Chapter 26 Antithrombotic Drugs

Abbreviations
APTT	Activated partial thromboplastin time
cAMP	Cyclic adenosine monophosphate
INR	International normalized ratio
IV	Intravenous
PT	Prothrombin time
t-PA	Tissue plasminogen activator
TXA₂	Thromboxane A₂
t-PA	Tissue plasminogen activator
u-PA	Urokinase plasminogen activator
vWF	Von Willebrand factor

Therapeutic Overview

Modifying pathways involved in coagulation, fibrinolysis, or platelet aggregation is useful in many patients undergoing surgery or with cardiovascular disease. Events leading to arterial thrombosis (usually a platelet thrombus) or venous thrombosis (usually a fibrin clot) or that cause clot lysis are activated and inhibited by many endogenous blood and tissue components, as well as exogenous materials. The main reasons for intervention are:

• To inhibit blood coagulation

• To stimulate lysis of an already formed but unwanted thrombus

• To inhibit platelet function

Certain procedures such as hip joint replacement and cardiopulmonary bypass, in which blood comes into

Therapeutic Overview
Anticoagulation
Heparin and heparin derivatives, coumarins, directly acting thrombin inhibitors	Arterial thrombosis, atrial fibrillation, cardiomyopathy, cerebral emboli, hip surgery, vascular prostheses, heart valve disease, venous thromboembolism
Fibrinolysis
Streptokinase, urokinase, tissue plasminogen activator and its derivatives	Acute myocardial infarction, deep venous thrombosis Pulmonary embolism
Platelet Aggregation Inhibition
Aspirin	Cerebrovascular accident, stroke, after coronary artery bypass surgery, coronary angioplasty/stenting or thrombolysis, myocardial infarction, transient ischemic attack
Clopidogrel	Coronary artery disease, cerebrovascular accident, stroke, peripheral arterial disease
Glycoprotein IIb/IIIa inhibitors	Acute coronary syndromes, after coronary artery stenting

contact with foreign materials, initiate coagulation and thrombus formation. In these settings prophylactic administration of anticoagulants diminishes unwanted thrombus formation. In situations where a thrombus has already formed, such as deep vein thrombosis, acute myocardial infarction, and pulmonary embolism, rapid activation of the fibrinolytic system to lyse the thrombus and initiation of anticoagulation therapy to minimize further clot formation are effective. In cardiovascular disease and stroke, clinical evidence supports the use of drugs that inhibit platelet function.

Therapeutic uses of drugs for preventing or lysing thrombi are summarized in the Therapeutic Overview Box.

Mechanisms of Action

The interactions of the coagulation, fibrinolytic, and platelet systems are summarized in Figure 26-1. Endothelial cells in the blood vessel lumen normally present a nonthrombogenic surface. If the endothelium is damaged, blood comes into contact with thrombogenic substances within the subendothelium, such as collagen, which activates platelets, and tissue factor, which initiates blood coagulation. Foreign surfaces, such as prosthetic vascular grafts or mechanical cardiac valves, can also trigger clotting. Removal of thrombi by the fibrinolytic system depends on generation of plasmin from plasminogen by plasminogen activators.

FIGURE 26–1 Involvement of thrombin and platelets and their interaction in thrombosis.

Blood coagulation occurs by sequential conversion of a series of inactive proteins into catalytically active proteases (Fig. 26-2). When the endothelium is damaged, blood comes into contact with cells that express tissue factor, a membrane-bound glycoprotein (the extrinsic pathway). A catalytically active complex of tissue factor and plasma factor VII is produced, which converts factor X to its enzymatically active form (Xa). In turn, factor Xa, in the presence of factor Va and a phospholipid surface (usually that of activated platelets), converts prothrombin to thrombin. Thrombin removes small peptides from fibrinogen (Fig. 26-3), converting it to fibrin monomer, which spontaneously polymerizes to form a clot. Fibrin is stabilized by factor XIIIa (transglutaminase), which introduces covalent bonds between fibrin molecules (see Fig. 26-3).

FIGURE 26–2 A simplified model of thrombin generation. Reactions fall into four phases, which occur preferentially on surfaces. Activated platelets provide the surface for two phases; the vascular subendothelium or nonvascular tissue provides the surface for the extrinsic phase, and foreign surfaces, such as glass and collagen, activate the contact phase. In each, a multicomponent complex is assembled, comprising an enzyme, its substrate (a proenzyme), and a cofactor. This complex affects conversion of proenzyme to its active form at a rate thousands of times faster than that of the enzyme alone.

FIGURE 26–3 Thrombin cleaves two small peptides from fibrinogen, allowing its polymerization to fibrin. Thrombin also converts factor XIII to an active transglutaminase. This enzyme stabilizes fibrin by introducing Glu-Lys isopeptide bonds between adjacent fibrin molecules. Fibrin and fibrinogen are both substrates for the thrombolytic enzyme plasmin.

In addition to clotting fibrinogen, thrombin activates platelets and converts factors V and VIII to their active forms (Va and VIIIa). Factor VIIIa participates with activated platelets in generation of factor Xa by an alternative route (the intrinsic pathway). This involves factor IX, which is activated by the factor VIIa-tissue factor complex, or by factor XIa. In vitro, upon contact of blood with a glass surface, the contact phase of coagulation involving factor XII, prekallikrein, and high molecular weight kininogen leads to activation of factor XI (the contact phase). The relevance of this pathway to initiation of coagulation in vivo is not clear, because people with defects in these proteins seldom demonstrate excessive bleeding.

