22 Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs Jeffrey S. Fedan DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Abciximab 263 Eptiﬁbatide 263 Antihemophilic factor 265 Factor VIIa 265 Ardeparin 260 Factor IX concentrate 265 Alteplase 264 Heparin (unfractionated) 259 Aminocaproic acid 265 Heparin (low molecular weight) 260 Anistreplase 265 Lipirudin 262 Anti-inhibitor coagulant complex 265 Phytonadione 261 Antithrombin III 262 Protamine 260 Aprotinin 265 Reteplase 265 Argatroban 262 Streptokinase 264 Aspirin 262 Tenecteplase 265 Bivalirudin 262 Ticlopidine 263 Clopidogrel 263 Tinzaparin 260 Dalteparin 260 Tiroﬁban 263 Danaparoid 260 Tranexamic acid 265 Desmopressin 265 Urokinase 264 Dipyridamole 263 Warfarin 260 Enoxaparin 260 Little intravascular coagulation of blood occurs in HEMOSTATIC MECHANISMS normal physiological conditions. Hemostasis involves Endothelial cells maintain a nonthrombogenic lining in the interplay of three procoagulant phases (vascular, blood vessels. This results from several phenomena, in- platelet, and coagulation) that promote blood clotting to cluding (1) the maintenance of a transmural negative prevent blood loss (Fig. 22.1). The ﬁbrinolytic system electrical charge, which is important in preventing ad- prevents propagation of clotting beyond the site of vas- hesion of circulating platelets; (2) the release of plas- cular injury and is involved in clot dissolution, or lysis minogen activators, which activate the ﬁbrinolytic path- (Fig. 22.2). way; (3) the activation of protein C, which degrades 256 Injury Vascular Phase Vasoconstriction Tissue injury Contact Exposure of blood to subendothelial activation vascular wall matrix Retarded blood flow ADP Tissue factor Circulating platelets VIII:vWF Fibronectin Platelet Phase Shape change Adhesion IIb/IIIa receptor upregulation Release reaction Aggregation Coagulating factors Platelet PL availability aggregate ADP, endoperoxides, TxA2 Activation of intrinsic pathway Activation of extrinsic pathway Intrinsic pathway Extrinsic pathway HMWK, Prek XII ” In tem XI tri Tissue factor ys ns “s ic IX “s ic ys ns PL VII tem tri Coagulation Phase Ex ” VIII Common pathway X V PL Prothrombin II Fibrinogen I XIII Insoluble fibrin FIGURE 22.1 Hemostatic mechanisms showing the relationships among the vascular, platelet, and coagulation phases. Action is denoted by broken arrows, transformation by solid arrows. Circled factors are those that require vitamin K for activity. Proteins C and S, which degrade factors Va and VIIIa and require vitamin K for activity, are not shown. This ﬁgure is a highly simpliﬁed summary; see supplemental reading for further details. PL, platelet phospholipid; HMWK, high , molecular weight kininogen; PreK, prekallikrein; ADP adenosine diphosphate; vWF, Von Willebrand factor; TxA2, thromboxane A2. (Modiﬁed with permission from Wintrobe MM et al. Clinical Hematology (7th ed.). Philadelphia: Lea & Febiger, 1974:390, 422.) 258 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Release Circulating Activation Plasmin Liver t-PA Plasminogen Fibrinogenolysis uptake Plasminogen Factor t-PA iv a t i o n A ct Plasmin Plas Inhibition min 2-antiplasmin e n n og t-PA PAI-1 smi Pla Fibrin A Degradation t-P threads Fibrinolysis Soluble FDP FIGURE 22.2 The ﬁbrinolytic system in blood vessels showing the physiological mechanisms of activation of plasminogen on ﬁbrin to cause ﬁbrinolysis and the pathophysiological mechanism in the blood to cause ﬁbrinogenolysis. The release of t-PA from vascular endothelium and the inhibitory effect of 2-antiplasmin on plasmin activity are depicted. PAI-1, plasminogen activator inhibitor-1; FDP , ﬁbrin degradation products; factor, coagulation factor. (Modiﬁed with permission from Wiman B and Hamsten A. The ﬁbrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Hemost 1990;16:207.) coagulation factors, a process involving thrombin and ane synthetase sequentially convert arachidonic acid its endothelial cofactor (thrombomodulin); (4) the pro- into cyclic endoperoxides and thromboxane A2 (TxA2). duction of heparinlike proteoglycans, which inhibit co- In contrast to endothelial cells, platelets lack PGI2 syn- agulation; and (5) the release of prostacyclin (PGI2), a thetase. Upon platelet activation with mediators of ag- potent inhibitor of platelet aggregation. gregation (ADP, serotonin, TxA2, epinephrine, throm- In normal individuals, injury severe enough to cause bin, collagen, platelet activating factor), the integrin hemorrhage initiates coagulation. Vasoconstriction, platelet receptor for plasma ﬁbrinogen, glycoprotein combined with increased tissue pressure caused by ex- IIb/IIa (GPIIb/IIa), is expressed. The arginine– travasated blood, results in a reduction, or stasis, of glycine–aspartic acid (RDG) tripeptide in the -chain blood ﬂow. Stasis favors the restriction of thrombus of ﬁbrinogen mediates binding of ﬁbrinogen to the formation to the site of injury. The extravasation of GPIIb/IIIa complex. Fibrinogen, forming a bridge be- blood exposes platelets and the plasma clotting factors tween platelets, and the binding of ﬁbrinogen and Von to subendothelial collagen and endothelial basement Willebrand’s factor to activated platelets via GPIIb/IIIa membranes, which result in activation of the clotting are key events in platelet–platelet interactions and play sequence. Several substances that participate in coagu- a major role in thrombus formation. Aggregation of cir- lation are released or become exposed to blood at the culating platelets to those already adherent ampliﬁes site of injury. These include adenosine diphosphate the release reaction. (ADP), a potent stimulus to platelet aggregation, and Other substances liberated from platelets during the tissue factor, a membrane glycoprotein cofactor of fac- release reaction include serotonin (which may promote tor VII. vasospasm in coronary vessels), platelet factor 4 (a ba- Platelet aggregation is the most