Page 2184 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 130 Acquired Disorders of Platelet Function 1937

drugs 1 day before surgery is sufficient. Naproxen, sulindac, diflunisal, chain structure alters the antibacterial and pharmacologic properties
and celecoxib have intermediate half-lives (7–15 hours) and should of the penicillins and cephalosporins, and may also determine their
be stopped 2 or 3 days before surgery. Nabumetone, meloxicam, and effects on platelet function. It is postulated that the antibiotic associ-
piroxicam have very long half-lives (>20 hours). The ACCP guide- ates with the platelet plasma membrane via a lipophilic mechanism
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lines recommend discontinuing these drugs 10 days before surgery. where it perturbs receptor–agonist interactions or signal transduc-
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Analgesics such as acetaminophen and sodium or choline salicylate tion. The characteristic laboratory findings are a prolonged bleeding
do not inhibit platelet function and have no adverse effects on time and abnormal platelet aggregation studies that occur after several
hemostasis. 80 days of high-dose parenteral therapy. 90,91,94 These abnormalities do not
usually subside until several days after the antibiotic is discontinued.
The frequency of clinically important bleeding in patients taking
Cardiovascular Drugs β-lactam antibiotics is low and is not predicted by a prolonged
bleeding time; consequently, the causal relation to antibiotic treat-
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Many cardiovascular drugs affect platelet functions through a variety ment is unproved. For each report implicating an antibiotic as a
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of mechanisms. Administration of nitroglycerin, isosorbide dini- cause of hemorrhage, many more patients receive the same antibiotics
trate, or nitroprusside can decrease platelet aggregation and secretion in large doses without bleeding complications. 95
in vitro, but their effects in vivo are minimal and inconsistently Although antibiotic-induced platelet dysfunction usually is of
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observed. The mechanism of platelet inhibition appears to involve little clinical importance, there are some exceptions to this rule. The
the production of nitric oxide from the drug, with concomitant frequency of clinically important hemorrhagic complications with
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increases in platelet cAMP and, more markedly, cGMP. β-Adrenergic moxalactam appears to be higher than with other antibiotics. This
receptor blockers such as propranolol, metoprolol, atenolol, and drug has been demonstrated to inhibit ADP- and collagen-induced
pindolol have also been shown to inhibit platelet aggregation, appar- platelet aggregation in a dose-dependent fashion and to decrease
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ently through mechanisms independent of β-adrenergic receptor TXA 2 generation, which suggests that, like aspirin, it acts on the
blockade. 83,84 Several of these agents have been shown to blunt platelet thromboxane synthesis pathway. Furthermore, in contrast to most
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aggregation to ADP and collagen, and to decrease platelet TXA 2 other β-lactam antibiotics, moxalactam contains a methylthiotetrazole-
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production in response to agonists. Blunting of serotonin uptake leaving group that has been implicated in the inhibition of synthesis
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by platelets and inhibition of the response to serotonin have also been of the vitamin K–dependent coagulation factors. Therefore,
demonstrated. There are numerous reports of antiplatelet effects of moxalactam-induced bleeding may be caused by the combination of
calcium channel blockers, such as nifedipine, verapamil, and diltia- deficiencies in vitamin K–dependent coagulation factors and impaired
zem. Most of these studies demonstrated inhibition of platelet platelet function.
aggregation in washed platelets at high concentrations (micromolar) Nitrofurantoin, an antibiotic structurally unrelated to the β-lactam
of the drug. This effect is mainly with epinephrine as the agonist, antibiotics, may mildly prolong the bleeding time and impair platelet
and it does not appear to be related to inhibition of calcium ion aggregation at plasma concentrations in excess of 20 µM. 99
influx. Proposed mechanisms include inhibition of epinephrine
binding to α 2 -adrenergic receptors, inhibition of the platelet response
to TXA 2 , and inhibition of serotonin-induced aggregation. In thera- Antifungal Drugs
peutic doses, the calcium channel blockers do not prolong the
bleeding time. At high concentrations, quinidine can act as an Miconazole has been shown to inhibit platelet aggregation in
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antagonist of platelet α 2 -adrenergic receptors. In one report, a patient rabbits; but there is no evidence that the drug causes platelet
taking 800 mg of quinidine and 650 mg of aspirin daily developed dysfunction in humans. Concomitant use of miconazole and vitamin
melena and generalized petechiae with a normal platelet count and a K antagonists may cause significant bleeding because miconazole is a
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bleeding time over 35 minutes. In a subsequent study in two healthy strong inhibitor of CYP2C9. 101
volunteers, quinidine caused a mild prolongation of the bleeding time Amphotericin B inhibits thrombin-induced platelet aggregation,
that was apparently potentiated by aspirin. Quinidine and its stereo- serotonin uptake, and thrombin-induced serotonin release in in vitro
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isomer, quinine, can also impair hemostasis by inducing drug- studies. Studies have shown that platelet transfusion immediately
dependent antibodies that cause thrombocytopenia. after amphotericin B infusion caused poor platelet recovery and
The commonly used angiotensin receptor antagonists losartan, survival. An interval of at least 2 hours should separate platelet
valsartan, and olmesartan interact with the TXA 2 receptor and inhibit transfusion from amphotericin B therapy. 103
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thromboxane-dependent platelet adhesion and aggregation. Valsar-
tan also inhibits the expression of major platelet receptors including
α IIb β 3 and glycoprotein (GP)Ib. 88 Psychiatric Drugs
Platelets from patients taking tricyclic antidepressant drugs (imipra-
Antibiotics mine, amitriptyline, nortriptyline) or phenothiazines (chlorproma-
zine, promethazine, trifluoperazine) can exhibit impaired in vitro
Antibiotics can also affect platelet function. Those implicated most aggregation and secretion responses to ADP, epinephrine, and colla-
often are the penicillins and cephalosporins, which share a β-lactam gen, but this effect is not associated with an increased risk for bleed-
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ring structure. Some of these drugs produce predictable dose- and ing. However, there are numerous reports of antiplatelet effects of
duration-related effects on the bleeding time. 89–91 Because the effect the widely used selective serotonin reuptake inhibitors (SSRIs; par-
on bleeding time is seen only in patients who are receiving large oxetine, sertraline, fluoxetine, citalopram), which block the only
parenteral doses of antibiotics, this is a potential problem only for means of platelet serotonin uptake for storage; 104–108 the effect of these
hospitalized patients. In a study of 74 hospitalized patients with a drugs in decreasing platelet serotonin levels has been documented. 109,110
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consistently prolonged bleeding time, the likely cause was penicillin Prolonged bleeding times, excessive bruising, and defective
in 39 patients (30 patients were receiving >15,000,000 U/day of platelet aggregation have all been noted in patients taking fluox-
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penicillin G, and 9 were receiving 6–8 g/day of ampicillin) and etine. SSRI use increases perioperative and postoperative bleed-
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aspirin or related drugs in 7 patients. Floxacillin (an isoxazolyl ing, increases red cell transfusion rates during and after surgery,
penicillin) has been shown to significantly impair platelet function and increases the risk of postpartum hemorrhage in pregnant
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and cause severe bleeding when used in high dose in a patient with women. On the other hand, the cessation of the SSRI antidepres-
infective endocarditis. 92 sant drug may cause discontinuation syndrome or depression relapse.
The structural properties that cause some, but not all, penicillins Thus the risk–benefit profile should be considered before cessation
and cephalosporins to affect platelet function are unknown. The side of an SSRI drug prior to elective surgery.