Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 26 Antithrombotic Drugs

MAJOR DRUG CLASSES

Parenteral anticoagulants

Oral anticoagulants

Fibrinolytics

Antiplatelet drugs

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.

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

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.

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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).

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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.

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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.

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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

Protein

Time

Coagulation Factors

Factor VII

5 hours

Factor IX

15 hours

Factor X

1 day

Prothrombin

2-3 days

Anticoagulant Proteins

Protein C

6 hours

Protein S

10 hours

Proteins C and S, two other vitamin K-dependent factors, also inhibit excessive coagulation in the activated state. This mechanism involves the binding of thrombin to thrombomodulin, an endothelial cell surface protein, which results in a different proteolytic specificity than free thrombin. In this state thrombin does not cleave fibrinogen or activate platelets. Rather, it activates protein C, which in combination with protein S proteolytically inactivates clotting factors Va and VIIIa (Fig. 26-5), thereby providing a feedback inhibition to down regulate blood clotting after vascular injury. Genetic deficiency of protein C or protein S can cause thromboembolic disease.

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FIGURE 26–5 The anticoagulant protein C pathway. Thrombin bound to thrombomodulin on the surface of vascular endothelial cells has a proteolytic selectivity different from that of free thrombin. Rather than cleaving fibrinogen, it cleaves protein C to activated protein C, which then cleaves factors Va and VIIIa to give inactive products. This process is accelerated in the presence of protein S and platelets. Both protein C and protein S are vitamin K-dependent and affected by warfarin.

Fibrinolytics

Fibrin clots are lysed mainly through the proteolytic action of plasmin, the enzyme produced by the proteolytic activation of plasminogen by plasminogen activators (Fig. 26-6). A minor aspect of clot lysis may result from release of proteolytic enzymes, such as elastase, from leukocytes. The two major classes of endogenous plasminogen activators are tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). Recombinant forms of these proteins are used as clot-dissolving drugs.

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FIGURE 26–6 Key components of the fibrinolytic system. Dotted lines depict inhibition of t-PA and u-PA by plasminogen activator inhibitor-1 (PAI-1) and the inhibition of plasmin by α2-antiplasmin.

Streptokinase, a protein produced by streptococci, forms a complex with plasminogen that activates free plasminogen molecules to plasmin and is also used as a thrombolytic agent. Plasmin formed by the action of plasminogen activators attacks not only fibrin but also several other proteins, including fibrinogen, factor V, and factor VIII. The recombinant forms of u-PA and t-PA may have some advantages over streptokinase because of their selectivity in binding to the fibrin clot, but streptokinase is less expensive. Streptokinase, however, is highly immunogenic and cannot be used repeatedly. Modified forms of t-PA, such as reteplase and tenecteplase, have deletions or mutations in domains responsible for clearance from the circulation.

Antiplatelet Drugs

The activation and subsequent aggregation of platelets is a major component of arterial thrombosis and may be involved in initiation of venous thrombosis. Interaction of platelets with vessel wall collagen appears to be a key step. Activation of platelets leads to formation and release of thromboxane A2 (TXA2) from arachidonic acid in platelet membranes (see Chapter 15). TXA2 is a potent aggregating agent and vasoconstrictor. Platelet activation also causes secretion of adenosine diphosphate from storage granules. Both TXA2 and adenosine diphosphate, which act through specific receptors, cause activation of integrin αIIbβIIIa receptors on the platelet surface for fibrinogen and for other adhesive proteins, including von Willebrand’s factor (vWF). Fibrinogen binding to its integrin receptor mediates aggregation, whereas vWF is involved primarily in adhesion of platelets to extracellular matrices in the vessel wall. Thrombin generated locally on the surface of activated platelets greatly amplifies the response by causing further activation and mediator secretion. Although TXA2, adenosine diphosphate, and thrombin all increase cytoplasmic Ca++, the mechanism by which thrombin activates its receptor is unique. Thrombin cleaves the N-terminal sequence of its platelet receptor (PAR1), forming a new N-terminus that serves as a “tethered ligand” and binds to and activates the receptor to induce transmembrane signaling (Fig. 26-7).

