THROMBOLYTIC THERAPY

INTRODUCTON

Thrombosis is an important part of the normal hemostatic response that limits hemorrhage
caused by microscopic or macroscopic vascular injury. Physiologic thrombosis is
counterbalanced by intrinsic antithrombotic properties and fibrinolysis. Under normal
conditions, a thrombus is confined to the immediate area of injury and does not obstruct flow
to critical areas, unless the blood vessel lumen is already diminished, as it is in atherosclerosis.
Under pathologic conditions, a thrombus can propagate into otherwise normal vessels. A
thrombus that has propagated where it is not needed can obstruct flow in critical vessels; it can
also obliterate valves and other structures that are essential to normal hemodynamic function.
Thrombolysis may involve the injection of clot-busting drugs through an intravenous (IV) line or
through a long catheter that delivers drugs directly to the site of the blockage. It also may involve
the use of a long catheter with a mechanical device attached to the tip that either removes the clot
or physically breaks it up.

Thrombolysis is often used as an emergency treatment to dissolve blood clots that form
in arteries feeding the heart and brain -- the main cause of heart attacks and ischemic strokes -- and
in the arteries of the lungs (acute pulmonary embolism). also known as thrombolytic therapy, is a
treatment to dissolve dangerous clots in blood vessels, improve blood flow, and prevent damage to
tissues and organs. Thrombolysis may involve the injection of clot-busting drugs through an
intravenous (IV) line or through a long catheter that delivers drugs directly to the site of the
blockage. It also may involve the use of a long catheter with a mechanical device attached to the
tip that either removes the clot or physically breaks it up.

Thrombolytics recanalize thrombotic occlusion associated with STsegment elevation

myocardial infarction (STEMI) and restoration of coronary flow reduces infarct size and
improves myocardial function and survival over the short-term and long-term. Thrombolytic
therapy for acute myocardial infarction (AMI) was incorporated into the armamentarium of
clinicians over 2 decades ago, and has evolved from first generation thrombolytic—
streptokinase (SK) to newer thrombolytics such as alteplase (t-PA), reteplase (rPA) and
tenecteplase (TNK). This article provides an overview of the various thrombolytic agents
utilized in the management of patients with AMI.
DEFINITION

Thrombolytic therapy is the use of drugs that dissolve blood clots.

PURPOSE

When a blood clot forms in a blood vessel, it may cut off or severely reduce blood flow to par
ts ofthe body that are served by that blood vessel. This can cause serious damage to those part
s ofthe body. If the clot forms in an artery that supplies blood to the heart, for example, it can
cause. A clot that cuts off blood to the brain can cause a stroke. Thrombolytic therapy isused
to dissolve blood clots that could cause serious, and possibly life-
threatening, damage ifthey are not removed. Research suggests that when used to treat stroke,
thrombolytic therapycan prevent or reverse paralysis and other problems that otherwise mig
ht result.
Thrombolytic therapy also is used to dissolve blood clots that form in tubes put into people'sb
odies for medical treatments, such as dialysis or chemotherapy.
USES
Thrombolytic drugs are used to dissolve blood clots (thrombi). Blood clots can occur in any
vascular bed; however, when they occur in coronary, cerebral or pulmonary vessels, they can
be immediately life-threatening – coronary thrombi are the cause of myocardial infarctions,
cerebrovascular thrombi produce strokes, and pulmonary thromboemboli can lead to
respiratory and cardiac failure. Therefore, it is important to rapidly diagnose and treat blood
clots.

PHYSIOLOGY OF HEMOSTASIS AND FIBRINOLYSIS

Physiologic hemostasis involves a delicate balance of three processes: coagulation or clot

formation, fibrinolysis or dissolution of clots, and naturally occurring serine protease inhibitors
that regulate the enzymatic activity of both the coagulative and fibrinolytic processes. This
complex system is driven by two major components: plasma proteins and the cellular
constituent of platelets, endothelial cells, neutrophils, and monocytes.

Hemostasis

Vessel wall injury exposes subendothelial collagen and tissue factors to initiate the extrinsic
pathway of the coagulation cascade. Platelets then adhere to the site of injury with the aid of
the von Willebrand factor and a signaling cascade is initiated within these cells, leading to the
release of granule contents. These molecules stimulate the coagulation cascade bringing
thrombin to the platelet surface. Thrombin formation and platelet activation leads to platelet
aggregation and formation of a hemostatic plug. Activation of the intrinsic pathway occurs
when contact is made between negatively charged blood surfaces; this also leads to stimulation
of the coagulative cascade and plug formation (Fig. 1).

Figure 1
Graph illustration of events that occur both during the coagulation cascade (via the intrinsic
and extrinsic pathways), and fibrinolysis.

Fibrinolysis

The fibrinolytic system consists of a network of proteins that provide regulation to the
hemostatic mechanism by maintaining the patency of the vessel wall through opposition of the
coagulation cascade. This regulatory system includes plasminogen, a zymogen or inactive
enzyme precursor, and naturally occurring plasminogen activators, such as tissue plasminogen
activator (tPA). Plasmin circulates as the inactive precursor form of plasminogen. The binding
of fibrinogen converts plasminogen into a configuration that promotes its further activation by
surrounding plasminogen activators and increases the efficiency of fibrinolysis. The
plasminogen activators cleave a specific component of the plasminogen molecules to generate
the active compound, plasmin. Cleavage of fibrin by plasmin then generates a substrate of
fragments that all function to activate the antithrombotic properties of plasmin.

HISTORY OF THROMBOLYTIC THERAPY

In 1933, Dr William Tillett discovered SK through sheer chance when he observed that
streptococci agglutinated plasma but not serum. He concluded that any plasma containing
streptococci would not clot and this laid the foundation for thrombolysis in various settings.
Christensen and MacLeod coined the term “streptokinase” in 1945.1 Streptokinase was
originally utilized in the treatment of patients with tuberculous hemorrhagic pleural effusions
and tuberculous meningitis. In 1958, Fletcher first reported the use of thrombolytic therapy for
the management of AMI.2 The breakthrough discovery of SK in the treatment of patients with
AMI was followed by a search for ideal thrombolytic agent, which led to the emergence of
second and third generation thrombolytics.
The history of thrombolytic therapy began in 1933, when it was discovered that filtrates of
broth cultures of certain streptococcal strains (beta-hemolytic streptococci) could dissolve a
fibrin clot. [1] Streptokinase found its initial clinical application in combating fibrinous pleural
exudates, hemothorax, and tuberculous meningitis. In 1958, streptokinase was first used in
patients with acute myocardial infarction (AMI), and this changed the focus of treatment.
Streptokinase infusion initially yielded conflicting results until the Gruppo Italiano per la
Sperimentazione della Streptochinasi nell’Infarto Miocardico (GISSI) trial in 1986, which
validated streptokinase as an effective therapy and established a fixed protocol for its use in
AMI.

