Clin. Cardiol.
7, 138-147 (1984)
0 Clinical Cardiology Publishing Co., Inc.
Recent Advances Using Streptokinase for Acute Coronary Thrombosis
J. A. UDALL. M.D.,F.A.C.P.,F.A.C.C.
Departments of Medicine, PioneerHospitalof Los Angeles and University of CaliforniaIrvine, Collegeof Medicine, Irvine,
California, USA
Summary: Most important in comparison to earlier
European trials, streptokinase (STK) is administered
now at the earliest time possible after acute coronary
thrombosis. In this series, STK was started 2.5 (f1.5)
h after onset of chest pain, with reperfusion achieved ap-
proximately 1 h later in 6 (55%) of 11 patients treated.
Posttreatment angiograms will not be required to identify
thrombolysis if noninvasive indicators will prvoide this
information correctly. Early creatine kinase enzyme
peaking 8 to 15 h after chest pain appears to be the most
accurate marker available. Among untreated and unsuc-
cessfully treated patients, creatine kinase peaking usual-
ly occurs 18-36 h after chest pain. A large intravenous
STK loading dose of 1,500,OOO IU produces a plasma
concentration of approximately 500 IU/ml, equal to that
concentration employed originally by intracoronary infu-
sions. Such large doses have been employed in 60 pa-
tients thus far, without an unusual incidence or severity
of hemorrhages. High dose, ultmshort-term treatment for
Address for reprints:
John A. Udall, M.D.
Division of Cardiology
University of California. Irvine
Medical Center
101 City Drive South
Omnge, CA 92668, USA
Received: October 3, 1983
Accepted: November 25, 1983
only 1 h is being investigated now. Systemic STK pene-
trates most “blind coronary pouches” and gains access
to acute thrombi, as identified by radiocontrast material
washout during angiogmphy in patients with severe
coronary occlusions. Streptokinase exerts a significant
anticoagulant effect, not previous considered, which
may be beneficial in the prevention of new clot forma-
tion and the rapid dissolution of acute coronary thrombi.
Key words: coronary thrombosis, coronary heart
disease, streptokinase
Introduction
Streptokinase (STK) has been administered intra-
venously (i.v.) to a large number of patients with acute
myocardial infarction in Europe during the last two
decades, but the results have been obscured by long
delays of 12 to 72 hours in treatment, reliance upon mor-
tality results to determine efficacy, and a lack of
discrimination between thrombogenic and nonthrom-
bogenic infarcts. These limitations notwithstanding, the
overall results from 11 European randomized clinical
trials have been favorable (Simon er al., 1973). In the
latest of these, death rates during the first six months
after infarct were 15.6% among 156 treated patients
compared to 30.6% among 159 controls (pC0.01) (Ver-
strate et al., 1979). Despite these reports, streptokinase
has been used very little in the United States, largely
 J. A. Udall: Use of streptokinase for acute coronary thrombosis
because risks of bleeding are perceived to outweigh
potential benefits. And these risks are real; cerebral
hemorrhages have occurred in 1% and other serious
bleeding in approximately 5% of several hundred pa-
tients treated for various thrombotic diseases (Sherry et
al., 1980;Thayer, 1981;Verstrate et al., 1979).
Long delays in the initiation of STK therapy in the
European trials stemmed from early animal experiments
which suggested that myocardial necrosis follows total
coronary occlusion rapidly, within 45-60 minutes (Blum-
gart et al., 1941;Prinzmetal et al., 1949;Savranoglu et
al., 1959; Tennant and Wiggers, 1935), and coronary
thrombolysis requires 3 to 7 hours of treatment (Rueg-
segger et al., 1959). Early investigators concluded that
clot lysis time exceeds the ischemic tolerance time for
myocardial necrosis (Ruegsegger et al., 1960). As a
result, treatment was not directed to the acute thrombus,
but to the prevention of secondary thrombi (Aber et al.,
1976). More recent evidence indicates an ischemic area
of canine myocardium usually remains viable for 3-6
hours or longer (Ginks et al., 1972; Reimer et al.,
1977), and coronay thrombolysis occurs within 20-60
minutes in both animals (Ganz er al., 1981)and humans
(Mathey er al., 1981;Rentrop et al., 1981) with acute
infarcts. Thus, a favorable time period exists in which
ischemic zones of myocardium may be preserved by
prompt coronary reperfusion, and the importance of an
immediate diagnosis followed by thrombolytic therapy at
the earliest possible time is becoming very clear.
Coronary catheters have been used to very good ad-
vantage recently in three new roles: angiographic identi-
fication of acute thrombosis, administration of nitro-
glycerin and/or streptokinase directly into an occluded
artery, and angiographic documentation of therapeutic
success or failure. Coronary thrombosis has been re-
established as the proximate cause of transmural infarcts
in 70-90% of patients studied recently by autopsy
(Ridolfi and Hutchins, 1977)and coronary angiography
(DeWood et al., 1980);and intracoronary (i.c.) throm-
bolysis has been successful in 80% of the first 90 pa-
tients reported (Ganz et d.,1981;Mathey et al., 1981;
Rentrop et al., 1981). In addition, thrombolysis and
reperfusion have been achieved rapidly in these patients,
in the first 25-30 min of treatment on the average.
These impressive results using i.c. streptokinase have
aroused new interest in the potential benefits of early in-
travenous (i.v.) therapy. Lee and associates (1981)were
first to document the successful use of i.v. STK with pre-
and posttreatment angiograms in 1981.Schroeder et al.