important defense sic glycoprotein that can neutralize the anticoagulant mechanism against leakage of blood from the circula- action of circulating heparin), platelet-derived growth tion. Ordinarily, unstimulated platelets do not adhere to factor (a mitogen that initiates smooth muscle cell pro- the endothelial cell surface. Following disruption of the liferation and may be involved in atherogenesis), and endothelial lining and exposure of blood to the suben- factors that are also found in the plasma (factor V, fac- dothelial vessel wall, platelets come into contact with tor VIII:vWF, and ﬁbrinogen). During aggregation, the and adhere within seconds to factor VIII:vWF polymers rearrangement of the platelet membrane makes avail- and ﬁbronectin. The platelets change shape and then able a phospholipid surface (platelet factor 3) that along undergo a complex secretory process termed the release with Ca is required for the activation of several clot- reaction. This results in the release of ADP from ting factors. The platelet aggregate becomes a hemostatic platelet granules and activation of platelet phospholi- plug and is the structural foundation for the assembly of pase A2. This enzyme, cyclooxygenase, and thrombox- the ﬁbrin network. 22 Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs 259 COAGULATION SYSTEMS Heparin binds to antithrombin III and induces a con- formational change that accelerates the interaction of Two interrelated processes, the intrinsic and extrinsic antithrombin III with the coagulation factors. Heparin coagulation systems (Fig. 22.1), converge on a common also catalyzes the inhibition of thrombin by heparin co- pathway that leads to the activation of factor X, the for- factor II, a circulating inhibitor. Smaller amounts of mation of thrombin (factor IIa), and the conversion by heparin are needed to prevent the formation of free thrombin of the soluble plasma protein ﬁbrinogen into thrombin than are needed to inhibit the protease activ- insoluble ﬁbrin. The extrinsic pathway appears to be im- ity of clot-bound thrombin. Inhibition of free thrombin portant for initiating ﬁbrin formation, while the intrin- is the basis of low-dose prophylactic therapy. sic pathway is involved in ﬁbrin growth and mainte- nance; both systems constitute the coagulation cascade. Absorption, Metabolism, and Excretion This series of linked and overlapping reactions involves Heparin is prescribed on a unit (IU) rather than mil- conversion of proenzymes (designated by roman nu- ligram basis. The dose must be determined on an indi- merals) into serine proteases (designated by roman nu- vidual basis. Heparin is not absorbed after oral admin- meral followed by the sufﬁx -a), and cofactors that istration and therefore must be given parenterally. speed the protease reactions (factors Va and VIIa). Intravenous administration results in an almost immedi- Exposure of blood to tissue factors activates the ex- ate anticoagulant effect. There is an approximate 2-hour trinsic system, beginning with the proteolytic conversion delay in onset of drug action after subcutaneous admin- of factor VII into factor VIIa. Degradation of factors V istration. Intramuscular injection of heparin is to be and VIII:C by protein C at locations distant from the site avoided because of unpredictable absorption rates, lo- of vascular injury aids in the localization of clot forma- cal bleeding, and irritation. Heparin is not bound to tion. The coagulation cascade is capable of tremendous plasma proteins or secreted into breast milk, and it does ampliﬁcation as the protease reactions progress. Many not cross the placenta. of the activated coagulation factors feed back positively Heparin’s action is terminated by uptake and me- in the extrinsic, intrinsic, and common pathways and ac- tabolism by the reticuloendothelial system and liver and celerate the reactions. Either deﬁciency in a single clot- by renal excretion of the unchanged drug and its de- ting factor or therapy with the drugs described in this polymerized and desulfated metabolite. The relative chapter will result in abnormal hemostasis. proportion of administered drug that is excreted as un- changed heparin increases as the dose increases. Renal insufﬁciency reduces the rate of heparin clearance from ANTICOAGULANT DRUGS the blood. Anticoagulant drugs inhibit the development and en- largement of clots by actions on the coagulation phase. Pharmacological Actions They do not lyse clots or affect the ﬁbrinolytic pathways. The physiological function of heparin is not com- pletely understood. It is found only in trace amounts in Heparin normal circulating blood. It exerts an antilipemic effect by releasing lipoprotein lipase from endothelial cells; Two types of heparin are used clinically. The ﬁrst and heparinlike proteoglycans produced by endothelial older of the two, standard (unfractionated) heparin, is cells have anticoagulant activity. Heparin decreases an animal extract. The second and newer type, called platelet and inﬂammatory cell adhesiveness to endothe- low-molecular-weight heparin (LMWH), is derived lial cells, reduces the release of platelet-derived growth from unfractionated heparin. The two classes are similar factor, inhibits tumor cell metastasis, and exerts an an- but not identical in their actions and pharmacokinetic tiproliferative effect on several types of smooth muscle. characteristics. Therapy with heparin occurs in an inpatient setting. Heparin inhibits both in vitro and in vivo clotting of Standard (Unfractionated) Heparin blood. Whole blood clotting time and activated partial Heparin (heparin sodium) is a mixture of highly elec- thromboplastin time (aPTT) are prolonged in propor- tronegative acidic mucopolysaccharides that contain tion to blood heparin concentrations. numerous N- and O-sulfate linkages. It is produced by and can be released from mast cells and is abundant in Adverse Effects liver, lungs, and intestines. The major