The coagulation mechanism in labor at term induced with prostaglandin Fza HELEN TOM

I. P.

Cincinnati,

GLUECK,

M.D.

BARDEN,

M.D.

Ohio

The prostaglandins, in uitro. It has been

especially the PGE reported

that

PGF,,

series, produce profound and the PGE series

eflects on platelet function do not affect the clotting

mechanism when used to induce midterm abortion, in conrast to that induced with hypertonic saline but the e#ect of these drugs on the clotting mechanism when used to induce term labor has not been reported. Labor was induced with intravenous PGF,, in eight patients, at 32 to 41 weeks’ gestation, with premature rupture of the membranes. Three samples were obtained: (1) anteceding the administration of the drug, (2) during the peak drug effect during active labor, and (3) app rorimately 12 hours post partum. No significant changes were seen in the prothrombin or partial thromboplastin times, platelet numbers or aggregation with ADP, ,fibrinogen levels, euglob,ulin lysis times, and circulating fibrin split products. The circulation of thrombin as shown by a specific test for fibrin monomer was not demonstrated.

Materials

P R o s T A G L A N D I N s of the PGE series have profound inhibitory effects on platelet function and aggregation in vitro.lm6 Prostaglandin FPa (PGF,,) and prostaglandin EP (PGE,) have been widely utilized to induce abortion’-lo but do not appear to influence the coagulation mechanism in contrast to the dramatic changes found in some abortions induced by hypertonic saline.*1-18 The prostaglandins have also been evaluated for their oxytocic action in advanced pregnancy I’-21 but little is known of their effect on the coagulation mechanism. This report is concerned with a study of the clotting mechanism of eight patients, at 32 to 41 weeks’ gestation, in whom labor was induced with intravenous PGF,,.

From the Departments of Medicine and and Gynecology, University of Cincinnati of Medicine. Supported in part by Grant States Public Health Service, from the Upjohn Company. Received

for

Accepted

June

publication

methods

The patients were from a previousIy reported study designed to evaluate PGF,, as an oxytocic agent for induction of labor in preterm and term patients presenting with premature rupture of membranes.** Each patient was given PGF,, by intravenous infusion, starting at 2.5 pg per minute and doubling the dosage every 60 minutes until there was laborlike uterine activity, or to a maximum dose of 20 pg per minute. The total dose ranged from 0.25 to 2.25 mg. All eight patients developed laborIike uterine activity which progressed to vagina1 delivery in six; two patients were delivered by cesarean section, one for fetal distress and the other for failure to progress in labor. There were no instances of excessive bleeding during delivery or post partum. The weight of infants ranged from 1,600 to 3,190 grams. The smallest died of respiratory distress syndrome but the others survived.

Obstetrics College

2904-18, United and a grant

April

and

laboratory Maternal tained prior late in the level, and Blood was volume of

16, 1974.

3, 1974.

Reprint requests: Dr. Helen I. Glueck, University of Cincinnati, College of Medicine, Department of Medicine, 6472 College of Medicine, Cincinnati, Ohio 45267. 213

studies blood for coagulation studies was obto the start of the infusion of PFG,,, induction of labor at the highest dose approximately 12 hours post partum. collected in O.lM buffered citrate, one anticoagulant being used for each 9 vol-

214

Glueck

and

January Am. J. Chtet.

Barden

TRCH I I

SOLUBLE

15, 197:, Gym01

FIBRIN

200 CXWTROLS f/67*47)

190-

1800

8-

0

R

7-

T

170-

T

160 -

A

:

;

150-

65-

0

0

5

d

140130-

24

T” X

B,-

h

n

X

p

120 -

w $

3-

--

2-

V

I-

i”

0

V f

1

IOO-

1

PTT

(sec.) (sec.)

TT (sec.) Fibrinogen (mg./lOO ml.) -

Pra parturn

1x1

1x1

I

MID

POST

1 Mid parturn

1

2,

I

1.3 14) 3.6

12.8? (11.331.5+

(26

36)

(27

37)

(26

Normal laboratory values: 33 _+ 4 sec.; TT, 12-18 sec. range.

-

I

I

WE

and

1 Post partum

12.8 + (ll.l31.5 +

16.4? 2.4 368 + 83 (225 -514)

8

(TRCHII), and soluble fibrin F?,. Each symbol represents pre, during, and approximately

1.2 14) 3.3

-

80

WJ&-$f$

12.82 (1l.G 30.2 i:

16.1 k 2.3 364 + 77 (280 -537)

n n

Table I. Mean values, prothrombin time (PT) , partial thromboplastin time (PTT) , thrombin time (TT) , and fibrinogen in term labor induced in eight patients with prostaglandin F,, PT

n

90-

H .