First-Generation Thrombolytic Agents

In 1933, Tillett and Garner first discovered that filtrates isolated from certain strains of
hemolytic bacteria could dissolve fibrin clot. In the late 1940s, Tillett and Sherry dissolved
loculated hemothoraces by administering streptokinase intrapleurally. In 1955, Tillett et al
intravenously injected a partially purified and concentrated streptokinase, which led to
systemic proteolysis, decreased fibrinogen and plasminogen, and increased prothrombin
time. However, because streptokinase is a bacterial protein, this was not without antigenic-
related systemic effects of fever and hypotension. In 1974, Dotter et al published an article
utilizing a low-dose protocol for the administration of streptokinase in an effort to decrease the
overall antigenicity and enhanced lytic state created by streptokinase. However, frequent
bleeding due to an intense systemic proteolytic state still occurred and prompted investigation
for an alternate treatment.

Streptokinase activates plasmin via a fibrin-dependent and fibrin-independent mechanism,

therefore degrading fibrinogen along with other proteins that all serve to enhance the “lytic”
state. The adverse effects and nonfibrin selectivity have curtailed its use in the United States.

In 1947, Macfarlane and Pilling first described the fibrinolytic potential inherent in human
urine. In 1952, Sobel et al were able to extract and isolate the active molecule, coining the term
“urokinase.” This compound activated the fibrinolytic system without evoking an antigenic
response, consequently making fever and hypotension rare occurrences. In contrast to
streptokinase, urokinase activates plasminogen directly. However, urokinase lacks fibrin
selectivity again resulting in a severe “lytic” state.

Second-Generation Thrombolytic Agents

Tissue plasminogen activator is a natural fibrinolytic agent produced by endothelial cells that
is involved in maintaining the delicate intravascular balance of thrombolysis and
thrombogenesis. Structurally, naturally occurring tPA is a 527-amino acid single-chain serine
protease with considerable activity (Fig. 2).
Figure 2

Molecular structure of the second-generation compound, alteplase, which is the predominant

thrombolytic agent used across the United States. The arrows point to the amino acid
modification sites in the creation of tenecteplase, the third-generation compound. (Picture
courtesy of Genentech.)

It has fibrin specificity, as it does not activate plasminogen freely floating in blood. On a
molecular level, the binding of both tPA and plasminogen to the fibrin surface of a blood clot
induce a conformational change in the two molecules. This change subsequently accelerates
the conversion of plasminogen to plasmin and subsequent dissolution of thrombus. In addition
to fibrin specificity, tPA exhibits strong binding to fibrin, also known as fibrin affinity.
Therefore, in addition to using fibrin, the plasmin at the clot surface also enhances the
conformational change that further accentuates the enzymatic activity of tPA. The
commercially available form of tPA is produced using recombinant technology and is called
alteplase (r-tPA); rtPA has been approved by the Food and Drug Administration (FDA) for
acute myocardial infarction, acute stroke, massive pulmonary embolism, and central venous
catheter occlusion. It has also been widely used (although off-label) for catheter-directed
venous and arterial thrombolysis.

Third-Generation Thrombolytic Agents

To improve upon tPA, modification of three amino acid enzymatic sites produced tenecteplase,
or TNK-tPA, to increase fibrin specificity and prolong its half-life (Fig. 2). Increasing fibrin
specificity leads to less depletion of fibrinogen, whereas prolonging the half-life allows for
single bolus administration rather than continuous intravenous (IV) infusion. To further
simplify administration of a thrombolytic, the development of reteplase or retavase targeted
decreasing affinity to hepatocytes and reducing fibrin-binding activity. Decreased affinity to
hepatocytes was hypothesized to prolong drug half-life, thus enabling single bolus
administration. Several deletions of domains of the tPA molecule resulted in the creation of
reteplase, which led to a fourfold increase in the plasma half-life (18 minutes vs 4 minutes for
tPA). Although synthesized by E. colibacteria, it has not been found to be immunogenic.
Reteplase is FDA approved for use in myocardial infarction (Table 1).

Table 1
Table Illustration of Characteristics of First-Generation, Second-Generation, and Third-
Generation Thrombolytic Agents

First-Generation Second-Generation Third-Generation

(Streptokinase) TPA (Alteplase) (Reteplase)

Molecular weight 47,000 70,000 39,000

(Daltons)

Half-life (min) 23 <5 13–16

Bolus No No Yes
administration

Allergic response Yes No No

Fibrin selective No Yes Yes

Plasminogen Indirect Direct Direct

binding

INDICATIONS

Fibrinolytic therapy is used in the treatment of a ST segment elevation myocardial infarction

(STEMI), acute stroke and other less common indications such as pulmonary embolism and
acute deep venous thrombosis.
During STEMI, fibrinolytic therapy must be instituted within 24 hours of symptom onset. After
this time frame, fibrinolytic therapy is contraindicated and likely will not be effective. Note
that fibrinolytic therapy is always given simultaneously with anticoagulation using
unfractionated heparin or low molecular weight heparin.

CONTRAINDICATIONS

When the decision to treat a patient experiencing a STEMI with fibrinolytic therapy is made,
because primary PCI is not available in a timely fashion, contraindications must be considered;
suspected aortic dissection, active bleeding (excluding menses) or a bleeding diathesis are
contraindications to fibrinolytic therapy.

Generally, if there is high risk for intracranial hemorrhage (ICH),defined as greater than 4%,
fibrinolytic therapy is contraindicated as well, and primary PCI is preferred (class I).

The following would place a patient in the high-risk category for ICH:

1. Prior intracranial hemorrhage

2. Ischemic stroke within 3 months
3. Known cerebrovascular abnormality such as aneurysm or arteriovenous malformation
4. Known malignant intracranial tumor
5. Significant closed-head trauma or facial trauma within 3 months
Relative contraindications (not absolute) to fibrinolytic therapy include:

1. Uncontrolled hypertension (BP > 180/110), either currently or in the past

2. Intracranial abnormality not listed as absolute contraindication (i.e. benign intracranial
tumor)
3. Ischemic stroke more than 3 months prior
4. Bleeding within 2 to 4 weeks (excluding menses)
5. Traumatic or prolonged cardiopulmonary resuscitation
6. Major surgery within 3 weeks
7. Pregnancy
 8. Current use of anticoagulants
9. Non-compressible vascular puncture
10. Dementia
Note that advanced age is not listed as an absolute or relative contraindication to fibrinolytic
therapy in the American College of Cardiology/American Heart Association guidelines.

tPA AND ITS ROLE IN THE TREATMENT OF PERIPHERAL VASCULAR DISEASE

Acute limb ischemia (ALI) is a sequela of peripheral arterial disease, producing risk for both
limb loss and death. The two most common etiologies behind nontraumatic ALI are arterial
thrombosis, in the context of atherosclerotic vascular disease, and arterial embolus, usually of
cardiac origin. Arterial thrombosis predominantly affects the lower extremities because the
upper extremities have an extensive and rich collateral blood supply. Patient outcome and
prognosis are largely dependent upon the rapid diagnosis and delivery of appropriate treatment
in a safe and timely fashion.

