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T U B AMERICAN JOURNAL OF CLINICAL PATHOLOGY
Vol. 41, No. 6, pp. 589-596
September, 1964
Copyright © 1864 by The Williams & Wilkins Co.
Printed in U.S.A.
T H E USE OF T H E SERIAL THROMBIN T I M E IN EVALUATING THERAPY
WITH EPSILON AMINOCAPROIC ACID IN MASSIVE THROMBOLYSIS
AND PROTEOLYSIS
TSADORE BRODSKY, M.D., EVELYN ROSS, AND WILLIAM 0. RE ID, M.D.
Department of Medicine, Section of Hematology, Hahnemann Medical College and Hospital,
Philadelphia, Pennsylvania
The serial thrombin time (STT) method,
originally developed by Wilhelm and associates,22 is an attractive test for thrombolysis and proteolysis because of its simplicity,
rapidity, and convenience. The value of the
STT has recently been emphasized by
Ingrain and Matchett, 9 Reid and his associates,10' " and Tocantins and his colleagues.21 Ingram and Matchett demonstrated a linear relation between
proportionate loss of clot weight and a
proportionate increase in thrombin clotting
time after adding increasing quantities of
streptokinase-activated plasma.9 In the
study reported below, the STT was used in
conjunction with the euglobulin lysis time
in order to evaluate epsilon aminocaproic
acid (EACA) therapy in massive thrombolysis and proteolysis secondary to metastatic carcinoma of the prostate. The STT
was a good measure of thrombolytic activity
and correlated better than the euglobulin
lysis time with the onset or cessation of
bleeding during therapy with EACA.
M A T E R I A L AND
METHODS
Pseudomonas polysaccharide (Piromen*)
50 Mg- per ml., was injected intravenously
in a dose of 25 MgReceived, October 4, 1963; revision received
January 13, 1964; accepted for publication March
2.
Dr. Brodsky is Assistant Professor of Medicine,
and Head of the Section of Hematology, Hahnemann Medical College and Hospital. Miss Ross is
Research Associate in Hematology. Dr. Reid is
Research Associate and Assistant Member,
Cardeza Foundation, Department of Medicine,
Jefferson Medical College, Philadelphia, Pennsylvania.
This work was aided by the Public Health
Service Grant H C3CS, Department of Health,
Education, and Welfare, Bethesda, Maryland.
* Travenol Laboratories Incorporated, Morton
Grove, Illinois.
EACAf was administered in the form of
500-mg. tablets or a parenteral preparation
(250 mg. per ml.), or both. Parenteral EACA
was administered in the form of a 10 per
cent solution in 5 per cent glucose in water.
Human thrombin (FibrindexJ) 50 units
per vial was used in the STT.
Coagulation studies included direct platelet count by means of the Brecher-Cronkite
technic;4 clotting time in glass and silicone;
1-stage prothrombin time using human
brain thromboplastin; 14 thrombotest; 13 Stypven time (to assay Factor X 3 ); Factor V;3
Factor All 1 0 assays, and thromboplastin
generation test. 2 Fibrinogen levels were
assayed by a semiquantitative method.10
Thrombolysis and proteolysis were studied
by means of the whole blood clot lysis time.
The euglobulin lysis time was performed
with the methods of Buckell6 (normal
range for this laboratory: 218 db 10 min.),
and Iatridis and Ferguson7 (normal range
for this laboratory: 371 ± 17 min.). The
method of Iatridis and Ferguson was used
only after the pyrogen stimulation and not
during EACA therapy.
The STT was performed by means of
the modified method of Reid and associates.16, 17 Blood (4.5 ml.) was collected in
an oxalated vacuum tube (Vacutainer
No. 3206 BD) by means of a nontraumatic
venipuncture. The blood was mixed thoroughly and immediately centrifuged at
3400 r.p.m. (International clinical centrifuge) for 5 min. After centrifugation, 1.4 ml.
of plasma was distributed in 0.2-ml. aliquots
into each of 7, 12- by 75-mm. test tubes
(non-siliconized). The rack of tubes was
placed in a water bath at 26 C. and tested
in sequence at 0, 1, 2, 4, and 24 hr. as
589
f Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York.
J Ortho Pharmaceutical Corporation, Raritan,
New Jersey.
590
BRODSKY BT
TABLE 1
N O R M A L VALUES OF S E R I A L T H R O M B I N
TIME
IN SECONDS
Immediate
1-hr.
2-hr.
4-hr.
24-hr.
