History Thrombolytics

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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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10 YEARS OF THROMBOLYTIC THERAPY

Ouriel

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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.

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