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The plasminogen activator content of the myometrium in nonpregnant, pregnant, and parturient women
The plasminogen activator myometrium
in nonpregnant,
and parturient MIECZYSLAW
content of the pregnant,
women
USZYRSKI
RYTA
USZYfiSKA-FOLEJEWSKA
Bialystok,
Poland
A quantitative evaluation of the plasminogen activator in the myometriunr of 20 nonpregnant women, 22 in various months of pregnancy, and 30 during labor was made. It was found that the highest concentration of the activator is ,?resent in the myometrium of nonpregnant women, a somewhat lower concentration at the end of pregnancy, and a very low concentration during the advanced stage of labor. A sudden fall in the complete plasminogen activator content during labor suggests the role of the uterine contractile activity in releasing the activator into the bloodstream. The possibility of fibrinogenolysis occurring after the release of the activator from the myometrium into the circulation is discussed.
THE EXCESSIVELY HIGH fibrinolytic activity in the plasma which accompanies disorders of the clotting system in obstetrics16, IQ can best be interpreted as due to a sudden rise in the concentration of the plasminogen activator in the circulation. As a result of the increase in the activator concentration, a rapid conversion of plasminogen into plasmin occurs and hyperplasminemia appears. The source of the plasminogen activator and the mechanism of its release into the blood in obstetric coagulation defects have not so far been elucidated in detail. The hypothesis that plasminogen activator from the uterus or the fetus and placenta may be the primary cause of the enhancement of the fibrinolysis processes in the plasmal”, O5 requires confirmation of the following assumptions: ( 1) the presence in the uterus, the fetus, or placenta of a form of plasminogen activator which is released into the plasma and brings about the conversion of
From the First and Gynecoloy, School.
Department Bialystok
plasminogen into plasmin; and (2) the presence in these tissues of sufficient quantity of plasminogen activator to bring about the formation of free plasmin in the plasma. This paper is concerned with determinations of the plasminogen activator content in extracts prepared with 0.9 per cent NaCl from the myometrium of nonpregnaat WOI~Ien, pregnant women and parturients. Material
and
Methods
Myometrial tissue sections from 20 nonpregnant women, 22 in various months of pregnancy, and 30 in the first stage of parturition were obtained from uteri during the course of such operative procedures as cesarean section or myomectomy. Sections were also taken from hysterectomy specimens. The myometrial sections during pregnancy were obtained as follows: in the second lunar month of an ectopic pregnancy; during the course of myomectomy in the third month of pregnancy; in the fourth month during an operation for abdominal extrauterine pregnancy; and at operation on the uterus for perforation during an induced abortion;
of Obstetrics Medical 825
826
Uszyfiski and Uszyfiska-Folejewska
in the ninth and tenth months, cesarean section because of diabetes mellitus (one case), Kh isosensitization (2 cases), placenta previa (8 cases), abnormal position of the fetus (2 cases), and others (2 cases). In the cases of advanced pregnancy, the myometrial sections were always taken from the lower portion of the uterus. The sections tvere kept at a temperature of -20° C. for 12 to 24 hours. The myometrium was homogenized in proportions of 1 Gm. to 2 ml. of 0.9 per rent NaCl for 5 minutes and centrifuged at 1,500 g for 15 minutes. The supernatant was tested in systems based on the modified euglobulin test3: 1 ml. of human plasma plus 18 ml. H,O, distilled at a temperature of 4’ C., plus 1 ml. of the muscle extract of various dilutions, 1 : 1 to 1 : 128, in the control experiments 1 ml. of 0.9 per cent NaCl. The samples were acidified with 1/6N
Fig. 1. Euglobulin nonpregnant (a),
July
15, 196i
CH,COOH to pH 5.3, centrifuged for 3 nlinutes, and the euglobulin sediment \\as dissolved in 0.25 ml. of a solvent consisting of Na,R,O,, 0.25 per cent; plus NaCI, 0.9 per c.ent. The euglobulin solution, 0.2 ~trl.: was then coa
activator
(units)
:-
1.300 --;
[ --I.:?”
where t stands for the fibrinolysis time Ininutes of the sample, and n the dilution
fibrinolysis time with various concentrations of the myometrial pregnant (b), and parturient women (c). Control.
