THERAPY AND PREVENTION
TH
RoMBOLYSIS
Hemorrhage and the products of fibrinogen
digestion after intracoronary administration of
streptokinase
GERALD C. TIMMIS, M.D., V. GANCADHARAN, M.D., RENATO G. RAMOS, M.D.,
ANDREW M. HAUSER, M.D., DOUGLAS C. WESTVEER, M.D., JAMES STEWART, M.D.,
ROBERT GOODFLIESH, PH.D., AND SEYMOUR GORDON, M.D.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
ABSTRACT Hemorrhage was prospectively identified in 26 of 116 consecutive patients (23%) who
were receiving intracoronary streptokinase for occlusive coronary thrombi producing infarction. Bleeding was not influenced by the dose of streptokinase or the method of cardiac catheterization. Before
treatment, prothrombin time and partial thromboplastin time were normal in both bleeders and nonbleeders. Fibrinogen levels measured by bioassay after streptokinase (mean + SEM) were 62 29
mg/dl in patients with major bleeding, 1 11 ±+ 26 mg/dl in patients with minor bleeding, and 109 + 13
mg/dl in nonbleeders (p - NS). The regression slope b calculated from poststreptokinase fibrinogen
time-concentration data in 71 patients was 4.7 mg/dl/hr. However, mean fibrinogen concentrations
calculated at sequential 5 hr intervals revealed no net regeneration for the first 20 hr after thrombolysis.
The apparent fibrinogen regeneration rate was less than normal (31 mg/kg/day) for more than 10 hr but
10 mg/kg/day by the second day. The initial apparent latency of
subsequently increased to 94
fibrinogen regeneration paralleled the sharp rise in fibrinogen degradation products, which began to
decline after 20 hr of treatment but remained elevated well into the second day. Because of their
anticoagulant effects, these products may interfere with the fibrinogen assay, causing spuriously low
results. Thus, whether the early delay in fibrinogen regeneration is real or simply a reflection of the
effects of fibrinogen degradation products on the bioassay, it signals the time for caution in initiating
systemic- heparin therapy.
Circulation 69, No. 6, 1146-1152, 1984.
THE ASSOCIATION of hemorrhage with fibrinolysis
was recognized well before the introduction of enzymatic thrombolytic therapy for coronary thrombosis. 8
Various degrees of bleeding complicating streptokinase therapy have been recorded in about 15% of patients with occlusions of arteries or veins of limbs,
pelvis, or trunk and in about 40% of patients treated for
pulmonary embolism.9 Bleeding complications occurred in up to 18% when streptokinase was administered systemically for myocardial infarction.9-13 Some
patients who have experienced severe bleeding after
streptokinase therapy had undergone surgery within 8
days of treatment,1. 4, while others had had some other
condition likely to cause bleeding (e.g., translumbar
aortography or menstruation).2- 8 However, in some
cases severe bleeding has occurred for no obvious reaFrom the Division of Cardiovascular Diseases, William Beaumont
Hospital, Royal Oak, MI.
Address for correspondence: Gerald C. Timmis, M.D., Division of
Cardiovascular Diseases, William Beaumont Hospital, 3601 West Thirteen Mile Rd., Royal Oak, MI 48072.
Received Oct. 14, 1983; revision accepted Feb. 28, 1984.
1146
son, even with relatively low doses of intracoronary
streptokinse. 'l-'
The occurrence of complicating hemorrhage has
usually been associated with plasma proteolysis and a
resulting lytic state characterized by a decrease in plasminogen, shortening of the whole blood euglobulin
lysis time, a decrease in plasma-clottable protein (fibrinogen), the appearance of fibrinogen and fibrin degradation products (FDP-fdp), and prolongation of the
prothrombin time and thrombin time. This may contribute to the dissolution of hemostatic plugs remote
from coronary arterial thrombi.'6 On the other hand,
we have found that the risk of hemorrhage is not a
function of the success of thrombolysis or of its degree. 17 This is probably true because the degree of clot
dissolution does not always parallel the extent of the
lytic state resulting from the systemic effects of streptokinase. 18 19 Duckert et al.20 stated that the lytic state,
if severe, can contribute to hemorrhage; others have
suggested that this may be caused by lysis of hemostatic plugs. 21 22
CIRCULATION
THERAPY AND PREVENTION-THROMBOLYSIS
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The anticoagulant activity of FDP-fdp has long been
recognized.23 25 Various fragments of FDP-fdp are
known to interfere with thrombin activation, fibrin
polymerization, and platelet function.26 27 An electron
microscopically indentifiable abnormality in clot
structure has also been described,28 which apparently is
caused by fragments of normal plasma protein that can
alter the functional capacity of a fibrin clot and contribute to a hemorrhagic diathesis.