(1981)then reported favorable results among 69 patients
treated i.v. with 500,000 IU. Ten of 22 patients in this
series exhibited coronary reperfusion by angiography
within one hour. Neuhaus and associates (1981)also
obtained successful coronary thrombolysis with angio-
graphic documentation among 6 of 9 patients treated
with 1,700,OOOIU of STK i.v. for one hour only. The
stage is set now for a critical comparison of the advan-
139
tages and disadvantages of i.v. versus i.c. STK delivery,
using pre- and posttreatment angiographic end points.
The National Institutes of Health initiated such a study
August 20, 1982 and a comparable study is also under-
way in Europe, headed by Professors P. Schroeder and
K. Neuhaus (Spaan et al., 1982). If emergency throm-
bolysis can be achieved in the majority of patients treated
intravenously, this will probably emerge as the preferred
technique because of its simplicity, lower risks and ex-
pense, and applicability in community hospitals which
do not have angiographic capabilities.
While coronary angiography will remain at the center
of a complete investigation of both routes of STK
therapy, pretreatment angiograms are not required for an
early diagnosis of acute thrombosis in most patients, and
posttreatment angiograms will not be required to deter-
mine the success or failure of thrombolysis if one or
more noninvasive indicators will provide this informa-
tion accurately. These indirect markers include an early
appearance and peaking of creatine kinase (CK) enzyme
curves, rapid EKG changes toward normal, reperfusion
arrhythmias, and scintigraphic evidence of myocardial
reperfusion (Udall, 1983).
Noninvasive Markers of Coronary Reperfusion
Rapid EKG changes toward normal and sudden car-
diac arrhythmias following coronary reperfusion in ex-
perimental animals were first identified almost 50 years
ago (Tennant and Wiggers, 1935). Schmutzler et al.
(1966) and other Europeans identified rapid EKG
changes and early CK peaking among certain patients
with STK-treated infarcts several years ago, but these
clues were not pursued as potential markers of successful
therapy, largely because angiographic correlations were
unavailable to validate these end points. Early CK peak-
ing and rapid EKG evolution have been identified with
certainty as useful markers of coronary thrombolysis on-
ly during the last three years.
CK enzymes peak faster after coronary reperfusion
consistently in patients treated successfully, compared to
untreated and unsuccessfully treated patients. Myocar-
dial reperfusion quite obviously changes the circulatory
characteristics of an evolving infarct and leads to a rapid
flush of cardiac enzymes into the blood stream. These
enzymes then rise quickly and peak early. Three in-
vestigators have reported early CK peaking at 9-14
hours after the onset of cardiac symptoms in 68 patients
treated successfully with STK, compared to 25 hours on
average among 19 patients in whom treatment failed
(Ganz et al., 1981;Mathey et al., 1981;Schwarz et al.,
1982).CK peaking has occurred late among 384 patients
with untreated myocardial infarcts at 26.4 h on the
average after the onset of chest pain (Udall, 1983). This
temporal separation is very distinct, and this differentia-
tion provides the most reliable noninvasive marker of
coronary thrombolysis now available.
140 Clin. Cardiol. Vol. 7, March 1984

Early reperfusion of acute infarcts and rapid evolution
of EKG ST-segment abnormalities are now well-
established correlates in both animal (Ganz et al., 1981)
and humans (Ganz et af., 1981; Mathey et al., 1981;
Rentrop et al., 1981). It has been shown by angiography
that ST segment changes appear within minutes after
coronary reperfusion has occurred in most patients. In
addition, many patients exhibit ventricular arrhythmias.
These EKG indicators serve to mark the approximate
time of coronary reperfusion, while early CK peaking
serves to confirm the event several hours later. Sudden
relief of chest pain may mark the occurrence of reperfu-
sion, but its subjectivity and the many variables which
influence pain during the treatment of acute infarcts
render this indicator of little value. Thallium 201
myocardial scintigraphy before and after STK therapy
may be used to assess therapeutic success or failure, but
various technical problems must be overcome before this
test can be applied widely in routine patient care (Udall,
1983).
Patients Treated
An initial experience with 11 patients is summarized
in Tables I and 11. Each sustained an acute myocardial
infarct as evidenced by more than 30 minutes of chest
pain, plus elevations of EKG ST segments and serum
CK enzymes including MB fractions. The average time
from pain onset to hospital arrival was 1.6 (f2.4) h and
from pain onset to STK therapy was 2.5 (f1.5) h. Ten
patients survived and one experienced bleeding. This pa-
tient developed a hematoma in the right gmin after the
femoral artery was punctured inadvertently during the
process of femoral vein cannulation for pulmonary artery
pressure measurements. A tight pressure dressing was
applied but bleeding continued, and this was diverted
subcutaneously into the scrotum by the tight dressing.
Complete resolution occurred within 8 weeks.
The patient who died (#3) was atypical. He was excep-
tionally young, experienced several additional chest
pains after admission, required multiple electrical car-
dioversions for ventricular fibrillation, developed car-
diogenic shock, and then died on the third hospital day
in spite of aggressive medical management. His CK
curve peaked early, 15 hours after chest pain onset,
probably due to multiple cardioversions rather than cor-
onary reperfusion. Autopsy revealed a large anteroseptal
infarct, exceptionally small coronary arteries, minimal
atherosclerosis and a small thrombus in the left anterior
artery which could not be dated by the pathologist as
having occurred pre- or postinfarct.