adverse reaction resulting from heparin therapy is hemorrhage. Bleeding can occur in the uri- Mechanism of Action nary or gastrointestinal tract and in the adrenal gland. The anticoagulation action of heparin depends on Subdural hematoma, acute hemorrhagic pancreatitis, the presence of a speciﬁc serine protease inhibitor (ser- hemarthrosis, and wound ecchymosis also occur. The pin) of thrombin, antithrombin III, in normal blood. incidence of life-threatening hemorrhage is low but 260 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM variable. Heparin-induced thrombocytopenia of imme- anticoagulant control without laboratory tests. LMWH diate and delayed onset may occur in 3 to 30% of pa- is more effective than standard heparin in preventing tients. The immediate type is transient and may not in- and treating venous thromboembolism. The incidence volve platelet destruction, while the delayed reaction of thrombocytopenia after administration of LMWH is involves the production of heparin-dependent an- lower than with standard heparin. Adverse drug reac- tiplatelet antibodies and the clearance of platelets from tions like those caused by standard heparin have been the blood. Heparin-associated thrombocytopenia may seen during therapy with LMWH, and overdose is be associated with irreversible aggregation of platelets treated with protamine. (white clot syndrome). Additional untoward effects of LMWH is available for subcutaneous administra- heparin treatment include hypersensitivity reactions tion as enoxaparin (Lovenox), dalteparin (Fragmin), (e.g., rash, urticaria, pruritus), fever, alopecia, hypoal- ardeparin (Normiﬂo), and tinzaparin (Innohep). Dana- dosteronism, osteoporosis, and osteoalgia. paroid (Orgaran), a heparinoid composed of heparin sulfate, dermatan sulfate, and chondroitin sulfate, has Contraindications, Cautions, and Drug greater factor Xa speciﬁcity than LMWH. Bleeding due Interactions to danaparoid is not reversed by protamine. Absolute contraindications include serious or active bleeding; intracranial bleeding; recent brain, spinal Orally Effective Anticoagulants cord, or eye surgery; severe liver or kidney disease; dis- secting aortic aneurysm; and malignant hypertension. The orally effective anticoagulant drugs are fat-soluble Relative contraindications include active gastrointesti- derivatives of 4-hydroxycoumarin or indan-1,3-dione, nal hemorrhage, recent stroke or major surgery, severe and they resemble vitamin K. Warfarin is the oral anti- hypertension, bacterial endocarditis, threatened abor- coagulant of choice. The indandione anticoagulants tion, and severe renal or hepatic failure. have greater toxicity than the coumarin drugs. Drugs that inhibit platelet function (e.g., aspirin) or produce thrombocytopenia increase the risk of bleeding Mechanism of Action when heparin is administered. Oral anticoagulants and Unlike heparin, the oral anticoagulants induce hypoco- heparin produce synergistic effects. Many basic drugs agulability only in vivo. They are vitamin K antagonists. precipitate in the presence of the highly acidic heparin Vitamin K is required to catalyze the conversion of the (e.g., antihistamines, quinidine, quinine, phenothiazines, precursors of vitamin K–dependent clotting factors II, tetracycline, gentamicin, neomycin). VII, IX, and X. This involves the posttranslational -car- boxylation of glutamic acid residues at the N-terminal Heparin Antagonist end of the proteins. The -carboxylation step is linked The speciﬁc heparin antagonist protamine can be to a cycle of enzyme reactions involving the active hy- employed to neutralize heparin in cases of serious hem- droquinone form of vitamin K (K1H2). The regeneration orrhage. Protamines are basic low-molecular-weight, of K1H1 by an epoxide reductase is blocked by the oral positively charged proteins that have a high afﬁnity for anticoagulants. These drugs thus cause hypocoagulabil- the negatively charged heparin molecules. The binding ity by inducing the formation of structurally incomplete of protamine to heparin is immediate and results in the clotting factors. formation of an inert complex. Protamine has weak an- Commercial warfarin is a racemic mixture of S- and ticoagulant activity. R-enantiomers; S-warfarin is more potent than R-war- farin. Low-Molecular-Weight Heparin Absorption, Metabolism, and Excretion Low-molecular-weight fragments produced by chemical depolymerization and extraction of standard heparin Warfarin is rapidly and almost completely absorbed af- consist of heterogeneous polysaccharide chains of mo- ter oral administration and is bound extensively lecular weight 2,000 to 9,000. The LMWH molecules ( 95%) to plasma proteins. Since it is the unbound contain the pentasaccharide sequence necessary for drug that produces the anticoagulant effect, displace- binding to antithrombin III but not the 18-saccharide ment of albumin-bound warfarin by other agents may sequence needed for binding to thrombin. Compared to result in bleeding. Although these drugs do not cross the standard heparin, LMWH has a 2- to 4-fold greater an- blood-brain barrier, they can cross the placenta and tifactor Xa activity than antithrombin activity. may cause teratogenicity and hemorrhage in the fetus. LMWH has greater bioavailability than standard Warfarin is inactivated by hepatic P450 isozymes; heparin, a longer-lasting effect, and dose-independent hydroxylated metabolites are excreted into the bile and clearance pharmacokinetics. The predictable relation- then into the intestine. Hepatic disease may potentiate ship between anticoagulant response and dose allows the anticoagulant response. 