extract
from
in of
Plasminogen
the extract in that sample. As a measure of the activator content in 1 Gm. of tissue, the mean value of 3 samples containing serial dilutions of the extract was taken. The samples with a dilution of 1: 32, 1:64, and 1 : 128 were the commonest. The above method has been described in detail in a previous paper.?” It is an adaptation of the method used for determinills the activator in the euglobulin test.s The activator content in the whole uterine muscle was calculated by multiplying the activator concentration (content of 1 Gm.) by the weight of the organ in grams, 60
ll
activator
contew
of
myometrium
An evaluation of the possible effect of the plasminogen activator from the myometrium on the plasma fibrinolytic system was made by dividing the “whole” activator content by the volume of the plasma (2,500 ml.). Results Fig. 1 shows an esample of the fibrinolysis time of a clot of euglobulin obtained from human plasma in the presence of various dilutions of myometriai extracts from nonpregnant women (a), pregnant women (b)? and parturients (c). Tk.e results given in the figure show : 1. The extract from the nonpregnant women possesses the highest fibrinolytic activity; the extract from the pregnant women
000 8000
.
5000 =0 r 4 > F ::
.
4000
3002
2 ul 9 0 2
z
2000
.
l
4
. .. r-l
.
6:
.
.
*a23
.
1000
.
~Ol(tHs OF PR l?6YAI(Cl ML
II
’
I I
l . *.a . .., I
.
vi r-7 I
.
‘I
WOUPRWYANT
I
I
Fig. 2. The plasminogen activator content pregnant, and parturient women (units).
827
I
DURING;
of 1 Gm. of the myometrium
LABOR
in nonpregnant,
-1
828
Uszytiski
and
Table I, The Staqe
Uszyhska-Folejewska
plasminogen
activator
No. of eases
of pregnancy
Not pregnant First trimester Ninth and tenth lurlar months Beginning
of labor
Advanced
Iabor
content
of 1 Gm. rnyometrium
) Mean
wiues
1
6
in units It
/P
20 6 15 7
.-~~
-__
‘7‘2) ._~.-.
exhibits a lower activity; and the lowest activity is noted in the myometrium during parturition. 2. There is a relation between the fibrinolytic activity of the extract and its dilution, the greatest reduction in fibrinolysis time being observed when the extract was diluted to 1:8 to 1:32. Table I and Fig. 2 present in units the plasminogen activator content of 1 Gm. of myometrium (concentration) of nonpregnant. pregnant, and parturient women. The mean values of the plasminogen activator content of 1 Gm. myometrium in nonpregnant women was found to be 2,311 units, in the first pregnancy trimester 3,940 units, in the ninth and tenth lunar months for pregnancy 1,023 lmits, at the beginning of labor 557 units, and in advanced labor 114 units. Fig. 3
an activator calculated approximately
concentration, from
as could easily bc 1 300 the formula -Lc, would be
3 minutes.
Comment
It is a known fact that the fibrinolytic: a.ctivity of tissue depends on the amount of pIasminogen activator contained in the tissue, Though this substance does not possess fibrinolytic properties, it influences the process of conversion of plasminogen into plasmin. In experiments, the tissue plasminogen acti\rator can be extracted from the tissues with 2M KCNS,? and to a lesser rxtent with 0.9 per cent NaCll’p ” and other solutions. In extracts of human myometrium, hi,gh cotlcentrations of plasminogen activator were found,“. ‘. Ii whereas only traces of plasmin activity were observed.” The extracts obtained with 0.9 per cent NaCll contained labile and stable activator. The present investigation concerned the activator obtained by means of extraction with 0.9 per cent NaCl. One may conjecture that this fraction is comparatively easily I’?‘leased from the vascular endothelium and the myometrial cells into the organic fluids and plays a part in the processes of fibrinolysis in the plasma. Our investigations showed that: 1. The concentration and content of plasIninocen activator in the myometrium of nonpregnant and pregnant women arr in
Plosminogen
activator
THE g’“*nn
40’”
HONTM OF THE PREDNhWCY
content
of myometrium
n
hWANCED STAGES OF LABOR CERVICAL l ILATATmn OVER 7 en9
i
Fig. 3. Total content of plasminogen nant, and a parturient woman.