Six patients (#I, 2, 4, 5 , 8, 9) exhibited early CK
peaking at 11.4 (53.9) h after chest pain onset (ex-
cluding patient #3 who died), whereas the remaining 4
peaked at 23.2 (f3.0)h. EKG ST segments descended
promptly to the baseline within four hours of STK
therapy in 5 patients having early CK peaking, but in
none of the other patients treated. Patient #4 exhibited
early CK peaking, but ST-segment elevations have re-
mained elevated for many months. Coronary angiog-
raphy in this patient thme weeks after infarct revealed
patency of the left anterior artery with a 30% residual
stenosis. A sizable anteroapical aneurysm was found on

TABLEI Results of streptokinase therapy for acute transmyocardial infarcts

Time (h) Loading Time to CPK peaking Max fold Time for EKG Reperfusion
Patients Age Date chest pain dose STK H after H after CK rise ST descent arrhythmias
to STK" Rx (U) STK Rx chest pain above normal (h p STK Rx) (h p STK Rx)
1 58 2/21/82 1.5 250,000 8.5 10.0 34 1 .o 1 .o
2 67 8/21/82 2.5 500,000 7.5 10.0 5 3.2
3 36 9/13/82 3.0 500,000 12.0 15.0 40b >4.0
4 47 9/14/82 2.2 500,000 5.3 7.5 21 >4.0
5 63 9/22/82 2.2 1,500,000 9.8 12.0 7 0.8 1.1
6 36 10116/82 2.1 500,000 19.2 24.0 9 >4.0
7 58 10128182 2.8 500,000 19.7 22.5 9 >4.0 0.8
8 70 11/23/82 2.3 500,000 10.7 13.0 11 2.2 1.2
9 58 1120183 3.0 500,ooo 10.8 13.8 8 2.6
10 63 7130183 4.0 500,000 17 21 6 >4.0
11 63 8/5/83 2.0 500,000 23 25 18" >4.0
Average 2.5 (f1.5)
~ ~ _ _ ~~~

" STK = streptokinase

After 5 electrical cardioversions
After 7 electrical cardioversions
 J. A. Udall: Use of streptokinase for acute coronary thrombosis 141

left ventriculography. In spite of early coronary throm-
bolysis and reperfusion, a major anterior infarct probably
occurred in this patient within 3 hours of chest pain
onset. Frequent premature ventricular beats were observ-
ed in 3 of the 6 patients having early CK peaking, at ap-
proximately 1 hour after treatment inititation, and these
were easily controlled with i.v. lidocaine. One patient
(#7) having late CK peaking exhibited frequent ven-
tricular premature beats approximately 1 hour after STK
was begun.
Coagulation tests and fibrinogen levels were distinctly
abnormal in all patients during therapy. Average pro-
thrombin times were elevated more than 1%-fold above
normal and average fibrinogen levels fell to % normal
(Table 11). Thus a substantial hypocoagulable state was
induced in each patient treated.
Coronary angiograms were performed 3 weeks after
infarction in 4 patients having early CK peaking. All
showed patent infarct-related arteries and a variable
degree of arteriosclerosis in each. Angiograms were ob-
tained in 3 patients having late CK peaking. The infarct-
involved artery was completely occluded in patient W I ,
slightly patent in patient #9 with severe underlying
atherosclerosis, and totally patent in patient #6 with a
large fusiform aneurysm of the infarct-related artery.
Coronary thrombolysis was concluded to be successful
in all patients having early CK peaking. The cause of
acute myocardial infarction in patients #3 and #6 remains
unclear.
Practical Recommendations
Streptokinase should be administered on an emergency
basis, within minutes of a clear diagnosis, because the
infarct process in most patients will be complete within
6 to 12 hours. Applying this same argument, treatment
will not be beneficial beyond 12 hours after chest pain
onset. A loading dose of 500,000 IU STK administered

TABLEI1 Results of streptokinase therapy for acute transmywardid infarcts

Coagulation tests during first six hours of therapy
Coronary Activated partial
angiography Serum Thrombin thromboplastin Prothrombin
% occlusion Therapeutic fibrogen time time time
Patients of infarct artery success (n=200-400 mg%) (n< 14 s) (n< 14 s) (n< 13 s)

1 20% RCA" + 75 27 38 16
95 21 56 18
2 90% RCA + 55 39 111 28
25 21 48 18
3 - 0 100 53 27
68 100 68 32
4 30% LAD^ + 52 100 51 16
0 100 68 19
5 85% RCA + 0 17 44 26
0 19 51 37
6 0% LAD - 90 20 36 17
75 41 42 21
7 100% RCA - 157 60 37 16
55 87 29 17
8 + 107 100 45 29
73 100 40 28
9 95% RCA + 15 100 48 32
32 100 100 48
10 - 20 100 26 27
20 100 38 31
11 - 75 44 18 15
100 65 17 16
Average 49 66 43 22

a RCA = right coronary artery

LAD = left anterior descending coronary artery
142 Clin. Cardiol. Vol. 7, March 1984
over five minutes is recommended at present, followed
by 200,000 IU/h for 6 to 9 hours in most patients treated.
Long periods of treatment for 24 to 72 hours are un-
necessary, and probably add to the risks of hemorrhage.
Following STK therapy, heparin should be administered
within 2 to 4 hours for at least four days, and warfarin
also for at least 30 days to prevent coronary rethrom-
bosis. Healing of a ruptured coronary plaque, the precip-
itating cause for most thrombi (Ridolfi ef al., 1977),
should be complete 30 days after the acute event. Acute
infarct-related thrombi are usually fresh when most pa-
tients reach hospitals, often only l to 3 hours old. In ad-
dition, these thrombi are usually small, measuring only
0.5-2 mm in diameter and 2-10 mm in length (Ridolfi
et al., 1977). Because of these favorable characteristics,
thrombi dissolve readily in most patients treated with
concentrated STK, usually within 20-60 minutes. Time
required for coronary thrombolysis varies directly with
the age of an occluding thrombus, according to recent
canine experiments (Karsch er al., 1983). The
therapeutic objective is a limited one-the rapid reper-
fusion of a thrombosed artery to that extent which will
abort the infarct process. To achieve this goal, it is
becoming more evident that STK should be administered
quickly, and in a substantial dosage.
