Acta Obstet Gynecol Scand 58: 27-30, 1979
IS THERE A PHYSIOLOGICAL INTRAVASCULAR COAGULATION IN OBSTETRICAL CASES? C. L. Arocha-Piriango,' Jesus Linares,* Armando Cova' and Paul Martinezz From 'Instituto Venezolano de Investiguciones Cient9cas (IVIC), and Waternidud Concepcion Palacios. Carucas. Venezuela
Absrracr. The concentrations of plasmatic fibrinogen and its degradation products (FDPs), and the paracoagulation test using serial dilution of protamine sulphate (SDPS) were determined during the third trimester of pregnancy, labor, and puerperium. Significant increases in the concentrations of fibrinogen and FDPs were observed throughout the process of pregnancy and birth, combined with both positive and negative SDPS tests. We suggest that these findings do not indicate a process of physiological DIC.
Kleiner and co-workers (IS) have suggested that during labor a physiological DIC process exists, while Hyde and co-workers (12) maintain that during normal pregnancy and puerperium there is an activation of both the clotting and the fibrinolytic mechanisms which can be detected by measuring the fibrin monomers and the amount of circulating fibrinogen/fibrin degradation products (FDPs) in the blood. In a previous paper ( 2 ) it was shown that during labor there is a high percentage of positive tests for serial dilution of protamine sulphate (SDPS) (lo), both in normal and in complicated cases (preeclampsia, dead fetus, premature membrane rupture, etc.). This paper reports the results obtained from a group of pregnancies in which SDPS, FDPs and fibrinogen concentration were determined concurrently. CLINICAL MATERIAL Blood samples were taken from a total of 31 1 women: 30 normal non-pregnant women used as controls, 42 in the third trimester of pregnancy, 112 during normal labor, and 127 during the first 48 hours post-partum. None of the cases showed any hemorrhagic complication during pregnancy, delivery or puerperium. During labor four samples were taken, at 3-hourly intervals, starting at the onset of the initial uterine contraction. For the series during puerperium, three samples were taken, at 12, 24 and 48 hours.
LABORATORY METHODS Citruted plasma. Blood was obtained by clean venipuncture and mixed 9 : 1 with 0.5 ml of 3.2% sodium citrate in 10% epsilon amino caproic acid. The plasma was separated by centrifuging the blood immediately at 3 000 r.p.m. for 10 minutes. Tests were performed the same day when possible; otherwise the samples were frozen at -20°C. All syringes, tubes, and caps were plastic disposable. Serial Dilution Protumine Sulphate (SDPS) test was performed according to the method described by Gurewich & Hutchinson (lo), using protamine sulphate (Roche). FibrinogenlFibrin Degradation Products (FDP's). Serum was obtained by mixing vlv citrate plasma with a solution of calciumlthrombin (2.5 U ml in 0.025 M CaCI,). The mixture was incubated at 37°C for 30 minutes. The clot was separated and kept. Merskey's haemagglutination inhibition test was performed (TRCHII) (18) on the remaining serum. Fibrinogen concentrution was determined by the clot weight method of lngram (13) using the clot obtained from the above procedure.
RESULTS The results obtained for the fibrinogen, FDPs and SDPS test during the third trimester of pregnancy, labor, and puerperium are shown in Figs. 1 and 2 . The fibrinogen and FDPs levels are expressed as mean plus standard deviation; the SDPS test as the percentage of positive tests. The total group has been subdivided into two series: those with SDPS positive and negative, respectively. None of the non-pregnant controls were SDPSpositive. During the third trimester of pregnancy, on the other hand, 37 % of the women had a positive SDPS test. The percentage had dropped to 11 % at the onset of labor, but rose to a peak of 27 % during the period of 3-6 hours during labor. Thereafter, the percentage dropped again until the first 12 hours of puerperium, when there was a still higher peak of 41 % SDPS positive, followed by another decline during the period of 12 to 48 hours of puerperium. Acto Ohstet G'yncw~/ScufidS6' I19791