activator
indirect proportion to each other, i.e., the activator concentration at the end of pregnancy is 50 per cent lower than before pregnancy, whereas the whole content is 10 times greater than before pregnancy. 2. The increase in plasminogen activator content in the myometrium occurs chiefly because the muscle increases to approximately 20 times its bulk during pregnancy. 3. A fall in the plasminogen activator con-
in the myometrium
in a nonpregnant,
829
I
a preg-
centration and content of the myometrium occurs during the late stages of labor. The sudden release of the salt fraction of the plasminogen activator from the myomet&m into the bloodstream could increase the plasminogen activator concentration in the plasma to approximately 450 units per milliliter (the activator content of 1 ml. plasma in physiological conditions varied from 4 to 18 unit+ 26); this would mean that euglobulin clot prepared from this
830
Uszyhki
and
Uszyhska-Folejewska
plasma would dissolve within 3 minutes. This indicates the possibility of fibrinogenolysis under the influence of the activator rcleased from the wall of the uterus and supports the view of the authorsljs lG* 25 who are of the opinion that the fibrinolytic system may be a primary factor in disorders of the clotting system in obstetrics. The possibility of fibrinolysis associated with rapid conversion of plasma plasminogen to plasmin by the released tissue activator would appear to be justified in the light of present knowledge of the plasminogen activator system.2” Many investigations have indicated that the tissue activator is the precursor of the plasma activator and plays the role of the plasma activator after its release from the tissues into the vascular bed.ll Th e quite rapid fall in the concentration and content of the tissue activator during labor seems to be of considerable interest. A comparison of the content at the end of pregnancy, the beginning of parturition, and in the advanced stage of parturition indicates the role of uterine contractile activity as a mechanism in secrchg the activator from the myometrium into the circulation. It has been confirmed by many authors that the increase in plasma fibrinolytic activity during labor,“, 12, 13* “9 *? which is even called the fibrinolytic crisis,?” is evidence of the presence of an increased amount of activator in the blood and indicates that it is secreted from tissue, such as the myometrium, into the blood. It is highly probable that the release of the activator from the uterus into the bloodstream is brought about by a mechanism similar to that causing an increase in the fibrinolytic activity of venous blood during stasis. The repeated contractions during labor bring about a periodic stasis in the circulation supplying the uterus. It is then, probably, that the release of the activator contained in the vascular wallzl and cellular lysosome? into the body fluids occurs. The cause of the increase in plasma fibrinolytic activity durin,? labor can thus be explained. The problem of the influence of substances cornin,? from the myometrium in disturbing
the normal coagulation process by promoting fibrinolysis during labor has been studied 1~) several authors.4* ‘* 15vBp Greenberg” was tilt* first to demonstrate that the extract of human myometrium shortens the fibrinolysis time of the clot in vitro. Phillips and Wworkers’” found in the myometrium of patturients a substance of a plasminogen ;I(‘tivator character (cytofibrinokinase) and ascribed to it a role in the orcurrenccl of afibrinogenemia in parturients. Niesert arrd co-workers’4 observed a rase of hypofibririogenemia which appeared during the rapid growth of uterine myomas. Rasmussen ;IJI~ Roberts,” however, found in their evaluatiorl that the activator concentration in a UI~omatous uterus is similar to that of the normal uterus. The investigations described above COJIfirm both our earlier observations of the IOU activator content in the myometriunl of parturient women”” and the data given b) Esposito” that the activator concentration iIt the myometrium is higher before pregnancy than in pregnancy. Observations of the behavior of the activator during labor justify the presentation of a hypothesis on the role of the contractile activity of the myometriurn in the release of the activator. The physiological significance of the plasminogen activator in the myometrium should be considered in connection with the cluantity of other constituents of the fibrinolytic system in the uterus, placenta, and fetus. 1~1 view of the great quantity of inhibitors of plasminogen activation contained in the placenta,“. ‘% ” it can be concluded that the Inyometriunl and placenta are responsibk for the condition of the fibrinolytic systenl during labor. These organs evidently influence the balance of the activator system and the plasminogen inhibitor system in the plasma. In conclusion the following observations may be stressed : 1. The concentration of the plasminogen activator in the myometrium extracts prepared with 0.9 per cent NaCl from the myometrium of pregnant women is about one half that observed in the nonpreqnant: the
Plasminogen
concentration during the late stage of labor is one tenth that observed during the terminal weeks of pregnancy. 2. It was calculated that in the ninth and tenth months of pregnancy there is 10 times as much plasminogen activator as before pregnancy, so that the myometrium must be
activator
content
of myometrium
looked upon as an important plasminogen activator of woman. The contractions of pear to be the mechanism the release of the plasminogen the myometrium.
