- Email: [email protected]
The fibrinolytic system in late pregnancy, labor, and the early puerperium
The fibrinolytic
system in late pregnancy,
labor, and the early puerperium FRANK
A.
AGNES
WODZICKI,
LYNDA
DUNBAR,
ASHLEY
MANNING,
T.
M.D., B.A.,
B.SC.(MED) A.R.T.
R.T.
COOPLAND,
M.D.,
F.R.C.S.(C),
F.A.C.O.G. Winnipeg,
Manitoba,
Canada
Controversy exists with regard to changes in the fibrinolytic system in late pregnancy, normal labor, and the puerperium, although it is generally thought that fibrinolytic activity is depressed in pregnancy and enhanced during the fiostpartum period. Twenty-one normal, pregnant patients were studied. The fibrinolytic system was investigated before labor, during the first stage of spontaneous labor, and then at intervals during the puerperium. Marked alterations in fibrinolytic activity were seen in the early puerperium. Plasma fibrinogen levels fell by 35 per cent, coincident with an increase in plasminogen activator activity. These and other changes tended to return to prelabor base-line values within the first 24 hours post parturn. The results are interpreted as indicating that fibrinolytic activity is enhanced during the immediate puerperium but that prelabor levels are rapidly regained. The significance of these changes and their possible relationship to post#artum thromboembolic disease is discussed.
“hypercoagulable state.” These dramatic changes in the coagulation system have prompted many investigators to examine the fibrinolytic system for reciprocal alterations. Rather than demonstrating increases in fibrinolytic activity (which would be expected to maintain equilibrium), most of the evidence available indicates a depression of fibrimolytic activity in pregnancy,3**p5p‘1 I49I6 reaching a minimum of activity late in the third trimester.3*5*7*I6 However, Woodfield and associates15were able to demonstrate that the concentration of fibrin breakdown products (FBP) in the serum of pregnant women increased as pregnancy progressed. Bonnar and associates,6on the other hand, were unable to show any increase in FBP concentration during pregnancy. The evidence presently available documenting the changes occurring in the fibrinolytic system during labor, delivery, and the early puerperium is also controversial.
THE BASIC PHYSIOLOGIC role of the fibrinolytic system is, to date, not entirely clear. A popular concept, supported by many investigators, is that the fibrinolytic system acts as a physiologic “counter” to coagulation by removing fibrin deposited on the vascular endothelium through the processof coagulation, with which it is in constant equilibrium.12 It is generally agreed that pregnancy and its state of relative hormonal excessproduces marked alterations in the concentration of many of the clotting factors. Indeed, it is frequently inferred that pregnancy represents a From the Department of Obstetrics and Gynaecology, University of Manitoba, and the Departments of Obstetrics/ Gynaecology and Clinical Investigation, Winnifieg General Hospital. Supported in part by grants Medical Research Council, 321-3123-02, and National Welfare, No. 343-3123-03.
from: No. Health
The and
900
Volume Number
Fibrinolytic
110 7
Most authors report diminished fibrinolytic activity during labor31‘IsI4 and delivery,a with an increase in the early puerperium to normal levels or higher.3s11*Is* x4However, Bonnar and associates6found a highly significant increase in FBP concentration during labor, as well as in the early puerperium. In this study we have examined the fibrinolytic system in late pregnancy and have investigated the responsesto the stressesof labor and to the physiologic adjustments made in the first few hours and days after delivery. A second major objective, via studies carried out on an age-comparable, nonpregnant group, also subjected to stress (surgical procedures), was to define the role of stressin the activation of the fibrinolytic system during labor and delivery. Methods
and
materials
The study group was composed of 40 healthy gravid patients, ranging from 36 to 40 weeks’ gestation, randomly selected from the antepartum clinic. Blood sampleswere drawn from these patients at each visit beginning at 36 weeks, and at each subsequent visit until admission to hospital in labor. Of the original 40 patients, 20 were followed completely through normal labor, delivery, and early puerperium (to 4 days post partum). Each of the patients studied had blood samples drawn while in the first stage of labor, within the first half hour after delivery, 3 hours after delivery, 24 hours after delivery, and on the fourth day post partum. All of the patients studied had spontaneousvaginal deliveries, and a large proportion of those studied received nitrous oxide analgesiawhile in the second stage of labor. The mean age of this study group was 23 years, with a range of 16 to 35 years. A second group of patients, admitted to th e gynecologic service for elective minor gynecologic operations, was chosen to serve asthe control series.These patients had blood samples drawn 24 hours before operation, one-half hour after operation, and 24 hours after operation. All of these patients received a general anesthetic. The mean age of the control group was 33 years, with a range of