C. L . Aroclici-Piticrngo et (11.
28
600r
T
Fig. 1 . Fibrinogen and FDPs compared with the incidence of positive SDPS tests. Normal Controls
6
Pregnoncy 3rd term
Labour (hours)
Statistical analysis of the SDPS-negative series showed that the values for fibrinogen and FDPs levels during the third trimester of pregnancy (320.3 mg% and 3.2 pg/ml) were significantly higher than in the control group (276.0 mg% and 1.07 pg/ml). Both the fibrinogen levels and the FDPs rose to somewhat higher values during labor; these values were maintained all through puerperium (Fig. 2). I n the SDPS-positive series the increased levels of fibrinogen and FDPs during the third trimester of pregnancy were more marked. Fibrinogen reached a level of 470.4 mg% and FDP 4.19 pg/ml. The high level of fibrinogen was maintained during labor, but as puerperium progressed the level dropped until the period of 2 4 4 8 hours, when the value (297.8 mg%) was less than that (361.7 mg%) for the SDPS-negative women during the same period. During labor and puerperium, FDPs were maintained at levels similar to those of pregnancy, with two exceptions. In the 9-12-hour period, 2 out of 35 cases had a positive SDPS test with very low values of FDPs (3.8 and 1.7 pg/ml). In the 3-6hour period only 6 out of 32 cases had a positive SDPS; their mean FDP was 10.8 pg/ml, but 5 of them gave titers as high as 13.6 pg/ml. A< f ( l OhJfrf
(;,YfIl'C"l/ ~ l ' O l l d . %
f 1979)
12 24 -8 Puerperium (hours)
comparing the variations in the group for fibrinogen and FDP, it was observed that in the series with positive SDPS tests there were correlation in the periods 3-6 hours from labor (r=-0.42) and 24-48 hours of puerperium (r=-0.76). In the rest of the group, there was no correlation between the two parameters. DISCUSSION The 38% incidence of positive SDPS during the third trimester of pregnancy found in this study agrees with the observations of Hyde (12). During labor, the percentage of positive SDPS varied in the period of 3-6 hours (27%), diminishing as expulsion approached. These results corroborate those reported by us in a previous paper (2). A renewed increase of positive SDPS tests (41 %) was observed during the first hours of puerperium and the percentage remained elevated up to 48 hours postpartum. Those authors who, like us, have used Merskey's method (18) differ somewhat concerning the presence of FDP during pregnancy and puerperium. Hahn (1 1) and Woodfield (21) reported an increase
Physiologiccil ititrm*mciil(ircotigiil~rtiori
2
0
0
29
1
T Fig. 2 . Variations of fibrinogen and FDPs throughout pregnancy, labor and puerperium in the SDPSnegative cases.
4t 0
L Normal Controls
Pregnancy 3rd term
Labour Ihours)
in FDP levels during pregnancy, while Bonnar (4) did not observe any change until the onset of labor. Hyde (12), using a different technique, observed an increase in the FDP level (4 pg/ml) in both pregnancy and puerperium. Keliner and co-workers (15) found FDP values within the normal range during labor, while in the immediate postpartum an increase was observed by Hyde (12). Statistically significant increases in FDP levels during late labor and puerperium were found by Hahn ( 1 1). Kleiner et al. (15) did not observe any significant changes in fibrinogen values during labor compared with pregnancy. In the puerperium, Kleiner (15) and Bonnar (6) found a significant decrease in the first 4 hours postpartum, while Nilsson (19) reported that the level of fibrinogen remained unchanged during the first 4 days after delivery. In this study, fibrinogen and FDPs were high in both series (SDPS positives and negatives) during the various stages. The statistical analysis showed only a slight correlation between the variations of fibrinogen and degradation products in the period 24-48 hours of puerperium ( r = - 0 . 7 6 ) . This suggests that the circulating FDPs do not derive from the lysis of plasmatic fibrinogen, which would be expected if one accepts that the fibrinolytic activity of the plasma is diminished during pregnancy and labor (3, 4, 5).