22 Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs 261 Pharmacological Actions Contraindications, Cautions, and Drug Interactions Warfarin is used both on an inpatient and outpatient basis when long-term anticoagulant therapy is indi- Oral anticoagulants are ordinarily contraindicated in cated. The onset of anticoagulation is delayed, the la- the presence of active or past gastrointestinal ulcera- tency being determined in part by the time required for tion; thrombocytopenia; hepatic or renal disease; malig- absorption and in part by the half-lives of the vitamin nant hypertension; recent brain, eye, or spinal cord sur- K–dependent hemostatic proteins. The anticoagulant ef- gery; bacterial endocarditis; chronic alcoholism; and fect will not be evident in coagulation tests such as pro- pregnancy. These agents also should not be prescribed thrombin time until the normal factors already present in for individuals with physically hazardous occupations. the blood are catabolized; this takes 5 hours for factor Minor hemorrhage caused by oral anticoagulant VII and 2 to 3 days for prothrombin (factor II). The an- overdosage can be treated by discontinuing drug ad- ticoagulant effect may be preceded by a transient pe- ministration. Oral or parenteral vitamin K1 (phytona- riod of hypercoagulability due to a rapid decrease in dione) administration will return prothrombin time to protein C levels. More rapid anticoagulation is pro- normal by 24 hours. This period is required for de novo vided, when necessary, by administering heparin. synthesis of biologically active coagulation factors. Warfarin is administered in conventional doses or Serious hemorrhage may be stopped by administration minidoses to reduce bleeding. The dose range is ad- of fresh frozen plasma or plasma concentrates contain- justed to provide the desired end point. ing vitamin K–dependent factors. Dietary intake of vitamin K and prior or concomi- Adverse Effects tant therapy with a large number of pharmacologically The principal adverse reaction to warfarin is hemor- unrelated drugs can potentiate or inhibit the actions of rhage. Prolonged therapy with the coumarin-type anti- oral anticoagulants. Laxatives and mineral oil may re- coagulants is relatively free of untoward effects. duce the absorption of warfarin. The patient’s pro- Bleeding may be observable (e.g., skin, mucous mem- thrombin time and international normalized ratio branes) or occult (e.g., gastrointestinal, renal, cerebral, (INR) should be monitored when a drug is added or hepatic, uterine, or pulmonary). Rarer untoward effects removed from therapy. Selected drug interactions in- include diarrhea, small intestine necrosis, urticaria, volving oral anticoagulants are summarized in Table alopecia, skin necrosis, purple toes, and dermatitis. 22.1. TA B L E 2 2 . 1 Drug Interactions Involving Oral Anticoagulants Drugs That Increase Oral Anticoagulant Effects Acetaminophen Chloral hydrate Fenoprofen Lovastatin Propranolol Alcohol (acute intoxica- Chlorpropamide Fluconazole Mefenamic acid Quinidine, quinine tion) Chymotrypsin Fluoroquinolones Metronidazole Ranitidine Allopurinol Cimetidine Fluoxetine Micolazole Sulfamethoxazole- Amiodarone Clarithromycin Fluvastatin Nabumetone trimethoprim Anabolic and andro- Cloﬁbrate Gemcitabine Nalidixic acid Sulﬁnpyrazone genic steroids Cotrimoxazole Gemﬁbrozil Naproxen Sulindac Aspirin Dextran Glucagon Omeprazole Tamoxifen Azapropazone Diazoxide Heparin Oral hypoglycemics Ticlopidine Bromelains Diﬂunisal Ibuprofen Pentoxifylline Tolmetin Cephalosporins Disulﬁram Indomethacin Phenylbutazone Tolterodine Carboplatin/Etoposide Ethacrynic acid Inhalation anesthetics Phenytoin Tricyclic antidepressants Celecoxib Felbamate Isoniazid Piroxicam Troglitazone Chenodiol Fenoﬁbrate Levamisole/Fluorouracil Propafenone Vitamin E Drugs That Decrease Oral Coagulant Effects Alcohol (chronic abuse) Barbiturates Dextrothyroxine Nafcillin Sucralfate Aminoglutethimide Carbamazepine Ginseng Oral contraceptives Trazodone Antacids Chlordiazepoxide Griseofulvin Penicillins (large doses) Vitamin K (large doses) Antihistamines Cholestyramine Haloperidol Primidone Azathioprine Corticosteroids Meprobamate Rifampin Oral anticoagulants also may potentiate hypoglycemia caused by oral hypoglycemic agents, and may enhance phenytoin toxicity. 262 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Direct Thrombin Inhibitor Anticoagulants Unstable Angina and Myocardial Infarction Two drugs that are direct inhibitors of thrombin but that do not involve antithrombin III or vitamin K in In patients with unstable angina and severe ischemia re- their mechanism of action have been approved to pro- quiring hospital admission, therapeutic doses of heparin vide intravenous anticoagulation in patients with he- along with antiplatelet therapy (discussed later) are parin-induced thrombocytopenia. Lepirudin (Reﬂudan) thought to provide additive protection of the patient and bivalirudin (Angiomax), which are analogues of the against myocardial reinfarction. Thrombolytic drugs are leech peptide anticoagulant hirudin, bind in a 1:1 com- more effective than anticoagulants in treating coronary plex with thrombin to inhibit its protease activity. thromboembolism and in establishing reperfusion of oc- Argatroban (Acova, Novastan), a synthetic analogue of cluded arteries after an infarction. Anticoagulants in arginine, interacts reversibly with and inhibits throm- combination with antiplatelet drugs reduce the inci- bin’s catalytic site. Both drugs have a short half-life. dence of thrombus formation and reocclusion after Lipuridin is cleared following metabolism and urinary coronary arterial bypass surgery and percutaneous excretion of changed and unchanged drug; hepatic me- coronary angioplasty. tabolism of argatroban is a therapeutic advantage in pa- tients with renal insufﬁciency. No antagonists for these Disseminated Intravascular Coagulation drugs are available. Disseminated intravascular coagulation is characterized by widespread systemic activation of the coagulation CLINICAL INDICATIONS FOR system, consumption of coagulation factors, occlusion of ANTICOAGULANT THERAPY small vessels by a coat of ﬁbrin, and a hypocoagulation state with bleeding. In conjunction with management