Antiplatelet Agents and Anticoagulants

Physiology of Blood Clotting

Vascular injury leads to thrombus formation. As a first step, a platelet plug is formed, which is then surrounded and strengthened by a fibrin polymer meshwork. Several steps are involved in this process (Fig. 22-1):

FIGURE 22-1 The three steps of thrombus formation. A, Platelet adhesion. B, Platelet aggregation: (1) granule release, (2) glycoprotein *(GP)* IIb/IIIa form shape and cross-linking, (3) flip-flop of phospholipids *(PL)*. C, Plasmatic coagulation (fibrin formation). *TF,* tissue factor.

1. Platelet adhesion: During the first step of hemostasis, von Willebrand factor multimers bind to exposed subendothelial collagen with one part of their structure and to the glycoprotein (GP)Ib receptor on the surface of platelets with another, thereby anchoring the platelet to the site of injury.

2. Platelet aggregation: Platelet adhesion leads to activation of the anchored platelet, which results in three major reactions:

• Release of platelet granules: Platelet granules contain platelet agonists such as thromboxane A₂, adenosine diphosphate (ADP), and epinephrine. Thromboxane A₂ is synthesized with the help of the enzyme cyclooxygenase (COX)-1. Once released into the bloodstream, the agonists bind to receptors on the surface of platelets trying to float by, thus activating and recruiting them to the site of injury. The platelet receptors for ADP are termed P2Y₁ and P2Y₁₂, and it appears both must be activated for platelet aggregation to take place.

• Activation of platelet surface GPIIb/IIIa receptors: Activation of the platelet leads to a change in shape of the GPIIb/IIIa receptor, enabling it to bind fibrinogen. One end of the fibrinogen molecule binds to the GPIIb/IIIa receptor of one activated platelet and the other to the receptor of another platelet, thus bridging platelets and creating a platelet plug.

• Flip-flop of phospholipids: In nonactivated platelets, phospholipids are located on the inner side of the cell membrane. Platelet activation leads to a flip-flop of these phospholipids to the outside of the platelet membrane, where then they can bind coagulation factors and calcium and facilitate the various reactions of the coagulation cascade that lead to formation of fibrin.

3. Plasmatic coagulation: Vascular injury brings tissue factor on extracellular cells (fibroblasts, monocytes) into contact with circulating coagulation factor VIIa, thereby initiating the coagulation cascade that leads to thrombin and eventually fibrin formation. Coagulation factor activation reactions require phospholipids, which are provided by platelets during the flip-flop mechanism that occurs during platelet aggregation. A fibrin meshwork forms around the platelets anchored at the site of vascular injury. A thrombus is formed.

Pathophysiology of Blood Clotting

Venous thrombosis occurs mostly via the plasma coagulation system, with only minor platelet participation. In contrast, platelets play a major role in arterial thrombus formation, with additional participation of the plasma coagulation system. This paradigm helps explain why drugs that block the plasmatic coagulation reaction (i.e., anticoagulants) are very active in preventing venous thrombosis and also effective in preventing arterial thrombosis, whereas antiplatelet drugs, which successfully prevent arterial thrombosis, are less or not at all effective in venous disease. Table 22-1 lists the important antiplatelet agents and anticoagulants, discussed in further detail in the following sections.