Puerperium (hours)
N o clear explanation has been found for the production of FDPs in obstetrical cases. The increase has been associated with the most varied mechanisms, such as the increase in the active intima1 surface area subsequent to the vasodilatation in late pregnancy (20). venous obstruction of the lower limbs ( 2 2 ) , an extravascular contribution from fibrinolysis of growing tissues (7, 12). the release of thromboplastin in the bloodstream from abnormal placental damage (2 l ) , and changes in the hormonal secretion of the placenta during labor (3). Some authors have shown that even in normal placentas there are fairly large amounts of fibrin deposits (8, 9), but it has also been reported that the uterus is a major source of plasminogen activators (17) that could induce the lysis of the fibrin deposited in the placenta. Abildgaard & Uszynski ( I ) have reported that the placenta is rich in inhibitors of the fibrinolytic system that could prevent such a lysis. Based on those findings it might be argued that if both systems are balanced, then the level of FDPs during pregnancy and labor would be normal or low if they were produced at uterine level. However, since there are many cases with a high incidence of elevated FDPs, it seems that an imbalance exists between the two systems, with the lytic phenomenon occurring predominantly at the placenta. But it is equally conceivable that circulat-
30
C. L . Arocha-Pinango et al.
ing FDPs are produced by lysis of the deposited fibrin by proteases other than plasmin, as already reported (14, 16). The presence of fibrin monomers in the circulation as determined by SDPS tests is not constant and the variation does not seem to be related to the uterine activity during labor. The activity developed by the myometrium increases as labor progresses and it is possible that such an increase of uterine tone could limit the passage of the fibrin monomers and the FDP formed at placental level, which would explain the drop in FDPs and the decreased incidence of positive SDPS during the last stages of labor. The increased incidence of positive SDPS tests during puerperium, which progressively diminished, could well be a result of the local activation of the hemostatic and fibrinolytic mechanisms which occur in the uterus at the moment of placental separation (6). However, it must be noted that this phenomenon was not constant in the present study. In view of the circumstances discussed above, we do not feel that it is possible to relate either the positive SDPS tests or the high values of FDPs as an expression of a physiological DIC in obstetrical cases, as has been previously suggested.
6. Bonnar, J., Prentice, C. R. N., McNicol, G. P. &
7. 8.
9. 10.
11. 12.
13. 14.
15.
16.
ACKNOWLEDGEMENT
17.
We wish to acknowledge the technical assistance of Lic. G. Montilla, G. Lopez and S. Rodriguez, and also Mr A. Vielma from the Banco Mercantil y Agricola of Caracas, and Dr S. Gorzula for the statistical analysis.
18.
REFERENCES I . Abildgaard, U. & Uszynski, M.: Separation and characterization of two fibrinolytic inhibitors from human placenta. Thromb Diath Haemorrh 25: 580, 1971. 2. Arocha-Piriango, C. L . , Linares, J., Cova, A,, Martinez, P., Montilla, G. & Rodriguez, S.: Intravascular coagulation in obstetrics: serial dilution protamine sulfate test throughout labor. Am J Obstet Gynecol124: 18, 1976. 3. Astedt, B.: Fibrinolytic inhibitors in human, retroplacental blood. Acta Obstet Gynecol Scand 53:227, 1974. 4. Bonnar, J . , Davidson, J. F., Pidgeon, C. F., McNicol, G. P. & Douglas, A. S.: Fibrin degradation products in normal and abnormal pregnancy and parturition. Br Med J iii: 137, 1969. 5 . Bonnar, J., McNicol, G. P. & Douglas, A. A.: Fibrinolytic enzyme system and pregnancy. Br Med J iii: 387. 1969.
19.
20. 21. 22.