Thus the mechanisms of abnormal coagulation occurring with thrombolytic therapy are complex and as
yet incompletely defined. For example, fibrinogen regeneration after streptokinase has not yet been studied.
The problem is further compounded by the fact that
bleeding seems more likely to occur during treatment
with both streptokinase and heparin than with streptokinase alone. This may be particularly troublesome
during the transition to anticoagulation therapy at the
end of the infusion of streptokinase.*6 29, 30 We therefore attempted to resolve some of these issues by prospectively identifying the relationship, if any, of hemorrhage, systemic fibrinolysis, generation of FDP-fdp,
and fibrinogen regeneration after intracoronary administration of streptokinase.
once or twice daily for an additional 2 days. Plasma samples
were sufficiently diluted (1:20) and additional thrombin was
added as recommended by Morse et al .33 to override the spurious effects of therapeutically administered heparin. From 227
such determinations obtained from 71 patients (fibrinogen study
group) in whom fibrinogen data were available for analysis, a
time-concentration slope was computed. To further confirm the
validity of these random observations, the time-concentration
slope was recomputed from 73 data points obtained from 15 of
the 71 patients in whom at least four serial measurements of
poststreptokinase fibrinogen levels had been made. The apparent fibrinogen regeneration rate was estimated from 107 paired
sequential samples obtained from 59 patients in the fibrinogen
study group. In the latter analysis, fibrinogen regeneration rates
were computed by an estimation of male and female blood
volumes indexed to body weight34 and a ratio of total extra
cellular-to-intravascular fibrinogen of 1.3:1 (Takeda et al.36) as
follows:
plasma volume (ml)
men = 23.7 x height (cm) + 9.0 x weight (kg) - 1709
women
=
40.5 x height (cm) + 8.4 x weight (kg) - 4811
fibrinogen (mg/kg)
=
assay (mg/l) x plasma volume
weight (kg)
regeneration rate (mg/kg/day)
=
F2(mg/kg) - F1(mg/kg)
F,
Methods
A prospective assessment of 116 consecutive patients treated
with intracoronary streptokinase for acute or impending myocardial infarction was made for any evidence whatsoever of
bleeding. All patients underwent a pretreatment analysis of
complete blood count, platelet count, prothrombin time, partial
thromboplastin time, and fibrinogen level.31 The criteria for
patient selection and the details of therapy have been previously
reported.17' 32 In brief, within 5 hr of the onset of characteristic
chest pain, 206,575 + 66,849 IU (mean + SD) of streptokinase was infused into the arteriographically identified vessel
supplying the zone of infarct over 60 + 24 min. Before arteriograpic examination 5000 IU of heparin and 100 mg of hydrocortisone were administered by bolus injection. At the conclusion of the procedure, heparin was infused at an initial dose of
800 IU/hr, which was adjusted to maintain the activated clotting
time at 150 sec.33 The arterial catheter was left in place for 24 to
48 hr until fibrinogen levels were restored to at least 100 mg/dl
or more.
After the patient was returned to the cardiac care unit, any
evidence of bleeding, including even minor oozing around the
catheters, was prospectively recorded as a hemorrhagic complication. Major bleeding was defined as that causing death or
requiring three or more units of packed red blood cells. Minor
bleeding included minimal-to-negligible hematemesis, hemoptysis, or hematuria, as well as the more frequent episodes of
oozing at the catheter site.