Optimal loading and maintenance doses of strep-
tokinase are unknown. Higher doses may achive throm-
bolysis more quickly, and in a higher percentage of pa-
tients treated. In view of the highly successful results ob-
tained recently with intracoronary STK, it is appropriate
now to explore the potential benefits and additional risks
of larger systemic doses of STK, e.g., a loading dose of
1,500,000 IU and a maintenance infusion of 250,000
IU/h. Preliminary results from high dose i.v. STK
therapy here and abroad are encouraging. Coronary
thrombolysis has been achieved in 58% of 60 patients
treated thus far with 1,500,000 to 1,700,000 IU ad-
ministered i.v. for 60 minutes, and with no serious
hemorrhages ob+rved to date (Spaan ef al., 1982).
Maintenance doses of STK may not be required follow-
ing a single infusion of 850,000 IU or more for one hour,
according to Spaan and Sherry (1982).
Contraindications to therapy are uncommon among
ambulatory and otherwise healthy patients, but each
should be evaluated specifically and quickly. These in-
volve a recent history of internal bleeding, major
surgery, or stroke within 2 months; and advanced age
( > than 75 years). Relative contraindications should be
evaluated specifically as well: severe hypertension
(210/110 mmHg), cardiopulmonary resuscitation, recent
trauma with possible internal injuries, and evidence of
hepatic or renal insufficiency (Sherry et al., 1980).
Serious bleeding can be minimized greatly by selecting
patients carefully, and by avoiding all invasive pro-
cedures immediately before and during treatment.
Severe adverse reactions to STK are rare. Most febrile
and allergic responses do not require discontinuation of
therapy. Mild bleeding of the gums and around
venapuncture sites are common and may be disregarded
safely. More serious bleeding should prompt a discon-
tinuation of treatment in most cases. Fresh whole blood
or frozen plama should be administered for severe
bleeding to replace blood loss and replenish fibrinogen
and other clotting factors. This will serve to offset the
anticoagulant effect of STK, to be discussed later. Ep-
silon aminocaproic acid therapy should be considered
also in the event of severe bleeding to arrest the
fibrinolytic action of STK.
Pretreatment thrombin time and fibrinogen tests are
recommended, then repeat tests one hour later. The sec-
ond results should be assessed within minutes by the
clinician to assure therapeutic efficacy. Significant ah-
normalities will occur in most patients, indicating a
desired fibrinolytic and anticoagulant effect of STK. A
thrombin test above 1% times normal and fibrinogen
level reduced by 30% or more are satisfactory end
points, Rarely these tests may not change with treatment,
and antibody resistance to STK is the usual cause.
Should this occur, a prompt switch to urokinase therapy
is recommended.
Three venous catheters should be placed in the arms
before treatment-one for the STK infusion, a second for
all other i.v. drugs and fluids, and a third for blood
samples to monitor treatment. Thrombin and fibrinogen
levels are recommended to monitor STK therapy, partial
thromboplastin and prothrombin times to monitor
heparin and warfarin therapy, hematocrit tests to detect
occult bleeding, and serial CK enzyme levels at 2 hour
intervals to assess thrombolytic therapy. These i.v. lines
should be well placed early to minimize bleeding from
multiple venapunctures during therapy. All arterial punc-
tures should be avoided. The deep jugular, subclavian
and femoral veins should not be cannulated because of
adjacent arterial punctures which may occur.
To determine the success or failure of thrombolytic
therapy, serum CK enzyme tests are recommended every
2 hours for 24 hours, plus a single EKG lead recorded
every 15 minutes for 4 hours. That EKG lead showing
the greatest ST-segment elevation should be recorded,
and double standardization is recommended to detect
early changes. The ST injury current configuration
usually changes several minutes before it begins to de-
scend in patients treated successfully. A return to the
isoelectric line usually follows within 30 to 90 minutes.
Reperfusion arrhythmias appear in many patients, about
the time ST segments begin their descent. These ar-
rhythmias are often evanescent and require close obser-
vation between 20 and 90 minutes after treatment
initiation.
Streptokinase therapy probably should be limited to
patients with transmural infarcts at present (Gorlin,
1982; Muller, 1983). These may be identified in other-
wise healthy adults who experience sudden precordial
pains lasting at least 30 minutes and who exhibit EKG
 J. A. Udall: Use of streptokinase for acute coronary thrombosis
ST-segment elevations in selected leads reflecting a
given area of ischemic myocardium. Approximately
80% of these infarcts are triggered by acute coronary
thrombi (DeWood et al., 1980; Ganz et al., 1981;
Mathey et al., 1981; Muller, 1983; Rentrop et al.,
1981). On the other hand, most patients having suben-
docardial infarcts probably should not be treated because
the majority of these are not thmmbogenic. Most result
from acute coronary insufficiency syndromes, including
arrhythmias, hypotension, hypovolemia, coronary spasm,
increased oxygen demand, or combinationsof the above.
Subendocardial infarcts tend to occur in patients having
other serious illnesses, and precordial pain is often not
their dominant complaint. Electrocardiogramsordinarily
show ST-segment depression and/or T-wave inversion in
multiple leads reflecting a large area of ischemic myo-
cardium. In the absence of angiographic evidence of
complete coronary occlusion, STK therapy is not recom-
mended for most patients with subendocardial infarcts.