system
901
16 to 44 years. All had uneventful operations and recovery, and none of the control patients was taking any form of oral estrogen/ progestin. Blood was drawn with the use of plastic syringes. Nine milliliters of blood was added to plastic tubes, each containing 1 ml. of acid citrate. The blood was centrifuged immediately at 10,000 r.p.m. for 10 min. at 4’ C., and the plasma was stored at -20° C. Five milliliters of blood was added to glasstubes, each containing 50 units of topical thrombin* and epsilon amino caproic acid (EACA) + to a final concentration of 0.04M (25 mg.). The glass tubes containing 5 ml. aliquots of blood were incubated at 37O C. until good clot retraction had occurred. The sera were stored at -20’ C. to be assayedfor FBP. Thrombin times were measured by the method described by Fletcher, Alkjaersig, and Sherry.8 Fibrinogen levels were determined by the method of Astrup, Brakman, and Nissor1.l Fibrinogen breakdown products were assayed by a microhemagglutination-inhibition technique described by IsraeIs and coIleagues.lO Fibrin plates for estimating fibrinolytic activity were prepared with the use of the method of Astrup and Miillertz2 Results
Fibrinogen (Table I, Fig. 1). The mean fibrinogen value for the late third-trimester samples was 626 mg. per cent, The control (nonpregnant) preoperative value was 349 mg. per cent, a value significantly lower than the comparable pregnancy value (p ‘= < 0.001). The fibrinogen values were decreased dramatically at one-half hour and three hours post partum, dropping to levels of 451 and 497 mg. per cent, respectively, with decreases significant at p = < 0.05. No similar trend was noted in the fibrinogen value of the patients subjected to operation (in fact, the fibrinogen values of these patients showed slight nonsignificant risesin the ‘Parke, SLede~le
Davis Labs.,
& Co.,
Detroit,
Pearl
River,
Michigan. New
York.
902
Manning
et al.
AuLqJst .
Amer.
J. Obstet.
1 1 19:i
(;ynw
400 )/--
--.-1+ -“t-q
350
TR,yE;,ER
, 2
151 STAGE LABOUR
-4
t
3 HR
Ii2
24 HR
4 DAY
24 HR POST-OP
24 HR PRE-OP
Fig. 1. Plasma fibrinogen
Table I. Plasma
fibrinogen
in milligrams
Time
of sample
Late third trimester First stage of labor s hr. post partum 3 hr. post partum 24 hr. post parturn 4 days post partum Numbers
in parentheses
value %)
Control
S.D. (mg. %)
626.07 (35)
118.16
569.28 (25)
93.05
451.39 (23)
97.17
497.0 (33) 577.25 (24)
83.63 98.83
572.88
80.77
refer
immediate postoperative after operation).
per cent.
(mg. per cent) Gravid patients
Mean (w.
‘p.p.
(27) to
the number
period
of
Time
of sample
Mean (mg.
patients (surgical) value %)
S.D. (ma %I
24 hr. before operation
349.63
(20)
61.76
fi hr. after operation
364.78 (20)
100.85
24 hr. after operation
375.09 (20)
94.64
patients.
and 24 hours
Thrombin times (Table II, Fig. 2). The late third-trimester mean thrombin time (2 TJ.) was 27.7 sec. as compared to a value of 28.4 sec. for the presurgical control series, a difference not statistically valid within the size of our study and control groups. A trend
to prolongation of the thrombin time during the first few hours after delivery was noted, but the increases were not significant. A similar trend of prolongation of the thrombin times of the surgical control series was also noted, but was not significant. Fibrin plates (Table III, Fig. 3). The mean lysis area recorded for the late third-
Volume Number
I10 7
Fibrinolytic
trimester samples was 45.21 mm.2. When this value is compared to the presurgical mean lysis area of 40.25 mm.2, a significant difference is found (p = < 0.01)) indicating that the amount of plasminogen activator found in the plasma of the late third-trimester patients was actually higher than the comparable presurgical control values. The areas of lysis produced by the one-half hour and three hour postpartum samples show dramatic increases over the third-trimester value, rising to 62.0 and 58.0 mm.2, respectively. These increases are highly significant when compared to the late third-trimester lysis area of 45.21 mm.2 (p < 0.001). The lysis area begins to diminish by 24 hours post partum (48.08 mm.2) and by 4 days post partum reaches a value of 41.81 mm.z, which is lower than the prelabor values of 45.21 mm.” but is not significant. FBP concentration (Table IV, Fig. 4). ?‘he values obtained in the nonpregnant patient are normally less than a titer of one quarter in our laboratory, with the use of the microhemagglutination-inhibition technique. The values were recorded as fractional serum titers but for the purpose of statistical evaluation were converted to decimal dilutions. Low decimal values are interpreted as meaning high concentrations of FBP. The prelabor (late third trimester) values for the study group were all greater than a titer of one quarter, with the mean being 0.127 (slightly less than a titer of one eighth) and the range being 0.25 to 0.0625 (titers of one quarter to
Table II. 2 U. thrombin
of
sample
I,ate third trimrster First stage of labor ‘4 hr. post partum 3 hr. post partum :!4 hr. post parturn 4 days post Parturn Numbers
in parentheses
29.75
Fig.
