillin, it is far less com- istered for several days at doses 24 g/day or greater. 150
mon than prolongation of the bleeding time. 127,135 Patients with coexist-
ing hemostatic defects (e.g., thrombocytopenia, vitamin K deficiency,
uremia) may be particularly prone to this complication. On the other CARDIOVASCULAR DRUGS
hand, high doses of penicillin G did not increase gastrointestinal blood Administration of nitroprusside, which increases platelet cGMP, 156–160
loss in a thrombocytopenic rabbit model. In our experience, bleeding nitroglycerine, and propranolol, 162,163 can decrease platelet aggrega-
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attributable to antibiotic-induced platelet dysfunction is uncommon tion and secretion ex vivo. Nitroprusside can increase the bleeding time
and unpredictable. Because β-lactam–induced platelet dysfunction twofold when administered at infusion rates of 6 to 8 mcg/kg/min. 156,164
resolves with time following cessation of the drug, this class of drugs Inhalation of NO advocated for the treatment of pulmonary hyperten-
should only be considered as a cause of bleeding in the appropri- sion and the adult respiratory distress syndrome, can impair agonist-
ate clinical setting. A similar pattern of platelet dysfunction has been induced platelet aggregation ex vivo, although the clinical significance
reported with some cephalosporins or related antibiotics, but not with of these observations is unclear. 165–167 Calcium channel blockers such
others. 127,137,138 Broad-spectrum antibiotics can also cause a bleeding as verapamil, nifedipine, and diltiazem inhibit platelet aggregation
diathesis attributable to killing of gut flora, resulting in vitamin K defi- when added at very high concentrations to washed platelets. This
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ciency. Nitrofurantoin, a structurally unrelated antibiotic, may cause a effect is seen primarily with epinephrine-induced aggregation and does
mild prolongation of the bleeding time and impair platelet aggregation not appear to be related to calcium channel blockade. At therapeu-
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when blood levels of the drug are higher than 20 μM, as may occur tic doses, calcium channel blockers do not prolong the bleeding time,
in patients with renal insufficiency. Miconazole, an antifungal agent, although one agent, nisoldipine, has been reported to inhibit agonist-
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inhibits human and rabbit platelet COX in vitro and rabbit platelet COX induced calcium transients and platelet aggregation after ten days of
after intravenous infusion. 140 oral administration. At high concentrations, the antiarrhythmic drug
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