831
source of the the pregnant the uterus apresponsible for activator from
REFERENCES
1. 2. 3. 4. 5. 6. 7.
8. 9.
10. 11. 12. 13. 14.
Ali, S. Y., and Lack, C. H.: B&hem. J. 96: 63, 1965. Astrup, T., and Albrechtsen, 0. K.: Scandinav. J. Clin. & Lab. Invest. 9: 233, 1957. Buluk, K.: Przegl. Lek. 5: 438, 1949. Esposito. A.: Clin. Ostet. 67: 126. 1965. Giilmanj T., Naido, S. S., and Hathorn, M.: Lancet 2: 70, 1959. Greenberg, E. M.: Bull. New York Acad. Med. 24: 397, 1948. Guilhem, P., Pontonnier, A., Baux, R., and Ducos, J.: Bull. Fed. sot. gym%. et obst. 4: 573, 1952. Januszko, T., and Dubinska, L.: Acta med. Polona 6: 269, 1965. Januszko, T., Buluk, K., Uszynska-Folejewska, R., and Uszynski, M.: Ginek. polska 37: 137, 1966; and Pol. M. J. 5: 914, 1966. Januszko, T., Horodenski, J., and Olbromski, 1.: Acta med. Polona 6: 225. 1965. McCall, D. C., and Kline, D. L.: Thrombosis et diathesis haemorrh. 14: 116, 1965. Margulis, R. R., Luzadre, J. H., and Hodgkinson, C. P.: Obst. & Gynec. 3: 487, 1954. Niesert, W. II.: Arch. Gynak. 187: 144, 1955 Niesert, W., Schneider, J., and Stegmann, H.: Geburtsh. u. Frauenh. 7: 594, 1964.
15.
16. 17. 18. 19. 20. 21. 22. 23.
24. 25.
26.
Phillips, L. L., Butler, B. C., and Taylor. H. Cl.: AM. J. OB.ST. & GYNEC. 71: 342, 1956. Phillips, L. L.: Clin. Obst. & Gynec. 7: 325, 1964. Rasmussen, J., Roberts, H. R., and Astrup, T.: Surg. Gynec. & Obst. 118: 1277, 1964. Ratnoff, 0. D., Colc+py, J. E., and Pritchard, J. A.: J. Lab. & Clin. Med. 44: 408, 1954. Schneider, C.: Clin. Obst. & Gynec. 7: 339. 1964. Sherry, S.: Series Haematologica 7: 70, 1965. Todd, A. S.: Brit. M. Bull. 20: 2 10, 1964. Ujec, M.: Ginek. polska 36: 853, 1965. UszyAski, M., Januszko, T., and UszynskaFolejewska, R.: Fotxth World Congress of F. T. G. O., Buenos Aires, 1964. Uszyfiski, M., Januszko, T., and UszynskaFolejewska, R.: Ginek. polska 36: 131, 1965. Uszynski, M., Januszko, T., Uszynska-Folejewska, R., and Buluk, K.: Ginek. polska 36: 315, 1965. Uszynski, M., and Uszynska-Folejewska, R : Gynaecologia 161: ;88, 1966.
in nonpregnant,
and parturient MIECZYSLAW
content of the pregnant,
women
USZYRSKI
RYTA
USZYfiSKA-FOLEJEWSKA
Bialystok,
Poland
A quantitative evaluation of the plasminogen activator in the myometriunr of 20 nonpregnant women, 22 in various months of pregnancy, and 30 during labor was made. It was found that the highest concentration of the activator is ,?resent in the myometrium of nonpregnant women, a somewhat lower concentration at the end of pregnancy, and a very low concentration during the advanced stage of labor. A sudden fall in the complete plasminogen activator content during labor suggests the role of the uterine contractile activity in releasing the activator into the bloodstream. The possibility of fibrinogenolysis occurring after the release of the activator from the myometrium into the circulation is discussed.