PRE

Fig. 1. Fibrin split products induced with prostaglandin values. Samples were obtained

X

110-

0 T.

1.7 14) 3.6

- 35)

17.5 2 3.3 381 5131 (257 -550)

PT, 11.5 2 1.2 sec.; PTT, Numbers in parentheses =

umes of blood. The prothrombin time (PT) , partial thromboplastin time (PTT), and thrombin time (TT) were determined by previously described methods.ll Fibrinogen was measured by the method of Ratnoff and Menzie. 23 Fibrinolytic split products were measured by the tanned red cell hemagglutination inhibition immunoassay (TRCHII) of Merskey and co-authorxZ4 The serial-dilution protamine test for fibrin monomer and/or fibrin degradation products employed the method of Gurewich and Hutchinson.2s Circulating soluble fibrin (fibrin monomer) was measured by the method of Kisker

MID

I

,

I

POST

(fibrin monomer) in labor at term, an individual patient; bars, mean 12 hours post partum (see text).

Rush.2”

The

method

is based

on

the

ability

of

Factor XIII to incorporate radioactive 14C-labeled glycine ethyl ester into circulating fibrin. The method differs from other methods for assaying fibrin monomer since it is insensitive to the products of plasmin digestion of either fibrinogen or fibrin and, hence, measures only fibrinogen altered by thrombin.Platelets were counted in the Coulter Counter by the method of Bull, Schneiderman, and Brecke? employing a platelet-rich plasma. Platelet aggregation was determined with a “Chrono-log” aggregometer by the method of Born and Cross,28 employing ADP in final concentrations of 1.0 and 0.5 pg, respectively. The euglobulin lysis time was determined on whole blood by the method of the urokinase pulmonary embolus trial cooperative study.29 Results Table thrombin

I presents the mean values for the protime (PT) , partial thromboplastin time

(PTT),

thrombin

time

(TT),

and

fibrinogen.

There were no significant changes in any of these parameters at any of the three time intervals. The values for fibrinogen varied from patient to patient but no significant trend was noted. There was a slight tendency for the thrombin time to be prolonged in the postpartum period, but these changes were not statistically significant.

Volume Numlm

121

Coagulation

2

Table II. Euglobulin prostaglandin F,,

lysis time

(EULT)

and protamine

gelation

EULT

(5) (1)

/ Mid

> 2 hr. l-f/l hr.

Normal Table

(5) (1)

EULT,

III.

hours partum

Immediate 1 Post partum

2 hr. 1 hr.

(6) (1)

nonpregnant,

Pre pnrtum

> 2 hr. 1-s hr.

0

protamine

gelation

partum

Pre partum

0 (6)

1 (6)

0 (6)

platelet

numbers -

numbers

(10-S)

(6 patients)

partum

1 Postpartum

/ Mid

291

256

Range : 116-316 *Calculated comitantly.

The

162-386

PG&

215

with

1Mid

reading partum

1Post partum

1 (6)

1 (‘3)

2 hours or more. Numbers in parentheses = number of patients.

Mean

Pre partum

with

24 hour

1 Post parturn

and aggregation

with

ADP

in term labor

induced

Aggregation Platelet

induced

test

reading

1 Mid

(6)

labor

tests in term labor induced

Positive .___ Pre partum

in term

with

with

253

1Mid

5/8*

Fz,

ADP 0.5 Pg

I &? Pre partum

prostaglandin

parturn)

Post partum

Pre partum

5/8

5/7

5/n

1Mid

partum

1Post partum

517

4/7

194-350

as optimum

clearing

denominator

equals

5 minutes after addition the

total

number

of ADP compared

of patients

Table II indicates that there was little change at any time interval in the euglobulin lysis time, a measure of plasminogen activator, although one patient showed a slightly accelerated initial value. A positive protamine gelation, a measurement of fibrin monomer and/or monomer complexed with fibrin split products, was not demonstrated in any of the patients when read at 30 minutes. In one patient all three examples were positive when read at 24 hours but in our hands this delayed reading is difficult to evaluate. Fibrin split products specificially measured by the TKCHII assay appeared initially moderately elevated as compared to nonpregnant controls (Fig. 1) but these differences were not statistically significant (P < 0. IO). There was a tendency for the values to be slightly higher in the postpartum period, as has been seen with normal deliveries.“? w ” Again, these differences when compared with the initial values were not statistically significant. Soluble fibrin (fibrin monomer) which reflects fibrinogen acted on by thrombin was within the normal range and showed no alteration at any time interval (Fig. 1) . Platelet numbers determined serially in six patients showed no significant change (Table III). Platelet aggregation was initially abnormal in three of eight samples tested with 1.0 pg of ADP and in two of seven with 0.5 pg. Since abnormalities in platelet aggregation may persist as long as 5 days after the ingestion of a single aspirin, and accurate

tested,

the

to normal

numerator,

histories of aspirin able, it is difficult noted to PGF,,.