of Anticoagulant therapy provides prophylactic treatment the underlying factor or factors leading to the disorder of venous and arterial thromboembolic disorders. and coagulation factor and platelet replacement, bleed- Anticoagulant drugs are ineffective against already ing may be managed with intravenous (IV) heparin, formed thrombi, although they may prevent their fur- LMWH, and antithrombin III (Thrombate). ther propagation. Generally accepted major indications for anticoagulant therapy with heparin and warfarin in- clude the following: ANTIPLATELET DRUGS The formation of platelet aggregates and thrombi in ar- Deep Vein Thrombosis terial blood may precipitate coronary vasospasm and Venous stasis resulting from prolonged bed rest, cardiac occlusion, myocardial infarction, and stroke and con- failure, or pelvic, abdominal, or hip surgery may precipi- tribute to atherosclerotic plaque development. Drugs tate thrombus formation in the deep veins of the leg or that inhibit platelet function are administered for the rel- calf and may lead to fatal pulmonary embolism. Heparin atively speciﬁc prophylaxis of arterial thrombosis and may also be used prophylactically following surgery. for the prophylaxis and therapeutic management of myocardial infarction and stroke. After an infarction or stroke, antiplatelet therapy must be initiated within 2 Arterial Embolism hours to obtain signiﬁcant beneﬁt. The antiplatelet Since arterial emboli formation involves platelet aggre- drugs are administered as adjuncts to thrombolytic gation and leukocyte and erythrocyte inﬁltration into the therapy, along with heparin, to maintain perfusion and ﬁbrin network, the treatment and prophylaxis of arterial to limit the size of the myocardial infarction. Recently, thrombi are more difﬁcult. Arterial embolism is treated antiplatelet drugs have found new importance in more successfully with heparin than with the oral antico- preventing thrombosis in percutaneous coronary inter- agulants. Anticoagulants are useful for prevention of sys- vention procedures (angioplasty and stent). Admin- temic emboli resulting from valvular disease (rheumatic istration of an antiplatelet drug increases the risk of heart disease) and from valve replacement. bleeding. Aspirin inhibits platelet aggregation and prolongs bleeding time. It is useful for preventing coronary Atrial Fibrillation thrombosis in patients with unstable angina, as an ad- Restoration of sinus rhythm in atrial ﬁbrillation may junct to thrombolytic therapy, and in reducing recur- dislodge thrombi that have developed as a result of rence of thrombotic stroke. It acetylates and irreversibly stasis in the enlarged left atrium. The risk of stroke and inhibits cyclooxygenase (primarily cyclooxygenase-1) systemic arterial embolism is decreased by anticoagula- both in platelets, preventing the formation of TxA2, and tion in such patients. in endothelial cells, inhibiting the synthesis of PGI2 (see 22 Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs 263 Chapter 26). While endothelial cells can synthesize cy- FIBRINOLYTIC SYSTEM clooxygenase, platelets cannot. The goal of therapy with aspirin is to selectively inhibit the synthesis of platelet The ﬁbrinolytic system (Fig. 22.2) is involved in restrict- TxA2 and thereby inhibit platelet aggregation. This is ac- ing clot propagation in the blood and in the removal of complished with a low dose of aspirin (160 to 325 mg ﬁbrin as wounds heal. Treatment of patients with ﬁbri- per day), which spares the endothelial synthesis of nolytic (thrombolytic) drugs that activate the ﬁbri- PGI2. If ibuprofen is taken concurrently, it will bind re- nolytic system is not a substitute for the anticoagulant versibly to cyclooxygenase and prevent the access of as- drugs. The purpose of thrombolytic therapy is rapid lysis pirin to its acetylation site and thus antagonize the abil- of already formed clots. ity of aspirin to inhibit platelets. Dipyridamole Fibrinolysis is initiated by the activation of the proen- (Persantine), a coronary vasodilator, is a phosphodi- zyme plasminogen (present in clots and in plasma) into esterase inhibitor that increases platelet cyclic adeno- plasmin, a protease enzyme not normally present in sine monophosphate (cAMP) concentrations. It also blood. Plasmin catalyzes the degradation of ﬁbrin. The may potentiate the effect of PGI2, which stimulates conversion of plasminogen to plasmin is initiated nor- platelet adenylate cyclase. However, dipyridamole itself mally by the plasminogen activators, tissue-type plas- has little effect on platelets in vivo. Dipyridamole in minogen activator (t-PA) and single-chain urokinase- combination with warfarin is beneﬁcial in patients with type plasminogen activator (scu-PA). t-PA and scu-PA artiﬁcial heart valves; it is also useful in combination are serine protease enzymes synthesized by the endothe- with aspirin (Aggrenox) for the secondary prevention lium and released into the circulation. The endothelium of stroke. also releases plasminogen activator inhibitor-1 (PAI-1), Ticlopidine (Ticlid) and clopidogrel (Plavix) are which complexes with and inactivates t-PA in the plasma. structurally related drugs that irreversibly inhibit t-PA and scu-PA bind with high afﬁnity to ﬁbrin on platelet activation by blocking speciﬁc purinergic recep- the clot surface. Circulating plasminogen binds to the tors for ADP on the platelet membrane. This action in- plasminogen activator–ﬁbrin complex to form a ternary hibits ADP-induced expression of platelet membrane complex consisting of ﬁbrin, activator, and plasmino- GPIIb/IIIa and ﬁbrinogen binding to activated platelets. gen. Therefore, the speciﬁcity of t-PA and scu-PA bind- Ticlopidine and clopidogrel are useful antithrombotic ing to ﬁbrin normally localizes plasmin protease activity drugs. Oral ticlopidine is indicated for prevention of to thrombi. thrombotic stroke in patients who cannot tolerate as- Circulating plasmin is rapidly neutralized by 2-an- pirin and for patients who have had thrombotic stroke. tiplasmin, a physiological serine protease inhibitor that Inhibition of ADP-induced platelet aggregation occurs forms an inert complex with plasmin. In contrast, ﬁbrin- within 4 days, and the full effect requires approximately bound plasmin is resistant to inactivation by 2-an- 10 days. Ticlopidine is taken with food, is well absorbed, tiplasmin. Under normal circumstances plasma t-PA is binds extensively to plasma proteins, and is metabolized inactive because it is inhibited by PAI-1, while t-PA that by the liver. Gastrointestinal disturbances, neutropenia, is bound to ﬁbrin is unaffected by PAI-1. In addition, and agranulocytosis have been observed. Clopidogrel plasma t-PA has a very rapid turnover in blood (half-life produces fewer side effects than ticlopidine. 