Complexing of Tissue Plasminogen Activator With PAI-1, a,-Macroglobulin, and
C1-Inhibitor: Studies in Patients With Defibrination and a Fibrinolytic State After
Electroshock or Complicated Labor
By Bruce Bennett, Alison Croll, Kathleen Ferguson, and Nuala A. Booth
Release of tissue plasminogen activator (t-PA) and its
interaction with plasma protease inhibitors were studied in
two patients with massive defibrination, one after electroshock and soft tissue injury and the other after complicated labor; both had very severe hemorrhage. Large
quantities of free t-PA were present in the circulation for
several hours. Complexes of t-PA with plasminogenactivator inhibitor 1 (PAI-11, a,-macroglobulin and C1-inhibitor
were also observed. PAI-1 antigen rose dramatically in
both patients, and complexes of t-PA with PAL1 rose
rapidly during the period of observation. In contrast, the
complexes of t-PA with a,-macroglobulin and C1-inhibitor,
present initially, persisted for short periods only and dis-
appeared when free t-PA disappeared from the circulation.
Plasmin was generated initially, as indicated by the presence of plasmin-a,-antiplasmin complexes. Plasma concentrations of a,-macroglobulin, C1-inhibitor, antithrombin 111,
and a,-antiplasmin were severely depleted initially, but
rapidly returned to normal. The observations demonstrate
that there is a major release of t-PA in such defibrinating
patients, that there is a role for protease inhibitors other
than PAI-1 in the regulation of,endogenous t-PA. and indicate the great rapidity with which such free t-PA is
complexed and cleared.
0 1990 by The American Society of Hematology.
T
surgery, severe generalized bleeding occurred and he was returned to
theater. Further surgical reconstruction of the major bleeding sites
in the femoral vessels was attempted but was unsuccessful, and
amputation of the left leg was undertaken; thereafter massive
bleeding ceased but generalized oozing continued for many hours.
Before admission to Aberdeen Royal Infirmary, this patient had
received massive but unquantified infusion of crystalloid. In the 12
hours after admission he received 13.5 L whole blood, 4.5 L packed
red cells, 4.5 L fresh frozen plasma, 6.4 L purified plasma protein
solution, 4.0 L synthetic volume expanders, 2.5 L crystalloid, 1.0 L
platelet-rich plasma, and 12 U platelet concentrate.
Patient 2 was a 37-year-old woman who had three previous
miscarriages. Her first completed pregnancy ended at term in
delivery of a healthy child, but labor was complicated by fetal
distress necessitating forceps delivery, with the child in the occipitoposterior position. Placenta and membranes were delivered apparently intact. One hour after delivery, severe vaginal bleeding and
cardiovascular collapse occurred. The initial coagulation data indicated in Table 2 were recorded. Resuscitation was accomplished
with blood transfusion (8.5 L, part as whole blood and part as packed
red cells), cryoprecipitate, and fresh frozen plasma, and ergometrine, syntocinon, and prostaglandin were administered during
this period. Cardiovascular stability was re-established, and from 5
hours after the delivery recovery was uncomplicated.
WO IMMUNOLOGICALLY distinct types of plasminogen activator (PA) occur in human blood. Tissue
plasminogen activator (t-PA) is the principal activator and
occurs in endothelial cells, from which it can be released by
stimuli such as physiologic stress. Urokinase (u-PA) circulates principally in an inactive precursor form, single chain
U-PA (XU-PA).
Both t-PA and u-PA can be inhibited by the circulating
plasma inhibitor PAI- 1, present in small quantities in cellfree plasma and in higher amounts in platelets.’s2 The
sequence of interactions between PA, PAI- 1, and the other
inhibitors that secure control of physiologic and pathologic
fibrinolysis is not defined. Since pathologic fibrinolytic bleeding is rare, this control is sufficiently powerful to prevent
plasmin generation in the circulation under normal circumstances. Certainly, plasmin is only generated in the circulation of normal individuals under extreme stress3 The manner
in which released plasminogen activator is cleared from the
circulation is uncertain, but it involves both interaction with
plasma inhibitors3s4and clearance from the circulation by the
liver. 5*6
This report examines interaction of endogenous t-PA,
released in large amounts over a very short period of time,
with plasma protease inhibitors; records the time for which
free and complexed t-PA persists in the circulation; and notes
the consequences of these events in terms of plasmin generation and depletion of plasma protease inhibitors.