The Streptokinase Dose
Doses of streptokinase for various thrombotic diseases
have been devised empirically for the most part. Optimal
dases and durations of treatment for acute coronary
thrombosis may be identified more scientifically now by
pre- and posttreatment angiogmphy, for both i.v. and
i.c. routes of administration. By the intravenous route,
loading doses of 100,000 to 1,250,000 IU were
employed in the 11 European trials conducted in the past
two decades, followed by maintenance doses of 100,000
to 250,000 IU/h for 3-72 h (Simon et al., 1973). Large
i.v. loading doses of 600,000 and 1,250,000 IU were ad-
ministered by Heinkinheimo et al. (1971) and Amery
(1969) in 219 and 83 patients, respectively. Unusual
severity and numbers of hemorrhagic complications
were not observed. The Frankfurt Group was first to sug-
gest a high dose, short-term course of therapy as the
most beneficial and least hazardous (Simon et al., 1973).
Accordingly, these investigators administered 250,000
IU/h for 3 h only and reported favorable results. Mortali-
ty rates were 12.7% among 122 patients treated and
27.9% among 104 controls (p<O.Ol). More recently
even larger doses of 1,500,000 IU and 1,700,000 IU
have been administered to 60 patients during a single
hour in an effort to arrest the progress of myocardial
necrosis (Spaan et al., 1982).
By the intracoronary route, 2000 IU/min of STK was
administered by the original investigators in 70 patients
for 30 to 90 min (Mathey et al., 1981; Rentrop et al.,
1981). By this route it has been assumed that throm-
bolysis results from the first pass of STK across the prox-
imal surface of coronary thrombi, and not from any
recirculating systemic effect. More recently, interest has
centered upon the earliest possible identification and
dissolution of acute coronary thmmbi in an effort to pro-
tect ischemic areas of myocardium. This objective leads
143
quite naturally to an exploration of large i.v. doses of
STK which might be administered rapidly, briefly, and
safely. It would be highly desirable to obtain total body
plasma concentrations by the i.v. mute equal to those
concentrations which have been administered directly by
the intracoronary route of delivery. Would it be safe to
infuse STK systemically in dosages sufficiently large to
achieve plasma levels comparable to those which have
been infused directly by intracoronary catheters? This
can be done more readily than has been supposed by us-
ing systemic doses in excess of 1,000,000 IU, already
shown to be relatively safe among 148 patients treated by
Amery et al. (1969), Schroeder et al. (1981), and
Neuhaus et al. (1981), as reported by Spaan et al.
(1983).
What are these intravenous and intracoronary dose
relationships? Intracoronary streptokinase was ad-
ministered by the original investigators in a dosage of
2000 IU/min. To obtain this dose, Rentrop et al. (1981)
prepared a saline solution of 250 IU/ml which was
delivered at 8 ml/min by infusion pump. Mathey and
associates (1981) employed a Ringers solution of 500
IU/ml which was delivered at 4 ml/min. These concen-
trations can be matched in the total plasma pool by ad-
ministering relatively large doses systemically. Adults of
average size (70 kg) contain a total plasma pool of ap-
proximately 3000 ml (43 ml/kg). In patients of average
size, 750,000 IU of i.v. STK given rapidly results in a
plasma concentration of 250 U/ml, which equals the
concentration that Rentmp administered by coronary
catheter. A larger dose of 1,500,ooO IU given rapidly
results in a plasma concentration of 500 U/ml in a patient
of average size. This was the concentration of STK that
Mathey administered by coronary catheter. Therefore,
STK concentrations which have been selected for cor-
onary catheter infusions can be matched in the total
plasma pool by rapid infusions of 750,000 to 1,500,000
IU in patients of average size. Based upon an estimated
streptokinase degradation rate of 20%/h in the plasma
pool, an i.v. maintenance dose of 150,000 to 300,000
IU/h would be required to sustain plasma concentrations
of 250 to 500 IU/ml for several hours of treatment. Such
large loading and maintenancedoses have been used suc-
cessfully and without great hazard by earlier (Amery et
al., 1969; Heinkinheirno et al., 1971) and more recent
(Spaan et al., 1982) investigators of i.v. STK therapy.
The dose relationships and concentrations of STK
employed by i.v. and i.c. routes of administration are
much more alike than have been identified thus far in the
literature.
Streptokinase Sprays and Blind Pouches
Two questions pertaining to hydraulics are of con-
siderable interest in a comparison of i.c. and i.v. throm-
bolytic therapy. An implication exists that STK is
144 Clin. Cadiol. Vol. 7, March 1984
sprayed form the tip of a coronary catheter onto the sur-
face of a fresh thrombus and this characteristic adds to
therapeutic efficacy. This may be visualized as a spray
of warm water on a snowball. This concept has been
fostered by the rapidity with which i.c. STK has been
shown to dissolve thrombi, i.e., within 25-30 min of
treatment (Ganz et al., 1981; Rentrop et al., 1981). This
perception, however, is probably more imagery than
reality. Fourto 8 ml/min of STK administered i.c. by the
original investigators equals no more than 1 and 2
dmpsls, respectively, which is hardly a spray. The cur-
rent method of dripping STK from a catheter in the
vicinity of a coronary thrombus probably does not repre-
sent a significant advantage over systemic therapy. On
the other hand, STK administered systemically in large
amounts probably reaches the distal surface of an oc-
cluding thrombus by retrograde flow through collateral
vessels in many patients, and this action may represent
a significant advantage for i.v. therapy.
Ganz et al. (1981) and others have implied that cir-
culating plasma fails to penetrate blind arterial pouches
created by acute coronary thrombi, and therefore cathe-
ters are required to fill such pouches directly with STK.