Douglas, A. S.: Haemostatic mechanism in the uterine circulation during placental separation. Br Med J ii:564, 1970. Das, P. C., Allan, A. G. E., Woodfield, D. C. & Cash, J. D.: Fibrin degradation products in sera of normal subjects. Br Med J iv: 718, 1967. Frigoletto, F., Tullis, L. J., Reid, D. E . & Hinman, J.: Hypercoagulability in the dysmature syndrome. Am J Obstet Gynecol 11: 867, 1971. Fox, H.: White infarcts of the placenta. J Obstet Gynaecol Br Commonw 70: 980, 1963. Gurewich, V. & Hutchinson, E.: Detection of intravascular coagulation by a serial dilution protamine sulfate test. Ann Int Med 75: 895, 1971. Hahn, L.: On fibrinolysis and coagulation during parturition. Acta Obstet Gynecol Scand, Suppl. 28, 1974. Hyde, E., Joyce, D., Gurewich, V. & Flute, P. T.: Intravascular coagulation during pregnancy and the puerperium. J Obst Gynaecol Br Commonw 80: 1059, 1973. Ingram, G. I. C.: The determination of plasma fibrinogen by the clot weight method. Biochem J 51: 583, 1952. Johnson, A. J. & Merskey, C.: On the origin of the proteolytic activity responsible for the release of fibrinogen-fibrin related antigen in vitro. Scand J Haematol, Suppl. 23: 87, 1971. Kleiner, G. J., Merskey, C., Johnson, A. J. & Markus, W. B.: Defibrination in normal and abnormal parturition. Br J Haematol19: 159, 1970. Latallo, Z., Teysseyre, E., Wegrzynowicz, Z. & Kopee, M.: Degradation of fibrinogen by proteolytic enzymes. Scand J Haematol, Suppl. 13: 15, 1971. McKay, A. V. P., Das, P. C., Myerscough, P. R. & Cash, J. B.: Fibrinolytic components of human uterine arterial and venous blood. J Clin Pathol20: 227, 1967. Merskey, C., Lalezari, P. & Johnson, A.: A rapid, simple, sensitive method measuring fibrinolytic split product in human serum. Proc SOCExp Biol131: 871, 1969. Nilsson, I . M. & Kullander, S.: Coagulation and fibrinolytic studies during pregnancy. Acta Obstet Gynecol Scand49: 363, 1967. Winner, W.: Role of placenta in systemic circulation. Obstet Gynecol Surv 20: 545, 1965. Woodfield, D. G., Cole, S. K., Allan, A. G. E. & Cash, J. D.: Serum fibrin degradation products throughout normal pregnancy. Br Med J iv: 665, 1968. Wright, H. T., Osbom, S. B. & Edmonds, D. G.: Flow of venous blood in leg during pregnancy. Surg Gynecol Obstet 90:481, 1950.
Submitted for publication Sept. I 1 1977 ~
C. L . Arocha-Piriango Laboratorio de Fisiopatologia I.V.1 .C. - Apartado 1827 Caracas 101 Venezuela
IS THERE A PHYSIOLOGICAL INTRAVASCULAR COAGULATION IN OBSTETRICAL CASES? C. L. Arocha-Piriango,' Jesus Linares,* Armando Cova' and Paul Martinezz From 'Instituto Venezolano de Investiguciones Cient9cas (IVIC), and Waternidud Concepcion Palacios. Carucas. Venezuela
Absrracr. The concentrations of plasmatic fibrinogen and its degradation products (FDPs), and the paracoagulation test using serial dilution of protamine sulphate (SDPS) were determined during the third trimester of pregnancy, labor, and puerperium. Significant increases in the concentrations of fibrinogen and FDPs were observed throughout the process of pregnancy and birth, combined with both positive and negative SDPS tests. We suggest that these findings do not indicate a process of physiological DIC.
Kleiner and co-workers (IS) have suggested that during labor a physiological DIC process exists, while Hyde and co-workers (12) maintain that during normal pregnancy and puerperium there is an activation of both the clotting and the fibrinolytic mechanisms which can be detected by measuring the fibrin monomers and the amount of circulating fibrinogen/fibrin degradation products (FDPs) in the blood. In a previous paper ( 2 ) it was shown that during labor there is a high percentage of positive tests for serial dilution of protamine sulphate (SDPS) (lo), both in normal and in complicated cases (preeclampsia, dead fetus, premature membrane rupture, etc.). This paper reports the results obtained from a group of pregnancies in which SDPS, FDPs and fibrinogen concentration were determined concurrently. CLINICAL MATERIAL Blood samples were taken from a total of 31 1 women: 30 normal non-pregnant women used as controls, 42 in the third trimester of pregnancy, 112 during normal labor, and 127 during the first 48 hours post-partum. None of the cases showed any hemorrhagic complication during pregnancy, delivery or puerperium. During labor four samples were taken, at 3-hourly intervals, starting at the onset of the initial uterine contraction. For the series during puerperium, three samples were taken, at 12, 24 and 48 hours.