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FIGURE 26–7 Predicted linear structure of the platelet thrombin receptor, protease activated receptor 1 (PAR1). It is thought to have a characteristic seven-transmembrane domain G-protein-coupled receptor structure (see Chapter 1). However, thrombin acts by cleaving the N-terminal extracellular tail of the receptor, releasing an activation peptide and leaving a new N-terminal sequence: Ser-Phe-Lys-Lys-Arg-. This sequence acts as a “tethered ligand,” which activates the receptor and is a powerful aggregating agent.

Platelet activation is inhibited by elevation of intracellular cyclic adenosine monophosphate (cAMP), and agents that increase this second messenger inhibit aggregation. The most active agent isprostacyclin, released by cells of the vessel wall (see Chapter 15). Other mediators from endothelial cells may also contribute.

The major therapeutic approach to reducing platelet aggregation is through inhibition of cyclooxygenase. Aspirin irreversibly inhibits platelet cyclooxygenase by acetylating a serine residue near the active site of the enzyme, thereby blocking TXA2 formation (see Chapter 36). Aspirin also blocks the synthesis of the endogenous vasodilator and platelet inhibitor prostacyclin, although at standard doses this prothrombotic effect is insignificant.

Clopidogrel (see Fig. 26-4) irreversibly blocks activation of the platelet P2Y receptor by adenosine diphosphate. Clopidogrel is a prodrug that is metabolized by cytochrome CYP3A to an active metabolite. Clopidogrel has become a mainstay in the treatment of patients with coronary artery disease, and it is also commonly administered to patients with peripheral arterial occlusive disease and cerebrovascular disease. It is routinely administered with aspirin, particularly to patients who have received coronary artery stents.

Dipyridamole acts as an antiplatelet drug by stimulating prostacyclin synthesis, enhancing its inhibitory action, inhibiting phosphodiesterase, and blocking the uptake of adenosine into vascular and blood cells, leading to accumulation of this platelet-inhibitory and vasodilatory compound. At therapeutic doses dipyridamole does not prolong bleeding time or inhibit ex vivo platelet aggregation. Aggrenox is a combination antiplatelet agent consisting of dipyridamole and aspirin that has been found to be useful in secondary prevention of stroke.

Inhibitors of glycoprotein IIb/IIIa (Fig. 26-8) bind to αIIbβIIIa, or glycoprotein IIb/IIIa, the platelet integrin receptor for fibrinogen, vWF, and other adhesive ligands. These inhibitors prevent fibrinogen cross-linking of platelets, which is the final common pathway of aggregation. These agents are administered by intravenous infusion, primarily to prevent platelet-dependent thrombosis during treatment of acute coronary artery syndromes and after implantation of intracoronary stents. Abciximab is the Fab fragment of a chimeric human-murine monoclonal antibody that binds to the glycoprotein IIb/IIIa receptor of human platelets (see Fig. 26-4). Abciximab also binds to the vitronectin receptor (αVβ3) present on platelets, vascular endothelial cells, and vascular smooth muscle cells. Platelet function gradually recovers after abciximab infusion is stopped. Plasma drug levels fall quickly, though platelet-bound abciximab can be detected for up to 15 days.

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FIGURE 26–8 Inhibition of platelet aggregation by glycoprotein (GP) IIb/IIIa receptor antagonists. The GP IIb/IIIa receptors on unstimulated platelets exist in an inactive conformation that does not support fibrinogen binding. Activation of platelets by agonists, such as adenosine diphosphate (ADP), epinephrine, thrombin, and thromboxane A2, converts the GP IIb/IIIa receptors to an active conformation capable of binding fibrinogen, which leads to the formation of platelet aggregates. Blocking of the GP IIb/IIIa receptors with antagonists, such as abciximab, eptifibatide, and tirofiban, prevents fibrinogen from cross-linking activated platelets, thereby inhibiting thrombus growth.

Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl (des-amino cysteinyl) residue. Eptifibatide inhibits platelet aggregation by blocking the binding of fibrinogen to glycoprotein IIb/IIIa. Inhibition of platelet aggregation by eptifibatide is reversible after the drug is stopped due to dissociation from the platelet surface.

Tirofiban is a nonpeptide antagonist of the platelet glycoprotein IIb/IIIa receptor. Platelet inhibition after tirofiban is reversible after infusion is stopped.

Pharmacokinetics

The principal pharmacokinetic parameters of the anticoagulants, fibrinolytics, and antiplatelet drugs are given in Table 26-3. Heparin is administered by IV infusion or subcutaneously. Because of different mechanisms of action, the anticoagulant effect of heparin is immediate, whereas that of warfarin typically occurs within 3 to 7 days. Heparin is not bound to plasma albumin, and the t1/2 of low molecular weight heparins is longer than that of the naturally occurring, unfractionated compound. Thus low molecular weight heparins are effective when administered by subcutaneous injection once or twice daily.

Warfarin is strongly bound to plasma albumin and is metabolized in the liver. Warfarin is typical of orally administered anticoagulants.

Aspirin is hydrolyzed in plasma to salicylic acid, with a t1/2 of 15 to 20 minutes, as discussed in Chapter 36. The antithrombotic effect of aspirin, however, persists for at least 2 days, because circulating platelets cannot synthesize cyclooxygenase. New platelets must be produced to restore TXA2 concentrations.

Reteplase and tenecteplase, modified forms of t-PA, have a prolonged t1/2, which enables them to be administered as a bolus, rather than a continuous infusion to patients with acute myocardial infarction.

Relationship of Mechanisms of Action to Clinical Response

Anticoagulants

Anticoagulants and antiplatelet compounds are commonly used to prevent thromboembolic disease. Heparin is effective in prevention and treatment of venous thrombosis and pulmonary embolism and related events and can be used either for prophylaxis or treatment. For prophylaxis, it is given by subcutaneous injection once or twice daily at a dose that does not affect in vitro clotting times, such as theactivated partial thromboplastin time (APTT). A higher dose is required for treatment of ongoing thrombotic processes. If unfractionated heparin is used, its anticoagulant effect must be monitored, such as by APTT. The anticoagulant response varies significantly among patients with thromboembolic disease. The risk of bleeding is increased as the dose increases. For this reason the APTT is used to monitor the degree of anticoagulation. Because of their shorter chain lengths, low molecular weight heparins have a greater capacity to inhibit factor Xa than thrombin. Consequently, at standard clinical doses they produce only a mild prolonging of the APTT. Self-administered low molecular weight heparins can be used to provide full anticoagulation in the outpatient setting without monitoring. Because they are cleared from the blood by the kidneys, their dosing must be adjusted in patients with renal insufficiency.

Oral coumarin anticoagulants are effective in primary and secondary prevention of arterial and venous thromboembolism. The one-stage PT) is used to measure their anticoagulant effects. Because different clinical laboratories use different thromboplastins, a formula was developed to transform the PT to an index that allows results from different laboratories to be compared. This index, the international normalized ratio (INR), is used routinely to report PT results. Warfarin therapy prolongs the PT and the INR.

Platelet function is assessed by measurement of bleeding time, which involves incising the forearm skin under standardized conditions and measuring the time required for bleeding to stop. Platelet aggregation in vitro can be monitored optically using an aggregometer.

If a patient has an acute thrombus or is at high risk of forming one within the next few days, heparin is used, because its antithrombotic effect is immediate, whereas that of warfarin is delayed. If long-term anticoagulation is necessary, warfarin can be started as soon as therapeutic anticoagulation with heparin is achieved. After therapeutic anticoagulation with warfarin is achieved, heparin is often continued for 1 to 2 days. This overlap is commonly used because the antithrombotic effect of warfarin can lag behind laboratory measurements of warfarin anticoagulation, which is largely affected by a reduction in the level of factor VII, which has a short t1/2 (Table 26-3). If warfarin is started for prophylaxis of thrombosis, and the short-term risk is not high (e.g., a patient with atrial fibrillation being started on warfarin to lower stroke risk), heparin may be unnecessary. Most experts recommend that loading doses of warfarin should not be used, that is, the patient be started on the anticipated maintenance dose. During the first week of warfarin therapy, the coagulation response should be checked at least twice. Depending on the rapidity and stability of this measure, the time interval between subsequent determinations is gradually increased.