MATERIALS AND METHODS
Plasminogen activators in circulating blood were demonstrated by
sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS~~
CASE REPORT
Patient 1, a 58-year-old man, purchased a disk-grinder (a tool
with a rotating head used to sharpen certain farm implements) in
April 1987. Under the influence of alcohol, he inserted the bare wires
into a wall socket. He was seen to fall to the ground immediately, and
was unconscious. The grinder functioned briefly, inflicting severe
injury to his left thigh and severing the femoral artery and vein. He
was pulseless when medical help arrived, but was vigorously resuscitated with external cardiac massage and the infusion of large
volumes of intravenous fluid. These measures restored heartbeat and
circulation, and he was transferred to Aberdeen Royal Infirmary,
where he arrived semi-conscious but grossly anemic and hemorrhagic. Table 1 lists the initial findings on admission. He was
transferred directly to theater and an attempt was made to repair the
injured blood vessels. On return to the intensive care unit after
Blood, Vol 75, No 3 (February 1). 1990: pp 671-676
~~
From the Department of Medicine and Therapeutics, University
of Aberdeen: and Intensive Care Unit. Aberdeen Royal Injirmary.
Scotland.
Submitted December 28, 1988: accepted October 4, 1989.
Supported by Grants from The British Heart Foundation, Grampian Health Board, and Scottish Hospitals Endowment Research
Trust.
Address reprint requests to B. Bennett, MD, Department of Medicine & Therapeutics, University of Aberdeen, Foresterhill, Aberdeen AB9 ZZD, Scotland. UK.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C.section 1734 solely to
indicate this fact.
0 1990 by The American Society of Hematology.
0006-4971/90/7503-0028$3.00/0
67 1
672
BENNElT ET AL
Table 1. Patient 1
Hours
Platelet
After
Count
TCT APlT
(SI
Admission ( x 109/L) (s)
0
7
139
116
64
133
151
63
18
19
17
16
14
15
180
95
71
63
58
55
200-400
13
40-50
11
17
19
21
(SI
Fibrinown
(g/L)
88
34
26
27
23
24
0.70
1.40
2.00
2.40
2.00
1.90
PT
Plasminogen
Activator:
a-,M
PAI-1
t-PA
t-PA-PAI-1
ATlll
Fibrin Plate
Plasminogen
a,AP
CI-inh
(% normal) (mm diameter) (% normal) (% normal) (% normal) (% normal) (ng/mL) (ng/mL) (% normal)
53
24
46
17
26
16
0
0
0
0
46
85
85
95
95
100
15
61
89
98
89
89
29
57
89
98
65
49
80
100
100
100
39
55
110
550
75
77
66
1,756
1,900
1.950
22
43
32
51
54
43
80-120
0
100
100
100
100
8-35
1.0-6.6
50
1,Ooo
700
1,OOO
800
800
Normal
values
12-17 1.5-4.0
PAGE) with zymography.' This involves separation by SDS-PAGE
of plasma proteins according to their molecular size, with subsequent
identification of plasminogen activators by applying an agarose gel
containing fibrin and plasminogen to the SDS gel. Plasminogen
activators diffuse from the SDS gel into the detector gel, where they
convert plasminogen to plasmin, producing a clear zone of lysis in the
opaque fibrin detector gel.
Identification of bands of plasminogen activator activity as complexes with a,-macroglobulin (a,-M) or C1-inhibitor (Cl-inh) was
made by incubating plasma samples with immunoglobulins (Ig)
specific for these inhibitors (Dako Ltd, High Wycombe, UK). The
treated samples were then centrifuged at 100.000 x g to remove
immune precipitates, and the supernatants were applied to SDS gels
for zymography as described above.
PAI- 1 was quantified by enzyme-linked immunosorbent assay
(ELISA),' as was &PA8; the latter assay was kindly performed by
Dr Ian R. MacGregor. These ELISAs do not discriminate between
free and complexed forms of t-PA8 or of PAI-1.9 T-PA-PAI-1 complexes were quantified by a two-site ELISA, using rabbit anti-t-PA
(Organon-Teknika, Cambridge, UK) as the capture antibody and
biotin-conjugated anti-PAI-19 as the second antibody. The quantities of complex detected were expressed as a percentage of that in
pooled plasma from 20 healthy resting normal subjects aged 20 to 40
years.