Over the past several decades, preferred treatment options for patients with ALI have alternated
between surgical intervention and medical approaches. Intraarterial catheter-directed
thrombolysis can achieve thrombus dissolution, with subsequent recanalization of the occluded
vessel and unveiling of an underlying lesion that can then be treated endovascularly. However,
one must take into consideration that the clinical success of thrombolysis management can lead
to delays in achieving arterial reperfusion.

Two landmark prospective, randomized, multicenter clinical trials deserve mention in the
approach to patients with ALI. In the STILE (Surgery versus Thrombolysis for Ischemia of the
Lower Extremity) Trial, patients with nonembolic native artery or bypass graft occlusion in the
lower limbs who presented with clinical symptoms of 14 days or less experienced lower rates
of amputation and death following catheter-directed intraarterial thrombolysis with tPA or
urokinase as compared with surgical intervention.Furthermore, at 6-month follow-up, there
was an improved amputation-free survival in the thrombolysis group. The TOPAS
(Thrombolysis or Peripheral Arterial Surgery) Trial also identified intraarterial catheter-
directed thrombolysis using urokinase to be a safe and effective treatment compared with
surgery in acute arterial occlusion, also with comparable rates of amputation-free survival and
death.10,11 However, the TOPAS Trial did show a higher frequency of hemorrhagic
complications in urokinase-treated patients, which is probably attributed to its lack of fibrin
selectivity as described earlier. Despite this increased rate of hemorrhagic complications in the
thrombolysis group, the need for open surgery was diminished with no significant risk of
amputation or death.

Lansdale et al performed a nonrandomized comparative trial examining the effects of

intraarterial streptokinase and tPA with arterial occlusion. Rates of amputation and death were
lower in tPA-treated patients (41% vs 59%), along with a shorter time to lysis (22 hours vs 40
hours). Since the STILE and TOPAS trials, a consensus proposal by a Working Group
including angiologists, hematologists, interventional radiologists, and vascular surgeons from
North America and Europe proposed that thrombolytic treatment should be considered as an
acceptable treatment option in patients with acute arterial occlusion in native vessel or in
bypass grafts. These recommendations are as follows:

1. In patients with native artery occlusion, thrombolysis followed by correction of the

underlying causative lesion is an appropriate strategy in patients presenting with
ischemic symptoms <14 days.

2. Surgical revascularization should be performed immediately if thrombolysis would

delay effective limb reperfusion.

3. Patients with irreversible ischemia should undergo primary amputation.

4. For occluded bypass grafts, options are surgical revision and thrombectomy, catheter-
directed thrombolysis, or insertion of a new graft.

Vascular Graft Occlusions

A subgroup analysis of the STILE Trial data did show that thrombolysis appears to be more
effective when used in the treatment of graft occlusions than when used for native artery
occlusions.9,14 As with native arterial occlusions, the Working Group recommendations also
involve additional factors that relate to the nature of the graft, duration and degree of ischemia.

Clear differences in the superior patency rates of vein grafts over polytetrafluoroethylene
(PTFE) grafts have been reported in the literature. Primary patency rates at 4 years for
infrapopliteal bypasses with saphenous vein have been measured at 49%, a significantly higher
rate than the 12% patency rates associated with PTFE grafts. When considering thrombolytic
interventions, it is important to understand the difference in the nature of thrombotic occlusions
in both vein and prosthetic bypass grafts. Thrombotic occlusions can occur with both types of
bypass grafts due to underlying technical problems, such as stenoses at insertion sites, which
can progressively delay antegrade blood flow through the system. Both types of grafts are also
affected by underlying progressive atherosclerotic disease that can alter the hemodynamics of
inflow and outflow through the graft entry and exit points. Neointimal hyperplasia also plays
a role in vascular occlusion, but differs in extent. For example, neointimal hyperplasia of vein
grafts can lead to either a diffuse luminal reduction in graft caliber, or can lead to a focal
isolated stenosis from either surgical anastomotic sites or at venous valves sites. In contrast,
the intimal hyperplasia that develops in PTFE grafts tends to occur predominantly at the
anastomotic sites from the adjacent artery. Vein bypass occlusions tend to occur less frequently
than PTFE grafts because they are lined with endothelium that allows maintenance of the
antithrombotic regulatory mechanism. PTFE grafts, however, are highly thrombogenic at the
time of implantation and remain so as long as they are in place (Fig. 3). Further studies looking
at different materials for graft prosthetics are still being developed.
Figure 3

A 65-year-old woman presented with acute limb ischemia of 5-days duration. She was referred
for thrombolytic intervention. (A) Digital subtraction angiography (DSA) of the proximal left
lower extremity demonstrates patent superficial femoral and profunda femoral arteries. (B)
DSA centered over the knee demonstrates site of proximal surgical anastomosis (arrow) of
popliteal-anterior tibial bypass vein graft. There is little antegrade flow through the graft. There
is abrupt occlusion of the native popliteal artery above the level of the trifurcation with multiple
small collateral vessels seen coursing around the midcalf. (C) DSA centered over the distal calf
demonstrates a distal surgical anastomosis (arrow), with poor flow seen coursing through the
graft. Multiple collateral vessels are again visualized around the midcalf region. (D) Roadmap
magnified view of the proximal anastomosis demonstrates positive “guidewire test” in which
a guidewire was able to be successfully introduced through the proximal end of the graft,
indicating acute thrombus. A thrombolysis infusion catheter was placed for infused therapy at
this proximal level (arrow). (E) Follow-up DSA after 2 days of thrombolysis demonstrates
good antegrade flow through the vein bypass graft, with visualization of underlying defect (i.e.,
tight stenosis) at the proximal graft anastomosis. (F) Follow-up angiogram after 2 days of
thrombolysis demonstrates visualization of flow through the distal end of the graft through the
anterior tibial anastomosis, and into the foot as the dorsalis pedis artery. (G) Magnified view
of the proximal anastomosis reveals adequate and successful placement of stent across the
stenotic segment of the proximal anastomosis. Excellent flow is seen through the bypass graft.
(H) Follow-up DSA after 3 days of thrombolysis demonstrates good antegrade flow through
the entire length of the popliteal-anterior tibial artery bypass graft.