Experience with mutine coronary angiography and the
fate of contrast material (CM) shed a good deal of light
on this question. Once the proximal segment of an oc-
cluded coronary artery has been filled with CM, we have
observed various sequelae which are dependent upon the
normal and pathologic anatomy of each artery involved,
as shown in Fig. 1. The fate of CM in each arrangement
probably represents an accurate model as to the flow of
FIG.1 Five illustrations of coronary arteries and acute thrombotic occlusions, proximal and distal, incomplete and total. Intravenous
streptokinase reaches those thrombi shown in arteries A to D, but does not penetrate readily the “blind pouch” created in artery E.
plasma containing STK in coronary arteries which are
occluded similarly.
Contrast material is usually washed out quickly if a
coronary occlusion is located close to the ostium, ap-
parently by reflux. CM is also washed out quickly by
direct flow if an occlusion is deep in the artery, but in-
complete (Fig. 1, A, B). CM is washed out equally fast
if there ate visible branches just proximal to a deep oc-
clusion which is complete (Fig. 1, C). CM usually
disappears more gradually, within 5 or 10 minutes after
angiography, in certain patients having no visible cor-
onary branches proximal to a deep occlusion which is
complete (Fig. 1, D). This washout of contrast material
is postulated to occur through microscopic branches
proximal to the occlusion. In certain other patients hav-
ing no visible branches proximal to a deep occlusion
which is complete, CM has been observed to hang up in
a blind coronary pouch for more than 30 minutes (Fig.
1, E). Thus, true blind coronary pouches come to exist
only in a small minority of patients having acute cor-
onary occlusion. In most cases, the proximal segments
of occluded arteries are flushed clear of contrast material
within a few seconds or minutes. It is logical to conclude
from these observations that plasma containing STK
gains access to most coronary thrombi within several
minutes after an i.v. infusion, and a continuous supply
of STK is maintained at thrombotic interfaces by
recognized blood flow patterns. Failure of intravenous
STK to penetrate tme blind pouches may account for a
small portion of therapeutic failures when the results of
i.v. and i x . coronary routes of ,therapy are compared.
 J. A. Udall: Use of streptokinase for acute coronary thrombosis
The Anticoagulant Action of Streptokinase
In the shadow of its powerful thrombolytic action there
exists a substantial anticoagulant effect of STK which
has been overlooked in early pharmacological reviews
(Fletcher et al., 1962) and clinical discussions (Moser
and Hajjar, 1960). The proof is well established. Strep-
tokinase converts circulating and clot-bound plasmino-
gen by enzymatic action into plasmin. This in turn exerts
a powerful proteolytic action, much like trypsin, in the
digestion of several plasma coagulation proteins in-
cluding factors I (fibrinogen), V (pmacceleran), VIII
(anti-hemophiliacglobulin), and possibly others, as well
as fibrin (Alkjaersig er al., 1959; Sherry, 1978). This
reduction or depletion of clotting factors leads to a pro-
longation of standard coagulation tests (thrombin, pro-
thrombin, and activated partial thromboplastin times),
and a hemorrhagic diathesis which may be observed
clinically in certain patients (Fletcher et al., 1959). Thus
all the criteria for an anticoagulant dtyg are fulfilled by
STK: i.e., a depletion (as with warfarin) or inhibition (as
with heparin) of certain clotting factors, the induction of
a hypocoaguable state, and a hemorrhagic diathesis.
Anticoagulation in this instance is effected by the
mechanism of a proteolytic coagulopathy, and it occurs
in all patients treated except for a few having very high
streptococcal antibody resistance to the action of STK.
Of further interest, is the anticoagulant effect of STK
which is measured routinely to assure therapeutic ef-
ficacy, i.e, the prolongation of one or more coagulation
tests, and not a shortening of the euglobulin lysis time or
other clot lysis tests which measure the “lytic state” in-
duced by STK (Sherry et al., 1980).
Routine coagulation tests ordinarily rise 1%-fold
above normal or higher within two hours of STK
therapy, and plasma fibrinogen levels usually fall to less
than one-half normal, as shown in Table 11. In their in-
itial investigationsof 2 1 patients, Fletcher and associates
(1959) found pretreatment fibrinogen levels fell from
344 ( f86) mg % on average to 183 ( f76) mg % after 14
to 20 hours of therapy. One stage prothrombin times rose
from 15.9 (&1,7) s to 29.9 (k11)s after 6 to 8 hours
of treatment. Prothrombin times rose exceptionally high
in several of these patients and STK therapy had to be
terminated in the interests of patient safety. Thrombin
time elevations paralleled the rise of prothrombin times.
While the coagulation defect induced by STK was
discussed thoroughly by Fletcher and Sherry (1959), the
therapeutic anticoagulant connection was not made. Nor
has this connection been made subsequently by these or
other investigators (Moser and Hajjar, 1960). This
hypocoaguable state has been perceived as an undesir-
able secondary effect only which adds to the risks of
hemorrhage, rather than a potentially beneficial con-
comitant action in the treatment of occlusive thrombi.
What are the advantages and disadvantages of this anti-
coagulant action of STK, if any, as a separate antithrom-
145
botic process during the course of therapy? These two
questions have several mmifications and the answers are
unclear.
The growth of clots and their disintegration are
dynamic and competitive processes which occur in the
maintenance of hemostasis, healing after vascular in-
juries, and in the natural evolution of intravascular throm-
botic occlusions. Clot growth and propagation dominate
during the early or acute phases, while clot dissolution
and organization dominate in the late or healing phases.
In this dynamic milieu, STK exerts three antithrombotic
effects simultaneously: the inhibition of new clot forma-
tion by anticoagulation, the proteolysis of new fibrin
strands as they polymerize at plasma-clot interfaces, and
the digestion of the fibrin matrix inside clots which have
already formed by the activation of clot-bound plasmin-
ogen (Alkjaersig et al., 1959; Fletcher et ul.. 1962).