TABLE 22-1

Antiplatelet Agents and Anticoagulants

Generic	Brand Name*	Dosing^†
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitor
Aspirin		50-325 mg qd PO.
Phosphodiesterase Inhibitors
Dipyridamole	Persantine	75-100 mg qid PO.
Dipyridamole + ASA	Aggrenox	1 tablet (200 mg/25 mg) q12h PO.
Cilostazol	Pletal	100 mg q12h PO.
ADP Receptor Blockers
Clopidogrel	Plavix	Loading dose 300 mg PO; then 75 mg qd PO.
Ticlopidine	Ticlid	Loading dose 500 mg PO; then 250 mg q12h PO.
Prasugrel	Effient	Loading dose 60 mg PO; then 10 mg qd PO.
Ticagrelor	Brilinta	Loading dose 180 mg PO; then 90 mg q12h PO.
Cangrelor		In development.
Elinogrel		Development stopped.
Glycoprotein IIb/IIIa Receptor Blockers
Abciximab	ReoPro	Bolus 0.25 mg/kg IV; then 0.125 µg/kg/min for 12 h IV.
Eptifibatide	Integrilin	Bolus 180 g/kg IV; then 0.5-2.0 µg/kg/min for up to 72 h IV.
Tirofiban	Aggrastat	0.4 µg/kg/min × 30 min IV; then 0.1 µg/kg/min × 12-24 h IV.
Oral agents^‡		Development stopped.
Orbofiban
Sibrafiban
Xemilofiban
Others
Pentoxifylline	Trental	400 mg tid PO.
Anticoagulants
Heparins
Unfractionated heparin	Various	Various nomograms—APTT or anti-Xa adjusted.
Enoxaparin	Lovenox	Prophylaxis: various doses
	Clexane	Full-dose: 1 mg/kg q12h or 1.5 mg/kg qd SQ.
Dalteparin	Fragmin	Prophylaxis: various doses; full-dose: 100 units/kg q12h SQ or 200 units/kg qd SQ.
Tinzaparin	Innohep	Prophylaxis: various doses; full-dose: 175 units/kg qd SQ.
Certoparin	Monoembolex	Prophylaxis: various doses.
Reviparin	Clivarin	Not approved for full-dose anticoagulant treatment.
Nadroparin	Fraxiparin
Anti-Xa Inhibitors
Pentasaccharides:
Fondaparinux	Arixtra	Prophylaxis: 2.5 mg qd SQ; full-dose: 7.5 mg qd SQ; 10 mg qd if body weight above 100 kg.
Idraparinux	None yet	In development.
Rivaroxaban	Xarelto	Atrial fibrillation with normal renal function: 20 mg qd PO. VTE prevention: 10 mg qd; Acute DVT or PE: 15 mg q12h for 3 weeks, then 20 mg qd PO with normal renal function.
Apixaban	Eliquis	2.5 mg q12h for VTE prevention. 5 mg bid for atrial fibrillation.
Edoxaban	Lixiana	30 mg PO once daily for VTE prevention after orthopedic surgery.
Thrombin Inhibitors
Argatroban	Acova	No bolus.
	Novastan	Continuous infusion: 2 µg/kg/min IV—APTT adjusted.
Lepirudin	Refludan	Bolus: 0.4 mg/kg IV.
		Continuous infusion: 0.15 mg/kg/h IV—APTT adjusted.
Desirudin	Iprivask	15 mg q12h SQ.
	Revasc
Bivalirudin	Angiomax	Bolus: 0.75 mg/kg IV.
		Continuous infusion: 1.75 mg/kg/h IV until 4 h after procedure; then 0.2 mg/kg/h for up to 20 h.
Danaparoid	Orgaran	Manufacturing discontinued.
Ximelagatran	Exanta	Withdrawn from market.
Dabigatran	Pradaxa	Atrial fibrillation with normal renal function: 150 mg q12h PO or 110 mg q12h.
Vitamin K Antagonists
Coumarins
Warfarin	Coumadin	Interindividual variability; dosing is INR adjusted.
	Jantoven
Phenprocoumon	Marcumar
	Falithrom
	Phenpro
Acenocoumarol	Sinthrome
Tioclomarol	Apegmone
Indandiones
Fluindione	Previscan
Anisindione	Miradon
Phenindione	Dindevan
	Pindione

ADP, Adenosine diphosphate; APTT, activated partial thromboplastin time; h, hour; INR, international normalized ratio; IV, intravenously; q, every; qd, once daily; tid, three times daily; PO, orally; SQ, subcutaneously; VTE, venous thromboembolism.

^*Other products may exist.

^†Drug approval and dosing regimens may vary depending on indication, country of use, presence or absence of renal or liver dysfunction, and concomitant use of antiplatelet drugs or anticoagulants.

^‡Specific agents printed in italics are investigational.

Aspirin (acetylsalicylic acid) inhibits the enzyme COX-1, which is needed to form thromboxane A₂ in platelets. Thromboxane A₂ is normally released from platelet granules upon platelet adhesion and during platelet aggregation (see Fig. 22-1, B) and serves as an agonist to activate and thereby recruit other platelets to the platelet plug. Because platelets do not synthesize new cyclooxygenase and aspirin binds irreversibly to the enzyme, aspirin’s action lasts for the lifespan of a platelet (i.e., 7-10 days). Complete inactivation of platelet COX-1 is typically achieved with a daily aspirin dose of 160 mg. When used as an antithrombotic drug, aspirin is maximally effective at doses between 50 and 325 mg/day. Higher doses do not improve efficacy. However, there is considerable interindividual variability in aspirin’s ability to inhibit COX-1. “Aspirin resistance” is a laboratory phenomenon in which there is an inability of aspirin to inhibit one or more in vitro tests of platelet function, such as platelet aggregometry, the Platelet Function Analyzer (PFA-100), the VerifyNow Aspirin rapid platelet function assay, or measurement of thromboxane generation in vitro or in vivo via serum levels of thromboxane B₂ or urinary levels of 11-dehydrothromboxane B₂. “Aspirin failure” is a clinical observation of treatment failure. Aspirin resistance does not necessarily lead to treatment failure, nor is clinical aspirin failure necessarily due to aspirin resistance.