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J ENDOVASC THER
2004;11(Suppl II):II-128II-133
l REVIEW
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 bioengineered 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 therapy
for 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-128II-133
Thrombolytic therapy, which offers a potentially less invasive option for the treatment of
patients with peripheral arterial and venous
occlusions, has gained prominence as an initial intervention, infusing thrombolytic agents
directly into the occluding thrombus via a
catheter-directed approach. Agents such as
urokinase, alteplase, and reteplase can recanalize occluded vessels, in many cases allowing 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 reocclusion. In other cases where open surgical intervention is still necessary, the procedure
can be performed on an elective basis in a
well-prepared patient.
While intellectually attractive, thrombolytic
therapy has been criticized on the basis of a
high reocclusion rate, prohibitive cost, and inferior long-term patency.1,2 Some of the criti-
EARLY DEVELOPMENT OF
THROMBOLYTIC THERAPY
The history of thrombolytic therapy begins in
1933, when Tillett and Garner4 at the Johns
Hopkins Medical School discovered that filtrates of broth cultures of certain strains of
Address for correspondence and reprints: Kenneth Ouriel, MD, Chairman, Division of Surgery, Desk
E32, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195 USA. Fax: 1-216445-6302; E-mail: ourielk@ccf.org
Q 2004 by the INTERNATIONAL SOCIETY
OF
ENDOVASCULAR SPECIALISTS
Available at www.jevt.org
J ENDOVASC THER
2004;11(Suppl II):II-128II-133
hemolytic Streptococcus bacteria could dissolve fibrin clot. This byproduct, originally
termed streptococcal fibrinolysin, was crude
and impure, so clinical use awaited adequate
purification. Tillett and Sherry5 administered
streptokinase (SK) intrapleurally to dissolve
loculated hemothoraces in the late 1940s, but
intravascular administration was not attempted until the following decade, when Tilletts
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 administered 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 sometimes 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 rather than the SK itself. Despite these reactions,
systemic proteolysis was observed, with a decrease in fibrinogen and plasminogen and an
increase in the prothrombin time.
These early studies were followed by reports on the use of SK in patients with occluding vascular thrombi. In 1956, E. E. Cliffton at the Cornell University Medical College
in New York was responsible for the first brief
description of the clinical effectiveness of intravascular 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: peripheral arterial thrombi, venous thrombi, pulmonary emboli, retinal occlusions, and occlusive carotid thrombi in 2 patients. Clifftons
clinical results were far from exemplary; recanalization was not uniform, and bleeding
complications were frequent. Nevertheless,
he must be credited with the first use of
thrombolytic agents for the treatment of pathological thrombi, as well as with the first catheter-directed administration of a thrombolytic
agent.
These early studies were followed by the
larger retrospective series of the 1970s and
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J ENDOVASC THER
2004;11(Suppl II):II-128II-133
the agent is associated with little plasminogen 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 facilitating
the 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 fibrin affinity.
Recombinant tPA (rtPA) was produced in
the 1980s after molecular cloning techniques
were used to express human tPA DNA.17 Activase (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 pulmonary embolism. rtPA has been studied extensively 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 slightly greater risk of intracranial hemorrhage with
rtPA, overall mortality was significantly reduced.
In an effort to lengthen the duration of bioavailability of tPA, the molecule was systematically bioengineered.19 Initial investigations
identified regions in kringle-1 and the protease 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 allowed 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 fibrinogen depletion. In studies of acute coronary 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 intravenous infusion, thereby simplifying ease of
administration. Reteplase (Retavase; Centocor, Malvern, PA, USA), produced in Esche-
J ENDOVASC THER
2004;11(Suppl II):II-128II-133
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While this trial failed to document improvement in survival or limb salvage with thrombolysis, fully 31.5% of the thrombolytic patients were alive without amputation at 6
months after nothing more than a percutaneous procedure. After 1 year, this number
had decreased only slightly, with 25.7% alive
without amputation and with only percutaneous 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 ischemia could be managed with catheter-directed
thrombolysis, achieving amputation and mortality rates similar to surgery but avoiding the
need for open procedures in a significant percentage 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. Thrombolysis for native arterial occlusions of the lower extremities: clinical outcome and cost. J
Vasc Surg. 2001;33:11481157.
3. Sullivan KL, Gardiner GA, Kandarpa K, et al.
Efficacy of thrombolysis in infrainguinal bypass 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 intravenous infusion of the streptococcal fibrinolytic principle (streptokinase) into patients. J
Clin Invest. 1955;34:169185.
7. Cliffton EE, Grunnet M. Investigations of intravenous plasmin (fibrinolysin) in humans. Circulation. 1956;14:919.
8. Cliffton EE. The use of plasmin in humans. Ann
N Y Acad Sci. 1957;68:209229.
9. Dotter CT, Rosch J, Seaman AJ. Selective clot
lysis with low-dose streptokinase. Radiology.
1974;111:3137.
10. van Breda A, Robison JC, Feldman L, et al. Lo-
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2004;11(Suppl II):II-128II-133
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
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2004;11(Suppl II):II-128II-133
24.
25.
26.
27.
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