Purified t-PA and a,-macroglobulin were from Organon Teknika
(Freiburg, FRG). In the experiments described in the text, 20 pL
t-PA (4 U/mL) was incubated at 37OC for 30 minutes with 10 pL
a,-macroglobulin (10 mg/mL) before study by SDS-PAGE with
zymography, as described above. As a control, t-PA was similarly
incubated in the absence of a,-macroglobulin.
Plasmin-a,-antiplasmin complexes were demonstrated by twodimensional immunoelectrophoresis (2DIEP) against antiserum to
a,-antiplasmin.lo Antithrombin 111 (ATIII) complexes were demon-
100
strated similarly." Plasminogen, a , - M , C1-inh, ATIII, and a2antiplasmin (a,-AP) were quantified by rocket immunoelectrophoresis against specific antisera." Fibrinogen was quantified by a
functional assay based on that of Ratnoff and Menzies." Coagulation screening techniques, prothrombin time (PT), activated partial
thromboplastin time (APTT), and thrombin time (TT) were performed by standard techniques. Overall plasma fibrinolytic activity
was assessed by applying untreated citrated plasma to plasminogenrich fibrin plates and measuring the diameter of the lysed zone after
24 hours at 37OC."
RESULTS
On admission to Aberdeen Royal Infirmary, patient 1
showed a gross reduction of the hemoglobin, and marked
prolongation of PT, APTT, and TT was observed (Table 1).
These abnormalities could have been due either to a defibrinating process or to severe hemodilution, as massive
amounts of fluid had been infused before hospital admission.
Evidence of activation of both coagulation and fibrinolytic
pathways was present because thrombin-AT111 and plasmin
a,-AP complexes could both be demonstrated in the admission blood sample (Fig 1). The former disappeared almost
immediately and fibrinogen and ATIII levels rose rapidly
toward normal after resuscitation and transfusion (Table 1).
Plasmin-a,-AP complexes persisted for many hours and
traces remained detectable 19 hours but had disappeared by
2 1 hours after admission (Fig 1) .
The explanation for the generation of plasmin in this
patient was evident from the studies of plasma plasminogen
activator. Figure 2 shows clearly that on admission to the
hospital, massive amounts of free plasminogen activator were
Table 2. Patient 2
Hours
Postpartum
Platelet
Count
(X
TCT
APlT
PT
Fibrinogen
(g/L)
diameter)
51
60
72
66
21
4
4
0
-
72
76
0
0
2.13
69
1.5-4.0
80-120
(SI
(S)
66
27
19
17
17
15
13
163
71
56
54
51
47
47
34
28
18
20
19
19
18
0.35
1.05
2.07
13
40-50
12-17
101
87
82
6
60
9
12
27
48
48
103
Normal
values 200-400
(mm
ATlll
(% normal)
1 0 ~ 1 ~(s)
)
1
2
5
Plasminogen
Activator:
Fibrin Plate
2.31
.
1-PA
t-PA-PAI-1
a-,M
PAI-1
CI-inh
a,AP
Plasminogen
(% normal) (% normal) (% normal) (% normal) (ng/mL) (ng/mL) (% normal)
57
55
66
66
69
69
69
37
51
60
54
57
60
89
24
44
58
63
63
72
70
49.5
189.9
613.1
m . 7
645.1
230.4
95.7
105
14
16
25
43
225
450
480
610
1.270
0
100
81
86
79
79
72
69
40
15
1,120
460
0
100
100
100
100
8-35
1.0-6.6
100
673
T-PA COMPLEXES WITH PAI-1, a,M, CI-INH IN DIC
I
Oh
7h
-7
:--------- 7
21h
Fig 1. Two-dlmensionel immunoelectrophoresis of plasma
agsinst antiserum to ATlll (right) and to u,-AP (left) of samples
from petient 1 et intervals after admission to the hospital as indicated in hours. The slow-moving peaks represent inhibitor complexed with active enzyme."