1
2. 2 Unit
thrombin
times
in seconds
patients
Mean value (sec.) 27.69
(48)
1.47
28.40
(41)
1.23
29.29
(28)
1.1162
28.86 27.42
(30) (22)
2.1501 1.19
27.68
(20)
0.8642
refer
to the
number
of patients
903
one sixteenth). A nonsignificant increase in the concentration of FBP was recorded between the prelabor and the first-stage labor values, with decimal dilutions of 0.127 and 0.0962, respectively. This trend of increasing concentration of FBP continued so that by one-half hour post partum the mean dilution was 0.0669 and by 3 hours post partuni the mean dilution was 0.0657. These increases are significant at p = < 0.01 when cornpared to the prelabor values. The increase in FBP concentration continued so th:rt by 4 days post partum a value of 0.0493 was recorded, now a highly significant increase
times in seconds Grad
Time
system
24 hr. before operation
“8.4
(20)
1.11’
xb hr. after operation
29.25
(20)
1.16
24 hr. after operation
27..57
(20)
1.-f::
904
Manning
et al.
Amer.
August J. Obstet.
1, 1971 Gym.
63, -
Pregnant patients
---Surgical
Fig. 3. Plasminogcn
Table III.
Time
of sample
Late third trimester First stage of labor % hr. post partum
(area in square millimeters of lysis)
patients
Mean value (mm.s)
Control
S.D. (mm.‘)
45.21 (23)
6.55
44.82 (23)
4.70
62.18 (22)
7.25
in parentheses
58.09 (21) 48.08 (22)
6.7% 6.68
41.81 (24)
3.85
refer
to the number
patients
(surgical)
Mean value (mm.‘)
S.D. (mm.s)
24 hr. before operation
40.25 (20)
5.17
5
43.70 (20)
6.06
39.53 (20)
4.68
Time
of sample
hr.
after
Comment
We have examined the fibrinolytic system in late pregnancy and demonstrated the changes in this system in response to the stresses of labor and to the physiologic adjustments made after delivery. The fibrinosystem of the surgical
patient
24 hr. after operation
of patients.
over the prelabor values at p = < 0.001. The control surgical patients all had titers of lessthan one quarter prior to operation and showed nonsignificant increasesin FBP concentration after operation.
lytic
area of lysis.
operation
3 hr. post partum 24 hr. post parturn 4 days post partum Numbers
activator activity in square millimeter
Plasminogen activator activity Gravid
controls
was also
studied in order to determine the importance
of stress in the production of increased fibrinolytic activity seen in response to the stressof labor and to the physiologic changes made after delivery. A remarkable increase in the fibrinolytic activity of the plasma of patients during the first few hours post partum was described by several authors.3>llp I39l4 The results of our study demonstrate similar alterations. There is a marked fall in the plasma fibrinogen concentration partum, with
in the first few hours post a dramatic increase in plas-
minogen activator activity, a trend to prolongation of the thrombin time, and a signifi-
v01umc Number
Fibrinolytic
110 7
.24
Pregnant Surgical
905
patients controls
--- 4
--C-LC---
_---
---
system
.28 t
Fig.
4. FBP concentration
in decimal dilutions.
Table IV. FBP concentration*
Numbers ‘Recorded
in
parentheses as a decimal
Mean 0.127
Control patients
patients
Gravid
of sample Late third trimester First stage of labor fi hr. post partum 3 hr. post partum 24 hr. post parturn 4 days post partum Time
value (25)
S.D.
0.0608
0.0962 (26)
0.0269
0.0669 (23)
0.0346
0.0657 (24) 0.0592 (24)
0.0274 0.0294
0.0493 (26)
0.0154
(surgical)
of sun&e 24 hr. before operation
Mean
0.264 (20)
--
!A hr. after operation
0.2.58 (20)
I
24 hr. after operation
0.250 (20)
Time
value
S.D.
-.--..__refer dilution.
to the
number
cant rise in the FBP concentration.
_-.-
of patients.