After infusion of streptokinase, serial fibrinogen levels were
measured with a daily calibrated fibrometer (BBL Fibrosystem)
at 4 to 6 hr intervals until estimated fibrinogen levels had
reached at least 100 mg/dl; fibrinogen levels were serialized
*Sherry S: Discussion of "intracardiac thrombolysis - treatment of
myocardial infarction in the community hospital" presented at American College of Angiology, March 1982.
Vol. 69, No. 6, June 1984
(I) x 1.31
F2 interval (days)
where F, and F2 represent serial fibrinogen determinations. Values were expressed in milligrams per kilogram per day to facilitate comparisons with reported normal ar*l abnormal fibrinogen
synthesis rates.3538
Degradation products (FDP-fdp) were measured before and
serially at 4 to 6 hr intervals after treatment by agglutination of
antibody-coated latex particles with a commercial preparation
(Wellcome Reagents Ltd. *).39 40
Data were stored in the Wayne State University Amdahl
Model V-6/470 computer, which was accessed by a HewlettPackard terminal (Model 9830) with Statistical Package for
Social Sciences software. Regression slopes (b) of the fibrinogen time-concentration relationship were calculated from these
data. Streptokinase doses, clotting factors, and catheterization
techniques were compared for two subgroups of bleeders and a
third group of nonbleeders by means of a one-way analysis of
variance.
Results
Prevalence of bleeding. Bleeding was observed in 26
(23%) of 116 consecutive patients who were fastidiously monitored prospectively for this complication
(table 1). In nonbleeders mean fibrinogen levels before
and the lowest levels estimated by bioassay after streptokinase were 281 ± 11 and 110 + 13 mg/dl compared with 302 + 14 and 91 + 21 mg/dl in bleeders;
the decrement in the two groups was not significantly
different (p = .125). Thus poststreptokinase sequelae
*Wellcome Reagents Ltd.: Thrombo-Wellcotest rapid latex test for
detection of fibrinogen degradation. Wellcome Research Laboratories,
Beckenham BR3 3BS England, October 1981.
1147
TIMMIS et al.
TABLE 1
Prospective identification of hemorrhagic complications (see text)
Minor
Catheterization site
(ooze, hematoma)
Gastrointestinal
(hematemesis, melena)
Pulmonary (hemoptysis)
Urinary (hematuria)
Intra-abdominal
(retroperitoneal, omental)
Skin (ecchymoses)
Total
All episodes
Major/fatal
Major
Fatal
11
7
2
1
1
1
1
1
22
3
26 (23%)
4 (3.5%)
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
did not appear to be dependent on the change in fibrinogen levels after treatment.
Most instances of bleeding (22 patients) were minor
and included minimal-to-negligible hematemesis, hemoptysis, and hematuria, as well as the more frequent
episodes of oozing at the catheter site. These were not
influenced by the method of cardiac catheterization or
by the dose of streptokinase (table 2). Sixteen of the 22
patients with minor bleeding did so on the second,
third, or fourth day after the infusion of streptokinase.
Blood transfusions were administered to all four patients with major bleeding and to four patients with
minor bleeding.
Coagulation factors. Prothrombin time and partial
TABLE 2
Relationship of hemorrhage to dose of streptokinase, selected
coagulation factors before and after treatment, and catheterization
technique
Hemorrhage
Major
(n 4)
SK (IU x 103)
n > 200,000 IU
Pre-SKPT
n 25% > control
Pre-SK PTT
n 25% > control
Lowest fibrinogen
(mg/dl)
n < 100 mg%
Catheterization
Sones
Judkins
Both
213+13
2
11.3±0.3
0
28.8+0.7
0
62+28A
3
2
2
0
Minor
(n
23)
No
119+23
11
108 10
42
10
26
60
1
1148
bc,
NS
J1
NS
e)
E
NS
z
350
z
250
5 00
400
NS
Values are expressed as means ± SEM.
PT = prothrombin time; PTT = partial thromboplastin time: SK
streptokinase.