detectable in this patient's plasma at an apparent molecular
mass of approximately 65 Kd, characteristic of free t-PA. A
band of plasminogen activator activity was detected at 110
Kd, as is the case in the plasma of normal individuals; this
represents t-PA complexed to PAI-I.' Additional new high
molecular mass bands of PA activity, not seen in normal
plasma, were detected. One had an estimated molecular
mass of 180 Kd, and the second had a very high mass but
migrated so little from the top of the gel that its size could not
realistically be estimated. All these bands represented t-PA,
all being removed when antiserum monospecific for t-PA was
included in the detector gel (Fig 3). The two bands of large
molecular size represented t-PA complexed with a,-M and
CI-inh. as demonstrated in Fig 3; antisera specific for a,-M
removed the highest molecular mass band and antibody to
C1-inh removed the 180-Kd band. A band of PA activity
with identical mobility to the slow-moving band was generated when purified t-PA was incubated with purified a,-M
(Fig 4). We previously showed that the band of activity of
180 Kd is generated when purified t-PA is incubated with
purified C1-inh.' All three types of t-PA-inhibitor complex,
namely with PAI-I, a,-M and C1-inh, appeared in the
euglobulin fraction of plasma (not shown).
The free t-PA at 65 Kd and the high molecular mass
complexes of t-PA with a,-M and C1-inh also disappeared
rapidly from the circulation, being present in the 7-hour
blood sample but absent from the 1 I-hour sample (Fig 5).
Immunoassay of PAL1 showed normal plasma levels of
the protein on admission to the hospital and its rapid increase
during the following hours. Table 1 and Figs 1 and 5
summarize the changes in plasmin, plasmin a,-AP, plasmino-
gen activator, and inhibitors during the first 24 hours after
admission. Rapid disappearance of free t-PA and of t-PA
complexes with a,-Mand C1-inh, and slightly slower disap
pearance of plasmin a,-AP complexes, occurred while the
plasma concentrations of a,-AP. a,-M and C1-inh were
returning toward normal and plasma PAL1 was increasing
rapidly.
The sequential changes in complexes of t-PA with PAI-1,
quantified by ELISA, are shown in Table 1. It is evident that
PAI-I rose massively and remained elevated throughout the
period of observation and that t-PA-PAL1 complex showed
a similar trend. It should be noted here that in the days after
this period of observation, this patient showed evidence of
gross cardiac, hepatic, and renal damage, the last requiring
hemodialysis.
Patient 2 also defibrinated when first studied, immediately
after complicated labor (Table 2). Like patient 1, her hemostatic profile was suggestive of disseminated intravascular
coagulation. She also showed the features of massive systemic activation of the fibrinolytic system, with evidence of
circulating plasmin-a,-AP complexes and severe transient
depletion of inhibitors of fibrinolysis, a,-AP, C1-inh, and
a,-M.Her plasma also contained free t-PA (Fig 2). with
additional bands of t-PA activity identifiable as complexes
with PAI-1, a , - M , and C1-inh (data not shown). Free t-PA
180kh
110 kDa
65kDa
Fig2. SDS-PAGE with zymography to show bands of plasminogen activator (clear lysed zones in the opaque fibrinagerose gel).
(A) Normal plasma: (e) petient 1 edmission sample: ( C )petient 2 , l
hour postpertum.
BENNETT ET AL
674
A
B
C
D
I
1
180kDe
6MtDa
Fig 3. SDS-PAGE with zymography of admission sample from
patient 1. (A) After treetment with nonimmune rabbit IgG: (9)
aiter treatment with IgG specific for a2-M: (C) &or treatment
with IgG specific for C1-inh; (D) in the presence of IgG specific for
t-PA. The same obaervationswere made on the plasme of petient
2 (not shown).
and t-PA complexed with a,M and CI-inh disappeared
rapidly from her plasma within 5 hours of their appearance,
confirming the pattern observed in patient 1.
This patient had massive quantities of t-PA antigen
present in her initial blood sample, and showed a dramatic
rise in levels of PAI-I and of t-PA-PAL1 complexes thereafter (Table 2). Her starting levels of PAI-1 were, of course,
elevated by pregnancy itself.“ The sequential changes, with a
rise and subsequent fall of PAI-I and t-PA-PAL1 complexes, differ from those of patient 1, in that the levels were
clearly returning toward normal at the end of the period of
study. Some of these changes may reflect her response to the
initial fibrinolyticevent, but this pattern may have been modified by the normal sequence of changes after labor and delivery. In notable contrast to patient l, this patient’s plasma
PAI-I concentration peaked and was falling at the end of the
study period. This seems likely to reflect the fact that she
made a totally uncomplicated recovery from her episode of
severe hemorrhage and did not go on to show any evidence of
the extensive organ damage sustained by patient 1.
been reported: High concentrations of exogenous t-PA
added to human plasma resulted in complex formation with
a,-AP and a2-M.” Thus our observations demonstrate that
a,-M participates in vivo in the control of t-PA as well as that
of plasminI6and u-PA.”