5.2
G.l
10.0
64.9
± 0.45*
± 0.54
± 2.63
± 33.80
>240
* Mean ± s t a n d a r d deviation.
follows: 1 ml. of 0.85 per cent saline solution
was added to a vial of Fibrindex and 0.2
ml. of this solution was added at each given
time interval. The tube was then tilted
gently through an arc of approximately 80
degrees from the vertical to the horizontal
and back at least 90 times per min. The
time required for a coagulum to form was
recorded with a stop-watch. If no coagulum
formed within 4 min., the test was discontinued and the result recorded as greater
than 4 min. ( > 4 ' ) . Normal values for the
STT in our laboratory are listed in Table 1.
The most significant determinations are
those made immediately, at 1 hr., and at 2
hr. The normal values are in close agreement
with those reported by Reid and his associates.17 In this paper only the immediate
and the 1-hr.. STT results are reported,
inasmuch as the values at these times
correlated quickly and accurately with the
response to EACA therapy and provided a
good measure of thrombolysis.
REPORT OF CASE
A 72-year-old white man was admitted to
Hahnemann Hospital in April 1963, with
massive epistaxis and hematuria. The
patient was known to have carcinoma of the
prostate gland for 10 years. The diagnosis
was established by means of biopsy following a transurethral resection. During this
time he was treated with diethylstilbestrol
5 mg. t.i.d. The patient refused orchiectomy.
In February 1963, he developed mild
hematuria that subsided spontaneously. At
that time he was admitted to Hahnemann
Hospital, and roentgenograms revealed
extensive osteoblastic metastases involving
the pelvis, lumbar spine, and ribs. Therapy
with estrogens was continued. The patient
Vol. 41
AL.
still refused orchiectomy. The pertinent
physical findings consisted of pallor, tachycardia, and obvious epistaxis and hematuria. The hemoglobin was 5.8 Gm. per 100
ml., white blood cell count 8500 per cu. mm.
The differential was within normal limits.
The BUN was 15 mg. per 100 ml., serum
calcium was 10 mg. per 100 ml., and phosphorus 4 mg. per 100 ml. The serum alkaline
phosphatase and serum acid phosphatase
were 19 and 3.0 Bodansky units, respectively. Therapy was immediately instituted
with EACA as indicated in the results
below. During the first 24 hr., the patient
received 2 units of whole blood after the
institution of EACA therapy. After the
cessation of bleeding, bone marrow studies
performed from both the sternum and posterior iliac crest demonstrated invasion of
the marrow with metastatic carcinoma cells.
Forty four days after the patient's admission to the hospital, treatment with EACA
was discontinued and no additional bleeding
occurred. The patient was discharged from
the hospital 62 days after admission.
RESULTS
Studies of blood coagulation prior to tire
start of therapy with EACA are summarized
in Table 2. The clotting times in glass and
silicone were normal, but thrombolysis
was greatly increased in view of the 10-min.
whole blood clot lysis time. By means of the
assay methods used in this study, there was
an apparent decrease in the 1-stage prothrombin time; thrombotest; Factors V,
VII, X, and fibrinogen. The platelet count
was elevated and the thromboplastin generation test was normal. Forty-two hours
after the start of treatment with EACA, the
blood coagulation factors returned to almost
normal limits and there was a significant
drop in the platelet count. Within 62 hr.,
all of the blood coagulation factors had
returned to normal. The STT, the euglobulin
lysis times, and their variations during
bleeding and EACA therapy are illustrated
graphically in Figures 1 and 2. The values
are plotted on a semilogarithmic scale for
purposes of convenience in presentation of
data and not to imply a first-order reaction.
Prior to the start of EACA therapy, the
June 196J,
591
AMIN0CAPR01C ACID THERAPY
TABLE 2
COAGULATION
PROFILES
Platelet count
Thromboplastin
tion test
genera-
1-stage prothrombin time
Thrombotest
Factor
V (accelerator
globulin)
Factor VJI (proconvertin)
Stypven time (Factor X)
Estimation of semiquantitative fibrinogen
Clotting time (in glass)
Clotting time (in silicone)
Whole blood clot lysis
time
BEFORE
AND D U R I N G
EPSILON
AMINOCAPROIC
ACID
(EACA)
0 Mr.*
18 Hr.
42 Hr.
62 Hr.
504,000
251,000
237,000
230,000
100%
(7.0 sec. in
3 min.)
23%
30%
43%
100%
(7.4 sec. in 4
min.)
41%
34%
73%
100%
(9.8 sec. in 3
min.)
55%
43%
74%
100%
(10.8 sec. in 5
min.)