It is con-
cluded from these observations, that the fibrinolytic system is profoundly activated in the first few hours after delivery and gradually falls to normal nonpregnant values by the fourth day post partum. This is similar to the results shown in the recent literature by Bonnar and associates? and Ygge.17 Stress, both physical and emotional, is known to be associated with activation of the fibrinolytic system.12Our results demonstrate minimal, nonsignificant increases in fibrinolytic activity in the very early postoperative patient, A comparison of our
gravid versus surgical patients indicates that, although the nonspecific stimulating effect of stressmay play a minor roIe in producing the increased
fibrinolytic
activity
in
the
post-
partum patients, clearly the main factor responsible for the enhancement of the fibrinolytic activity is not stress alone. We have observed a slight elevation of plasminogen activator activity in the late third-trimester patients, whereas most other authors report a depression or no change
in
the
activator
activity
in
such pa-
tients.3* 4, 7l I41 x6>l”i We have also demonstrated a rise in FBP in late pregnancy, simi-
906
Manning
lar to those in the reports of Woodfield and associates.l” This observed increase in activator activity and a rising concentration of FBP, however slight, is significant and may indicate that a localized increase in fibrinolysis is responsible for these changes. The vascular endothelium of the placental bed represents a potent source of plasminogen activator. This uteroplacental reservoir of plasminogen activator, when subjected to the congestion and stasis associated with uterine contractions of late pregnancy, may result in an increased release of activator in this region with overflow into the draining venous blood. This could account for the rise in plasminogen activator activity and FBP titers we have observed in the plasma in the late thirdtrimester patients. The much more vigorous contractions associated with the second and third stages of labor, together with the possible release of small amounts of amniotic fluid, another potent source of activator, may elevate the plasminogen activator activity in the maternal blood to a degree sufficient to overcome the influence of the circulating fibrinolytic inhibitors (also elevated in pregnancy). This could explain the marked increase in fibrinolytic activity we have observed in patients during the first few hours after delivery. This increased plasma fibrinolytic activity, coupled with the deposition of fibrinogen in the form of fibrin at the placental site after delivery, may well account for the dramatic fall in fibrinogen concentration we have demonstrated. The FBP concentration increases greatly after delivery, presumably because of the increased activity and local fiplasma fibrinolytic brinolysis occurring in the placental bed. AS
REFERENCES
1. 2. 3. 4.
August 1, 1571
et al.
Astrup, T.: Brakman, P., and N&on, U.: Stand. J. Clin. Lab. Invest. 17: 57, 1965. Astrup, T.: and Miillertz, S.: Arch. Biochem. 40: 346, 1952. Biezenski, J. J., and Moore, H. C.: J. Clin. Path. 11: 306, 1958. Brakman, P.: AMER. J. OBSTET. GYNEC. 94: 14, 1966.
Amer.
.I. Obstet.
Gynec.
expected, the FBP concentration continues to rise even after the spontaneous plasma fibrinolytic activity decreases, because of continued release of split products arising from local fibrinolysis, in the placental bed. The rise of FBP prior to the onset of labor, in the absence of a generalized increase in plasma fibrinolytic activity, again suggests a localized uteroplacental source. Certainly the presence of fibrin deposition within the placenta increases with gestation, and lysis here may represent the source of the rising concentration of split products noted prior to labor. It would be extremely interesting to assay the uterine venous blood for FBP and plasminogen activator activity prior to delivery. The incidence of thromboembolic disease is significantly higher in labor and the early puerperium than in the gravid state.g Our study has shown that it is during this “danger period” that the most remarkable stimulation of the fibrinolytic system occurs. Woodfield and associatest6 have suggested, as a result of their studies, that a small percentage of the normal population show a diminished ability to activate the fibrinolytic system in response to stress. In our study group, although the mean values demonstrate significant increases in the fibrinolytic activity in the early puerperium, a closer look at the individual values reveals that a small percentage of those studied demonstrate a much less obvious rise in fibrinolytic activity. It is interesting to speculate that perhaps it is an impaired ability to activate the fibrinolytic system which causes puerperal thromboembolic complication in these patients when they are subjected to complicating factors such as operative delivery or postpartum sepsis.
5. 6.
7. 8.
Brakman, P., and Astrup, T.: Stand. J. Clin. Invest. 15: 603, 1963. Bonnar, J., Davidson, J. F., Pidgeon, C. F., McNicol, G. P., and Douglas, A. S.: Brit. Med. J. 3: 137, 1969. Bonnar, J., McNicol, G. P., and Douglas, A. S.: Brit. Med. J. 3: 387, 1969. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: J. Clin. Invest. 38: 1096, 1959.
Volume Number
110 7
9.
Husni, A. E.: 1967. Israels, Zipursky, 1968. Margulis, kinson, Pechet, Ratnoff,
10.
11. 12. 13.
Fibrinolytic
E. A., AMER.
Leopoldo, I. D., and J. OBSTET. GYNEC.
E. D., A.:
Rayner, J. Lab.
Lenhert, 97: 901,
H., Israels, L. G., and Clin. Med. 71: 333,
R. R., Luzadre, J. C. P.: Obstet. Gynec. L.: New Eng. J. Med. 0. D., Colopy, J. E.,
H., and Hodg3: 487, 1954. 273: 966, 1965. and Pritchard,
14. 15.
16. 17.
J. A.: J. Shaper, M., and Woodfield, E., and 1968. Woodfield, D.: AMER. Ygge,
1969.
J.:
system
307
Lab. Clin. Med. 44: 408, 1954, A. G., Macintosh, D. M., Evans, C. Kyobe, J.: Lancet 2: 706, 1965 D. G., Cole, S. K., Allan, A. G. Cash, J. D.: Brit. Med. J. 4: 6h.5, D.