Dosage and Delivery

IV administration of thrombolytics should not be performed for ALI, as there is a high

incidence of hemorrhagic complications concurrent with poor outcomes. Patients who undergo
intraarterial catheter-directed therapy usually undergo the guidewire test, initially proposed by
McNamara and Fischer. This test detects the ease with which a guidewire can be passed into
an area of occluded native artery or bypass graft. A wire that passes easily though the occlusion
indicates the presence of an acute thrombus with a high probability of successful lysis. Once
the guidewire crosses across the occluded segment, a thrombolysis infusion catheter can be
advanced into the occluded segment and appropriate thrombolysis treatment initiated.

A multicenter randomized trial by Braithwaite et al compared high-dose bolus administration

of tPA (3–5 mg bolus doses, then 3.5 mg/h for a maximum of 4 hours, followed by 0.5–1.0
mg/h) versus low dose tPA (0.5–1.0 mg/h) in patients with acute leg ischemia.18 No statistically
significant differences were seen between the two groups in terms of limb salvage or
complication rates. The Advisory Panel on Catheter-Directed Thrombolytic Therapy in 1999
has since provided guidelines for the use of tPA. Suggested dosing regimes are either a weight-
adjusted dose of 0.001–0.2 mg/kg/h or a nonweight-adjusted dose of 0.12–2.0 mg/h. Maximum
total dose should be no greater than 40 mg for catheter-directed therapy.20 The authors'
preference is a low-dose regimen of 0.5 mg–1.0 mg/h.

tPA AND ITS ROLE IN THE TREATMENT OF STROKE

A majority of ischemic strokes are either thrombotic and/or thromboembolic in nature. The
clinical application of thrombolysis has been a long-studied phenomenon with major
breakthroughs occurring only within the last two decades. The first study to claim that tPA is
effective in the treatment of acute ischemic stroke was a multicenter clinical trial coordinated
by the National Institute of Neurological Disorders and Stroke (NINDS) Study Group. 26 An
effective thrombolytic therapy necessitates the recognition of a therapeutic window; this
window is challengingly brief in ischemic stroke as neuronal death and brain infarction evolve
progressively in a time-dependent fashion, determined by both duration and severity of the
ischemic insult.

Since the landmark report from the National Institute of Neurological Disorders and Stroke
(NINDS) demonstrated substantial benefit from the careful use of IV tPA in patients with
ischemic stroke, the use of IV tPA within the first 3 hours of onset of acute ischemic stroke has
received regulatory approval in the United States, Canada, Europe, Australia, and many Asian
countries. A meta-analysis has concluded that IV thrombolytic therapy within 3 hours of
symptoms onset significantly reduced the number of patients suffering the endpoint of death
or dependency. Meta-analysis restricted current IV protocols, such as the Cochrane stroke
group, also demonstrated a much more favorable trend toward the use of tPA within the first 3
hours.

Other studies that have analyzed tPA trials that were initiated >3 hours after onset of symptoms
have concluded that there was substantial evidence of benefit for tPA therapy delivered within
the first 180 minute, with evidence of declining benefit up to 4.5 hours. Once the time interval
is in excess of >4.5 hours, the benefit of IV tPA therapy becomes small. Therefore, the
implications of early treatment are profound and require the clinician to provide rapid
evaluation, imaging and treatment, all preferably within 3 hours, with a diminishing small
benefit persisting for up to 4.5 hours. Effective thrombolytic therapy is accompanied by a set
of approved inclusion/exclusion criteria.
Table 2

Eligibility Criteria for Consideration of Intravenous tPA Thrombolysis (Grade IA) in the
Setting of Acute Stroke

Inclusion Criteria Exclusion Criteria

Age >18 years Minor or rapidly improving signs or symptoms

Clinical dx of stroke with clinical CT signs of intracranial hemorrhage

neurologic deficit

Clearly defined time of onset of <180 Seizure at stroke onset

min before treatment

Baseline CT showing no hemorrhage Stroke or serious head injury in the past 3 months

Major surgery or serious trauma in past 3 months

GI or urinary tract hemorrhage within 3 weeks

Systolic BP >185 or diastolic >110 or aggressive

tx required to lower BP

Glucose <50 or >400

 Inclusion Criteria Exclusion Criteria

Symptoms of subarachnoid hemorrhage

Platelets <100,000; INR >1.7: elevated PTT

Clinical presentation suggesting postmyocardial

pericarditis

Pregnancy

Lumbar puncture within 1 week

BP, blood pressure; CT, computed tomography; dx, diagnosis; GI, gastrointestinal; INR,
international normalized ratio; PTT, partial thromboplastin time; tx, treatment

Thrombolytics are frequently delivered by an IV route; however, other modes of delivery have
shown promising results. In severe cases like basilar artery occlusion, where mortality rates are
as high as 80 to 90%, more aggressive therapy may be warranted. Intraarterial catheter-directed
thrombolysis therapy may be delivered directly into the thrombus using selective catheters.
Intraarterial therapy allows for a local thrombolytic drug delivery directly onto the clot and
access for mechanical clot disruption. This offers the added potential advantages of increased
recanalization rates, improved accuracy of diagnosis, and reduction in the amount of drug
administered thus increasing the safety profile of the thrombolytic agent.30 The use of
intraarterial thrombolytic therapy is currently limited to facilities with personnel who are
capable of performing this procedure with precision, and which offer adequate preprocedural
and postprocedural care to patients. There is limited evidence to provide recommendations for
proper intraarterial thrombolytic agent, dose, delivery technique, or duration of therapeutic
window; these limitations are bound to change in the near future as more trials are currently
under scrutiny. A highly variable therapeutic window has been demonstrated and this will be
significantly altered with intraarterial thrombolysis. Some cases of basilar artery occlusion
have shown exceptional recovery even for up to 12 hours after onset of symptoms.30 Current
guidelines note that IA thrombolysis is reasonable in patients who have contraindications to IV
thrombolysis.

New and investigational therapies using tPA in the context of ischemic stroke include novel
ideas like combination therapy with abciximab, a monoclonal antibody with platelet
glycoprotein IIb-IIIa receptor, or a combination IV/IA tPA therapy. Mechanical devices are
also used as an adjunct to expedite clot lysis or extraction. The concentric MERCI retriever
system has received FDA-approval for clot retrieval in acute ischemic stroke based on the result
on the MERCI trial, which showed up to 46% recanalization rates, compared with a historical
control rate of 18%. Another innovative approach uses transcranial Doppler sonography to
enhance the thrombolytic effect of tPA. Data for most of these innovative ideas are insufficient
and further clinical trials are needed before they can be recommended for the treatment of acute
ischemic stroke.