THE EXCESSIVELY HIGH fibrinolytic activity in the plasma which accompanies disorders of the clotting system in obstetrics16, IQ can best be interpreted as due to a sudden rise in the concentration of the plasminogen activator in the circulation. As a result of the increase in the activator concentration, a rapid conversion of plasminogen into plasmin occurs and hyperplasminemia appears. The source of the plasminogen activator and the mechanism of its release into the blood in obstetric coagulation defects have not so far been elucidated in detail. The hypothesis that plasminogen activator from the uterus or the fetus and placenta may be the primary cause of the enhancement of the fibrinolysis processes in the plasmal”, O5 requires confirmation of the following assumptions: ( 1) the presence in the uterus, the fetus, or placenta of a form of plasminogen activator which is released into the plasma and brings about the conversion of
From the First and Gynecoloy, School.
Department Bialystok
plasminogen into plasmin; and (2) the presence in these tissues of sufficient quantity of plasminogen activator to bring about the formation of free plasmin in the plasma. This paper is concerned with determinations of the plasminogen activator content in extracts prepared with 0.9 per cent NaCl from the myometrium of nonpregnaat WOI~Ien, pregnant women and parturients. Material
and
Methods
Myometrial tissue sections from 20 nonpregnant women, 22 in various months of pregnancy, and 30 in the first stage of parturition were obtained from uteri during the course of such operative procedures as cesarean section or myomectomy. Sections were also taken from hysterectomy specimens. The myometrial sections during pregnancy were obtained as follows: in the second lunar month of an ectopic pregnancy; during the course of myomectomy in the third month of pregnancy; in the fourth month during an operation for abdominal extrauterine pregnancy; and at operation on the uterus for perforation during an induced abortion;
of Obstetrics Medical 825
826
Uszyfiski and Uszyfiska-Folejewska
in the ninth and tenth months, cesarean section because of diabetes mellitus (one case), Kh isosensitization (2 cases), placenta previa (8 cases), abnormal position of the fetus (2 cases), and others (2 cases). In the cases of advanced pregnancy, the myometrial sections were always taken from the lower portion of the uterus. The sections tvere kept at a temperature of -20° C. for 12 to 24 hours. The myometrium was homogenized in proportions of 1 Gm. to 2 ml. of 0.9 per rent NaCl for 5 minutes and centrifuged at 1,500 g for 15 minutes. The supernatant was tested in systems based on the modified euglobulin test3: 1 ml. of human plasma plus 18 ml. H,O, distilled at a temperature of 4’ C., plus 1 ml. of the muscle extract of various dilutions, 1 : 1 to 1 : 128, in the control experiments 1 ml. of 0.9 per cent NaCl. The samples were acidified with 1/6N
Fig. 1. Euglobulin nonpregnant (a),
July
15, 196i
CH,COOH to pH 5.3, centrifuged for 3 nlinutes, and the euglobulin sediment \\as dissolved in 0.25 ml. of a solvent consisting of Na,R,O,, 0.25 per cent; plus NaCI, 0.9 per c.ent. The euglobulin solution, 0.2 ~trl.: was then coa
activator
(units)
:-
1.300 --;
[ --I.:?”
where t stands for the fibrinolysis time Ininutes of the sample, and n the dilution
fibrinolysis time with various concentrations of the myometrial pregnant (b), and parturient women (c). Control.
extract
from
in of
Plasminogen
the extract in that sample. As a measure of the activator content in 1 Gm. of tissue, the mean value of 3 samples containing serial dilutions of the extract was taken. The samples with a dilution of 1: 32, 1:64, and 1 : 128 were the commonest. The above method has been described in detail in a previous paper.?” It is an adaptation of the method used for determinills the activator in the euglobulin test.s The activator content in the whole uterine muscle was calculated by multiplying the activator concentration (content of 1 Gm.) by the weight of the organ in grams, 60
ll
activator
contew
of
myometrium
An evaluation of the possible effect of the plasminogen activator from the myometrium on the plasma fibrinolytic system was made by dividing the “whole” activator content by the volume of the plasma (2,500 ml.). Results Fig. 1 shows an esample of the fibrinolysis time of a clot of euglobulin obtained from human plasma in the presence of various dilutions of myometriai extracts from nonpregnant women (a), pregnant women (b)? and parturients (c). Tk.e results given in the figure show : 1. The extract from the nonpregnant women possesses the highest fibrinolytic activity; the extract from the pregnant women
000 8000
.