G.,
Cole,
S. K.,
1. OBSTET. GYNEC. AMER. J. OBSTET.
and Cash, J. 102: 440. 1968. GYNEC. 1114: 2.
system in late pregnancy,
labor, and the early puerperium FRANK
A.
AGNES
WODZICKI,
LYNDA
DUNBAR,
ASHLEY
MANNING,
T.
M.D., B.A.,
B.SC.(MED) A.R.T.
R.T.
COOPLAND,
M.D.,
F.R.C.S.(C),
F.A.C.O.G. Winnipeg,
Manitoba,
Canada
Controversy exists with regard to changes in the fibrinolytic system in late pregnancy, normal labor, and the puerperium, although it is generally thought that fibrinolytic activity is depressed in pregnancy and enhanced during the fiostpartum period. Twenty-one normal, pregnant patients were studied. The fibrinolytic system was investigated before labor, during the first stage of spontaneous labor, and then at intervals during the puerperium. Marked alterations in fibrinolytic activity were seen in the early puerperium. Plasma fibrinogen levels fell by 35 per cent, coincident with an increase in plasminogen activator activity. These and other changes tended to return to prelabor base-line values within the first 24 hours post parturn. The results are interpreted as indicating that fibrinolytic activity is enhanced during the immediate puerperium but that prelabor levels are rapidly regained. The significance of these changes and their possible relationship to post#artum thromboembolic disease is discussed.
“hypercoagulable state.” These dramatic changes in the coagulation system have prompted many investigators to examine the fibrinolytic system for reciprocal alterations. Rather than demonstrating increases in fibrinolytic activity (which would be expected to maintain equilibrium), most of the evidence available indicates a depression of fibrimolytic activity in pregnancy,3**p5p‘1 I49I6 reaching a minimum of activity late in the third trimester.3*5*7*I6 However, Woodfield and associates15were able to demonstrate that the concentration of fibrin breakdown products (FBP) in the serum of pregnant women increased as pregnancy progressed. Bonnar and associates,6on the other hand, were unable to show any increase in FBP concentration during pregnancy. The evidence presently available documenting the changes occurring in the fibrinolytic system during labor, delivery, and the early puerperium is also controversial.
THE BASIC PHYSIOLOGIC role of the fibrinolytic system is, to date, not entirely clear. A popular concept, supported by many investigators, is that the fibrinolytic system acts as a physiologic “counter” to coagulation by removing fibrin deposited on the vascular endothelium through the processof coagulation, with which it is in constant equilibrium.12 It is generally agreed that pregnancy and its state of relative hormonal excessproduces marked alterations in the concentration of many of the clotting factors. Indeed, it is frequently inferred that pregnancy represents a From the Department of Obstetrics and Gynaecology, University of Manitoba, and the Departments of Obstetrics/ Gynaecology and Clinical Investigation, Winnifieg General Hospital. Supported in part by grants Medical Research Council, 321-3123-02, and National Welfare, No. 343-3123-03.
from: No. Health
The and
900
Volume Number
Fibrinolytic
110 7
Most authors report diminished fibrinolytic activity during labor31‘IsI4 and delivery,a with an increase in the early puerperium to normal levels or higher.3s11*Is* x4However, Bonnar and associates6found a highly significant increase in FBP concentration during labor, as well as in the early puerperium. In this study we have examined the fibrinolytic system in late pregnancy and have investigated the responsesto the stressesof labor and to the physiologic adjustments made in the first few hours and days after delivery. A second major objective, via studies carried out on an age-comparable, nonpregnant group, also subjected to stress (surgical procedures), was to define the role of stressin the activation of the fibrinolytic system during labor and delivery. Methods
and
materials
The study group was composed of 40 healthy gravid patients, ranging from 36 to 40 weeks’ gestation, randomly selected from the antepartum clinic. Blood sampleswere drawn from these patients at each visit beginning at 36 weeks, and at each subsequent visit until admission to hospital in labor. Of the original 40 patients, 20 were followed completely through normal labor, delivery, and early puerperium (to 4 days post partum). Each of the patients studied had blood samples drawn while in the first stage of labor, within the first half hour after delivery, 3 hours after delivery, 24 hours after delivery, and on the fourth day post partum. All of the patients studied had spontaneousvaginal deliveries, and a large proportion of those studied received nitrous oxide analgesiawhile in the second stage of labor. The mean age of this study group was 23 years, with a range of 16 to 35 years. A second group of patients, admitted to th e gynecologic service for elective minor gynecologic operations, was chosen to serve asthe control series.These patients had blood samples drawn 24 hours before operation, one-half hour after operation, and 24 hours after operation. All of these patients received a general anesthetic. The mean age of the control group was 33 years, with a range of