5 to 8 minutes). For these reasons, ﬁbrinolysis is nor- Pharmacological agents, such as abciximab (ReoPro), mally restricted to the thrombus. eptiﬁbatide (Integrillin), and tiroﬁban (Aggrastat), that Activation of the ﬁbrinolytic system with throm- interrupt the interaction of ﬁbrinogen and Von bolytic drugs can disturb the balance of these regulatory Willebrand’s factor with the platelet GPIIb/IIIa complex mechanisms and elevate circulating plasmin activity. are capable of inhibiting aggregation of platelets acti- Plasmin has low substrate speciﬁcity and degrades ﬁb- vated by a wide variety of stimuli. These drugs are given rinogen (ﬁbrinogenolysis), plasminogen, and coagula- intravenously. The chimeric monoclonal antibody abcix- tion factors. The systemic unphysiological activation of imab binds to the GPIIb/IIIa complex, preventing inter- the ﬁbrinolytic system with thrombolytic drugs causes actions of ﬁbrinogen and Von Willebrand’s factor with consumption of the coagulation factors, a lytic state, and the integrin receptor. Abciximab is used in conjunction bleeding. with angioplasty and stent procedures and is an adjunct to ﬁbrinolytic therapy (discussed later). Patients who Thrombolytic (Fibrinolytic) Drugs have murine protein hypersensitivity or who have re- Thrombolytic drugs cause lysis of formed clots in both ceived abciximab previously may produce an immune re- arteries and veins and reestablish tissue perfusion. sponse after second administration. Eptiﬁbatide, a cyclic peptide, and tiroﬁban, a small nonpeptide molecule, both Mechanism of Action bind reversibly to the GPIIb/IIIa complex and competi- tively prevent the interaction of the clotting factors with Thrombolytic drugs are plasminogen activators. The this receptor. ideal thrombolytic agent is one that can be administered 264 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM intravenously to produce clot-selective ﬁbrinolysis with- cocci, is an indirectly acting activator of plasminogen. It out activating plasminogen to plasmin in plasma. Older forms a 1:1 complex with plasminogen, which results in (ﬁrst generation) thrombolytic agents are not clot selec- a conformational change and exposure of an active site tive, and appreciable systemic ﬁbrinogenolysis accompa- that can convert additional plasminogen into plasmin. nies successful clot lysis. Newer (second generation) The systemic administration of streptokinase can pro- thrombolytic agents bind to ﬁbrin and activate ﬁbrinoly- duce signiﬁcant lysis of acute deep vein and pulmonary sis more than ﬁbrinogenolysis. Third-generation agents emboli and acute arterial thrombi. Intravenous or intra- have improved ﬁbrin speciﬁcity and pharmacokinetic coronary artery (IC) streptokinase is effective in estab- properties. lishing recanalization after myocardial infarction and in increasing short-term survival. The greatest beneﬁt of Pharmacological Actions and Clinical Uses streptokinase appears to be achieved by early intra- venous drug administration. Complications associated Thrombolytic drugs are indicated for the management of with the administration of streptokinase include hemor- severe pulmonary embolism, deep vein thrombosis, and rhage, pyrexia, and allergic or anaphylactic reactions. arterial thromboembolism and are especially important Patients may be refractory to streptokinase during ther- therapy after myocardial infarction and acute ischemic apy because of preexisting or streptokinase-induced an- stroke. Thrombolysis must be accomplished quickly after tibodies. Streptokinase has two half-lives. The faster one myocardial or cerebral infarction, since clots become (11 to13 minutes) is due to drug distribution and inhibi- more difﬁcult to lyse as they age. Recanalization after ap- tion by circulating antibodies, and the slower one (23 to proximately 6 hours provides diminishing beneﬁt to the 29 minutes) is due to loss of enzyme activity. infarcted area. The incidence of rethrombosis and rein- Urokinase (Abbokinase) is a two-polypeptide chain farction is greater when thrombolytic drugs with shorter serine protease that does not bind avidly to ﬁbrin and that plasma half-lives are used. Concurrent administration directly activates both circulating and ﬁbrin-bound plas- with heparin followed by warfarin, as well as antiplatelet minogen. The plasma half-life of urokinase is approxi- drugs, is advocated to reduce reocclusion. Adjunctive an- mately 10 to 20 minutes. Urokinase is derived from hu- ticoagulant and antiplatelet drugs may contribute to man cells and thus is not antigenic. Urokinase produces a bleeding during thrombolytic therapy. signiﬁcant resolution of recent pulmonary emboli. Adverse Effects Second- and Third-generation The principal adverse effect associated with throm- Thrombolytic Drugs bolytic therapy is bleeding due to ﬁbrinogenolysis or ﬁbrinolysis at the site of vascular injury. Hypo- The principal physiological activator of plasminogen in ﬁbrinogenemia may occur and should be monitored the blood, tissue-type plasminogen activator (t-PA, al- with laboratory tests. At effective thrombolytic