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    II-128 J ENDOVASC THER

    2004;11(Suppl II):II-128–II-133

     2004 by the INTERNATIONAL SOCIETY OF  ENDOVASCULAR  SPECIALISTS   Available at www.jevt.org 

    REVIEW  

    A History of Thrombolytic Therapy

    Kenneth Ouriel, MD

    Department of Vascular Surgery, The Cleveland Clinic Foundation,Cleveland, Ohio, USA.

     

    Thrombolytic therapy has been available for the last 5 decades, but the modern era of 

    thrombolysis began in the early 1990s, with the execution of 3 multicenter trials designed

    to compare this potentially less invasive therapy to the then standard of care for acute

    limb ischemia, open surgical revascularization. Even with the development of several bio-

    engineered lytic agents, the major risk of thrombolytic therapy continues to be bleeding

    complications. Nevertheless, data exist to suggest that thrombolysis should be considered

    as an adjunct to open surgery, percutaneous interventions, or, occasionally, as sole therapyfor acute vascular occlusion. This review summarizes the developmental milestones in the

    history of thrombolysis and reviews data supporting its use in acute arterial occlusions.

    J Endovasc Ther 2004;11(Suppl II):II-128–II-133 

    Key words:  thrombosis, thrombolytic therapy, peripheral arteries, occlusion, streptokinase,

    urokinase, reteplase, tenecteplase

     

    Address for correspondence and reprints: Kenneth Ouriel, MD, Chairman, Division of Surgery, DeskE32, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195 USA. Fax: 1-216-445-6302; E-mail:  [email protected] 

    Thrombolytic therapy, which offers a poten-

    tially less invasive option for the treatment of 

    patients with peripheral arterial and venous

    occlusions, has gained prominence as an ini-

    tial intervention, infusing thrombolytic agentsdirectly into the occluding thrombus via a

    catheter-directed approach. Agents such as

    urokinase, alteplase, and reteplase can recan-

    alize occluded vessels, in many cases allow-

    ing the clinician to identify and address the

    culprit lesions responsible for the occlusion.

    Oftentimes, an endovascular procedure, e.g.,

    balloon dilation of a vein graft stenosis or

    stenting of a common iliac venous web, can

    be performed to minimize the risk of reocclu-

    sion. In other cases where open surgical in-

    tervention is still necessary, the procedure

    can be performed on an elective basis in awell-prepared patient.

    While intellectually attractive, thrombolytic

    therapy has been criticized on the basis of a

    high reocclusion rate, prohibitive cost, and in-

    ferior long-term patency.1,2 Some of the criti-

    cisms were based on a misunderstanding of 

    therapeutic expectations. The need for sub-

    sequent intervention to address unmasked le-

    sions was often neglected. Experience has

    demonstrated that thrombolysis must be fol-lowed by definitive therapy to address the

    culprit lesion that caused the occlusion. In

    fact, when no such lesion can be found, the

    risk of early rethrombosis is unacceptably

    high. As testimony to this caveat, Sullivan et

    al.3 observed post-thrombolytic 2-year paten-

    cy rates of 79% in bypass grafts with flow-

    limiting lesions corrected by angioplasty or

    surgery versus only 9.8% in grafts without

    such lesions.

    EARLY DEVELOPMENT OFTHROMBOLYTIC THERAPY

    The history of thrombolytic therapy begins in

    1933, when Tillett and Garner4 at the Johns

    Hopkins Medical School discovered that fil-

    trates of broth cultures of certain strains of 

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    hemolytic   Streptococcus   bacteria could dis-

    solve fibrin clot. This byproduct, originally

    termed streptococcal fibrinolysin, was crude

    and impure, so clinical use awaited adequate

    purification. Tillett and Sherry5 administeredstreptokinase (SK) intrapleurally to dissolve

    loculated hemothoraces in the late 1940s, but

    intravascular administration was not attempt-

    ed until the following decade, when Tillett’s

    group injected a concentrated and partially

    purified SK (Varidase; Lederle Laboratories,

    Wayne, NJ, USA) into 11 volunteers. The

    study was intended to gain data on the safety

    of the agent; in no case was the SK adminis-

    tered to dissolve pathological thrombi. Fever

    and hypotension developed as the amount of 

    SK approached therapeutic levels. Whereas

    fever was generally mild and controllable

    with antipyretics, hypotension was some-

    times prominent. The mean fall in systolic

    pressure was 31 mmHg, and 3 of the patients

    manifested systolic pressures   80 mmHg.

