Page 2182 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 130 Acquired Disorders of Platelet Function 1935

at high risk for arterial thrombosis, to insure that sufficient platelet Abciximab
inhibition is achieved by a given aspirin dose; (2) for estimating the
bleeding risks in patients who need surgery or who have experienced The first α IIb β 3 inhibitor approved for clinical use, abciximab
trauma. (ReoPro), is a human-murine chimeric Fab fragment of a monoclonal
The antiplatelet effect of aspirin can be screened by different antibody that targets the β 3 subunit of α IIbβ 3 and therefore also reacts
techniques, including light-transmission aggregometry, whole-blood with another integrin that shares the β 3 subunit, α Vβ 3. Although
aggregometry, platelet function analyzer (PFA)-100, VerifyNow α IIbβ 3 expression is restricted to megakaryocytes and platelets, α Vβ 3
Aspirin, measurement of serum/plasma or urinary TXB 2 metabolites, is expressed on platelets; at low levels; and in cells of the vascular wall,
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thromboelastography, flow cytometry, or other tests (see Chapters including endothelial cells and fibroblasts. In addition to its anti-
128 and 129). thrombotic properties, abciximab may also reduce infarct size, prevent
stent thrombosis, and modulate inflammatory responses by virtue of
β 3 subunit inhibition in other tissues. 48
Adenosine Diphosphate Receptor Antagonists Abciximab administered intravenously as a standard 0.25 mg/kg
bolus blocks approximately 80% of surface α IIb β 3 and inhibits platelet
The thienopyridines selectively and irreversibly inhibit ADP-mediated aggregation to a similar extent, although the extent of inhibition is
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platelet activation and aggregation. ADP activates platelets by variable. This level of blockade increases the bleeding time only
2+
raising the concentration of cytoplasmic Ca through influx from mildly. The bleeding time only becomes markedly prolonged when
the extracellular fluid and mobilization from internal stores, and by receptor blockade exceeds 90%. After the bolus dose, abciximab is
decreasing the concentration of intracellular cyclic adenosine mono- infused at 0.125 µg/kg/min for 12 hours. Several trials have estab-
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phosphate (cAMP) coupled to inhibition of adenylyl cyclase. ADP lished this as a clinically effective regimen. Plasma levels of free
receptors can be divided into two groups: the G protein–coupled abciximab drop rapidly after its administration, with an initial half-life
receptors, termed P2Y, and the ionotropic receptors, P2X. Platelets of approximately 30 min. Most of the drug is bound to platelets. This
contain two P2Y receptors, P2Y 1 and P2Y 12 , complexed to the het- explains why patients with thrombocytosis may require larger weight-
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erotrimeric G proteins G q and G i2 , respectively. ADP binding to P2Y 1 adjusted doses of abciximab to attain a therapeutic antiplatelet effect
is necessary for platelet aggregation but is not sufficient. Rather, P2Y 1 and why patients with lower platelet counts treated with the usual
is responsible for ADP-induced platelet shape change, and its engage- dose of abciximab display more profound platelet inhibition. Abcix-
ment by ADP triggers a transient aggregatory response. P2Y 12 , imab is not excreted in the urine and is probably metabolized by the
coupled to inhibition of adenylyl cyclase, mediates the amplification reticuloendothelial system at the time platelets (with bound abcix-
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of the aggregation response. The thienopyridine derivatives have no imab) are cleared from the circulation. The dose of abciximab does
effects on arachidonic acid metabolism and hence act synergistically not have to be adjusted in patients with renal impairment. Although
with aspirin to inhibit platelet function. a daily platelet turnover rate of 10% would predict that no abciximab
The thienopyridines are all prodrugs of similar structure that would be detected in blood after 10 days of its administration, platelet-
produce active metabolites that bind irreversibly to P2Y 12 , inhibiting bound abciximab has been observed up to 3 weeks after its initial
ADP-mediated aggregation for up to 10 days after withdrawal of the administration, suggesting platelet-to-platelet redistribution of the