doses, teplase) (Activase), has a high binding afﬁnity for ﬁbrin the second- and third-generation agents cause less ex- and produces, after IV administration, a ﬁbrin-selective tensive ﬁbrinogenolysis, but bleeding occurs with a sim- activation of plasminogen. This selectivity is not ab- ilar incidence for all agents. Life-threatening intracra- solute; circulating plasminogen also may be activated nial bleeding may necessitate stoppage of therapy, by large doses or lengthy treatment. After intravenous administration of whole blood, platelets or fresh frozen administration, alteplase is more efﬁcacious than strep- plasma, protamine (if heparin is present), and an an- tokinase in establishing coronary reperfusion. At equief- tiﬁbrinolytic drug (discussed later). fective thrombolytic doses, alteplase causes less ﬁb- rinogenolysis than streptokinase, but bleeding occurs Contraindications with a similar incidence. The rate of rethrombosis after t- PA is greater than after streptokinase, possibly because The contraindications to the use of thrombolytic drugs alteplase is rapidly cleared from the blood (half-life is 5 are similar to those for the anticoagulant drugs. to 10 minutes), and several administrations may be war- Absolute contraindications include active bleeding, car- ranted. Reocclusion may be lessened by administration diopulmonary resuscitation (trauma to thorax is possi- of heparin and antiplatelet drugs. Alteplase is a product ble), intracranial trauma, vascular disease, and cancer. of recombinant DNA technology and consists predomi- Relative contraindications include uncontrolled hyper- nantly of the single-chain form (recombinant human tis- tension, earlier central nervous system surgery, and any sue-type plasminogen activator, rt-PA). Upon exposure known bleeding risk. to ﬁbrin, rt-PA is converted to the two-chain dimer. Two genetically engineered variants of human t-PA First-Generation Thrombolytic Drugs have better pharmacological properties than alteplase. Streptokinase (Streptase, Kabikinase), a nonenzymatic Reteplase (Retavase) contains only the peptide domains protein from Lanceﬁeld group C -hemolytic strepto- required for ﬁbrin binding and protease activity. These 22 Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs 265 changes increase potency and speed the onset of action. following surgery. They also are useful adjuncts to co- Reteplase may penetrate further into the ﬁbrin clot agulation factor replacement during dental surgery in than alteplase. The half-life of the drug remains short, hemophiliac patients. Antiﬁbrinolytic drugs are con- however. Tenecteplase (TNK-tPA) (TNKase) has a traindicated if intravascular coagulation is present. longer half-life than alteplase, binds more avidly to ﬁ- These drugs may cause nausea. brin, and in contrast to many other thrombolytic agents, may be administered as an IV bolus. Anistreplase (Eminase) consists of streptokinase in a Agents for Controlling Blood Loss noncovalent 1:1 complex with plasminogen. Anistreplase is catalytically inert because of acylation of the catalytic Cardiopulmonary bypass, with extracorporeal circula- site of plasminogen. However, the afﬁnity of plasmino- tion during cardiac artery bypass graft or heart valve re- gen binding to ﬁbrin is maintained. It has a long catalytic placement surgery, causes transient hemostatic defects half-life (90 minutes), and the time required for nonen- in blood cells and perioperative bleeding. The protease zymatic deacylation lengthens its thrombolytic effect af- inhibitor aprotinin (Trasylol) inhibits kallikrein (coagu- ter IV injection. Anistreplase is more effective than lation phase) and plasmin (ﬁbrinolysis) and protects streptokinase in establishing coronary reperfusion, but it platelets from mechanical injury. The overall effect after causes considerable ﬁbrinogenolysis and is antigenic. infusion is a decrease in bleeding. Several biological agents are used intravenously to maintain coagulability in the face of factor deﬁciencies Antiﬁbrinolytic Drugs in hemophilia or Von Willebrand’s disease patients. Hyperplasminemia resulting from thrombolytic therapy Manufacture of these substances involves extraction exposes ﬁbrinogen and other coagulation factors, plas- from human blood or recombinant technology. They in- minogen, and 2-antiplasmin to nonspeciﬁc proteolysis clude antihemophilic factor (factor VIII) (Alphanate, by plasmin, a process normally regulated by 2-antiplas- Bioclate, others) for hemophilia A patients, factor IX min. Consumption of these factors and extensive ﬁbrin concentrate (Bebulin, AlphaNine, Mononine, others) dissolution leads to hemorrhage. The binding of plas- for hemophilia B patients, and factor VIIa (NovoSeven) minogen to ﬁbrin involves interactions with lysine- for hemophilia and Von Willebrand patients. An in- binding sites in plasminogen. These interactions are crease in factor VIII levels by desmopressin (DDAVP, blocked by antiﬁbrinolytic drugs such as aminocaproic Concentraid, others), an analog of vasopressin, is useful acid (Amicar) and tranexamic acid (Cyklokapron); for managing bleeding in hemophilia A and mild Von plasminogen activation primarily and plasmin prote- Willebrand’s disease patients. Anti-inhibitor coagulant olytic activity are inhibited. complex (Autoplex, FEIBA) provides activated vitamin In addition to being an antidote to ﬁbrinogenoly- K–dependent clotting factors to return coagulability to sis during thrombolytic therapy, antiﬁbrinolytic drugs the blood in hemophilia patients and other patients are used orally and intravenously to control bleeding with acquired inhibitors to clotting factors. 