    These untoward reactions were more likely a

    result of contaminants in the preparation rath-

    er than the SK itself. Despite these reactions,

    systemic proteolysis was observed, with a de-

    crease in fibrinogen and plasminogen and an

    increase in the prothrombin time.

    These early studies were followed by re-

    ports on the use of SK in patients with oc-cluding vascular thrombi. In 1956, E. E. Cliff-

    ton at the Cornell University Medical College

    in New York was responsible for the first brief 

    description of the clinical effectiveness of in-

    travascular thrombolytic administration.7 The

    following year, Cliffton8 published his results

    in 40 patients with occlusive thrombi treated

    with an SK-plasminogen in combination. The

    location of the occlusions was diverse: pe-

    ripheral arterial thrombi, venous thrombi, pul-

    monary emboli, retinal occlusions, and occlu-

    sive carotid thrombi in 2 patients. Cliffton’s

    clinical results were far from exemplary; re-canalization was not uniform, and bleeding

    complications were frequent. Nevertheless,

    he must be credited with the first use of 

    thrombolytic agents for the treatment of path-

    ological thrombi, as well as with the first cath-

    eter-directed administration of a thrombolytic

    agent.

    These early studies were followed by the

    larger retrospective series of the 1970s and

    1980s. Dotter and colleagues9 followed the

    lead of Cliffton, employing a regional ap-

    proach to thrombolytic administration. Strep-

    tokinase was the agent administered accord-

    ing to a low-dose protocol. In theory, such anapproach should have been associated with a

    lower rate of complications, but this was not

    the case.10 Bleeding was all too frequent, pos-

    sibly occurring as a result of the intense sys-

    temic proteolytic state that was common de-

    spite local administration.11

    The fibrinolytic potential of human urine

    was first described by Macfarlane and Pilling

    in 1947.12 The active molecule was extracted,

    isolated, and named ‘‘urokinase’’ (UK) in

    1952.13 The high-molecular-weight form pre-

    dominates in UK isolated from urine, while

    the low-molecular-weight form is found in UK

    obtained from tissue culture of kidney cells.

    Unlike SK, UK directly activates plasminogen

    to form plasmin; prior binding to plasmino-

    gen or plasmin is not necessary for activity.

    Also in contrast to SK, preformed antibodies

    to UK are not observed. The agent is nonan-

    tigenic, and untoward reactions of fever or

    hypotension are rare.

    The most commonly employed UK in the

    US has been of tissue-culture origin, manu-

    factured from human neonatal kidney cells

    (Abbokinase; Abbott Laboratories, AbbottPark, IL, USA). UK has been fully sequenced,

    and a recombinant form of UK (rUK) was test-

    ed in a single trial of patients with acute myo-

    cardial infarction (MI) and in two multicenter

    trials of patients with peripheral arterial occlu-

    sion.14 rUK is fully glycosylated, since it is de-

    rived from a murine hybridoma cell line. rUK

    differs from Abbokinase in several respects:

    rUK has a higher molecular weight than Ab-

    bokinase and a shorter half-life than its low-

    molecular-weight counterpart. Despite these

    differences, however, the clinical effects of the

    two agents have been quite similar.A precursor of UK was discovered in urine

    in 1979.15 Prourokinase was characterized and

    subsequently manufactured by recombinant

    technology using   Escherichia coli   (nonglyco-

    sylated) or mammalian cells (fully glycosylat-

    ed). This single-chain form is an inactive zy-

    mogen, inert in plasma but activated by

    kallikrein or plasmin to form active 2-chain

    UK, which accounts for amplification of the

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    fibrinolytic process. As plasmin is generated,

    more prourokinase is converted to active uro-

    kinase, and the process is repeated. Prouro-

    kinase is relatively fibrin-specific, that is, its

    fibrin degrading (fibrinolytic ) activity greatlyoutweighs its fibrinogen degrading (fibrino- 

    genolytic ) activity. This feature is explained

    by the preferential activation of fibrin-bound

    plasminogen found in a thrombus over the

    free plasminogen in flowing blood. Nonselec-

    tive activators such as SK and UK activate

    free and bound plasminogen equally and in-

    duce systemic plasminemia, with resultant fi-

    brinogenolysis and degradation of factors V

    and VII.