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drug, paralleling the platelet life span. Because most platelet agonists drug or release of new platelets from megakaryocytes that had previ-
require ADP for their full activity, the thienopyridines inhibit platelet ously bound the drug. Several in vitro and in vivo studies confirm
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activation by all agonists except strong agonists at high concentra- abciximab’s ability to exchange between platelets. Because of the low
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tions. They have a further hypothetical advantage over aspirin in plasma levels of unbound abciximab, the drug’s inhibitory effect can
that they inhibit shear-induced platelet aggregation. 46 be rapidly reversed by platelet transfusion, and hemostasis should be
There are three generations of thienopyridine drugs, represented normal when the concentration of infused platelets exceeds 50,000/µL,
by ticlopidine, clopidogrel, and prasugrel. The use of ticlopidine has as it is in normal individuals. However, because of abciximab’s ability
been greatly curtailed because of serious side effects such as agranu- to redistribute to the newly transfused platelets, the platelet-bound
locytosis, thrombocytopenia, and thrombotic thrombocytopenic abciximab may produce a gradual inhibitory effect on the infused
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purpura. 47 platelets; in severe or refractory bleeding, it may be necessary to
infuse a very large dose of platelets, sufficient to leave 50% of α IIb β 3
receptors free, a number shown to be sufficient for normal hemostasis
Platelet αIIbβ3 (Glycoprotein IIb/IIIa) Inhibitors in studies of Glanzmann thrombasthenia heterozygotes. Without
platelet transfusions, platelet aggregation generally returns to baseline
A myriad of pathways lead to platelet aggregation, the final common levels within 12–24 hours after discontinuing abciximab.
step being activation of the major platelet integrin α IIb β 3 to a ligand-
competent form, which can bind multivalent ligands such as fibrino-
gen or von Willebrand factor (vWF) to cross-link the platelets into Eptifibatide
an aggregate. Conventional antiplatelet agents such as aspirin and
clopidogrel each inhibit only one pathway leading to platelet aggrega- Eptifibatide (Integrilin) is a cyclic heptapeptide based on the Lys-Gly-
tion, aspirin preventing thromboxane production, and clopidogrel Asp (KGD) sequence found in barbourin, a platelet-inhibitory dis-
blocking ADP receptors. Dual therapy with aspirin and clopidogrel integrin from the venom of the Southeastern Pigmy rattlesnake,
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improves the clinical benefit of antiplatelet therapy, but aggregation Sistrurus miliarius barbouri. Barbourin differs from other integrin-
is still able to proceed through the action of other agonists such as binding proteins with the Arg-Gly-Asp (RGD) canonical sequence
thrombin. Because α IIb β 3 engagement is required for aggregation in that the arginine is conservatively substituted by lysine, a change
through all pathways, blocking this receptor inhibits platelet aggrega- that renders the protein a specific inhibitor of α IIb β 3 . Eptifibatide
tion more effectively. incorporates the KGD sequence within a cyclic seven-member
Inhibitors of α IIbβ 3 work selectively and competitively to inhibit peptide of high potency. Eptifibatide differs pharmacokinetically
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platelet aggregation. 48,49 These agents are intended to produce a from abciximab in several important ways. For example, unlike
transient effect akin to the defect in Glanzmann thrombasthenia, but abciximab, intravenous eptifibatide infusion produces high levels of
there are important differences between the drug effect and the unbound drug because of its lower affinity for the receptor. Platelet
disease. transfusions therefore are not a good method for acutely reversing
Although these agents share many similarities in their antithrom- eptifibatide’s antiplatelet effect because the newly transfused platelets
botic properties, they also have a number of clinically important are rapidly inhibited. However, its short plasma half-life (≈2.5 hours)
pharmacokinetic and off-target effect differences. Three drugs are allows for rapid clearance of eptifibatide and the reversal of its
available: eptifibatide, tirofiban, and abciximab. antiplatelet effect when administration is discontinued. Platelet