system
901
16 to 44 years. All had uneventful operations and recovery, and none of the control patients was taking any form of oral estrogen/ progestin. Blood was drawn with the use of plastic syringes. Nine milliliters of blood was added to plastic tubes, each containing 1 ml. of acid citrate. The blood was centrifuged immediately at 10,000 r.p.m. for 10 min. at 4’ C., and the plasma was stored at -20° C. Five milliliters of blood was added to glasstubes, each containing 50 units of topical thrombin* and epsilon amino caproic acid (EACA) + to a final concentration of 0.04M (25 mg.). The glass tubes containing 5 ml. aliquots of blood were incubated at 37O C. until good clot retraction had occurred. The sera were stored at -20’ C. to be assayedfor FBP. Thrombin times were measured by the method described by Fletcher, Alkjaersig, and Sherry.8 Fibrinogen levels were determined by the method of Astrup, Brakman, and Nissor1.l Fibrinogen breakdown products were assayed by a microhemagglutination-inhibition technique described by IsraeIs and coIleagues.lO Fibrin plates for estimating fibrinolytic activity were prepared with the use of the method of Astrup and Miillertz2 Results
Fibrinogen (Table I, Fig. 1). The mean fibrinogen value for the late third-trimester samples was 626 mg. per cent, The control (nonpregnant) preoperative value was 349 mg. per cent, a value significantly lower than the comparable pregnancy value (p ‘= < 0.001). The fibrinogen values were decreased dramatically at one-half hour and three hours post partum, dropping to levels of 451 and 497 mg. per cent, respectively, with decreases significant at p = < 0.05. No similar trend was noted in the fibrinogen value of the patients subjected to operation (in fact, the fibrinogen values of these patients showed slight nonsignificant risesin the ‘Parke, SLede~le
Davis Labs.,
& Co.,
Detroit,
Pearl
River,
Michigan. New
York.
902
Manning
et al.
AuLqJst .
Amer.
J. Obstet.
1 1 19:i
(;ynw
400 )/--
--.-1+ -“t-q
350
TR,yE;,ER
, 2
151 STAGE LABOUR
-4
t
3 HR
Ii2
24 HR
4 DAY
24 HR POST-OP
24 HR PRE-OP
Fig. 1. Plasma fibrinogen
Table I. Plasma
fibrinogen
in milligrams
Time
of sample
Late third trimester First stage of labor s hr. post partum 3 hr. post partum 24 hr. post parturn 4 days post partum Numbers
in parentheses
value %)
Control
S.D. (mg. %)
626.07 (35)
118.16
569.28 (25)
93.05
451.39 (23)
97.17
497.0 (33) 577.25 (24)
83.63 98.83
572.88
80.77
refer
immediate postoperative after operation).
per cent.
(mg. per cent) Gravid patients
Mean (w.
‘p.p.
(27) to
the number
period
of
Time
of sample
Mean (mg.
patients (surgical) value %)
S.D. (ma %I
24 hr. before operation
349.63
(20)
61.76
fi hr. after operation
364.78 (20)
100.85
24 hr. after operation
375.09 (20)
94.64
patients.
and 24 hours
Thrombin times (Table II, Fig. 2). The late third-trimester mean thrombin time (2 TJ.) was 27.7 sec. as compared to a value of 28.4 sec. for the presurgical control series, a difference not statistically valid within the size of our study and control groups. A trend
to prolongation of the thrombin time during the first few hours after delivery was noted, but the increases were not significant. A similar trend of prolongation of the thrombin times of the surgical control series was also noted, but was not significant. Fibrin plates (Table III, Fig. 3). The mean lysis area recorded for the late third-
Volume Number
I10 7
Fibrinolytic
trimester samples was 45.21 mm.2. When this value is compared to the presurgical mean lysis area of 40.25 mm.2, a significant difference is found (p = < 0.01)) indicating that the amount of plasminogen activator found in the plasma of the late third-trimester patients was actually higher than the comparable presurgical control values. The areas of lysis produced by the one-half hour and three hour postpartum samples show dramatic increases over the third-trimester value, rising to 62.0 and 58.0 mm.2, respectively. These increases are highly significant when compared to the late third-trimester lysis area of 45.21 mm.2 (p < 0.001). The lysis area begins to diminish by 24 hours post partum (48.08 mm.2) and by 4 days post partum reaches a value of 41.81 mm.z, which is lower than the prelabor values of 45.21 mm.” but is not significant. FBP concentration (Table IV, Fig. 4). ?‘he values obtained in the nonpregnant patient are normally less than a titer of one quarter in our laboratory, with the use of the microhemagglutination-inhibition technique. The values were recorded as fractional serum titers but for the purpose of statistical evaluation were converted to decimal dilutions. Low decimal values are interpreted as meaning high concentrations of FBP. The prelabor (late third trimester) values for the study group were all greater than a titer of one quarter, with the mean being 0.127 (slightly less than a titer of one eighth) and the range being 0.25 to 0.0625 (titers of one quarter to
Table II. 2 U. thrombin
of
sample
I,ate third trimrster First stage of labor ‘4 hr. post partum 3 hr. post partum :!4 hr. post parturn 4 days post Parturn Numbers
in parentheses
29.75
Fig.