ASee text for individual values.
200
bleeding
(n
87) p value
224+12
202+8
13
47
11.7+0.2 11.7+0.2
0
1
26.1+1.0 27.8+0.5
0
13
0
thromboplastin time measured before infusion of
streptokinase were the same in patients developing
major and minor hemorrhage compared with those in
patients who did not display evidence of bleeding (table 2). Although about 10% of the "normal" population may have deficient levels of factor X114' and another small percentage of patients may have a lupuslike
anticoagulant,42 no patient in our study demonstrated a
partial thromboplastin time greater than 40 sec (our
upper limit of normal) and only 15 had values in excess
of 30 sec. Fibrinogen levels after streptokinase appeared to be most depressed in patients with major
hemorrhage but not to a significantly different degree;
individual values in this group were 20 mg/dl (patient
14), 26 mg/dl (patient 44; fatal), 60 mg/dl (patient 5 1),
and 140 mg/dl (patient 59). Approximately half of the
patients in both the groups with and without bleeding
displayed poststreptokinase fibrinogen levels of less
than 100 mg/dl.
A sufficient number of fibrinogen assays were performed in 71 patients to calculate a fibrinogen timeconcentration slope (figure 1). These data were further
analyzed by calculating the mean levels of fibrinogen
measured in 5 hr cells for the first 55 hr after streptokinase administration (figure 2). Although fibrinogen
levels remained above 1 00 mg/dl in many patients after
treatment, the pooling of all data suggested an apparent
latency in the restoration of fibrinogen levels lasting
for at least 20 hr.
To test the accuracy of the fibrinogen time-concentration slope displayed in figure 1, which was constructed from multiple random fibrinogen levels of
various numbers per patient, a second time-concentration slope was calculated from a subset of 15 patients
ct
W
m--
I.
150
100
50
0
*2
22.
b
u
Ibu
ur
El
,r.
(S
In
-
-
C
0
N
,n-
c'.
C
m
=
'1
C
U-
ID
tm
'It
4.7 mg/dl * hr-1
L1-
Xi
i
L.
I
0
w)
.D U W
G
N
HOURS POST-SK
FIGURE 1. Fibrinogen time-concentration relationship after streptokinase infusion. A regression slope (b) was calculated from 227 data
points obtained from 71 patients.
CIRCULATION
THERAPY AND PREVENTION-THROMBOLYSIS
400
380
360
340
450 F
400 1-
-J
350 t
-I1
3220
300
m
300
0n
E
280
260
250
m
240
200
z
LL
(D
0
-D
z
Lil
0
-D
z
150
m
5-4
100
m
L
50
LL
220
200
180
160
140
z
#.I
1 '20
100
80
60
1n
40
20 .n=
SK
0
-50
n
1
66
16
CD
U1
m
21
24
26
12
20
19
X
-
6
8
4
15
I
A
Ufl
-
N
m
m
t
to,8_.,,,5.,, ,.t
r-
1-
2
9
o3
In
In
t
Cna
ri
HOURS POST-SK
2
9
10
5
9
LA1
m
X
In
N
.1
rm
M
0
W)
IT
'r
D
X
HOURS POST-SK
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
FIGURE 2. Mean (-+- SEM) fibrinogen levels calculated for each serial
5 hr interval after the intracoronary infusion of streptokinase.
in whom at least four serial levels had been measured
after the infusion of streptokinase at intervals of no less
than 4 and usually 6 hr (figure 3). The nearly identical
slope b of 4.9 mg/dl/hr attests to the validity of figure
1. A similar apparent latency of fibrinogen regeneration was identified in these patients (figure 4). The
mean rate of apparent fibrinogen regeneration was estimated from 107 paired sequential samples obtained
from 59 of the 71 patients in the fibrinogen study group
(figure 5). This revealed that for 10 to 15 hr after
streptokinase infusion, the fibrinogen regeneration rate
was apparently depressed below reported normal levels (31.3 1.4 mg/kg/day).4 Thereafter the regeneration rate progressively increased to a new steady rate,
FIGURE 4. Mean (±+ SEM) fibrinogen levels calculated in serial 5 hr
cells after treatment. Data were obtained from that subset of patients in
whom at least four serial fibrinogen determinations had been measured
at 4 to 6 hr intervals.