TABLE 26–3 Selected Pharmacokinetic Parameters

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Antiplatelet Drugs

Clinical trials have shown that aspirin reduces the incidence of myocardial infarction and death from cardiac causes by 30% to 50% in patients with unstable angina. Aspirin also significantly reduces the incidence of a first myocardial infarction in men with stable angina and is effective as an antithrombotic agent after coronary angioplasty/stenting or bypass grafting. Aspirin is effective in secondary prevention of myocardial infarction. Aspirin is also recommended for use in patients with transient ischemic attacks. There are, of course, adverse effects of long-term aspirin therapy (see Chapter 36).

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The major problem associated with antithrombotic agents is bleeding, even when used in therapeutic doses. Thrombocytopenia (heparin), drug interactions (warfarin), and platelet aggregation caused by other drugs also pose significant problems (see Clinical Problems Box).

The anticoagulant effect of unfractionated heparin can be reversed rapidly with protamine sulfate, a positively charged molecule that binds avidly to the negatively charged heparin. Rapid reversal of the effect of warfarin can be achieved only by transfusion of plasma containing clotting factors. If the patient is overly anticoagulated with warfarin and is not actively bleeding, anticoagulation can be restored with 24 hours in most patients by small oral doses of vitamin K.

Transient thrombocytopenia is a well recognized, usually asymptomatic complication of heparin therapy. Thrombocytopenia induced by heparin is generally considered clinically significant if the platelet count falls to less than 100 × 109/L. Heparin-induced thrombocytopenia can be mediated by immune and by nonimmune mechanisms, with the immune form involving formation of complexes of heparin, platelet factor 4, and immunoglobulin. Its

CLINICAL PROBLEMS

Heparin

Bleeding, thrombocytopenia, hypersensitivity, transient hypercoagulability when discontinued

Warfarin

Bleeding, drug interactions, some patients are resistant

Streptokinase

Bleeding, immunogenic

Urokinase and Recombinant Tissue Plasminogen Activator

Bleeding, expensive

Aspirin

Dose-dependent gastrointestinal upset, hypersensitivity, Reye’s syndrome in children

Clopidogrel

Bleeding

Glycoprotein IIB/IIIA Inhibitors

Bleeding, thrombocytopenia

Directly Acting Thrombin Inhibitors

Bleeding

Fondaparinux

Bleeding, thrombocytopenia

incidence ranges from 0.3% to 3% in patients exposed to unfractionated heparin for greater than 4 days and is less common with low molecular weight heparins than with unfractionated heparin. It is associated with arterial or venous thrombosis in a small but significant subset of patients and occasionally can be extremely serious and even fatal. Platelet counts should be monitored at regular intervals in patients receiving heparin for prolonged periods. When heparin is discontinued, the platelet count usually returns to normal within 4 days.

Heparin does not cross the placenta and does not produce untoward effects in the fetus. Warfarin crosses the placenta and is a teratogen. Characteristic abnormalities associated with warfarin embryopathy include nasal bridge deformities and abnormal bone formation. Fetal risk from warfarin exposure is greatest during weeks 6 to 12 of development. Any woman with the potential to become pregnant should be advised of warfarin’s potential teratogenic effects and instructed to contact her healthcare provider immediately, if she believes that she may be pregnant.

Because warfarin treatment often extends over months or years, the possibility of drug-drug interactions is high because of a high degree of plasma protein binding and renal elimination. Common warfarin-drug interactions are listed in Box 26-1. Hereditary resistance to warfarin is rare but has been described; those affected require 5 to 20 times the average normal dose.