    Given the potential advantages of prouro-

    kinase over urokinase, Abbott Laboratories

    produced a recombinant form of prourokina-

    se (r-proUK) from a murine hybridoma cell

    line. Named Prolyse, this recombinant agent

    is converted to active 2-chain UK by plasmin

    and kallikrein. Prolyse has been studied in the

    settings of MI, stroke, and peripheral arterial

    occlusion. To date, it appears that r-proUK of-

    fers the advantages associated with an agent

    that does not originate from a human cell

    source.

    McNamara and Fischer16 were the first to

    describe the use of urokinase for local throm-

    bolytic treatment, using a high-dose protocolfeaturing graded, stepwise reductions in dose

    as the infusion progressed. For the first time,

    clinicians felt comfortable with the risk-bene-

    fit equation when treating patients with

    thrombolytic agents. McNamara’s work set

    the scene for the large randomized trials of 

    the 1990s, many of which employed doses

    similar to those initially investigated by Dr.

    McNamara.

    Tissue plasminogen activator (tPA), origi-

    nally developed in the mid 1980s for acute

    coronary artery occlusion, is a naturally oc-

    curring fibrinolytic agent produced by endo-thelial cells and is intimately involved in the

    balance between intravascular thrombogen-

    esis and thrombolysis. Natural tPA is a single-

    chain (527 amino acid) serine protease, and

    in contrast to most serine proteases (e.g., uro-

    kinase), the single-chain form has significant

    activity. tPA has potential benefits over other

    thrombolytic agents. For one, the agent ex-

    hibits significant   fibrin specificity ; in plasma,

    the agent is associated with little plasmino-

    gen activation. At the site of the thrombus,

    however, the binding of tPA and plasminogen

    to the fibrin surface induces a conformational

    change in both molecules, greatly facilitatingthe conversion of plasminogen to plasmin

    and dissolution of the clot. tPA also manifests

    the property of   fibrin affinity,   that is, it binds

    strongly to fibrin. Other fibrinolytic agents,

    such as prourokinase, do not demonstrate fi-

    brin affinity.

    Recombinant tPA (rtPA) was produced in

    the 1980s after molecular cloning techniques

    were used to express human tPA DNA.17 Ac-

    tivase (Genentech, Inc., South San Francisco,

    CA, USA), a predominantly single-chain form

    of rtPA, was eventually approved in the US for

    the indications of acute MI and massive pul-

    monary embolism. rtPA has been studied ex-

    tensively in the setting of coronary occlusion.

    In the GUSTO-I study of 41,000 patients with

    acute MI, rtPA was more effective than SK in

    achieving vascular patency.18 Despite a slight-

    ly greater risk of intracranial hemorrhage with

    rtPA, overall mortality was significantly re-

    duced.

    In an effort to lengthen the duration of bio-

    availability of tPA, the molecule was system-

    atically bioengineered.19 Initial investigations

    identified regions in kringle-1 and the prote-ase portion of tPA, which mediated hepatic

    clearance, fibrin specificity, and resistance to

    plasminogen activator inhibitor. Three sites

    were modified to create TNK-tPA, a novel

    molecule with a greater half-life and fibrin

    specificity. The longer half-life of TNK-tPA al-

    lowed successful administration as a single

    bolus, in contrast to the infusion required for

    rtPA. In addition, TNK-tPA manifests greater

    fibrin specificity than rtPA, resulting in less fi-

    brinogen depletion. In studies of acute coro-

    nary occlusion, TNK-tPA performed at least as

    well as rtPA, concurrent with greater ease of administration.20

    Similar to TNK-tPA, the novel recombinant

    plasminogen activator reteplase comprises

    the kringle-2 and protease domains of tPA.21

    Reteplase was developed with the goal of 

    avoiding the necessity of a continuous intra-

    venous infusion, thereby simplifying ease of 

    administration. Reteplase (Retavase; Cento-

    cor, Malvern, PA, USA), produced in   Esche- 

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    FigureThirty-day outcome measures from the