THROMBOLYTIC DRUGS

Thrombolytic drugs are used to dissolve (lyse) blood clots (thrombi). Blood clots can occur in
any vascular bed; however, when they occur in coronary, cerebral or pulmonary vessels, they
can be immediately life-threatening - coronary thrombi are the cause of myocardial infarctions,
cerebrovascular thrombi produce strokes, and pulmonary thromboemboli can lead to
respiratory and cardiac failure. Therefore, it is important to rapidly diagnose and treat blood
clots.
Mechanisms of Thrombolysis

Thrombolytic drugs dissolve blood clots by activating plasminogen, which forms a cleaved
product called plasmin. Plasmin is a proteolytic enzyme that is capable of breaking cross-links
between fibrin molecules, which provide the structural integrity of blood clots. Because of
these actions, thrombolytic drugs are also called "plasminogen activators" and "fibrinolytic
drugs."

There are three major classes of fibrinolytic drugs: tissue plasminogen activator
(tPA), streptokinase (SK), and urokinase (UK). While drugs in these three classes all have
the ability to effectively dissolve blood clots, they differ in their detailed mechanisms in ways
that alter their selectivity for fibrin clots.

The figure to the right illustrates the fibrinolytic mechanisms for tPA and SK. Derivatives of
tPA are the most commonly used thrombolytic drugs, especially for coronary and cerebral
vascular clots, because of their relative selectivity for activating fibrin-bound plasminogen.
Tissue plasminogen activator produces clot lysis through the following sequence:
 1. tPA binds to fibrin on the surface of the clot
2. Activates fibrin-bound plasminogen
3. Plasmin is cleaved from the plasminogen associated with the fibrin
4. Fibrin molecules are broken apart by the plasmin and the clot dissolves

Plasmin is a protease that is capable of breaking apart fibrin molecules, thereby dissolving the
clot. However, it is important to note that plasmin also breaks down other circulating proteins,
including fibrinogen. But because of the relative fibrin specificity of tPA, clot dissolution
occurs with less breakdown of circulating fibrinogen than occurs with SK and UK. Although
tPA is relatively selective for clot-bound plasminogen, it still activates circulating plasminogen
thereby releasing plasmin, which can lead to the breakdown of circulating fibrinogen and cause
an unwanted systemic fibrinolytic state. Normally, circulating α2-antiplasmin inactivates
plasmin, but therapeutic doses of tPA (and SK) lead to sufficient plasmin formation to
overwhelm the limited circulating concentrations α2-antiplasmin. In summary, although tPA is
relatively selective for clot-associated fibrin, it can produce systemic lytic state and undesirable
bleeding.

SK is not a protease and has no enzymatic activity; however, it forms a complex with
plasminogen that releases plasmin. Unlike tPA, it does not bind preferentially to clot-associated
fibrin and therefore binds equally to circulating and non-circulating plasminogen. Therefore,
SK produces significant fibrinogenolysis along with clot fibrinolysis. For this reason, tPA is
generally preferred as a thrombolytic agent over SK, especially when used for dissolving
coronary and cerebral vascular thrombi. Because SK is derived from streptococci, patients who
have had recent streptococci infections can require significantly higher doses of SK to produce
thrombolysis.

It is important to note that the efficacy of thrombolytic drugs depends on the age of the clot.
Older clots have more fibrin cross-linking and are more compacted; therefore, older clots are
more difficult to dissolve. For treating acute myocardial infarction, the thrombolytic drugs
should ideally be given within the first 2 hours. Beyond that time, the efficacy diminishes and
higher doses are generally required to achieve desired lysis.

Specific Thrombolytic Drugs

Tissue Plasminogen Activators
This family of thrombolytic drugs is used in acute myocardial infarction, cerebrovascular
thrombotic stroke and pulmonary embolism. For acute myocardial infarctions, tissue
plasminogen activators are generally preferred over streptokinase.

 Alteplase (Activase®; rtPA) is a recombinant form of human tPA. It has a short

half-life (~5 min) and therefore is usually administered as an intravenous bolus
followed by an infusion.
 Retaplase (Retavase®) is a genetically engineered, smaller derivative of
recombinant tPA that has increased potency and is faster acting than rtPA. It is
usually administered as IV bolus injections. It is used for acute myocardial
infarction and pulmonary embolism.
 Tenecteplase (TNK-tPA) has a longer half-life and greater binding affinity for
fibrin than rtPA. Because of its longer half-life, it can be administered by IV
bolus. It is only approved for use in acute myocardial infarction.

Streptokinase

Streptokinase and anistreplase are used in acute myocardial infarction, arterial and venous
thrombosis, and pulmonary embolism. These compounds are antigenic because they are
derived from streptococci bacteria.

 Natural streptokinase (SK) is isolated and purified from streptococci bacteria. Its
lack of fibrin specificity makes it a less desirable thrombolytic drug than tPA
compounds because it produces more fibrinogenolysis.
 Anistreplase (Eminase®) is a complex of SK and plasminogen. It has more fibrin
specificity and has a longer activity than natural SK; however, it causes
considerable fibrinogenolysis.
Urokinase

Urokinase (Abbokinase®; UK) is sometimes referred to as urinary-type plasminogen activator

(uPA) because it is formed by kidneys and is found in urine. It has limited clinical use because,
like SK, it produces considerable fibrinogenolysis; however, it is used for pulmonary
embolism. One benefit over SK is that UK is non-antigenic; however, this is offset by a much
greater cost.
THROMBOLYTIC AGENTS IN ACUTE MYOCARDIAL INFARCTION:
CLASSIFICATION AND MECHANISM OF ACTION

Thrombolytic agents act by converting the proenzyme, plasminogen to plasmin, the active
enzyme. Plasminogen activators that preferentially activate fibrin-bound plasminogen are
fibrin-specific. In contrast, nonspecific plasminogen activators do not discriminate between
fibrin-bound and circulating plasminogen. Activation of circulating plasminogen results in the
generation of unopposed plasmin that can trigger the systemic lytic state (Figure 1).
Thrombolytic agents can be categorized in several ways. Classification schemes can be devised
on the basis of the source of the agent, the propensity for enhanced enzymatic activity on fibrin
or cell surface or the mechanism of action (enzymatic versus nonenzymatic) or different
generation wise. Newer thrombolytic agents have been developed in order to provide longer
half-life to enable bolus administration, fibrin specificity and to be resistant to natural inhibitors
such as plasminogen activator inhibitor-1 (PAI-1).