LABORATORY METHODS Citruted plasma. Blood was obtained by clean venipuncture and mixed 9 : 1 with 0.5 ml of 3.2% sodium citrate in 10% epsilon amino caproic acid. The plasma was separated by centrifuging the blood immediately at 3 000 r.p.m. for 10 minutes. Tests were performed the same day when possible; otherwise the samples were frozen at -20°C. All syringes, tubes, and caps were plastic disposable. Serial Dilution Protumine Sulphate (SDPS) test was performed according to the method described by Gurewich & Hutchinson (lo), using protamine sulphate (Roche). FibrinogenlFibrin Degradation Products (FDP's). Serum was obtained by mixing vlv citrate plasma with a solution of calciumlthrombin (2.5 U ml in 0.025 M CaCI,). The mixture was incubated at 37°C for 30 minutes. The clot was separated and kept. Merskey's haemagglutination inhibition test was performed (TRCHII) (18) on the remaining serum. Fibrinogen concentrution was determined by the clot weight method of lngram (13) using the clot obtained from the above procedure.
RESULTS The results obtained for the fibrinogen, FDPs and SDPS test during the third trimester of pregnancy, labor, and puerperium are shown in Figs. 1 and 2 . The fibrinogen and FDPs levels are expressed as mean plus standard deviation; the SDPS test as the percentage of positive tests. The total group has been subdivided into two series: those with SDPS positive and negative, respectively. None of the non-pregnant controls were SDPSpositive. During the third trimester of pregnancy, on the other hand, 37 % of the women had a positive SDPS test. The percentage had dropped to 11 % at the onset of labor, but rose to a peak of 27 % during the period of 3-6 hours during labor. Thereafter, the percentage dropped again until the first 12 hours of puerperium, when there was a still higher peak of 41 % SDPS positive, followed by another decline during the period of 12 to 48 hours of puerperium. Acto Ohstet G'yncw~/ScufidS6' I19791
C. L . Aroclici-Piticrngo et (11.
28
600r
T
Fig. 1 . Fibrinogen and FDPs compared with the incidence of positive SDPS tests. Normal Controls
6
Pregnoncy 3rd term
Labour (hours)
Statistical analysis of the SDPS-negative series showed that the values for fibrinogen and FDPs levels during the third trimester of pregnancy (320.3 mg% and 3.2 pg/ml) were significantly higher than in the control group (276.0 mg% and 1.07 pg/ml). Both the fibrinogen levels and the FDPs rose to somewhat higher values during labor; these values were maintained all through puerperium (Fig. 2). I n the SDPS-positive series the increased levels of fibrinogen and FDPs during the third trimester of pregnancy were more marked. Fibrinogen reached a level of 470.4 mg% and FDP 4.19 pg/ml. The high level of fibrinogen was maintained during labor, but as puerperium progressed the level dropped until the period of 2 4 4 8 hours, when the value (297.8 mg%) was less than that (361.7 mg%) for the SDPS-negative women during the same period. During labor and puerperium, FDPs were maintained at levels similar to those of pregnancy, with two exceptions. In the 9-12-hour period, 2 out of 35 cases had a positive SDPS test with very low values of FDPs (3.8 and 1.7 pg/ml). In the 3-6hour period only 6 out of 32 cases had a positive SDPS; their mean FDP was 10.8 pg/ml, but 5 of them gave titers as high as 13.6 pg/ml. A< f ( l OhJfrf
(;,YfIl'C"l/ ~ l ' O l l d . %
f 1979)
12 24 -8 Puerperium (hours)
comparing the variations in the group for fibrinogen and FDP, it was observed that in the series with positive SDPS tests there were correlation in the periods 3-6 hours from labor (r=-0.42) and 24-48 hours of puerperium (r=-0.76). In the rest of the group, there was no correlation between the two parameters. DISCUSSION The 38% incidence of positive SDPS during the third trimester of pregnancy found in this study agrees with the observations of Hyde (12). During labor, the percentage of positive SDPS varied in the period of 3-6 hours (27%), diminishing as expulsion approached. These results corroborate those reported by us in a previous paper (2). A renewed increase of positive SDPS tests (41 %) was observed during the first hours of puerperium and the percentage remained elevated up to 48 hours postpartum. Those authors who, like us, have used Merskey's method (18) differ somewhat concerning the presence of FDP during pregnancy and puerperium. Hahn (1 1) and Woodfield (21) reported an increase
Physiologiccil ititrm*mciil(ircotigiil~rtiori
2
0
0
29
1
T Fig. 2 . Variations of fibrinogen and FDPs throughout pregnancy, labor and puerperium in the SDPSnegative cases.