However, the formation of t-PA complexes with PAI-1,
a,-M, and C1-inh in our patients was insufficient to remove
free t-PA activity from the circulation, where it remained
detectable for several hours. These events were accompanied
by severe depletion of many of the protease inhibitors
operating in the fibrinolytic system, namely a,-AP, a2-M,
and C1-inh. Clearly the circulating plasma inhibitory mechanisms were overwhelmed by the enormous release of t-PA
into the circulation, such that plasmin generation resulted, as
indicated by the presence of plasmin-a,-AP complexes.
Initially thrombin was also generated, as indicated by the
presence of thrombin-AT111 complexes, but this phenomenon was more short-lived and these complexes disappeared
rapidly, while the fibrinolytic abnormalities persisted for
many hours. PAI-1 rose progressively and dramatically in
both patients to very high levels. This contrasts the findings
relating to the other inhibitors, a,AP. a , M . CI-inh, and
ATIII, and indicates that the level of this protein is under
different control from the other inhibitors, consonant with
evidence that it is an acute phase
A
B
C
-
180kDa
1lOkDa
65kDa
DISCUSSION
It is evident that the trauma suffered by these patients,
either electroshock with tissue injury or complicated labor,
resulted in defibrination with systemic activation of the
fibrinolytic system. Free t-PA was released into the circulation in both patients. This resulted in the formation of
complexes of t-PA, not only with the principal inhibitor of
plasminogen activator, PAI-I, but also with a,-macroglobulin and CI-inh. C1-inh was previously found to inhibit t-PA
released after exercise.) Inhibition of endogenous (postexercise) t-PA by a,-antitrypsin and a,-antiplasmin has also
Fig 4. SDS-PAGE with zymography of (A) purified t-PA: (B)
purified t-PA after incubationwith puritied a2-M;(C) plasma from
patient 1 (admission sample).
T-PA COMPLEXES WITH PAI-1, a,M, C~N
IH
oh
7h
llh
675
IN DIC
21h
18OkDa
iiokDa
mkDa
65kDa
Fig 6. SDS-PAGE with rymogrephy on the series of semples
from petient 1 et the indicated intervals efter edmission, to show
diseppearance of free t-PA end its complexes with a,-M and
C1-inh.
The plasma concentration of t-PA-PAL1 complex rose
and remained elevated over the entire period of observation
in patient I . who developed major organ damage after the
episode of defibrination. In patient 2, who recovered rapidly
from the hemorrhagic episode, PAI-I and t-PA-PAI-I rose
strikingly, but the concentrations were returning to normal
after about 24 hours. Complexes of t-PA with a,-M and
C1-inh were, in contrast, cleared very rapidly from the
circulation, disappearing between 7 and 11 hours. Free t-PA
was also cleared rapidly, becoming undetectable between the
7-and 1 1-hour observations,consistent with its short half-life
in humans' as well as in other species.,@,,
In a previous study that showed release of large amounts of
free t-PA after exercise, complexing of t-PA with PAI-I and
C1-inh wasdemonstrated, but complexes with a,-M were not
observed. Interestingly, in that study only traces of plasmin
were generated, in striking contrast to the situation in the
patients studied here. Possibly plasmin generation in the
circulation occurs only if thecapacity of all three inhibitors is
overwhelmed.
In summary, this study indicates that massive release of
t-PA may occur in certain circumstances; a part of this t-PA
complexes with PAI-I and, in the extreme circumstances
described here, with a,-M and C1-inh. However, such
complexing was insufficient to prevent plasmin formation as
indicated by the generation of plasmin-a,-AP complexes.
The released plasminogen activator, whether free or complexed with a,-M or C1-inh, was cleared rapidly from the
circulation. t-PA complexes with PAL1 remained in the
circulation for considerably longer than the three other forms
of t-PA. The rapidity of clearance was such that definite
conclusions as to whether clearance of free t-PA occurs or
whether clearance requires its complexing with inhibitor
proteins cannot be drawn; this area requires further study.
ACKNOWLEDGMENT
We thank Dr Ian MacGregor. Scottish National Blood Transfusion Service, Edinburgh, for performing the t-PA antigen determinations.
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