Streptokinase

Streptokinase is a nonfibrinogen-specific fibrinolytic agent, produced by hemolytic

streptococci that activates plasminogen independent of its association with fibrin. It is not an
enzyme and therefore does not exhibit plasmin activity by proteolytic cleavage of plasminogen.
Instead, it binds noncovalently to plasminogen in a 1:1 equimolar fashion and thereby confers
plasmin activity (Figure 2). The Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto
Miocardico (GISSI) and the International Study of Infarct Survival (ISIS) trials3-5 firmly
established the efficacy of intravenous SK in the management of patients with AMI. In the
GISSI trial, at 21 days there was 18% reduction in overall hospital mortality following the
administration of SK compared with the control group. The extent of the beneficial effect
appeared to be related to the time of onset of chest pain to SK infusion [risk ratio (RR) 0.74,
0.80, 0.87 and 1.19 for the 0–3, 3–6, 6–9 and 9–12 hours subgroups].3 Likewise in the ISIS2
trial, patients with AMI randomized to SK and aspirin compared with neither treatment resulted
in significant reduction not only in death (8% versus 13.2%), but also stroke (0.6% versus
1.1%) and reinfarction (1.8% versus 2.9%).4 The early survival benefit obtained with SK and
aspirin persisted up to 10 years during follow-up.5 Allergic reaction manifesting as rash, fever,
chills, rigors and rarely, anaphylaxis occurs in about 5% of patients treated with SK. Transient
hypotension is common with SK and reflects plasminmediated release of bradykinin. Patients
given SK invariably develop antistreptococcal antibodies, precluding readministration.
Tissue Plasminogen Activator (Alteplase)

The tissue plasminogen activator (t-PA) molecule contains the following five domains: (1)
finger, (2) epidermal growth factor, (3) Kringle 1 and (4) Kringle 2 and (5) serine protease
(Figure 3). 6 In the absence of fibrin, t-PA is a weak plasminogen activator. Plasma clearance
of t-PA is mediated to a varying degree by residues in each of the domains except the serine
protease domain, which is responsible for the enzymatic activity of t-PA. Alteplase is a t-PA
produced by recombinant deoxyribonucleic acid (DNA) technology. The accelerated dose
regimen of t-PA over 90 minutes produces more rapid thrombolysis than the standard 3 hours
infusion of t-PA. The recommended dosage regimen for t-PA is a 15 mg intravenous bolus
followed by an infusion of 0.75 mg/kg (maximum 50 mg) over 30 minutes, followed by an
infusion of 0.5 mg/kg (maximum 35 mg) over 60 minutes. The Global Use of Strategies to
Open Occluded Coronary Arteries (GUSTO), GISSI-27 and ISIS-38 investigators compared
intravenous SK and t-PA in the treatment of AMI. Although no significant difference was
observed between SK and t-PA in GISSI-2 and ISIS-3, the GUSTO trial demonstrated that an
accelerated regimen of t-PA resulted in significant reductions in death and disabling strokes
among patients with AMI. Accelerated t-PA group resulted in 14% reduction in mortality at 30
days compared with the SK strategies. There was slight excess of hemorrhagic stroke for
accelerated t-PA when compared with the SK strategies. However, the combined endpoint of
death or disabling stroke was significantly lower in the accelerated t-PA group than in the SK
only groups (6.9% versus 7.8%, P = 0.006).9 The Phase-I Thrombolysis in Myocardial
Infarction (TIMI) trial demonstrated that the administration of alteplase in patients with AMI
resulted in reperfusion in twice as many occluded infarct-related arteries compared with SK
during the first 90 minutes of initiation of treatment.

Reteplase

Reteplase is a recombinant deletion mutant form of t-PA, and has a longer half-life of 13–16
minutes. It binds fibrin, and has the ability to penetrate into thrombi. Reteplase when compared
with accelerated alteplase infusion regimen was demonstrated to offer no significant benefit in
terms of reduction in 30 days mortality among patients with AMI.11 Likewise, rPA in
combination with abciximab did not provide significant benefit in terms of 30 days survival.12
However a double dose rPA (10 + 10 MU) utilized in the Revitalising Areas by Planning,
Investment and Development (RAPID) trial resulted in complete, rapid and sustained
thrombolysis of infarct-related arteries (IRAs) at 90 minutes and 5–14 days (63% versus 49%,
P = 0.019; and 88% versus 71%, P < 0.001) compared with alteplase and improved regional
and global left ventricular function at discharge. The RAPID II trial further confirmed the
advantage of rPA over accelerated alteplase in achieving higher rates of early reperfusion in
the IRA and fewer acute coronary interventions. This, however, did not translate into improved
clinical outcomes in the International Joint Efficacy Comparison of Thrombolytics (INJECT)
trial, which demonstrated no significant difference between rPA and SK in reducing 35-day
mortality.

Tenecteplase

Tenecteplase is a mutant form of t-PA with specific amino acid substitutions in the Kringle 1
domain and protease domain. A single bolus TNK was demonstrated to be associated with
increased IRA patency rates (64% TIMI 3 flow with 50 mg bolus dose) in the TIMI 10A trial.14
In the TIMI 10B trial, TNK (40 mg) and alteplase produced similar rates of TIMI grade 3 flow
at 90 minutes (62.8% versus 62.7%, respectively, P = NS).15 Subsequently the Assessment of
the Safety and Efficacy of a New Thrombolytic (ASSENT-1) Trial demonstrated that the safety
profile of TNK was comparable to alteplase.16 ASSENT-217 compared single-bolus TNK
with accelerated dose t-PA and the 30-days mortality rate with TNK was 6.179% and with t-
PA 6.151%. The rate of intracranial hemorrhage (ICH) was 0.93% with TNK and 0.94% with
t-PA. Major bleeding occurred in 4.66% of TNK-treated patients compared with 5.94% of t-
PA-treated patients (P = 0.0002). There was no specific subgroup of patients for whom TNK
or t-PA was significantly better, with the exception of patients treated after 4 hours from the
onset of symptoms, among whom the mortality rate was 7.0% with TNK and 9.2% with t-PA.
Furthermore, the ASSENT-3 Trial demonstrated that the addition of enoxaparin or abciximab
to TNK reduced ischemic complications.18 Despite the differences observed between the
thrombolytic agents in individual studies, a subsequent meta-analysis, however, did not
demonstrate significant differences between the various thrombolytic agents (alteplase, SK,
rPA and TNK) in reducing mortality (Figure 4)19 though total stroke and hemorrhagic stroke
rates were lower in SK group.

