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									  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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