Page 2435 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 149 Antithrombotic Drugs 2173

a nonpeptidic tyrosine derivative that acts as an RGD mimetic. Dosing
Abciximab has a long half-life and can be detected on the surface of
platelets for up to 2 weeks. Eptifibatide and tirofiban have shorter Vorapaxar is given orally at a dose of 2.5 mg once daily.
half-lives.
In addition to targeting the GPIIb/IIIa receptor, abciximab also
inhibits the closely related α v β 3 receptor, which binds vitronectin, Side Effects
and α M β 2, a leukocyte integrin. In contrast, eptifibatide and tirofiban
are specific for GPIIb/IIIa. Inhibition of α v β 3 and α M β 2 may endow The major side effect is bleeding, including intracranial and fatal
abciximab with antiinflammatory and/or antiproliferative properties bleeding.
that extend beyond platelet inhibition.
ANTICOAGULANTS
Indications
There are both parenteral and oral anticoagulants. Currently available
These agents are used in high-risk patients undergoing PCIs, particu- parenteral anticoagulants include heparin, low-molecular-weight
larly those with ST-segment elevation acute myocardial infarction heparin (LMWH), fondaparinux, and direct thrombin inhibitors
who have not been adequately pretreated with antiplatelet drugs or (hirudin, bivalirudin, and argatroban). The oral anticoagulants
in those requiring rapid platelet inhibition. Tirofiban and eptifibatide include the vitamin K antagonists, of which warfarin is the agent
are occasionally used upstream for intervention in high-risk patients most often used in North America, and the non–vitamin K antagonist
with unstable angina. oral anticoagulants (NOACs) that target either thrombin (dabigatran
etexilate) or factor Xa (rivaroxaban, apixaban, and edoxaban). 14

Dosing
Parenteral Anticoagulants
All of the GPIIb/IIIa antagonists are given as an intravenous bolus
followed by an infusion. Because they are cleared by the kidneys, the Heparin
doses of eptifibatide and tirofiban must be reduced in patients with
renal impairment. A sulfated polysaccharide, heparin is isolated from mammalian tissues
rich in mast cells. Most commercial heparin is derived from porcine
intestinal mucosa and is a polymer of alternating D-glucuronic acid
Side Effects and N-acetyl-D-glucosamine residues.

In addition to bleeding, thrombocytopenia is the most serious Mechanism of Action
complication. Thrombocytopenia is immune mediated and is Heparin acts as an anticoagulant by activating antithrombin (previ-
caused by antibodies directed against neoantigens on GPIIb/IIIa ously known as antithrombin III) and accelerating the rate at which
that are exposed upon antagonist binding. With abciximab, throm- antithrombin inhibits clotting enzymes, particularly thrombin and
bocytopenia occurs in up to 5% of patients. Thrombocytopenia is factor Xa. Antithrombin, the obligatory plasma cofactor for heparin,
severe in about 1% of these individuals. Thrombocytopenia is less is a 58,000-Da single-chain polypeptide that is a member of the
common with the other two agents, occurring in about 1% of treated serine protease inhibitor (serpin) superfamily. Synthesized in the liver
patients. and circulating in plasma at a concentration of 2.6 ± 0.4 µM, anti-
thrombin acts as a suicide substrate for its target enzymes.
To activate antithrombin, heparin binds to the serpin via a unique
Vorapaxar pentasaccharide sequence that is found on one-third of the chains of
commercial heparin (Fig. 149.4); heparin chains lacking this penta-
An orally active inhibitor of the type 1 protease-activated recep- saccharide sequence have little or no anticoagulant activity. Once
tor (PAR-1), vorapaxar inhibits the major thrombin receptor on bound to antithrombin, heparin induces a conformational change in
platelets. 12–14 the reactive center loop of antithrombin that renders it more readily
accessible to its target proteases. This conformational change enhances
the rate at which antithrombin inhibits factor Xa by at least two
Mechanism of Action orders of magnitude, but it has little effect on the rate of thrombin
inhibition by antithrombin (Fig. 149.5). To catalyze thrombin inhibi-
14
Thrombin is a potent platelet activator that acts through the PARs. tion, heparin serves as a template that binds antithrombin and
PAR-1 is the highest-affinity thrombin receptor on platelets; PAR-1 thrombin simultaneously. Formation of this ternary complex brings
15
also is expressed on endothelial cells and atherosclerotic plaques. the enzyme in close apposition to the inhibitor, thereby promoting
Vorapaxar is a synthetic analogue of himbacine, which is a natural the formation of a stable covalent thrombin–antithrombin complex.
product. Given orally, vorapaxar is rapidly absorbed form the gastro- Only pentasaccharide-containing heparin chains composed of at
intestinal tract and inhibits platelet PAR-1 in a reversible fashion; least 18 saccharide units (which correspond to a molecular weight of
however, because of its long half-life (8 to 12 days) and its high- 5400) are of sufficient length to bridge thrombin and antithrombin
affinity interaction with PAR-1, vorapaxar is effectively an irreversible together. With a mean molecular weight of 15,000 and a range of
inhibitor of PAR-1. 5000 to 30,000, almost all of the chains of unfractionated heparin
are long enough to affect this bridging function. Consequently, by
definition, heparin has equal capacity to promote the inhibition of
Indications thrombin and factor Xa by antithrombin and is assigned an anti-
factor Xa to anti-factor IIa (thrombin) ratio of 1 : 1.
Vorapaxar is indicated for reduction of thrombotic cardiovascular In addition to activating antithrombin, heparin also can catalyze
events in patients with a history of myocardial infarction or peripheral heparin cofactor II. This 66,000-Da serpin, which is found in plasma
artery disease. The drug is administered in conjunction with aspirin at a concentration of 1.2 ± 0.4 µM, is a specific inhibitor of throm-
and/or clopidogrel. Vorapaxar is contraindicated in patients with a bin. Two features account for the specificity of heparin cofactor II.
prior history of intracranial bleeding, stroke, or transient ischemic First, the reactive site of heparin cofactor II contains the sequence
attack. Leu444–Ser445, a peptide bond that is not readily susceptible to