Other Fibrinolytic Agents

Derived from cultured fetal kidney cells, urokinase is a two-chain serine protease, which
directly converts plasminogen to plasmin. It was used on rare occasions as an intracoronary
(IC) infusion [6,000 international unit (IU)/minutes] to an average cumulative dose of
5,000,000 IU to lyse IC thrombi that were believed to be responsible for an evolving STEMI.20
Saruplase or prourokinase (scuPA), a naturally occurring glycoprotein, is converted by plasmin
into urokinase, and seems to have intrinsic plasminogen activating potential. Saruplase was
compared with SK in the Prourokinase in Myocardial Infarction (PRIMI) and Comparative
Trial of Saruplase versus Streptokinase (COMPASS) and with alteplase in Study in Europe
with Saruplase and Alteplase in Myocardial Infarction (SESAM) Trial. Although the mortality
rates were comparable between scuPA and other agents, scuPA was overcome by other adverse
events such as increased reinfarction rates and hemorrhagic stokes.1 Anistreplase or
anisoylated plasminogen-SK activator complex (APSAC) is another form of SK, an equimolar
acylated complex of human lys-plasminogen and SK. This complex acts on plasminogen upon
deacylation spontaneously in plasma. Usually administered in a dose of 30 mg over 2 to 5
minutes intravenously, it has a side effect profile similar to that of SK, a patency profile similar
to that of conventional dose t-PA and a mortality benefit similar to that of SK or t-PA (ISIS-
3).8 Staphylokinase, a highly fibrin-specific plasminogen activator requires priming on the
surface of a clot. Recombinant staphylokinase in STAR Trial achieved TIMI flow grade 3
(TFG3) at 90 minutes in 62% of STAR patients versus 58% of t-PA patients. Study of
Tamoxifen and Raloxifene therapy was not associated with increased mortality, hemorrhagic
or allergic complications. However, there was an occurrence of antibody-mediated
STARneutralizing activity from the 2nd week following treatment.21 The pegulated-
staphylokinase (PEG-Sak) evaluated in the Collaborative Angiographic Patency Trial of
Recombinant Staphylokinase (CAPTORS) II Trial demonstrated comparable TFG3 rates to
that with t-PA.22 Lanoteplase (nPA), a variant of t-PA with greater fibrinolytic activity and
slower clearance from the plasma, resulted in equivalent thrombolytic efficacy to alteplase
(InTIME).23 However, nPA was associated with an increased risk of hemorrhagic strokes.

Precautions

For thrombolytic therapy to be effective in treating stroke or heart attack, prompt medical
attention is very important. The drugs must be given within a few hours of the beginning of a
stroke or heart attack. This type of treatment is not right, however, for every patient who has a
heart attack or a stroke. Only a qualified medical professional can decide whether a
thrombolytic agent should be used. To increase the chance of survival and reduce the risk of
serious permanent damage, anyone who has signs of a heart attack or stroke should get
immediate medical help.
Thrombolytic therapy may cause bleeding in other parts of the body. This side effect is usually
not serious, but severe bleeding does occur in some patients, especially older people. Some
people have had minor hemorrhagic strokes in which there has been a small amount of bleeding
into the brain. These hemorrhagic strokes have been blocked by clots that would be broken up
by use of a thrombolytic agent, so that removal of the harmful clot would cause equally
dangerous bleeding. To lower the risk of serious bleeding, people who are given thrombolytic
medications should move around as little as possible and should not try to get up on their own
unless told to do so by a health care professional. Following all the instructions of the health
care providers in charge is very important.

Thrombolytic therapy may be more likely to cause serious bleeding in people who have certain
medical conditions or have recently had certain procedures. Before being given a thrombolytic
agent, anyone with any of these problems or conditions should tell the physician in charge:

 blood disease or current or past bleeding problems in any part of the body
 heart or blood vessel disease
 stroke (recent or in the past)
 high blood pressure
 brain tumor or other brain disease
 stomach ulcer or colitis
 severe liver disease
 active tuberculosis
 recent falls, injuries, or blows to the body or head
 recent injections into a blood vessel
 recent surgery, including dental surgery
 tubes recently placed in the body for any reason
 recent delivery of a baby

In addition, anyone who has had a recent streptococcal (strep) infection should tell the
physician in charge. Some thrombolytic agents may not work properly in people who have just
had a strep infection, so the physician may want to use a different drug.

People who take certain medicines may be at greater risk for severe bleeding when they are
given a thrombolytic agent.
Women who are pregnant should tell the physician in charge before being given a thrombolytic
agent. There is a slight chance that a woman who is given thrombolytic therapy during the first
five months of pregnancy will have a miscarriage. Streptokinase and urokinase, however, have
both been used without problems in pregnant women.

After being treated with thrombolytic therapy, women who are breastfeeding should check
with their physicians before starting to breastfeed again.

Side effects

Anyone who has fever or who notices bleeding or oozing from their gums, from cuts, or from
the site where the thrombolytic agent was injected should immediately tell their health care
provider.

People who are given thrombolytic therapy should also be alert to the signs of bleeding inside
the body and should check with a physician immediately if any of the following symptoms
occur:

 blood in the urine

 blood in the stool, or black, tarry stools
 constipation
 coughing up blood
 vomiting blood or material that looks like coffee grounds
 nosebleeds
 unexpected or unusually heavy vaginal bleeding
 dizziness
 sudden, severe, or constant headaches
 pain or swelling in the abdomen or stomach
 back pain or backache
 severe or constant muscle pain or stiffness
 stiff, swollen, or painful joints

Other side effects of thrombolytic agents are possible. Anyone who has unusual symptoms
during or after thrombolytic therapy should tell a health care professional.
Interactions

People who take certain medicines may be at greater risk for severe bleeding when they receive
a thrombolytic agent. Anyone who is given a thrombolytic agent should tell the physician in
charge about all other prescription or nonprescription (over-the-counter) medicines he or she
is taking. Among the medicines that may increase the chance of bleeding are:

 aspirin and other medicines for pain and inflammation

 blood thinners (anticoagulants)
 antiseizure medicines, including divalproex (Depakote) and valproic acid (Depakene)
 cephalosporins, including cefamandole (Mandol), cefoperazone (Cefobid), and
cefotetan (Cefotan)

In addition, anyone who has been treated with anistreplase or streptokinase within the past year
should tell the physician in charge. These drugs may not work properly if they are given again,
so the physician may want to use a different thrombolytic agent.

Patients who are taking thrombolytic medications should not take vitamin E supplements or
certain herbal preparations without consulting their doctor. High doses of vitamin E can
increase the risk of hemorrhagic stroke. Ginger, borage, angelica, dong quai, feverfew, and
other herbs can intensify the anticlotting effect of thrombolytic medications and increase the
risk of bleeding.

Complications

One of the most significant complications encountered during catheter-directed arterial

thrombolysis is bleeding, particularly intracranial hemorrhage. Bleeding complications lead to
significant morbidity, such as lengthy hospital stays and multiple transfusions. The
International Study Group (1990) and the Collaborative Group (1988) have reported that
bleeding rates associated with treatment of acute myocardial infarction are less than 5%;
however, bleeding rates associated with catheter-directed techniques are usually greater than
5%. This occurs despite the fact that the total lytic dose administered for treatment of acute
myocardial infarction is higher than that for catheter-directed lysis.