266 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Study Questions 1. Which of the following statements describe why ANSWERS warfarin is not used to prevent blood coagulation in 1. B. Warfarin does not produce an anticoagulant blood collection devices used at blood donating effect in vitro. It inhibits coagulation of blood only centers? in vivo, because the effect depends upon warfarin’s (A) Warfarin does not bind to plastic tubing or effect in the liver on the production of clotting fac- glass. tors. Warfarin does not require conversion into an (B) The anticoagulant effect of warfarin occurs active drug. It inhibits the post-ribosomal carboxy- only in vivo. lation of glutamic acid residues in the vitamin (C) Warfarin is a prodrug, which must be activated K-dependent clotting factors. Therefore, heparin in the liver into the active compound. rather than warfarin is used when blood is collected (D) The gastric enzymes needed to convert R- from donors and stored. warfarin into S-warfarin are unstable near plastic. 2. D. Warfarin is metabolized in the liver by P450 (E) Warfarin is chemically unstable and is de- enzyme system and is appreciably metabolized be- graded unless made fresh and used immediately. fore it is eliminated. Adverse drug reactions are 2. All of the following statements about warfarin are seen in patients taking warfarin if a second drug dis- true EXCEPT which one? places warfarin from its protein binding sites in the (A) An adverse drug reaction may occur if war- blood or induces or inhibits the hepatic P450 sys- farin is displaced from plasma protein binding sites. tem. Warfarin can cross the placenta and exert anti- (B) Warfarin crosses the placenta. coagulant and other effects in the fetus at normal (C) Drugs that are metabolized by the liver can al- doses given to the mother. ter the anticoagulant effect of warfarin. 3. B. Thrombocytopenia is a frequent side effect as- (D) Warfarin is eliminated from the body un- sociation with heparin. This reduction in the level of changed in the urine. circulating platelets increases bleeding. Purple toes (E) Warfarin is a vitamin K antagonist. are encountered during warfarin therapy. Heparin 3. Which of the following is an adverse effect associ- may be administered to pregnant mothers without ated with pharmacotherapy using heparin? risk to the fetus. Heparin requires antithrombin III (A) An increase in the number of circulating for its anticoagulant action, but does not increase platelets the level of this protein in the blood. (B) Thrombocytopenia 4. C. Aspirin inhibits platelet cyclooxygenase. (C) Purple toe syndrome Abciximab, a monoclonal antibody, binds to and in- (D) Teratogenicity to the fetus hibits the platelet glycoprotein IIb/IIIa receptor. (E) An increase in the circulating level of an- Dipyridamole inhibits platelet cyclic AMP phospho- tithrombin III diesterase and raises cyclic AMP levels. Eptiﬁbatide 4. Which of the following is a drug that blocks the binds to the glycoprotein IIb/IIIa complex. ADP receptor on the antiplatelet membrane? 5. C. Reteplase binds to ﬁbrin to cause a selective (A) Aspirin activation of ﬁbrin-bound plasminogen. All ﬁbri- (B) Abciximab nolytic drugs are administered IV. Streptokinase is (C) Dipyridamole antigenic, whereas reteplase is not. (D) Clopidogrel Thrombocytopenia is not normally caused by (E) Eptiﬁbatide thrombolytic drugs. 5. The thrombolytic drug reteplase is improved over older drugs like streptokinase in what respect? (A) Reteplase may be taken orally. SUPPLEMENTAL READING (B) Reteplase is antigenic. Bennett JS. Novel platelet inhibitors. Annu Rev Med (C) Reteplase binds to ﬁbrin. 2001;52:161–184. (D) Bleeding does not occur with reteplase. Collen D. The plasminogen (ﬁbrinolytic) system. (E) Reteplase produces less thrombocytopenia. Thromb Haemost 1999;82:259–270. 22 Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs 267 Diener HC. Stroke prevention: Antiplatelet and an- Mannucci PM and Poller L. Venous thrombosis and an- tithrombolytic therapy. Haemostasis 2000;30:14–26. ticoagulant therapy. Br J Haematol Ferguson JJ and Zaqqa M. Platelet glycoprotein 2001;14:258–270. IIb/IIIa receptor antagonists: Current concepts and Mousa SA. Antiplatelet therapies: Recent advances in future directions. Drugs 1999;58:965–982. the development of platelet glycoprotein IIb/IIIa Goldhaber SZ. A contemporary approach to throm- antagonists. Curr Interv Cardiol Rep bolytic therapy for pulmonary embolism. Vasc Med 1999;1:243–252. 2000;5:115–123. Shord SS and Lindley CM. Coagulation products and Hirsh J et al. Oral anticoagulants: Mechanism of action, their uses. Am J Health Syst Pharm clinical effectiveness, and optimal therapeutic range. 2000;57:1403–1417. Chest 2001;19:8S–21S. Sinnaeve P and Van de Werf F. Thrombolytic therapy: Hirsh J et al. Heparin and low-molecular-weight hep- State of the art. Thromb Res 2001;103:S71–79. arin: Mechanisms of action, pharmacokinetics, dos- Verstraete M. Third-generation thrombolytic drugs. Am ing, monitoring, efﬁcacy, and safety. Chest J Med 2000;109:52–58. 2001;119:64S–94S. Vorchheimer DA. Current state of thrombolytic ther- Lever R and Page CP. Novel drug development oppor- apy. Curr Cardiol Rep 1999;1:212–220. tunities for heparin. Nature Rev Drug Disc Weitz JI. Low-molecular-weight heparins. N Engl J 2002;1:140–148. Med 1997;337:688–698. Levine GN, Ali MN, and Schafer AI. Antithrombotic therapy in patients with acute coronary syndromes. Arch Intern Med 2001;61:937–948. Case Study Treatment of Thrombosis A 23-year old pregnant woman who has been ad- ministered IV heparin for treatment of deep vein thrombosis has developed heparin-induced ANSWER: Treatment of thrombosis can be initiated during pregnancy with infusion of argatroban, a di- rect inhibitor of thrombin. This drug does not cross thrombocytopenia. Altering therapy by removing the placenta and has not been reported to produce heparin and adding warfarin is not a viable option, effects in the fetus. Argatroban is discontinued at because warfarin can cross the placenta and exert the time of delivery, and thrombosis is then man- an anticoagulant effect in the fetus. Suggest a treat- aged postpartum for 2 months with warfarin. ment approach.
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