the

aggregation number

with

determined normal

convalues.

ingestion were not always availto ascribe the few abnormalities

Comment Disseminated intravascular coagulation in abortion induced with hypertonic saline was reported from our laboratoryl’l ‘* and confirmed by numerous other observers.13W1!’ In later studies the moment of fetal death was monitored.12 Circulating soluble fibrin and fibrin split products were noted within 15 minutes of fetal death in every instance, even though the remainder of the clotting profile was within the normal range. Thus subclinical disseminated intravascular coagulation (DIC) appears as a regular event in abortions so induced even when frank evidence of clotting factor deficiencies are absent. Because of these findings, prostaglandins have been utilized to induce midterm abortions. During termination of pregnancy with intra-amnionic PGF,,, Badraoui and co-authorsl” observed shortening of the prothrombin time and increases in Factors V, VIII, and X. Twenty-four hours after abortion the coagulation profile returned to preinduction values. They believed that prostaglandin activated the clotting system. Anderson and co-authors7 utilized intra-amnionic PGF,, to induce abortion in midtrimester pregnancy in 40 patients. In two patients in whom the coagulation mechanism was studied no changes were noted in platelet numbers,

216

Glueck

and

prothrombin times, PTT’s, fibrinogen, or fibrin split products. Brenner and co-authors” noted no changes in the PT, PTT, Factor V, Factor VIII, fibrin degradation products, fibrinogen levels, or fibrinogen turnover rates when abortion was so induced, in contrast to those previously noted by the same group when hypertonic saline was used to induce abortion. Abortion at midterm with PGF,, cannot be directly compared to its use at term labor. It is well known that certain minimal changes in coagulation may be seen in normal labor. Kleiner and co-authors:“’ studied the clotting mechanism in normal and abnormal deliveries. In the former group, fibrinogen and Factor VIII levels were elevated at the onset of labor and fell slightly 1 to 2 hours post partum but by 24 hours they had again attained their initial levels. Some depression of the fibrinolytic activity as measured by the euglobulin lysis time before and at the time of delivery was noted, followed thereafter by a rapid activation of this enzyme system. By 24 hours the activity tended to return to normal. In pathologic pregnancies, however, these changes were markedly accentuated. Bonnar and associates”l found increases in Factors V and VIII and a decrease in fibrinogen with placental separation. A fall in plasminogen level was noted at this time, followed in approximately 1 hour by a prolongation of the euglobulin lysis time and

REFERENCES

1.

2. 3. 4. 5. 6. 7. 8. 9. 10.

January Am. J. Obstet.

Barden

Emmons, P. R., Hampton, J. R., Harrison, M. J. G., Honour, A. J., and Mitchell, J. R. A.: Br. Med. J. 2: 468, 1967. Wolfe, S. M., Muenzer, J., Shulman, R., and Wolfe, S. M.: J. Clin. Invest. 49: 104 (abst., 335) 1970. Mustard, J. F., and Packham, M. A.: Circulation 42: 1, 1970. Kloeze, J.: Experientia 26: 307, 1970. Phillips, L.: AM. J. OBSTET. GYNECOL. 115: 227, 1973. Mustard, J., Kinlough-Rathbone, R. L., Jenkins, C. S. P., and Packham, M. A.: Ann. N. Y. Acad. Sci. 201: 343, 1972. Anderson, G. G., Hobbins, J. C., Rajkovic, V., Speroff, L., and Caldwell, B. V.: Prostaglandms 1: 147, 1972. Hendricks, C. H., Brenner, W. E., Ekbladh, L., Brotanek, V., and Fishburne, J. I.: AM. J. OBSTET. GYNECOL. 111: 564, 1971. Brenner, W. E., Fishburne, J. I., McMillan, C. W., Johnson, A. M., and Hendricks, C. H.: AM. J. OBSTET. GYNECOL. 117: 1080. 1973. Badraoui, M. H. H., Bonna;, J., Hillier, H., and Embrey, M. P.: Br. Med. J. 1: 19, 1973.