One important concept introduced by Swischuk and Smouse to explain this discrepancy is that
a distinction should be made of two separate processes: fibrinolysis—the breakdown of
crosslinked fibrin and fibrinogenolysis—the breakdown of freely circulating fibrinogen. tPA,
like other lytic agents, causes fibrinolysis that involves the breakdown of fibrin into fibrin
degradation products (FSPs). One moiety of FSPs subsequently enters the circulation and
functionally serves to stimulate tPA activation of systemic plasminogen to plasmin, which in
turn breaks down further fibrin. This extra moiety also breaks down freely circulating
fibrinogen, leading to fibrinogenolysis.

During fibrinogenolysis, various degradation products are created. One of the fragments
produced has been shown in multiple experimental and clinical studies to play a role in the
occurrence of bleeding during catheter-directed thrombolysis. This entity decreases the
strength of thrombus hemostatic plug in a concentration-dependent fashion, such that higher
levels of this product lead to acceleration of clot lysis. It is believed that this fragment may be
incorporated in any existed thrombus including a distant hemostatic plug, thus leading to
increased rates of distant bleeding. Clinically measuring fibrinogen levels, therefore, does not
reliably predict bleeding complications because it is only a small factor in the cascade of events
occurring at a molecular level contributing to possible bleeding. Measuring specific FSPs is
not realistic in the typical hospital setting.

Precautions need to be taken even when using the more specific fibrin-specific drugs. Swischuk
and Smouse (2005) demonstrated that using tPA in doses greater than 1.5 mg/h in conjunction
with full heparinization led to higher rates of major bleeding. Their subsequent report in a
nonrandomized dose ranging study demonstrated that using lower doses of tPA as outlined
earlier with subtherapeutic heparinization significantly reduced bleeding. Therefore, the newer
fibrin-specific agents such as tPA should be used with caution because they have a relatively
narrower window of dosing safety. The authors' preference is to use tPA with subtherapeutic
heparinization at rates of 200 to 400 units per hour.

NURSES ROLE

PREINFUSION CARE

 Obtain nursing history, and perform a physical assessment. Information obtained from
the history and physical exam helps determine whether thrombolytic therapy is
appropriate. The goal is to initiate thrombolytic therapy within 30 minutes of arrival.
 Evaluate for contraindications to thrombolytic therapy: recent surgery or trauma
(including prolonged CPR), bleeding disorders or active bleeding, cerebral vascular
 accident, neurosurgery within the last 2 months, gastrointestinal ulcers, diabetic
hemorrhagic retinopathy, and uncontrolled hypertension.
 Thrombolytic agents dissolve clots and therefore may precipitate intracranial, internal,
or peripheral bleeding. Inform the client of the purpose of the therapy.
 Discuss the risk of bleeding and the need to keep the extremity immobile during and
after the infusion.Minimal movement of the extremity is necessary to prevent bleeding
from the infusion site.

DURING THE INFUSION

 Assess and record vital signs and the infusion site for hematoma or bleeding every 15
minutes for the first hour, every 30 minutes for the next 2 hours, and then hourly until
the intravenous catheter is discontinued.
 Assess pulses, color, sensation, and temperature of both extremities with each vital sign
check. Vital signs and the site are frequently assessed to detect possible complications.
Remind the client to keep the extremity still and straight.
 Do not elevate head of bed above 15 degrees. Extremity immobilization helps prevent
infusion site trauma and bleeding. Hypotension may develop keeping the bed flat helps
maintain cerebral perfusion.
 Maintain continuous cardiac monitoring during the infusion. Keep antidysrhythmic
drugs and the emergency cart readily available for treatment of significant
dysrhythmias. Ventricular dysrhythmias commonly occur with reperfusion of the
ischemic myocardium.

POSTINFUSION CARE

 Assess vital signs, distal pulses, and infusion site frequently as needed. The client
remains at high risk for bleeding following thrombolytic therapy.
 Evaluate response to therapy: normalization of ST segment, relief of chest pain,
reperfusion dysrhythmias, early peaking of the CK and CK-MB band. These are signs
that the clot has been dissolved and the myocardium is being reperfused.
 Maintain bed rest for 6 hours. Keep the head of the bed at or below 15 degrees.
Reinforce the need to keep the extremity straight and immobile.
 Avoid any injections for 24 hours after catheter removal. Precautions such as these are
important to prevent bleeding.
 Assess puncture sites for bleeding. On catheter removal hold direct pressure over the
site for at least 30 minutes. Apply a pressure dressing to any venous or arterial sites as
needed.
 Perform routine care in a gentle manner to avoid bruising or injury. Thrombolytic
therapy disrupts normal coagulation. Peripheral bleeding may occur at puncture sites,
and there may not be sufficient fibrin to form a clot. Direct or indirect pressure may be
needed to control the bleeding.
 Assess body fluids, including urine, vomitus, and feces, for evidence of bleeding;
frequently assess for changes in level of consciousness and manifestations of increased
intracranial pressure, which may indicate intracranial bleeding.
 Assess surgical sites for bleeding. Monitor hemoglobin and hematocrit levels,
prothrombin time (PT), and partial thromboplastin time (PTT). These provide
additional means of assessing for bleeding.
 Administer platelet-modifying drugs (e.g., aspirin, dipyridamole) as ordered. Platelet
inhibitors decrease platelet aggregation and adhesion and are used to prevent
reocclusion of the artery.
 Report manifestations of reocclusion, including changes in the ST segment, chest pain,
or dysrhythmias. Early recognition of reocclusion is vital to save myocardial tissue.
CONCLUSION

The native thrombolytic system, involving a balanced interaction between hemostasis and
fibrinolysis, can be enhanced via the administration of pharmacologic agents that aid in
intensifying the breakdown of thrombus/embolus by the production of a “lytic” state. This
“lytic” state occurs predominantly via the ultimate activation of plasminogen. Ever since
streptokinase became available, modifications have been made biochemically in efforts to
improve the specificity and efficiency of thrombolytic agents, and to minimize overall
complication rates. Although all thrombolytic agents ultimately result in the dissolution or
fragmentation of thrombus, these agents differ in their pharmacologic properties. The
management of patients with thromboembolic disease can be complex, and it is important to
understand the physiologic mechanisms that are undertaken when using thrombolytics in
various interventional treatment strategies.

In the setting of STEMI, fibrinolysis continues to be an option for reperfusion in non-PCI

centers and in patients presenting early (≤ 3 hours) where delay to invasive strategy is expected.
The evolution of thrombolytic drugs over the last 2 decades has seen transition from first
generation (SK, urokinase) to fibrin-specific, nonantigenic, second (alteplase, t-PA) and third
generation thrombolytics (rPA, TNK) with longer half lives, resistance to PAI-1, better 90
minutes patency rates and TFG3. In a given clinical setting, the choice of thrombolytic agent
should consider risk of mortality, ICH, age, timing of thrombolytic treatment and cost
effectiveness in a given health care system. Future research might see development of optimal
thrombolytic strategy with ability of maximal reperfusion and with minimal bleeding and
reocclusion complications.

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