5000 =0 r 4 > F ::
.
4000
3002
2 ul 9 0 2
z
2000
.
l
4
. .. r-l
.
6:
.
.
*a23
.
1000
.
~Ol(tHs OF PR l?6YAI(Cl ML
II
’
I I
l . *.a . .., I
.
vi r-7 I
.
‘I
WOUPRWYANT
I
I
Fig. 2. The plasminogen activator content pregnant, and parturient women (units).
827
I
DURING;
of 1 Gm. of the myometrium
LABOR
in nonpregnant,
-1
828
Uszytiski
and
Table I, The Staqe
Uszyhska-Folejewska
plasminogen
activator
No. of eases
of pregnancy
Not pregnant First trimester Ninth and tenth lurlar months Beginning
of labor
Advanced
Iabor
content
of 1 Gm. rnyometrium
) Mean
wiues
1
6
in units It
/P
20 6 15 7
.-~~
-__
‘7‘2) ._~.-.
exhibits a lower activity; and the lowest activity is noted in the myometrium during parturition. 2. There is a relation between the fibrinolytic activity of the extract and its dilution, the greatest reduction in fibrinolysis time being observed when the extract was diluted to 1:8 to 1:32. Table I and Fig. 2 present in units the plasminogen activator content of 1 Gm. of myometrium (concentration) of nonpregnant. pregnant, and parturient women. The mean values of the plasminogen activator content of 1 Gm. myometrium in nonpregnant women was found to be 2,311 units, in the first pregnancy trimester 3,940 units, in the ninth and tenth lunar months for pregnancy 1,023 lmits, at the beginning of labor 557 units, and in advanced labor 114 units. Fig. 3
an activator calculated approximately
concentration, from
as could easily bc 1 300 the formula -Lc, would be
3 minutes.
Comment
It is a known fact that the fibrinolytic: a.ctivity of tissue depends on the amount of pIasminogen activator contained in the tissue, Though this substance does not possess fibrinolytic properties, it influences the process of conversion of plasminogen into plasmin. In experiments, the tissue plasminogen acti\rator can be extracted from the tissues with 2M KCNS,? and to a lesser rxtent with 0.9 per cent NaCll’p ” and other solutions. In extracts of human myometrium, hi,gh cotlcentrations of plasminogen activator were found,“. ‘. Ii whereas only traces of plasmin activity were observed.” The extracts obtained with 0.9 per cent NaCll contained labile and stable activator. The present investigation concerned the activator obtained by means of extraction with 0.9 per cent NaCl. One may conjecture that this fraction is comparatively easily I’?‘leased from the vascular endothelium and the myometrial cells into the organic fluids and plays a part in the processes of fibrinolysis in the plasma. Our investigations showed that: 1. The concentration and content of plasIninocen activator in the myometrium of nonpregnant and pregnant women arr in
Plosminogen
activator
THE g’“*nn
40’”
HONTM OF THE PREDNhWCY
content
of myometrium
n
hWANCED STAGES OF LABOR CERVICAL l ILATATmn OVER 7 en9
i
Fig. 3. Total content of plasminogen nant, and a parturient woman.