more than three times normal, which lasted for at least
55 hr after streptokinase infusion. Because test data
deviated so strikingly in opposite directions from normal in the early and late fibrinogen recovery period,
regeneration rates were not assessed in additional normal controls; that is, reported values were accepted as
a reasonable fiducial benchmark.43
Serial levels of FDP-fdp were measured in 19 patients. These data are represented in figure 6 by a thirddegree polynomial curve of midrange data points because the Thrombo-Wellcotest yields range data rather
than specific levels (<10, 10 to 40, and >40 ug/ml).
This shows that these degradation products (the anti-
700
Lii
-,00
t,00
a:
180
550
-D
160
C
a:
E
35 03
140
z
3500
120
z
250
z
5-
r0
LU)
0
*~~~~~~~~~~~~ .
v
400
mean (20-55
hbs.)
94 + 10
mg/kg/day
100
WI
80
z
Lii
5-4
150
LID
C)
60
E
300
?j*w
250
4.88
b
t(
50
mg/dI
hr-
40
m
(L
20
1
---505
1
T.
n
&
-
-
-
Cm
OJ
IS
CO
L
m
IT
I
-
U-n
CD
Lin
W
W
n
HOURS POST-SK
FIGURE 3. Poststreptokinase fibrinogen time-concentration regression
slope (b) calculated from 73 data points obtained from 15 patients in
whom at least four fibrinogen levels were calculated at intervals of 4 to 6
hr after treatment.
Vol. 69, No. 6, June 1984
0
r_
(i)197.1
n lpairs)-=
_20
C- ti
10
15
19
17
10
13
an
a
5
7
4
-
C
(S
_i
m
( mn
C
mi-
Ci
Wr
HOURS POST-SK
FIGURE 5. Fibrinogen regeneration rate calculated from 107 pairs of
sequential fibrinogen determinations in 15 patients (see text).
1149
TIMMIS
et
al.
-J
E
3
crl0
m
-o
(4.
0
z
CL
It
U,
-
a
U,
X
N
a
W
U1
W
0
19
ID
W
HOURS POST-SK
FIGURE 6. Stylized time-concentration curve of fibrinogen degradation products superimposed on a plot of mean sequential 5 hr fibrinogen
levels.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
FDP globulin used in the assay reacts primarily with
the D and E fractions of the fibrinogen dimer) are most
plentiful during the period when the apparent latency
of fibrinogen regeneration is extant.
Discussion
Hemorrhage. The prevalence of bleeding after either
systemic or selective administration of streptokinase
for coronary thrombosis has ranged from 0% to
18%. 10-15 Although enzyme doses tend to be less with
intracoronary instillation, hemorrhage is not necessarily less likely when administered by this route. Thus
Merx et al. ,13 summarizing the experience of four West
German institutions, reported that 7% of their 204 patients had evidence of bleeding severe enough to require blood transfusions. Similarly, eight of our 116
patients (7%) also received transfusions.
Bleeding in our patients was neither related to a
preexisting hemorrhagic diathesis nor, in contrast to
other reports, to streptokinase dose.9 Moreover, the
fact that 16 of the 22 patients who displayed minor
bleeding did so on the second to fourth day after treatment suggests that influences other than fibrinolysis
may have been responsible. Thus the relatively short
half-life of FDP-fdp (9 hr) and the rapidly spent systemic proteolytic state resulting from streptokinase
(see below) suggest that anticoagulants may be the
basis for bleeding.
