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C H A P T E R 149

ANTITHROMBOTIC DRUGS

Iqbal H. Jaffer and Jeffrey I. Weitz

Arterial or venous thromboembolism is a major cause of morbidity in current use, new agents in advanced stages of development also
and mortality. Arterial thrombosis is the most common cause of are discussed.
acute myocardial infarction, ischemic stroke, and limb gangrene,
whereas deep vein thrombosis can lead to pulmonary embolism,
which can be fatal, and to the postthrombotic syndrome. Most ANTIPLATELET DRUGS
arterial thrombi are superimposed on disrupted atherosclerotic
plaque because plaque rupture exposes thrombogenic material in Role of Platelets in Arterial Thrombosis
1
the plaque core to the blood. This material then triggers platelet
aggregation and fibrin formation, which results in the generation In healthy vasculature, circulating platelets are maintained in an
of a platelet-rich thrombus that can temporarily or permanently inactive state by nitric oxide (NO) and prostacyclin released by
occlude blood flow. In contrast to arterial thrombi, venous thrombi endothelial cells lining the blood vessels. In addition, endothelial cells
1
rarely form at sites of obvious vascular disruption. Although they also express ADPase on their surface, which degrades ADP released
can develop after surgical trauma to veins or secondary to indwelling from activated platelets. When the vessel wall is damaged, release of
central venous catheters, venous thrombi usually originate in the these substances is impaired and the subendothelial matrix is exposed.
valve cusps of the deep veins of the calf or in the muscular sinuses, Platelets adhere to exposed collagen and to von Willebrand factor via
where they are triggered by stasis. Sluggish blood flow in these veins glycoprotein (GP) VI and GPIb–IX, respectively; receptors are con-
reduces the oxygen supply to the avascular valve cusps. Endothelial stitutively expressed on the platelet surface. Adherent platelets
cells lining the valve cusps become activated and express adhesion undergo a change in shape, secrete ADP from their dense granules,
molecules on their surface. These adhesion molecules tether tissue and synthesize and release thromboxane A 2 . Released ADP and
factor–bearing leukocytes and microparticles to the surface of acti- thromboxane A 2 , which are platelet agonists, activate ambient plate-
vated endothelial cells, where the tissue factor triggers coagulation. lets and recruit them to the site of vascular injury.
Local thrombus formation is exacerbated by reduced clearance of Disruption of the vessel wall also exposes tissue factor–expressing
activated clotting factors as a result of impaired blood flow. If the calf cells to the blood. Tissue factor initiates coagulation. Activated
vein thrombi extend into more proximal veins of the leg, thrombus platelets potentiate coagulation by binding clotting factors and sup-
fragments can dislodge, travel to the lungs, and produce a pulmonary porting the assembly of activation complexes that enhance thrombin
embolism. generation. In addition to converting fibrinogen to fibrin, thrombin
Arterial and venous thrombi are composed of platelets and fibrin, amplifies its own generation and serves as a potent platelet agonist,
but the proportions differ. Arterial thrombi are rich in platelets thereby recruiting additional platelets to the site of injury.
because of the high shear in the injured arteries. In contrast, venous When platelets are activated, GPIIb/IIIa (α IIb β 3 ), the most abun-
thrombi, which form under low-shear conditions, contain relatively dant receptor on the platelet surface, undergoes a conformational
few platelets and are composed predominantly of fibrin and trapped change that enables it to ligate fibrinogen. Divalent fibrinogen mol-
red cells. Because of the predominance of platelets, arterial thrombi ecules bridge adjacent platelets together to form platelet aggregates.
appear white, whereas venous thrombi are red in color, reflecting the Fibrin strands, generated through the action of thrombin, then weave
trapped red cells. these aggregates together to form a platelet–fibrin mesh.
Antithrombotic drugs are used for prevention and treatment of Antiplatelet drugs target various steps in this process (Fig. 149.2).
thrombosis. Targeting the components of thrombi, these agents The commonly used drugs include aspirin, thienopyridines (clopi-
include (1) antiplatelet drugs, which inhibit platelets; (2) anticoagu- dogrel and prasugrel), ticagrelor, cangrelor, dipyridamole, GPIIb/
lants, which attenuate coagulation; and (3) fibrinolytic agents, which IIIa antagonists, and vorapaxar. Each is briefly described in the
induce fibrin degradation (Fig. 149.1). With the predominance of following.
platelets in arterial thrombi, strategies to inhibit or treat arterial
thrombosis are focused mainly on antiplatelet agents, although in the
acute setting they often include anticoagulants and fibrinolytic Aspirin
agents. Anticoagulants are the mainstay of prevention and treatment
of venous thromboembolism because fibrin is the predominant The most widely used antiplatelet agent is aspirin. As a cheap and
component of venous thrombi. Antiplatelet drugs are less effective effective antiplatelet drug, aspirin serves as the foundation of most
than anticoagulants in this setting because of the limited platelet antiplatelet strategies.
content of venous thrombi. Fibrinolytic therapy is used in selected
patients with venous thromboembolism. For example, patients with
massive pulmonary embolism can benefit from systemic or catheter- Mechanism of Action
directed fibrinolytic therapy. Catheter-directed fibrinolytic therapy
also can be used as an adjunct to anticoagulants for treatment of Aspirin produces its antithrombotic effect by irreversibly acetylating
certain patients with extensive deep vein thrombosis involving the and inhibiting platelet cyclooxygenase-1 (COX-1), a critical enzyme
iliac and femoral veins. in the biosynthesis of thromboxane A 2 (see Fig. 149.2). At high doses
This chapter is focused on antithrombotic agents. In addition to (about 1 g/day), aspirin also inhibits COX-2, an inducible COX
describing antiplatelet, anticoagulant, and fibrinolytic drugs that are isoform found in endothelial cells and inflammatory cells. In

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