Most enzymes involved in coagulation are trypsin-like serine proteases with considerable homology. Plasma contains many inhibitors that regulate the coagulation cascade (Table 26-1). These proteins prevent inappropriate clotting and prevent appropriate, localized activation of the coagulation cascade from progressing to systemic coagulation.

TABLE 26–1 Plasma Protease Inhibitors That Regulate Blood Coagulation and Fibrinolysis

Name	Principal Target
α₁-Protease inhibitor	Elastase
α₁-Antichymotrypsin	Cathepsin G₁
Antithrombin	Thrombin, Xa, IXa
α₂-Macroglobulin	Plasmin, kallikrein, and other proteases
C1 inhibitor	Complement, XIIa
α₂-Antiplasmin	Plasmin
Heparin cofactor II	Thrombin, Xa
Plasminogen activator inhibitor-1 (PAI-1)	t-PA, u-PA

Anticoagulant drugs function by either blocking thrombin formation or inhibiting the activity of thrombin after it is formed.

Parenteral Anticoagulant Drugs

Heparin is a linear polysaccharide with alternating residues of glucosamine and either glucuronic or iduronic acid (Fig. 26-4) derived from animal sources. The amino group of glucosamine is either acetylated or sulfated, and there is a variable degree of sulfation (≤40%) on the hydroxyl groups, rendering heparin a heterogeneous compound. Heparin acts by increasing the activity of antithrombin, a plasma glycoprotein that inhibits serine protease clotting enzymes. Heparin binds to antithrombin, causing a conformational change that renders the reactive site on antithrombin more accessible to serine proteases, inactivating thrombin and factors IXa and Xa; low molecular weight heparin inhibits mainly factor Xa. After the binding of antithrombin to thrombin, the heparin molecule is released and can bind to another antithrombin molecule. Although low doses of heparin act primarily by neutralizing factor Xa, at high doses it acts by preventing thrombin-induced platelet activation and prolongs bleeding time. Although the heparin-antithrombin complex is a very efficient inhibitor of free thrombin, clot-bound thrombin is resistant to inhibition.

FIGURE 26–4 Structures of selected anticoagulants. Top left: Structure of a repeating unit in heparin. There is considerable variation in the extent of sulfation of different hydroxyl groups. Lower right: Abciximab is a Fab fragment of a chimeric human-murine monoclonal antibody. The variable (V) and constant (C) regions of the light (L) and heavy (H1) chains are shown.

Fondaparinux is a synthetic pentasaccharide that binds to antithrombin and selectively catalyzes inactivation of factor Xa. Because of its short chain length, it does not promote thrombin inhibition, making it an antithrombin-dependent selective factor Xa inhibitor. Fondaparinux is used to prevent and treat deep venous thrombosis and does not affect platelet function.

Several agents directly inhibit thrombin. Hirudin is a 65-amino-acid leech salivary gland protein that directly inhibits thrombin activity by blocking the active site of thrombin, as well as another site that mediates fibrinogen binding. Recombinant hirudins include desirudin and lepirudin, while analogs include bivalirudin. These compounds are used primarily in patients intolerant of heparin.

Argatroban is a synthetic, directly acting thrombin inhibitor derived from l-arginine that reversibly binds to active site of thrombin. Argatroban is used as an alternative to the hirudin analogs.

Oral Anticoagulant Drugs

The oral anticoagulants, typified by warfarin and the coumarins (Fig. 26-4), represent a very important class of agents whose action involves their ability to inhibit vitamin K. A subset of blood coagulation factors (II, VII, IX, X) and anticoagulant proteins C and S are activated via the γ-carboxylation of several glutamic acid residues, which mediate their Ca⁺⁺-dependent binding to phospholipid surfaces, critical for assembly of complexes necessary to generate thrombin. This activation requires vitamin K as a cofactor, and carboxylation of these vitamin K-dependent coagulation factors leads to the concomitant oxidation of vitamin K to its corresponding epoxide. The regeneration of vitamin K necessary to sustain the carboxylation reaction is mediated by vitamin K epoxide reductase, an enzyme inhibited by warfarin and the coumarins. Thus these compounds block recycling of the oxidized form of vitamin K to the reduced form required for cofactor function. Because these compounds inhibit the synthesis of clotting factors but have no direct effect on previously synthesized factors, plasma levels of preexisting vitamin K-dependent factors must decline before the anticoagulant effect of these agents becomes apparent, which requires several days. The first to decline is factor VII, followed by other factors with longer half-lives (see Table 26-2). The full anticoagulant effect of warfarin is typically reached within 4 to 7 days. Because of genetic variations in metabolism, drug interactions, and differences in vitamin K intake, significant variations between individuals exist in the time required for a maximal effect and in doses required for maintenance. Consequently, careful monitoring of prothrombin time (PT), a standard laboratory measure, is necessary.

TABLE 26–2 Rates of Disappearance (Half-Lives) of Vitamin K-dependent Proteins from Blood

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