S9%
50%
00%
54%
81%
88%
100%
THERAPY
Normal Values
150,000400,000
S0-100%
80-100%
40-100%
70-100%
S0-100%
30.0 sec.
<75 mg.
18.G sec.
75-125 mg.
10.9 sec.
75-125 mg.
15.2 sec.
125 mg.
13-15 sec.
125 mg.
13 min.
23 min.
10 min.
8 min. 30 sec.
15 min. 0 sec.
13 min.
7 min. 45 sec.
19 min. 0 sec.
24 hr.
9 min. 30 sec.
17 min. 0 sec.
>24 hr.
8-12 min.
10-20 min.
24 hr.
Immediately before s t a r t of EACA therapy.
STT was greatly prolonged immediately
and at 1 hr. (54 sec. and >240 sec, respectively). The euglobulin lysis time was unobtainable because of failure of a clot to
form.1 Lack of a coagulum with the euglobulin lysis time is recorded as 0 in Figures 1,
2, and 3. The patient was treated initially
with 5 Gm. of parenteral EACA. The EACA
was infused in 30 min. and bleeding stopped
promptly in approximately 20 to 30 min.,
at which time blood transfusions were
started. Three hours after the first infusion
of EACA, the STT immediate was 18 sec.
and 1 hr. >240 sec. The euglobulin lysis
time was still unobtainable. Severe bleeding
again developed and another 5 Gm. of
parenteral EACA were administered over a
30-min. period, and again the bleeding was
controlled. In addition to the parenteral
EACA, 2 Gm. of oral EACA were administered to the patient every 4 hr. Although
the epistaxis stopped, mild hematuria
continued until the STT immediate and 1
hr. reached normal limits. This occurred
approximately 18 to 20 hr. after the start
of treatment. It is of interest that at this
point the euglobulin lysis time was still
reduced and did not return to normal limits
until approximately 32 to 40 hr. after the
start of treatment. In 4 days, the EACA
dosage was reduced to 1 Gm. every 6 hr.
(Fig. 2). Six days later, there was a sharp
rise in the STT and reduction in euglobulin
lysis time. Within 24 hr., epistaxis and
hematuria developed. Five grams of parenteral EACA were administered and the oral
dose increased to 1 Gm. every 3 hr. The oral
dosage was continued for 48 hr. and then
reduced to 1 Gm. every 6 hr. Five days later
the STT again became elevated, the euglobulin lysis time becoming unobtainable. EACA
dosage was increased to 2 Gm. every 4 hr.
in an attempt to prevent hemorrhage, but
severe bleeding again developed and 5 Gm.
of parenteral EACA was administered.
EACA was then continued in an oral dose of
8 Gm. per day for the next 12 days, and the
dosage was then reduced to 6 Gm. daily.
Slight elevations in the 1-hr. STT occurred
on the 29th, 40th, and 47th day after admission. These elevations were not associated with any significant bleeding. EACA
was discontinued on the 44th day and there
was a sharp reduction in euglobulin lysis
time as well as an increase in the 1-hr. STT.
Slight hematuria occurred, but there was no
592
BRODSKY ET
NO
II
J
EL
Vol. 41
AL.
SLEEPING
a
EUGLOBULIN CLOT LYSIS
THROMBIN TIMEfimmedwte reading)
THROMBIN TIMEIc™ hour main,)
I.V. DOSAGE
16
20
24
HOURS
FIG. 1. Effect of epsilon aminocaproic acid (EACA) on serial thrombin time
(STT) and euglobulin lysis time for first 48 hr. of therapy.
* Lower limit of normal for euglobulin lysis time—2 standard deviations from
mean; normal range, 218 ± 10.0 min.
** Upper limit of normal for STT at 1 hr.—3 standard deviations from the mean;
normal range, 6.1 ± 0.54 sec.
massive bleeding. The hematuria subsided
spontaneously, no further therapy with
EACA being required.
Seven days after stopping EACA, a dose
of pyrogen was injected, and a typical response was noted. There was a conspicuous
rise in temperature, white blood cell count,
and significant reduction in the euglobulin
lysis time. The results of pyrogen stimulation are illustrated graphically in Figure 3.
The euglobulin lysis time remained reduced
for 48 hr. On the first day there was only a
slight rise in the 1-hr. STT, but by the second
day the immediate and 1-hr. STT were
elevated. At this point the euglobulin lysis
time was unobtainable. The STT immediate
and 1-hr. became normal in 24-hr. In this
experiment the euglobulin lysis times were
performed by means of the Buckell as well
as the Iatridis methods. There was no significant difference in the results. In Figure 3,
only the results of the Buckell method are
illustrated. Mild hematuria occurred within
24 hr. after injection, but the bleeding
stopped spontaneously. There was no change
in the blood coagulation factors at this time.