4t 0
L Normal Controls
Pregnancy 3rd term
Labour Ihours)
in FDP levels during pregnancy, while Bonnar (4) did not observe any change until the onset of labor. Hyde (12), using a different technique, observed an increase in the FDP level (4 pg/ml) in both pregnancy and puerperium. Keliner and co-workers (15) found FDP values within the normal range during labor, while in the immediate postpartum an increase was observed by Hyde (12). Statistically significant increases in FDP levels during late labor and puerperium were found by Hahn ( 1 1). Kleiner et al. (15) did not observe any significant changes in fibrinogen values during labor compared with pregnancy. In the puerperium, Kleiner (15) and Bonnar (6) found a significant decrease in the first 4 hours postpartum, while Nilsson (19) reported that the level of fibrinogen remained unchanged during the first 4 days after delivery. In this study, fibrinogen and FDPs were high in both series (SDPS positives and negatives) during the various stages. The statistical analysis showed only a slight correlation between the variations of fibrinogen and degradation products in the period 24-48 hours of puerperium ( r = - 0 . 7 6 ) . This suggests that the circulating FDPs do not derive from the lysis of plasmatic fibrinogen, which would be expected if one accepts that the fibrinolytic activity of the plasma is diminished during pregnancy and labor (3, 4, 5).
Puerperium (hours)
N o clear explanation has been found for the production of FDPs in obstetrical cases. The increase has been associated with the most varied mechanisms, such as the increase in the active intima1 surface area subsequent to the vasodilatation in late pregnancy (20). venous obstruction of the lower limbs ( 2 2 ) , an extravascular contribution from fibrinolysis of growing tissues (7, 12). the release of thromboplastin in the bloodstream from abnormal placental damage (2 l ) , and changes in the hormonal secretion of the placenta during labor (3). Some authors have shown that even in normal placentas there are fairly large amounts of fibrin deposits (8, 9), but it has also been reported that the uterus is a major source of plasminogen activators (17) that could induce the lysis of the fibrin deposited in the placenta. Abildgaard & Uszynski ( I ) have reported that the placenta is rich in inhibitors of the fibrinolytic system that could prevent such a lysis. Based on those findings it might be argued that if both systems are balanced, then the level of FDPs during pregnancy and labor would be normal or low if they were produced at uterine level. However, since there are many cases with a high incidence of elevated FDPs, it seems that an imbalance exists between the two systems, with the lytic phenomenon occurring predominantly at the placenta. But it is equally conceivable that circulat-
30
C. L . Arocha-Pinango et al.
ing FDPs are produced by lysis of the deposited fibrin by proteases other than plasmin, as already reported (14, 16). The presence of fibrin monomers in the circulation as determined by SDPS tests is not constant and the variation does not seem to be related to the uterine activity during labor. The activity developed by the myometrium increases as labor progresses and it is possible that such an increase of uterine tone could limit the passage of the fibrin monomers and the FDP formed at placental level, which would explain the drop in FDPs and the decreased incidence of positive SDPS during the last stages of labor. The increased incidence of positive SDPS tests during puerperium, which progressively diminished, could well be a result of the local activation of the hemostatic and fibrinolytic mechanisms which occur in the uterus at the moment of placental separation (6). However, it must be noted that this phenomenon was not constant in the present study. In view of the circumstances discussed above, we do not feel that it is possible to relate either the positive SDPS tests or the high values of FDPs as an expression of a physiological DIC in obstetrical cases, as has been previously suggested.
6. Bonnar, J., Prentice, C. R. N., McNicol, G. P. &
7. 8.
9. 10.
11. 12.
13. 14.
15.
16.
ACKNOWLEDGEMENT
17.
We wish to acknowledge the technical assistance of Lic. G. Montilla, G. Lopez and S. Rodriguez, and also Mr A. Vielma from the Banco Mercantil y Agricola of Caracas, and Dr S. Gorzula for the statistical analysis.