activator
indirect proportion to each other, i.e., the activator concentration at the end of pregnancy is 50 per cent lower than before pregnancy, whereas the whole content is 10 times greater than before pregnancy. 2. The increase in plasminogen activator content in the myometrium occurs chiefly because the muscle increases to approximately 20 times its bulk during pregnancy. 3. A fall in the plasminogen activator con-
in the myometrium
in a nonpregnant,
829
I
a preg-
centration and content of the myometrium occurs during the late stages of labor. The sudden release of the salt fraction of the plasminogen activator from the myomet&m into the bloodstream could increase the plasminogen activator concentration in the plasma to approximately 450 units per milliliter (the activator content of 1 ml. plasma in physiological conditions varied from 4 to 18 unit+ 26); this would mean that euglobulin clot prepared from this
830
Uszyhki
and
Uszyhska-Folejewska
plasma would dissolve within 3 minutes. This indicates the possibility of fibrinogenolysis under the influence of the activator rcleased from the wall of the uterus and supports the view of the authorsljs lG* 25 who are of the opinion that the fibrinolytic system may be a primary factor in disorders of the clotting system in obstetrics. The possibility of fibrinolysis associated with rapid conversion of plasma plasminogen to plasmin by the released tissue activator would appear to be justified in the light of present knowledge of the plasminogen activator system.2” Many investigations have indicated that the tissue activator is the precursor of the plasma activator and plays the role of the plasma activator after its release from the tissues into the vascular bed.ll Th e quite rapid fall in the concentration and content of the tissue activator during labor seems to be of considerable interest. A comparison of the content at the end of pregnancy, the beginning of parturition, and in the advanced stage of parturition indicates the role of uterine contractile activity as a mechanism in secrchg the activator from the myometrium into the circulation. It has been confirmed by many authors that the increase in plasma fibrinolytic activity during labor,“, 12, 13* “9 *? which is even called the fibrinolytic crisis,?” is evidence of the presence of an increased amount of activator in the blood and indicates that it is secreted from tissue, such as the myometrium, into the blood. It is highly probable that the release of the activator from the uterus into the bloodstream is brought about by a mechanism similar to that causing an increase in the fibrinolytic activity of venous blood during stasis. The repeated contractions during labor bring about a periodic stasis in the circulation supplying the uterus. It is then, probably, that the release of the activator contained in the vascular wallzl and cellular lysosome? into the body fluids occurs. The cause of the increase in plasma fibrinolytic activity durin,? labor can thus be explained. The problem of the influence of substances cornin,? from the myometrium in disturbing
the normal coagulation process by promoting fibrinolysis during labor has been studied 1~) several authors.4* ‘* 15vBp Greenberg” was tilt* first to demonstrate that the extract of human myometrium shortens the fibrinolysis time of the clot in vitro. Phillips and Wworkers’” found in the myometrium of patturients a substance of a plasminogen ;I(‘tivator character (cytofibrinokinase) and ascribed to it a role in the orcurrenccl of afibrinogenemia in parturients. Niesert arrd co-workers’4 observed a rase of hypofibririogenemia which appeared during the rapid growth of uterine myomas. Rasmussen ;IJI~ Roberts,” however, found in their evaluatiorl that the activator concentration in a UI~omatous uterus is similar to that of the normal uterus. The investigations described above COJIfirm both our earlier observations of the IOU activator content in the myometriunl of parturient women”” and the data given b) Esposito” that the activator concentration iIt the myometrium is higher before pregnancy than in pregnancy. Observations of the behavior of the activator during labor justify the presentation of a hypothesis on the role of the contractile activity of the myometriurn in the release of the activator. The physiological significance of the plasminogen activator in the myometrium should be considered in connection with the cluantity of other constituents of the fibrinolytic system in the uterus, placenta, and fetus. 1~1 view of the great quantity of inhibitors of plasminogen activation contained in the placenta,“. ‘% ” it can be concluded that the Inyometriunl and placenta are responsibk for the condition of the fibrinolytic systenl during labor. These organs evidently influence the balance of the activator system and the plasminogen inhibitor system in the plasma. In conclusion the following observations may be stressed : 1. The concentration of the plasminogen activator in the myometrium extracts prepared with 0.9 per cent NaCl from the myometrium of pregnant women is about one half that observed in the nonpreqnant: the
Plasminogen
concentration during the late stage of labor is one tenth that observed during the terminal weeks of pregnancy. 2. It was calculated that in the ninth and tenth months of pregnancy there is 10 times as much plasminogen activator as before pregnancy, so that the myometrium must be
activator
content
of myometrium
looked upon as an important plasminogen activator of woman. The contractions of pear to be the mechanism the release of the plasminogen the myometrium.
831
source of the the pregnant the uterus apresponsible for activator from
REFERENCES
1. 2. 3. 4. 5. 6. 7.
8. 9.
10. 11. 12. 13. 14.
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