1
2. 2 Unit
thrombin
times
in seconds
patients
Mean value (sec.) 27.69
(48)
1.47
28.40
(41)
1.23
29.29
(28)
1.1162
28.86 27.42
(30) (22)
2.1501 1.19
27.68
(20)
0.8642
refer
to the
number
of patients
903
one sixteenth). A nonsignificant increase in the concentration of FBP was recorded between the prelabor and the first-stage labor values, with decimal dilutions of 0.127 and 0.0962, respectively. This trend of increasing concentration of FBP continued so that by one-half hour post partum the mean dilution was 0.0669 and by 3 hours post partuni the mean dilution was 0.0657. These increases are significant at p = < 0.01 when cornpared to the prelabor values. The increase in FBP concentration continued so th:rt by 4 days post partum a value of 0.0493 was recorded, now a highly significant increase
times in seconds Grad
Time
system
24 hr. before operation
“8.4
(20)
1.11’
xb hr. after operation
29.25
(20)
1.16
24 hr. after operation
27..57
(20)
1.-f::
904
Manning
et al.
Amer.
August J. Obstet.
1, 1971 Gym.
63, -
Pregnant patients
---Surgical
Fig. 3. Plasminogcn
Table III.
Time
of sample
Late third trimester First stage of labor % hr. post partum
(area in square millimeters of lysis)
patients
Mean value (mm.s)
Control
S.D. (mm.‘)
45.21 (23)
6.55
44.82 (23)
4.70
62.18 (22)
7.25
in parentheses
58.09 (21) 48.08 (22)
6.7% 6.68
41.81 (24)
3.85
refer
to the number
patients
(surgical)
Mean value (mm.‘)
S.D. (mm.s)
24 hr. before operation
40.25 (20)
5.17
5
43.70 (20)
6.06
39.53 (20)
4.68
Time
of sample
hr.
after
Comment
We have examined the fibrinolytic system in late pregnancy and demonstrated the changes in this system in response to the stresses of labor and to the physiologic adjustments made after delivery. The fibrinosystem of the surgical
patient
24 hr. after operation
of patients.
over the prelabor values at p = < 0.001. The control surgical patients all had titers of lessthan one quarter prior to operation and showed nonsignificant increasesin FBP concentration after operation.
lytic
area of lysis.
operation
3 hr. post partum 24 hr. post parturn 4 days post partum Numbers
activator activity in square millimeter
Plasminogen activator activity Gravid
controls
was also
studied in order to determine the importance
of stress in the production of increased fibrinolytic activity seen in response to the stressof labor and to the physiologic changes made after delivery. A remarkable increase in the fibrinolytic activity of the plasma of patients during the first few hours post partum was described by several authors.3>llp I39l4 The results of our study demonstrate similar alterations. There is a marked fall in the plasma fibrinogen concentration partum, with
in the first few hours post a dramatic increase in plas-
minogen activator activity, a trend to prolongation of the thrombin time, and a signifi-
v01umc Number
Fibrinolytic
110 7
.24
Pregnant Surgical
905
patients controls
--- 4
--C-LC---
_---
---
system
.28 t
Fig.
4. FBP concentration
in decimal dilutions.
Table IV. FBP concentration*
Numbers ‘Recorded
in
parentheses as a decimal
Mean 0.127
Control patients
patients
Gravid
of sample Late third trimester First stage of labor fi hr. post partum 3 hr. post partum 24 hr. post parturn 4 days post partum Time
value (25)
S.D.
0.0608
0.0962 (26)
0.0269
0.0669 (23)
0.0346
0.0657 (24) 0.0592 (24)
0.0274 0.0294
0.0493 (26)
0.0154
(surgical)
of sun&e 24 hr. before operation
Mean
0.264 (20)
--
!A hr. after operation
0.2.58 (20)
I
24 hr. after operation
0.250 (20)
Time
value
S.D.
-.--..__refer dilution.
to the
number
cant rise in the FBP concentration.
_-.-
of patients.