BOX 26–1 Drug Interactions with Warfarin

Decreased Anticoagulation

Increased warfarin metabolism by cytochrome P450: barbiturates, carbamazepine, griseofulvin, rifampin

Reduced warfarin absorption: cholestyramine

Increased Anticoagulation

Inhibition of warfarin clearance: disulfiram, amiodarone, metronidazole, sulfinpyrazone

Displacement of warfarin from plasma albumin: salicylates, chloral hydrate

Increased clearance of clotting factors: thyroid hormones

Functional Synergism

Inhibition of coagulation: heparin, thrombolytic agents

Inhibition of platelet function: aspirin and other nonsteroidal antiinflammatory drugs, clopidogrel, glycoprotein IIb/IIIa inhibitors

New Horizons

Although the fibrinolytics currently available for the treatment of stroke have yielded success with a limited number of patients, their narrow therapeutic window and frequent occurrence of side effects has led to concerted efforts to develop newer compounds with better benefit/risk ratios. The newer agents such as reteplase have both pharmacokinetic and pharmacodynamic advantages relative to t-PA, and newer developments offer hope for the future, particularly for those patients who do not reach a healthcare professional until hours after the stroke has occurred. Similarly, thrombolytics to treat acute myocardial infarction have their limitations particularly as related to their ability to achieve complete reperfusion without significant bleeding. The new antiplatelet drugs in combination with fibrinolytics and anticoagulants may yield faster lysis of clots and greater flow rates than using a single approach. Clinical trials are underway evaluating such combinations.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are available in the United States.)

Anticoagulants

Heparin Ca++ (Calciparine)

Low molecular weight heparins

Dalteparin (Fragmin)

Enoxaparin (Lovenox)

Nadroparin (Fraxiparin)

Tinzaparin (Innohep)

Bivalirudin (Angiomax)

Fondaparinux (Arixtra)

Lepirudin (Refludan)

Vitamin K1, phytonadione (Aquamephyton)

Warfarin Na+ (Coumadin)

Fibrinolytics

Recombinant tissue plasminogen activator (Activase)

Reteplase (Retavase)

Streptokinase (Streptase, Kabikinase)

Tenecteplase (TNKase)

Urokinase (Abbokinase)

Platelet Function Inhibitors

Abciximab (ReoPro)

Clopidogrel (Plavix)

Eptifibatide (Integrilin)

Tirofiban (Aggrastat)

FURTHER READING

Martínez-Sánchez et al. 2007 Martínez-Sánchez P, Díez-Tejedor E, Fuentes B, et al. Systemic reperfusion therapy in acute ischemic stroke. Cerebrovasc Dis. 2007;24:143-152.

Mukherjee D, Eagle KA. The use of antithrombotics for acute coronary syndromes in the emergency department: Considerations and impact. Prog Cardiovasc Dis. 2007;50:167-180.

McRae SJ, Ginsberg JS. New anticoagulants for venous thromboembolic disease. Curr Opin Cardiol. 2005;20:502-508.

SELF-ASSESSMENT QUESTIONS

1. Heparin:

A. Has thrombolytic activity.

B. Has most prolonged activity when given orally.

C. Acts by binding to antithrombin.

D. Inhibits the aggregation of platelets caused by TXA2.

E. Acts by blocking hepatic vitamin K regeneration.

2. Warfarin:

A. Acts rapidly when given orally.

B. Is potentiated by barbiturates.

C. Is antagonized by protamine sulfate.

D. Affects the activity of clotting factors.

E. Is potentiated by platelet factor 4.

3. The risk of bleeding in patients receiving heparin is increased by aspirin because aspirin:

A. Inhibits heparin anticoagulant activity.

B. Inhibits platelet function.

C. Displaces heparin from plasma protein-binding sites.

D. Inhibits prothrombin formation.

E. Causes thrombocytopenia.

4. In patients taking warfarin, the antithrombotic effect is decreased when they are also given which of the following drugs?

A. Chloral hydrate

B. Heparin

C. Aspirin

D. Cholestyramine

E. Clopidogrel

5. Aspirin can:

A. Prevent formation of TXA2.

B. Prolong whole blood clotting time.

C. Shorten bleeding time.

D. Inhibit fibrinolysis.

E. Inhibit the effects of warfarin.