15, 1975 Gynecol.

increases in the level of fibrin split products. In contrast to the saline-induced abortion, these changes were of short duration and were followed post partum by increases of fibrinogen, Factor VIII, and platelets. Minimal changes were noted by Spivak and co-authors” in normal deliveries with fibrinogen levels and slightly elevated fibrin degradation titers during labor and delivery. The changes in fibrin split products persisted for 12 to 18 hours post partum. In the present series the only observed changes were a slight increase in the fibrin degradation products measured with the TRCHII test, after completion of delivery as compared to the preinduction levels. Although these slight differences ,were not of statistical significance, they resembled the changes noted with normal deliveries. There were no significant changes in platelet numbers or function, fibrinogen levels, prothrombin times, PTT’s, or euglobulin lysis times. With the exception of one test read at 24 hours, the protamine test for fibrin monomer-fibrin degradation complexes was negative. Most significantly, the circulation of thrombin as shown by a specific assay for fibrin monomer was never demonstrated. Thus, it appears that labor at term can be induced with PGF,, with no deleterious effect on the clotting mechanism and no evidence of disseminated intravascular coagulation.

11. 12. 13.

14.

15. 16. 17. 18. 19.

20.

Stander, R. W., Flessa, H. C., Glueck, H. I., and Kisker, C. T.: Obstet. Gynecol. 37: 660, 1971. Glueck. H. I.. Flessa. H. C.. Kisker. C. T.. and Stande;, R. W:: J. A.‘M. A. 525: 28,‘1973. ’ Weiss, A. E., Easterllng, W. E., Jr., Odom, M. H., McMillan, C. W., Johnson, A. M., and Talbert, L. M.: AM. J. OBSTET. GYNECOL. 113: 868, 1972. Easterling, W. E., Jr., Weiss, A. E., Odom, M. H., and Talbert, L. M.: AM. J. OBSTET. GYNECOL. 113: 1065, 1972. Beller, F. K., Rosenberg, M., Kolker, M., and Douglas, G. W.: AM. J. OBSTET. GYNECOL. 112: 534, 1972. Halbert, D. R., Buffington, J. S., Crenshaw, C., Brame, R. G., and Silver, D.: Obstet. Gynecol. 39: 41, 1972. Spivak, J. L., Spangler, D. B., and Bell, W. R.: N. Enel. T. Med. 287: 321. 1972. S&wa&, R., Greston, W., and Kleiner, G. J.: Obstet. Gynecol. 40: 728, 1972. K&im, S. M. M.., Trussell, R. R., Hillier, K., and Patel. R. C.: T. Obstet. Gvnaecol. Br. Commonw. 76: 769, 1969. ” Vakhariya, V. R., and Sherman, ‘A. I.: AM. J, OBSTET. GYNECOL. 113: 212, 1972.

Volume Number

21. 22. 23. 24. 25. 26.

121 2

Coagulation

Anderson, G. G., Hobbins, J. C., and Speroff, L.: AM. J, OBSTET. GYNECOL. 112: 382, 1972. Barden, T. P.: J. Reprod. Med. 9: 339, 1972. Ratnoff, 0. D., and Me&e, C.: J. Lab. Clin. Med. 37: 316, 1951. Merskey, C., Lalezari, P., and Johnson, A. J.: Proc. Sot. Exp. Biol. Med. 131: 871, 1969. Gurewich, V., and Hutchinson, E.: Ann. Intern. Med. 75: 895, 1971. Kisker, C. T., and Rush, R.: J. Clin. Invest. 50: 2235, 1971.

Note The

to Authors: Editors

Publisher

OF OBSTETRICS

have

in Reference

AND

agreed

to add

28. 29. 30. 31.

induced

with PGf$,

GYNECOLOGY.

217

Bull, B. S., Schneiderman, N. A., and Brecker, G.: Am. J. Clin. Pathol. 44: 678, 1965. Born, G. V. R., and Cross, M. J.: J. Physiol. (Lond.) 168: 178, 1963. Am. Heart Assoc. Monograph 39: Circulation 47: 33, 1973. Kleiner, G. J., Merskey, C., and Johnson, A. J.: Br. J. Haematol. 19: 159, 1970. Bonnar, J., McNicol, G. P., and Douglas, A. S.: Br. Med. J. 2: 200, 1970.

Style

the article title to references in the AMERICAN References will now conform to the style of the Cumulated Index Medicus, viz., name of author, title of article, name of periodical, volume, page, and year. Authors are always encouraged to limit references to sixteen for the following JOURNAL sections: Obstetrics, Gynecology, and Fetus, Placenta, and Newborn.

JOURNAL

and

Change

27.

in term labor

The coagulation mechanism in labor at term induced with prostaglandin F2 alpha.

The prostaglandins, especially the PGE series, produce profound effects on platelet function in vitro. It has been reported that PGF2alpha and the PGE...
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