18.
REFERENCES I . Abildgaard, U. & Uszynski, M.: Separation and characterization of two fibrinolytic inhibitors from human placenta. Thromb Diath Haemorrh 25: 580, 1971. 2. Arocha-Piriango, C. L . , Linares, J., Cova, A,, Martinez, P., Montilla, G. & Rodriguez, S.: Intravascular coagulation in obstetrics: serial dilution protamine sulfate test throughout labor. Am J Obstet Gynecol124: 18, 1976. 3. Astedt, B.: Fibrinolytic inhibitors in human, retroplacental blood. Acta Obstet Gynecol Scand 53:227, 1974. 4. Bonnar, J . , Davidson, J. F., Pidgeon, C. F., McNicol, G. P. & Douglas, A. S.: Fibrin degradation products in normal and abnormal pregnancy and parturition. Br Med J iii: 137, 1969. 5 . Bonnar, J., McNicol, G. P. & Douglas, A. A.: Fibrinolytic enzyme system and pregnancy. Br Med J iii: 387. 1969.
19.
20. 21. 22.
Douglas, A. S.: Haemostatic mechanism in the uterine circulation during placental separation. Br Med J ii:564, 1970. Das, P. C., Allan, A. G. E., Woodfield, D. C. & Cash, J. D.: Fibrin degradation products in sera of normal subjects. Br Med J iv: 718, 1967. Frigoletto, F., Tullis, L. J., Reid, D. E . & Hinman, J.: Hypercoagulability in the dysmature syndrome. Am J Obstet Gynecol 11: 867, 1971. Fox, H.: White infarcts of the placenta. J Obstet Gynaecol Br Commonw 70: 980, 1963. Gurewich, V. & Hutchinson, E.: Detection of intravascular coagulation by a serial dilution protamine sulfate test. Ann Int Med 75: 895, 1971. Hahn, L.: On fibrinolysis and coagulation during parturition. Acta Obstet Gynecol Scand, Suppl. 28, 1974. Hyde, E., Joyce, D., Gurewich, V. & Flute, P. T.: Intravascular coagulation during pregnancy and the puerperium. J Obst Gynaecol Br Commonw 80: 1059, 1973. Ingram, G. I. C.: The determination of plasma fibrinogen by the clot weight method. Biochem J 51: 583, 1952. Johnson, A. J. & Merskey, C.: On the origin of the proteolytic activity responsible for the release of fibrinogen-fibrin related antigen in vitro. Scand J Haematol, Suppl. 23: 87, 1971. Kleiner, G. J., Merskey, C., Johnson, A. J. & Markus, W. B.: Defibrination in normal and abnormal parturition. Br J Haematol19: 159, 1970. Latallo, Z., Teysseyre, E., Wegrzynowicz, Z. & Kopee, M.: Degradation of fibrinogen by proteolytic enzymes. Scand J Haematol, Suppl. 13: 15, 1971. McKay, A. V. P., Das, P. C., Myerscough, P. R. & Cash, J. B.: Fibrinolytic components of human uterine arterial and venous blood. J Clin Pathol20: 227, 1967. Merskey, C., Lalezari, P. & Johnson, A.: A rapid, simple, sensitive method measuring fibrinolytic split product in human serum. Proc SOCExp Biol131: 871, 1969. Nilsson, I . M. & Kullander, S.: Coagulation and fibrinolytic studies during pregnancy. Acta Obstet Gynecol Scand49: 363, 1967. Winner, W.: Role of placenta in systemic circulation. Obstet Gynecol Surv 20: 545, 1965. Woodfield, D. G., Cole, S. K., Allan, A. G. E. & Cash, J. D.: Serum fibrin degradation products throughout normal pregnancy. Br Med J iv: 665, 1968. Wright, H. T., Osbom, S. B. & Edmonds, D. G.: Flow of venous blood in leg during pregnancy. Surg Gynecol Obstet 90:481, 1950.
Submitted for publication Sept. I 1 1977 ~
C. L . Arocha-Piriango Laboratorio de Fisiopatologia I.V.1 .C. - Apartado 1827 Caracas 101 Venezuela