Injection of pyrogen into 4 normal controls resulted in a characteristic response,
with reduction in euglobulin lysis time, and
no change in the STT.
DISCUSSION
A hemorrhagic state in patients with
prostatic carcinoma secondary to abnormal
June 1964
593
AMINOCAPHOIC ACID THERAPY
NO
, HO BLEEDING, B * > BLEEPINGg
BLEE D I N G
EUGLOBULIN CLOT LYSIS
THROMBIN TlMEpmf'ediott reading)
THROMBIN TIMEtor* nojr reading)
I.V. DOSAGE
ORAL DOSAGE
240
D A Y S
Fro,. 2. Effect of epsilon aminocaproic acid (EACA) on serial thrombin
time (STT), euglobulin lysis time, and clinical course from the 3rd to 51st
clays of treatment.
"fibrinolytic activity" has been well documented.20 Sherry and associates18 have suggested that the terms "fibrinolysis" and
"fibrinolytic activity" are misleading and
should be restricted to the action of proteolytic enzymes upon the protein fibrin.
In this paper the term "thrombolysis"
describes the entire mechanism or activity by
which thrombi are lysed and the term "proteolysis" describes the series of changes
produced by plasmin or other proteolytic
enzymes acting upon susceptible plasma
proteins.18 In the past, the term "fibrinolysis" was used to encompass thrombolysis,
fibrinolysis, and proteolysis. Present theory
suggests that when plasminogen is activated
in the plasma (soluble phase), the resulting
plasmin is rapidly neutralized by antiplasmin, whereas plasminogen activation in a
clot (gel phase) leads to thrombolysis. 6 In
abnormal hemorrhagic states, excess free
plasmin in the plasma causes fibrinolysis,
proteolysis, and severe coagulation defects.13
It is of interest that the prostate gland is
known to contain high levels of soluble
plasminogen activator. 18 In the example
described in this paper, massive thrombolysis
and proteolysis were present. Prior to EACA
therapy the coagulation profile demonstrated
decreased levels of fibrinogen, prothrombin,
Factor V, Factor VII, and Factor X. The
decreased levels of the above factors could
be explained on the basis of: (1) initial
hypofibrinogenemia, (2) fibrinolytic activity during performance of the assay procedure, and (3) release of anti-thrombin 6
(fibrinogen polymerization inhibitor) during
fibrinolysis.17 A direct proteolytic effect on
the individual coagulation factor must also
be considered. Severe thrombolysis was
594
BRODSKY ET
Vol. 41
AL.
n
NO
BLEEDING
i
NO
_, :
-BLEEDING..;
NO
BLEEDING
•120
2
•EUGLOBULIN CLOT LYSIS
'THROMBIN TIMEl immediate reading)
•THROMBIN TIME lone hour reading)
BO
27
21
\
15
9
',(^Ofc>—
DAY
51
OAY
52
DAY
53
FIG. 3. Effect of administration of pyrogen on the STT, euglobulin lysis
time, and clinical course for 48 hr.
* Lower limit of normal for euglobulin lysis time—2 standard deviations
from mean; normal range, 218 ± 10.0 min.
** Upper limit of normal for STT at 1 hr.—3 standard deviations from the
mean; normal range, 6.1 ± 0.54 sec.
indicated by the whole blood clot lysis time,
euglobulin lysis time, and STT. The platelet
count was elevated and the first stage of
coagulation, as measured by the thromboplastin generation test, was normal to accelerated. Hyperplasminemia is associated
with proteolysis and results in a decrease in
fibrinogen, prothrombin, Factor V, and
complement.6 Although it would seem, on
the basis of the above findings, that abnormal activation of the plasminogen-plasmin
system was entirely responsible for the
hemorrhagic state, a second explanation
must also be considered. It is possible that
the release of a thromboplastic substance
into the circulation might also lead to a
hemorrhagic state by causing intravascular
clotting with resultant defibrination and
consumption of coagulation factors.
Prior to the start of EACA the platelet
count was elevated and the thromboplastin
generation test was slightly accelerated. This
might suggest a hypercoagulable state in the
first stage of coagulation; however, it would
be difficult to explain depressions of Factor
VII and X on the basis of intravascular
clotting. These 2 factors are activated by
clotting. In a case of prostatic carcinoma
presented by Rapaport and Chapman, 16 the
second explanation was believed to be the
major factor in the hemorrhagic state because of the demonstration of hypercoagulability in the presence of hypofibrinogenemia.