    STILE data.

    richia coli   cells, is nonglycosylated, demon-

    strating a lower fibrin-binding activity and a

    diminished affinity to hepatocytes. This latter

    property accounts for a longer half-life than

    rtPA, potentially enabling bolus injection ver-sus prolonged infusion. Similar to UK, the fi-

    brin affinity of reteplase was only 30% of that

    exhibited with tPA. The decrease in fibrin af-

    finity was hypothesized to reduce the inci-

    dence of distant bleeding complications in a

    manner similar to that of SK over rtPA in the

    GUSTO trial.18 In fact, several properties of re-

    teplase may account for a decreased risk of 

    hemorrhage, including poor lysis of older,

    platelet-rich clots.22 Reteplase has been stud-

    ied in several small trials, and its safety and

    efficacy appear to be similar to alteplase.23–25

    THROMBOLYSIS FOR PERIPHERALARTERIAL OCCLUSION

    The modern era of thrombolytic therapy be-

    gan with the organization and execution of 3

    multicenter trials designed to compare this

    potentially less invasive therapy to the then

    standard of care for acute limb ischemia,

    open surgical revascularization. The first

    study, the Rochester series, compared uroki-

    nase to primary operation in a single-center

    experience of 114 patients presenting withwhat has subsequently been called ‘‘hyper-

    acute ischemia.’’26 Enrolled patients in this tri-

    al all had severely threatened limbs (Ruther-

    ford category IIb) with mean symptom

    duration of 2 days. After 12 months, 84% of 

    patients randomized to UK were alive com-

    pared to only 58% of patients allocated to pri-

    mary operation. By contrast, the rate of limb

    salvage was identical at 80%. A closer inspec-

    tion of the raw data revealed that the defining

    variable for mortality differences was the de-

    velopment of cardiopulmonary complications

    during the periprocedural period. The rate of long-term mortality was high when cardio-

    pulmonary sequelae occurred but was rela-

    tively low when they did not. It was only the

    fact that these complications occurred more

    commonly in patients taken directly to the op-

    erating theater that explained the greater

    long-term mortality in the operative group.

    The second prospective, randomized anal-

    ysis of thrombolysis versus surgery was the

    Surgery or Thrombolysis for the Ischemic

    Lower Extremity (STILE) trial.27 Genentech,

    the manufacturer of the Activase brand of 

    rtPA, funded the study. At its termination, 393

    patients had been randomized to rtPA, uroki-

    nase, or primary operation. Subsequently, the

    2 thrombolytic groups were combined for

    purposes of data analysis when the outcome

    was found to be similar. While composite un-

    toward events were more frequent in throm-

    bolytic patients, the more relevant and objec-

    tive endpoints of amputation and death were

    equivalent (Figure). In separate subgroup

    analyses of the STILE data, one relating to na-

    tive artery occlusions28 and another to bypass

    graft occlusions,29

    thrombolysis appearedmore effective in patients with graft occlu-

    sions. The rate of major amputation was high-

    er in native arterial occlusions treated with

    thrombolysis (10% versus 0% surgery at 1

    year; p0.0024). By contrast, amputation was

    lower in patients with acute graft occlusions

    treated with thrombolysis (p0.026). These

    data suggest that thrombolysis may be of 

    greatest benefit in patients with acute bypass

    graft occlusions  14 days old.

    The third and final randomized comparison

    of thrombolysis and surgery was the Throm-

    bolysis Or Peripheral Arterial Surgery (TO-PAS) trial, funded by Abbott Laboratories. Fol-

    lo win g c omp le tio n o f a p re lim in ar y

    dose-ranging trial in 213 patients,30 544 pa-

    tients were randomized to a recombinant

    form of UK or primary operative interven-

    tion.31 After a mean 1-year follow-up, the rate

    of amputation-free survival was identical in

    the 2 treatments: 68.2% in the urokinase

    group and 68.8% in the surgical patients.

