Page 2219 - Hematology_ Basic Principles and Practice ( PDFDrive )

1966 Part XII Hemostasis and Thrombosis

Thrombocytopenia of rapid onset is commonly seen with GPIIb/IIIa Approach to Patients With Thrombocytopenia Following Percutaneous
receptor antagonists (see next section). Coronary Intervention

THROMBOCYTOPENIA CAUSED BY GLYCOPROTEIN IIB/ Four diagnoses should be considered in patients who develop thrombo-
cytopenia within minutes or a few hours after a PCI and have received
IIIA RECEPTOR ANTAGONISTS one or more of the following agents: (1) platelet GPIIb/IIIa inhibitor
(e.g., abciximab, eptifibatide, tirofiban), (2) heparin, or (3) iodinated
Several thrombocytopenic syndromes have been reported with use of contrast agent.
GPIIb/IIIa receptor antagonists (abciximab, eptifibatide, tirofiban) • GPIIb/IIIa inhibitor–induced pseudothrombocytopenia. The patient
administered during percutaneous coronary intervention (e.g., angio- has no symptoms or signs of bleeding, and platelet aggregates
plasty, stenting): (1) rapid-onset, severe thrombocytopenia within 12 are seen in the blood film. The platelet count is falsely reported
as low by the automated particle counter, which fails to count
hours of drug administration (in 0.4%–2% of patients), (2) rapid- aggregated platelets. No treatment is required.
onset pseudothrombocytopenia (in approximately 1% of patients • GPIIb/IIIa inhibitor–induced thrombocytopenia. The platelet count
exposed to abciximab [ReoPro]), (3) rapid-onset thrombocytopenia falls abruptly, often to profoundly reduced levels (typical nadir,
within 12 hours of a second exposure to a GPIIb/IIIa antagonist, and <20 × 10 /L). Hemostatic impairment is variable, ranging from
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(4) delayed-onset thrombocytopenia beginning 5–7 days after drug petechiae to fatal hemorrhages; occasionally, patients develop
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administration (rare). The frequency of rapid-onset thrombocyto- anaphylactoid reactions or even associated thrombosis. Treatment
penia is higher among patients who receive a second course of therapy, involves stopping all platelet antagonists and anticoagulants and
especially if it follows the initial exposure by only a few weeks. giving platelets if the patient has signs of bleeding. Prophylactic
Thrombocytopenia is typically severe (median platelet count nadir, platelet transfusions can also be considered if the platelet count
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is very low (e.g., <10 × 10 /L). Testing for drug-dependent
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about 5 × 10 /L to 10 × 10 /L), but clinical effects vary dramatically, antibodies can be accomplished using flow cytometry or ELISA.
ranging from absence of petechiae or other signs of bleeding (in 50% • Rapid-onset HIT. In patients who have preexisting HIT antibodies
of patients) to fatal hemorrhage (in less than 5%). Some patients because of recent heparin exposure (generally within the
develop anaphylactoid reactions accompanying the abrupt platelet past 100 days), rapid-onset HIT can occur when heparin is
count declines. The antibodies may cause thrombosis in some given during PCI. This is much less common than GPIIb/IIIa
patients, likely because the pathogenic antibodies also activate inhibitor–induced thrombocytopenia or pseudothrombocytopenia,
platelets. 21 so presumptive treatment of HIT with a nonheparin anticoagulant
These syndromes are caused by at least three mechanisms. First, is rarely indicated in this situation. The platelet count nadir
antibodies of IgG (and possibly IgM) class can bind to neoepitopes is usually much higher than with GPIIb/IIIa inhibitor–induced
thrombocytopenia.
on the GPIIb/IIIa complex generated by these drugs (or their metabo- • Radiocontrast-induced ITP. Very rarely, patients who have
lites), that is, ligand-induced binding sites (see Fig. 132.4). Up to 5% previously received iodinated contrast can develop abrupt-onset,
of humans and nonhuman primates have naturally occurring IgG severe thrombocytopenia after exposure to contrast during