Clot growth and new clot formation may be arrested
completely by the powerful thrombolytic action of con-
centrated streptokinase. If this is true, the anticoagulant
effect of STK would be inconsequential fmm a thera-
peutic viewpoint. In like manner, the anticoagulant ac-
tion of heparin given concurrently with STK would be
therapeutically inconsequential. If this is not true, the
anticoagulant effect of STK, and also that of heparin,
may be quite beneficial by allowing thrombolysis to pro-
ceed rapidly, uninhibited by new fibrin formation at
plasmaclot interfaces. More research is needed on this
question.
Concurrent heparin anticoagulation was avoided by
the early investigators who were aware of the proteolytic
coagulopathy induced by STK and who were rightly con-
cerned about hemorrhagic complications which may be
exacerbated by heparin therapy. Moser speculated about
the benefits of combined heparin and STK therapy in
1962 and suggested that the advantages in achieving
prompt thrombolysis and avoiding rethrombosis out-
weigh the added risks of hemorrhagic complications.
Very recently, Schroeder et al. (1981), Neuhaus et al.
(1981), and Spaan er al. (1982) have administered hepa-
rin and STK concurrently in patients with acute coronary
thrombosis in an effort to achieve rapid and maximal
thrombolysis during a very short course of therapy, i.e.,
60 minutes. Is combined therapy more efficacious, more
hazardous, neither, or both? The answers are not yet
known.
Recognizing that STK exerts an anticoagulant action
of its own, that hemorrhagic complications of a serious
nature may occur without warning, that heparin may ex-
acerbate such hemorrhages, and that added benefit from
heparin therapy has not been established, it is recom-
mended presently that heparin and STK should not be
administered concurrently in the treatment of acute cor-
onary thrombosis. Approximately 2-4 hours after STK
therapy, however, both heparin and warfarin should be
administered, and the latter should be continued for at
least 30 days to prevent rethrombosis at the site of the
original ulcerated coronary plaque I
146 Clin. Cardiol. Vol. 7, March 1984
Hemorrhagic Complications
Hemostasis, the containment of blood in vascular
channels, is served by 3 interrelated mechanisms: the in-
tegrity of vascular walls, adequate numbers of healthy
platelets and nonnal coagulation. Any one of these
systems may be severely impaired under various cir-
cumstances without serious or fatal hemorrhages in most
patients, if the other two mechanisms are functioning
normally. To illustrate, multiple dental extractions in-
volving innumerable vascular disruptions can be carried
out at one sitting without serious bleeding in most
healthy people. However, if teeth are extracted from a
hemophiliac patient having a major factor VIII deficien-
cy, severe osteal and gingival bleeding will usually
follow. These illustrations serve as models to predict
hemorrhagic events which may occur during aggressive
STK therapy. Such treatment is very well tolerated in
most patients having adequate platelets and normal
vasculature throughout the body. Ordinarily there will be
no bleeding at all, or a mild bleeding tendency may be
observed. However, moderate to severe bleeding may be
expected regularly among patients having significant
vascular disruptions before or during STK therapy.
These include arterial punctures with large needles,
arterial catheterizations, and active gastrointestinal
ulcerations most commonly. In this framework it is ob-
vious why patients should be selected for STK therapy
with great caution, why patients who may have signifi-
cant vascular injuries or diseases should not be treated,
and why arterial punctures and other invasive procedures
should be avoided assiduously during treatment.
Intracranial hemorrhages Rpresent a particularly
serious risk incurred by patients treated with STK.
Hemorrhagic strokes have o c c u d in 4 of 461 patients
reported to date (Thayer, 1981; Verstrate er al., 1979).
Most have appeaTd in patients treated for relatively long
periods, from 24 to 72 hours, and the risks of hemor-
rhage may be a function of treatment time. Shorter treat-
ment periods have been suggested recently and very brief
treatments for 60 minutes only are being investigated
now (Spaan er al., 1982). Hopefully, infrashort-term
therapy for only an hour may result in fewer hemorrhagic
strokes, and other types of hemorrhages as well. It is not
clear why certain patients experience hemorrhagic
cerebd events while a great majority do not, even
though large doses of STK are administered for 24 to 72
hours. An underlying cerebral artenovenous malforma-
tion has been suspected in those having bled. Suda con-
genital anomalies are not detectable ordinarily by clinical
examination or by routine brain x-rays. In the future,
computerized tomographic x-rays of the brain may pro-
vide a valuable pretreatment screening test for arterio-
venous malformations, and for other types of intracranial
pathology as well which may predispose to hemorrhage.
References
Aber CP, Bass NM, Beny CL: Streptokinase in acute myocar-
dial infarction: A controlled multicenter study in the
United Kingdom. Br Med J 2, 1100 (1976)
Alkgaersig N, Fletcher AP, Sherry S: The mechanism of clot
dissolution by plasmin. J Clin Invest 38, 1086 (1959)
Amery A, Reber G, Vermeulen HE: Single-blind randomized
multicenter trial comparing heparin and streptokinase
treatment in recent myocardial infarction. Acta Med Scund
(Suppl) 505. 5 (1969)
Blumgart HL, Gilligan DR, Schlesinger MJ: Experimental
studies on the effect of temporary occlusion of coronary
arteries. Am Heurt J 22, 374 (1941)
DeWood MA, Spores J, Notske R Prevalance of total cor-
onary occlusion during the early hours of transmud
myocardial infarction. N Engl J Med 303, 897 (1980)
Fletcher AP, Alkjaersig N, Sheny S: Pathogenesis of the
coagulation defect developing during pathological plasma
proteolytic (“Fibrinolytic”) states. J Clin Invest 41, 896
(1962)
Fletcher AP, Alkjaersig N, Sheny S: The- maintenance of sus-
tained thrombolytic state in man. I. Induction and effects.