Plasma proteolysis and the lytic state. Although Gottlob
and Blumel4 and Gross et al. ,45 using autoradiographic
techniques, have shown that streptokinase diffuses into
blood clots in vitro over a period of several hours, the
digestion of circulating fibrinogen and fibrin occurs in
a matter of minutes.9 Accordingly, clot lysis and the
development of a systemic lytic state may be largely
independent of each other. 16 46 47 Streptokinase binds
1150
to amino acids of the plasminogen chain48 and changes
the conformation of this /82-globulin49 to form an equimolar activator complex. Once the plasminogen-activator complex has been formed it cleaves a single
arginyl-valine bond from other free plasminogen molecules to form plasmin,5-53 which is a nonspecific proteolytic enzyme with a modest preference for fibrinogen and fibrin.54 A lytic state may promptly ensue,
even though most if not all of the circulating plasmin is
almost immediately neutralized by union with an a2macroglobulin plasmin inhibitor, which forms an irreversible55 or weakly dissociable53 complex. Haysel and
Mosesson56 suggested that the plasmin-a2-macroglobulin complex retains some limited capacity to hydrolyze fibrinogen and chains of fibrinogen. Awareness of
this continuing hydrolysis (perpetuation of the lytic
state) is important in terms of the anticoagulant effects
of FDP-fdp, since the half-life of the plasmin-antiplasmin complex is 12 hr.55 The resulting intermediate (Y)
and late (D and E) soluble digestion fragments of fibrinogen may both spuriously affect the assay of fibrinogen and interact with heparin to cause bleeding.7"
Anticoagulation. The patients in this study were infused with heparin at the conclusion of the cardiac
catheterization. However, recommendations have recently been made that the inauguration of anticoagulant therapy be delayed for several hours, even though
no data exist on poststreptokinase fibrinogen or FDPfdp time-concentration curves. * On the other hand, the
need for anticoagulation after streptokinase is recognized by all who use thrombolytic therapy, since the
rethrombosis rate may exceed 15%. 17 Moreover, FDPfdp may paradoxically and unpredictably produce a
state of hypercoagulability during which factor VIIIlike activity increases the amount of thrombin that is
generated along with an increase in factor X. This may
shift the balance of an unstable coagulation system
toward further coagulation and extension of thrombosis.24 Therefore, in spite of its risk, anticoagulation is
essential.
Clinical implications. For several reasons, we suspect
that the apparent latency of fibrinogen recovery may
be an artifact reflecting the effects of FDP-fdp on the
fibrinogen assay itself since the usually reported latency of fibrinogen regeneration after stimuli such as injury, trauma, or surgery is only an hour or
two. 58, 58a, 58b, 59 Moreover, the production of FDP-fdp
within minutes of administration of streptokinase
would be expected to result in a positive feedback
*Sherry S: Discussion of -intracardiac thrombolysis -treatment of
myocardial infarction in the community hospital" presented at American College of Angiology, March 1982.
CIRCULATION
THERAPY AND PREVENTION-THROMBOLYSIS
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
mechanism (fractions D and E) on fibrinogen synthesis.60 Whether or not the initial flat (20 hr) portion of
the poststeptokinase fibrinogen time-concentration
curve is an artifact must await more precise methods of
determining the effect of FDP-fdp on the bioassay of
fibrinogen. Immunologic assays of fibrinogen and its
soluble serum derivatives should shed further light on
the extent and duration of fibrinolysis after streptokinase. In the meantime, a reasonable conclusion regarding the significance of the apparent latency of fibrinogen regeneration is that it reflects a sustained increase
in circulating FDP-fdp. Because of their anticoagulant
and antiplatelet effects, these degradation products
may be troublesome in the presence of heparin therapy. Accordingly, consideration may be given to delaying the infusion of heparin until the effects of FDPfdp have begun to dissipate.
15.
16.
17.
18.
19.
20.
21.
22.
We extend our thanks to Sheri Londal, R.N., and Constance
Kanelas, R.N., for their fastidious prospective monitoring of
this project and for their assistance in data acquisition.
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CIRCULATION
Hemorrhage and the products of fibrinogen digestion after intracoronary administration
of streptokinase.
G C Timmis, V Gangadharan, R G Ramos, A M Hauser, D C Westveer, J Stewart, R
Goodfliesh and S Gordon
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Circulation. 1984;69:1146-1152
doi: 10.1161/01.CIR.69.6.1146
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