antibodies that will bind to GPIIb/IIIa receptors in the presence of PCI. Platelet transfusions (with or without high-dose IVIg) are
drug, which could explain why rapid-onset thrombocytopenia occurs appropriate for a bleeding patient.
so frequently with these agents. A second mechanism is applicable to ELISA, Enzyme-linked immunosorbent assay; HIT, heparin-induced thrombocy-
abciximab, a chimeric Fab fragment comprised of murine GPIIb/ topenia; ITP, induced thrombocytopenia; IVIg, intravenous immunoglobulin; PCI,
IIIa-reactive sequences and human framework sequences. Interest- percutaneous coronary intervention.
ingly, although a high frequency of normal persons (74%) have
antibodies that recognize platelets coated with abciximab, these
“normal” antibodies were shown to differ from those detected in
patients in whom thrombocytopenia developed after a second expo-
sure to abciximab: whereas the pathogenic antibodies recognized Various in vitro assays using flow cytometry or enzyme-linked
murine sequences within abciximab, the “normal” (nonpathogenic) immunosorbent assay (ELISA) have been developed to detect these
antibodies were specific for the carboxyl terminus (papain cleavage antibodies. Because some pathogenic antibodies are naturally occur-
site) of Fab fragments prepared from normal human IgG. Drug- ring, it is theoretically possible to identify patients at high risk for
dependent antibodies can also be generated about 1 week after rapid-onset thrombocytopenia in elective situations (see box on
exposure. The antibodies differ among patients with respect to the Approach to Patients With Thrombocytopenia Following Percutane-
precise neoepitopes recognized and display variable degrees of cross- ous Coronary Interventions).
reactivity among the different GPIIb/IIIa receptor antagonists
(“fibans”); this explains why a repeat treatment course with another
GPIIb/IIIa receptor antagonist may not necessarily cause thrombo- MISCELLANEOUS DRUG-INDUCED
cytopenia. A third mechanism involves eptifibatide-dependent anti- THROMBOCYTOPENIC SYNDROMES
bodies that activate platelets via their FcγIIa receptors. 21
Some naturally occurring antibodies only bind to GPIIb/IIIa Drug-Induced Thrombotic Microangiopathy
when the calcium concentration is low, thus explaining
pseudothrombocytopenia—falsely low platelet count estimates Several drugs can trigger a syndrome of thrombocytopenia, fragmen-
caused by ex vivo aggregation of platelets in blood samples collected tation hemolysis, and renal failure known as drug-induced thrombotic
into calcium-chelating anticoagulants, especially EDTA. The rare microangiopathy (TMA). This syndrome has been established for
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syndrome of delayed-onset thrombocytopenia after brief exposure quinine, in which multiple quinine-dependent antibodies reactive
might result from high-titer GPIIb/IIIa-reactive antibodies that bind against platelets, RBCs, leukocytes, and endothelial cells have been
even in the absence of the drug. reported. Although TMA has been reported with ticlopidine and
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Platelet transfusions are indicated in patients who are bleeding, clopidogrel, a recent systematic review failed to confirm this
although their efficacy has not been established. Platelet transfusions association.
are most likely to be effective for the treatment of abciximab-induced Although a similar syndrome may be caused by mitomycin,
thrombocytopenia because the drug binds so tightly to GPIIb/IIIa gemcitabine, cyclosporine, and tacrolimus, it should be noted that
that little abciximab is free to bind to the transfused platelets. Platelet many patients who receive these drugs have an underlying illness
transfusions are not indicated in pseudothrombocytopenia, which (e.g., gastric adenocarcinoma, BM transplantation, collagen vascular
underscores the importance of reviewing the blood film when a disease) that itself can be complicated by TMA; moreover, high
low platelet count is reported after treatment with one of these cumulative doses of the implicated drug have usually been received,
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agents. suggesting a nonimmune (e.g., toxic) pathogenesis. Furthermore,