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    While this trial failed to document improve-

    ment in survival or limb salvage with throm-

    bolysis, fully 31.5% of the thrombolytic pa-

    tients were alive without amputation at 6

    months after nothing more than a percuta-neous procedure. After 1 year, this number

    had decreased only slightly, with 25.7% alive

    without amputation and with only percuta-

    neous interventions. Thus, the original goal of 

    the TOPAS trial, to generate data on which

    regulatory approval of recombinant UK would

    be based, was not achieved. Nevertheless,

    the findings confirmed that acute limb ische-

    mia could be managed with catheter-directed

    thrombolysis, achieving amputation and mor-

    tality rates similar to surgery but avoiding the

    need for open procedures in a significant per-

    centage of patients.

    REFERENCES

    1. Faggioli GL, Peer RM, Pedrini L, et al. Failure

    of thrombolytic therapy to improve long-term

    vascular patency.   J Vasc Surg.   1994;19:289–

    296.

    2. Korn P, Khilnani NM, Fellers JC, et al. Throm-

    bolysis for native arterial occlusions of the low-

    er extremities: clinical outcome and cost.   J 

    Vasc Surg.  2001;33:1148–1157.

    3. Sullivan KL, Gardiner GA, Kandarpa K, et al.

    Efficacy of thrombolysis in infrainguinal by-

    pass grafts.  Circulation.   1991;83(2 Suppl):I99–

    105.

    4. Tillett WS, Garner RL. The fibrinolytic activity

    of hemolytic streptococci.  J Exp Med.  1933;58:

    485.

    5. Tillett WS, Sherry S. The effect in patients of 

    streptococcal fibrinolysin (streptokinase) and

    streptococcal desoxyribonuclease on fibrinous,

    purulent, and sanguinous pleural exudations. J 

    Clin Invest.  1949;28:173.

    6. Tillett WS, Johnson AJ, McCarty WR. The in-

    travenous infusion of the streptococcal fibri-

    nolytic principle (streptokinase) into patients. J Clin Invest.  1955;34:169–185.

    7. Cliffton EE, Grunnet M. Investigations of intra-

    venous plasmin (fibrinolysin) in humans.   Cir- 

    culation. 1956;14:919.

    8. Cliffton EE. The use of plasmin in humans. Ann 

    N Y Acad Sci.  1957;68:209–229.

    9. Dotter CT, Rösch J, Seaman AJ. Selective clot

    lysis with low-dose streptokinase.   Radiology.

    1974;111:31–37.

    10. van Breda A, Robison JC, Feldman L, et al. Lo-

    cal thrombolysis in the treatment of arterial

    graft occlusions.  J Vasc Surg.  1984;1:103–112.

    11. Graor RA, Risius B, Denny KM, et al. Local

    thrombolysis in the treatment of thrombosed

    arteries, bypass grafts, and arteriovenous fis-tulas.  J Vasc Surg.  1985;2:406–414.

    12. Macfarlane RG, Pilling JJ. Fibrinolytic activity

    of normal urine.  Nature.  1947;159:779.

    13. Sobel GW, Mohler SR, Jones NW, et al. Uro-

    kinase: an activator of plasma fibrinolysin ex-

    tracted from urine.   Am J Physiol.   1952;171:

    768–769.

    14. Credo RB, Burke SE, Barker WM, et al. Recom-

    binant urokinase (r-UK): biochemistry, phar-

    macology, and clinical experience. In: Sasa-

    hara AA, Loscalzo J, eds.   New Therapeutic 

    Agents in Thrombosis and Thrombolysis. New

    York: Marcel Dekker, Inc.; 1997:513–537.

    15. Husain SS, Lipinski B, Gurewich V. Isolation of plasminogen activators useful as therapeutic

    and diagnostic agents (single-chair, high-fibrin

    affinity urokinase). US patent 4,381,346. 1979.