It is con-
cluded from these observations, that the fibrinolytic system is profoundly activated in the first few hours after delivery and gradually falls to normal nonpregnant values by the fourth day post partum. This is similar to the results shown in the recent literature by Bonnar and associates? and Ygge.17 Stress, both physical and emotional, is known to be associated with activation of the fibrinolytic system.12Our results demonstrate minimal, nonsignificant increases in fibrinolytic activity in the very early postoperative patient, A comparison of our
gravid versus surgical patients indicates that, although the nonspecific stimulating effect of stressmay play a minor roIe in producing the increased
fibrinolytic
activity
in
the
post-
partum patients, clearly the main factor responsible for the enhancement of the fibrinolytic activity is not stress alone. We have observed a slight elevation of plasminogen activator activity in the late third-trimester patients, whereas most other authors report a depression or no change
in
the
activator
activity
in
such pa-
tients.3* 4, 7l I41 x6>l”i We have also demonstrated a rise in FBP in late pregnancy, simi-
906
Manning
lar to those in the reports of Woodfield and associates.l” This observed increase in activator activity and a rising concentration of FBP, however slight, is significant and may indicate that a localized increase in fibrinolysis is responsible for these changes. The vascular endothelium of the placental bed represents a potent source of plasminogen activator. This uteroplacental reservoir of plasminogen activator, when subjected to the congestion and stasis associated with uterine contractions of late pregnancy, may result in an increased release of activator in this region with overflow into the draining venous blood. This could account for the rise in plasminogen activator activity and FBP titers we have observed in the plasma in the late thirdtrimester patients. The much more vigorous contractions associated with the second and third stages of labor, together with the possible release of small amounts of amniotic fluid, another potent source of activator, may elevate the plasminogen activator activity in the maternal blood to a degree sufficient to overcome the influence of the circulating fibrinolytic inhibitors (also elevated in pregnancy). This could explain the marked increase in fibrinolytic activity we have observed in patients during the first few hours after delivery. This increased plasma fibrinolytic activity, coupled with the deposition of fibrinogen in the form of fibrin at the placental site after delivery, may well account for the dramatic fall in fibrinogen concentration we have demonstrated. The FBP concentration increases greatly after delivery, presumably because of the increased activity and local fiplasma fibrinolytic brinolysis occurring in the placental bed. AS
REFERENCES
1. 2. 3. 4.
August 1, 1571
et al.
Astrup, T.: Brakman, P., and N&on, U.: Stand. J. Clin. Lab. Invest. 17: 57, 1965. Astrup, T.: and Miillertz, S.: Arch. Biochem. 40: 346, 1952. Biezenski, J. J., and Moore, H. C.: J. Clin. Path. 11: 306, 1958. Brakman, P.: AMER. J. OBSTET. GYNEC. 94: 14, 1966.
Amer.
.I. Obstet.
Gynec.
expected, the FBP concentration continues to rise even after the spontaneous plasma fibrinolytic activity decreases, because of continued release of split products arising from local fibrinolysis, in the placental bed. The rise of FBP prior to the onset of labor, in the absence of a generalized increase in plasma fibrinolytic activity, again suggests a localized uteroplacental source. Certainly the presence of fibrin deposition within the placenta increases with gestation, and lysis here may represent the source of the rising concentration of split products noted prior to labor. It would be extremely interesting to assay the uterine venous blood for FBP and plasminogen activator activity prior to delivery. The incidence of thromboembolic disease is significantly higher in labor and the early puerperium than in the gravid state.g Our study has shown that it is during this “danger period” that the most remarkable stimulation of the fibrinolytic system occurs. Woodfield and associatest6 have suggested, as a result of their studies, that a small percentage of the normal population show a diminished ability to activate the fibrinolytic system in response to stress. In our study group, although the mean values demonstrate significant increases in the fibrinolytic activity in the early puerperium, a closer look at the individual values reveals that a small percentage of those studied demonstrate a much less obvious rise in fibrinolytic activity. It is interesting to speculate that perhaps it is an impaired ability to activate the fibrinolytic system which causes puerperal thromboembolic complication in these patients when they are subjected to complicating factors such as operative delivery or postpartum sepsis.
5. 6.
7. 8.
Brakman, P., and Astrup, T.: Stand. J. Clin. Invest. 15: 603, 1963. Bonnar, J., Davidson, J. F., Pidgeon, C. F., McNicol, G. P., and Douglas, A. S.: Brit. Med. J. 3: 137, 1969. Bonnar, J., McNicol, G. P., and Douglas, A. S.: Brit. Med. J. 3: 387, 1969. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: J. Clin. Invest. 38: 1096, 1959.
Volume Number
110 7
9.
Husni, A. E.: 1967. Israels, Zipursky, 1968. Margulis, kinson, Pechet, Ratnoff,
10.
11. 12. 13.
Fibrinolytic
E. A., AMER.
Leopoldo, I. D., and J. OBSTET. GYNEC.
E. D., A.:
Rayner, J. Lab.
Lenhert, 97: 901,
H., Israels, L. G., and Clin. Med. 71: 333,
R. R., Luzadre, J. C. P.: Obstet. Gynec. L.: New Eng. J. Med. 0. D., Colopy, J. E.,
H., and Hodg3: 487, 1954. 273: 966, 1965. and Pritchard,
14. 15.
16. 17.
J. A.: J. Shaper, M., and Woodfield, E., and 1968. Woodfield, D.: AMER. Ygge,
1969.
J.:
system
307
Lab. Clin. Med. 44: 408, 1954, A. G., Macintosh, D. M., Evans, C. Kyobe, J.: Lancet 2: 706, 1965 D. G., Cole, S. K., Allan, A. G. Cash, J. D.: Brit. Med. J. 4: 6h.5, D.
G.,
Cole,
S. K.,
1. OBSTET. GYNEC. AMER. J. OBSTET.
and Cash, J. 102: 440. 1968. GYNEC. 1114: 2.