June 1964
595
AMINOCAPHOIC ACID THERAPY
It is possible that activation of the plasminogen-plasmin system as well as release
of thrornboplastic substance into the circulation is responsible for the hemorrhagic
state in this case. Recent studies by Iatridis
and Ferguson7 have demonstrated that
Hageman Factor will activate not only the
coagulation system but also the plasminogen-plasmin system, as measured by means
of the euglobulin lysis time. In this study,
with the exception of a slightly elevated
platelet count prior to therapy, we were
unable to demonstrate definitely a hypercoagulable state. All studies indicated that
thrombolysis and proteolysis were the major
factors in the abnormal bleeding. EACA, a
potent and specific inhibitor of plasminogen
activators such as streptokinase, stopped the
bleeding almost immediately.19 Within 24
hr. depressed clotting factors returned to
normal levels. The inhibitory effect of EACA
on plasmin is almost negligible.19
EACA was first administered parenterally
but, because of the rapid renal clearance,
oral EACA was instituted. Oral administration is highly effective because the drug
is rapidly and predictably absorbed from the
gastrointestinal tract. Peak plasma levels
are obtained approximately 2 hr. after a
single oral dose.11,12
The 2 technics used serially to follow this
patient's disordered thrombolytic activity
were the euglobulin lysis time and the STT.
The euglobulin lysis time has been frequently
used as a measure of over-all plasma "fibrinolytic activity," but recent studies have
demonstrated that it is a qualitative and
perhaps even quantitative measure of
plasminogen activators. 8 After the start of
EACA, the STT correlated well with the
cessation of bleeding, but the euglobulin
lysis time remained decreased for approximately 40 hr. Each episode of subsequent
bleeding requiring increased dosage of EACA
was preceded by an increase in the STT.
Cessation of bleeding coincided with an
immediate decrease in the STT, but the
euglobulin lysis time remained reduced for
approximately 24 hr. The pyrogen injection
resulted in an immediate significant reduction in the euglobulin lysis time, but only a
slight increase in the 1-hr. STT occurred.
Both the euglobulin lysis time and the immediate and 1-hr. STT were abnormal 24
hr. later. This was associated with minimal
hematuria. The euglobulin lysis time was
still reduced and the STT was well within
normal limits 48 hr. later. Injection of
pyrogen into 4 apparently normal persons in
our laboratory resulted in a significant
reduction in the euglobulin lysis time but no
change in the STT. I t is apparent that the
STT does not correlate well with the
euglobulin lysis time, during spontaneous
thrombolysis and proteolysis or during
pyrogen-induced activation of the plasminogen-plasmin system. The euglobulin
lysis time is probably a much more sensitive
test for plasminogen activator than the
STT. However, significant elevation in
plasminogen activator will result in an
elevation of the STT, probably because of
production of net excess of circulating
proteolytic and thrombolytic enzyme.
The lack of correlation between the
euglobulin lysis time and the STT might be
expected, inasmuch as the former test
measures primarily plasminogen activator,
whereas actual proteolytic and thrombolytic
activity in man as detailed in this case by
the STT, is a complex process involving
both plasminogen activation and inhibition
by anti-plasmin. The complex nature of the
STT may explain its better correlation with
bleeding than the euglobulin lysis time.
Although it is unlikely, the differences
between the euglobulin lysis time and STT
could be explained by removal of the EACA
during the precipitation of the euglobulin
fraction. Therefore, the euglobulin lysis
time may be conducted in the absence of
and STT in the presence of EACA. The STT
may be particularly useful in following
therapy in cases of thrombolysis and proteolysis treated with EACA. Present evidence tends to support the Irypothesis that
the STT is a good over-all measure of thrombolysis and proteolysis, and that this test
can be performed with great speed, convenience, and accuracy.
SUMMARY
A patient with massive thrombolysis and
proteolysis secondary to metastatic car-
596
BRODSKY
cinoma of the prostate gland was treated
with epsilon aminocaproic acid (EACA).
The effect of therapy was evaluated by
means of clinical course, euglobulin lysis
time, and serial thrombin time (STT). The
STT coincided better than the euglobulin
lysis time with cessation or onset of bleeding and the necessity for varying doses of
EACA. The STT is regarded as being a
rapid, convenient, and accurate test for
evaluating thrombolysis, proteolysis, and a
concomitant hemorrhagic diathesis.
SUMMAKIO
IN
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commode, e accurate test pro le evalutation
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