    16. McNamara TO, Fischer JR. Thrombolysis of 

    peripheral arterial and graft occlusions: im-

    proved results using high-dose urokinase. AJR 

    Am J Roentgenol.  1985;144:769–775.

    17. Hoylaerts M, Rijken DC, Lijnen HR, et al. Kinet-

    ics of the activation of plasminogen by human

    tissue plasminogen activator. Role of fibrin.   J 

    Biol Chem.  1982;257:2912–2919.

    18. The GUSTO Investigators. An international

    randomized trial comparing four thrombolytic

    therapies for acute myocardial infarction.   N Engl J Med.  1993;329:673–682.

    19. Keyt BA, Paoni NF, Refino CJ, et al. A faster-

    acting and more potent form of tissue plasmin-

    ogen activator.  Proc Natl Acad Sci USA.  1994;

    91:3670–3674.

    20. Cannon CP, McCabe CH, Gibson CM, et al.

    TNK-tissue plasminogen activator in acute

    myocardial infarction. Results of the Throm-

    bolysis in Myocardial Infarction (TIMI) 10A

    dose-ranging trial.   Circulation.   1997;95:351–

    356.

    21. Martin U. Clinical and preclinical profile of the

    novel recombinant plasminogen activator re-teplase. In: Sasahara AA, Loscalzo J, eds.  New 

    Therapeutic Agents in Thrombosis and Throm- 

    bolysis.   New York: Marcel Dekker, Inc.; 1997:

    495–511.

    22. Meierhenrich R, Carlsson J, Seifried E, et al.

    Effect of reteplase on hemostasis variables:

    analysis of fibrin specificity, relation to bleed-

    ing complications and coronary patency.   Int J 

    Cardiol.  1998;65:57–63.

    23. Ouriel K, Katzen B, Mewissen M, et al. Retepla-

  • 8/18/2019 History Thrombolytics

    6/6

    J ENDOVASC THER

    2004;11(Suppl II):II-128–II-133

    10 YEARS OF THROMBOLYTIC THERAPY

    Ouriel

    II-133

    se in the treatment of peripheral arterial and

    venous occlusions: a pilot study.   J Vasc Interv 

    Radiol. 2000;11:849–854.

    24. McNamara TO, Dong P, Chen J, et al. Bleeding

    complications associated with the use of rt-PAversus r-PA for peripheral arterial and venous

    thromboembolic occlusions.   Tech Vasc Interv 

    Radiol. 2001;4:92–98.

    25. Mewissen MW. Catheter-directed thrombolysis

    for lower extremity deep vein thrombosis. Tech

    Vasc Interv Radiol.  2001;4:111–114.

    26. Ouriel K, Shortell CK, DeWeese JA, et al. A

    comparison of thrombolytic therapy with op-

    erative revascularization in the initial treatment

    of acute peripheral ischemia.   J Vasc Surg.

    1994;19:1021–1030.

    27. Results of a prospective randomized trial eval-

    uating surgery versus thrombolysis for ische-

    mia of the lower extremity: the STILE trial.  Ann 

    Surg. 1994;220:251–268.

    28. Weaver FA, Comerota AJ, Youngblood M, et al.

    Surgical revascularization versus thrombolysis

    for nonembolic lower extremity native artery

    occlusions: results of a prospective random-

    ized trial. The STILE Investigators.  J Vasc Surg.1996;24:513–523.

    29. Comerota AJ, Weaver FA, Hosking JD, et al.

    Results of a prospective, randomized trial of 

    surgery versus thrombolysis for occluded low-

    er extremity bypass grafts.   Am J Surg.   1996;

    172:105–112.

    30. Ouriel K, Veith FJ, Sasahara AA. Thrombolysisor peripheral arterial surgery: phase I results.

    TOPAS Investigators. J Vasc Surg. 1996;23:64–

    75.

    31. Ouriel K, Veith FJ, Sasahara AA. A comparison

    of recombinant urokinase with vascular sur-

    gery as initial treatment for acute arterial oc-

    clusion of the legs. Thrombolysis or PeripheralArterial Surgery (TOPAS) Investigators.  N Engl 

    J Med.  1998;338:1105–1111.