J Clin Invest 38, 1096 (1959)
Ganz W, Buchbinder N, Marcus H: Intracoronary thmm-
bolysis in evolving myocardial infarction. Am Heart J 101,
4 (1981)
Ginks WR,Sybers HD, Maroko PR, Covell JW, Sobel BE:
Coronary artery reperfusion. J Clin Invest 5 1,2717 (1 972)
Gorlin R: Fibrinolytic therapy in thromboembolic disease.
Hosp Pruct 17, 146 (1982)
Heikinheimo R, Ahrenberg P, Honkapohja H: Fibrinolytic
treatment in acute myocardial infarction. Acta Med Scund
189, 7 (1971)
Karsch KR, Hoffman M, Rentrop KP, Blanke H, Schaper W:
Thrombolysisin acute experimental myocardial infarction.
J Am Coll Cardiol 1 (2), 427 (1983)
Lee G, Amsterdam EA, Low RL, DeMaria AN, Mason DT:
Coronary thrombolysis in acute myocardial infarction. Am
Heart J 102, 783 (1981)
Mathey Mi, Kuck KH, Tilsner V, Krebber HJ, Bleifeld W:
Nonsurgical coronary artery recanalization in acute
transmural myocardial infarction. Circulation 63, 489
(1981)
Moser KM, Hajjar GC:The combined use of fibrinolytic and
anticoagulant drugs. Laboratory and clinical considera-
tions. Am J Cardiol6, 496 (1960)
Muller JE: Coronary artery thrombosis: Historical aspects. J
Am Coll Cardiol 3, 893 (1983)
Neuhaus KL, Koestering H, Tebbe W, Sauer G, Kreuzer H:
High-dose intravenous streptokinase infusion in acute
myocardial infamion. 2 Kurdiol70, 791 (1981)
Prinzmetal M, Schwartz LL, Corday E, Spritzler R, Bergman
HC, Kmger HE: Studies on the coronary circulation. IV
loss of myocardial contractility after coronary occlusion.
Ann Intern Med 3 1, 429 (1949)
Reimer KA, Lowe JE, Rasmussen MM, Jennings RB: The
wave front phenomenon of ischemic cell death. Circula-
tion 56, 786 (1977)
Rentmp P, Blanke H, Karsch KR, Kaiser H, Koestering H,
Leitz K: Selective intracoronary thrombolysis in acute
myocatdial infaiction and unstable angina pectoris. Cir-
culation 63, 307 (1981)
 J. A. Uddl: Use of stqtokinase for acute cornnary thrombosis
Ridolfi RL, Hutchins GM: The relationship between coronary
arterial lesions and myocardial infarcts: Ulceration of
atherosclerotic plaques precipitating coronary thrombosis.
Am Heart J 93, 468 (1977)
Ruegsegger P, Nydick I, Hutter RC: Fibrinolytic (plasmin)
therapy of experimental c0r0~1-ythrombi with alteration
of the evolution of myocardial infarction. Circulation 19,
7 (1959)
Ruegsegger P, Nydick I, Abarquez R, Reichel R, Clifton EE,
LaDue JS: Effect of fibrinolytic (plasmin) therapy on the
physiopathology of myocardial infarction. Am J Cardiol 6 ,
519 (1960)
Savranoglu N, Boucek RJ, Casten GG: The extent of revers-
ibility of myocardial ischemia in dogs. Am Heart J 58,726
(1959)
Schmutzler VR, Heckner F, Kortage P: On the thrombolytic
therapy for recent myocardial infarction. Dtsch Med
Wochenschr 91, 55 (1966)
Schmeder R, Biamino G, Von Leitner ER: Intravenous short-
time thrombolysis in acute myocardial infarction. Circula-
tion 64 (Supp IV) IV-10 (abstr) (1981)
Schwan F, Schuler G, Katus H, Mehmel HC, Olshausen K,
Hoffman M, Hemnann H, Kubler W: Intracoronary
thrombolysis in acute myocardial infarction: Correlations
147
among serum enzyme, scintigraphic and hemodynamic
findings. Am J Cardiol 50, 32 (1982)
Sherry S: Personal reflections on the development of throm-
bolytic therapy and its application to acute coronary throm-
bosis. Am Heart1 102 (#6, part 2), 1134 (1981)
Sherry S, Bell WR, Duckert FH, Fletcher AP, Gurewich V,
Long DM, Marder VJ, Roberts H, Salzman EW,Sasahara
A, Verstraete M: Thrombolytic therapy in thrombosis: A
National Institute of Health Concensus Development Con-
ference. Ann Intern Med 93, 141 (1980)
Simon TL, Ware JH, Stengle JM: Clinical trials of throm-
bolytic agents in myocardial infarction. Ann Intern Med
79, 712 (1973)
Spaan JF, Sherry S, Cahello BA: High-dose intravenous strep-
tokinase early in acute myocardial infarction. Am Heart J
104, 939 (1982)
Tennant R, Wiggers CJ: The effects of coronary occlusion on
myocardial contraction. Am J Physiol 112, 351 (1935)
Thayer CF: Results of post-marketing surveillance program on
streptokinase. Curr Therap Res 30, 129 (1981)
Udall JA: Noninvasive markers of intravenous streptokinase
coronary thrombolysis. Clin Cardiol 6, 86 (1983)
Verstrate M,Amery A, Besteman E: *ptokinase in acute
myocardial infarction. N Engl J Med 301, 797 (1979)