Fibrinolytic fibrinogenopenia

FIBRINOLYTIC Occurrence

FIBRINOGENOPENIA”

in a Case of Abruptio

Placentae

JESSICA H. LEWIS, M.D., ** DEBORAH JAMES W. FRESH, B.S., ANI) JOHN H. CHAPEL HILL, N. C. (From the Departments of Carolina, School of Medicine)

Physiology

and

Obstetrics

and

Gynecology,

C. LEARY,

C’witlersity

Ml)..

M.l).,

FiQWIiSON,

of

h’ortb

T

HE serious and often alarming complication of uterine hemorrhage in the parturient, frequently associated with abruptio placentae, has been the SU~Jject of a number of recent investigations, which have beeu thoroughly IXviewed.l-* Depressed levels of fibrinogen (in contrast to the elevated level of ttlt> normal woman at childbirth”) are usually found, and have been attributed to various mechanisms : (a) intravascular coagulation associated with the entrants of placental or amniotic thromboplastic material into the maternal circulation: (b) activation of the maternal fibrinolytic system by placental or uterine fibrioolysokinase; or (c) a combination of these two. The demonstration of fibrinolysis has been rare, which may be due to the fleeting presence of fibrinolysin (plasmin) in active form. This present communication presents a single cast. in which the fibrinogenopenia and associated coagulation abnormalities can be clearly attributed to the presence of active fibrinolysin in the maternal circulation. C. J., a Negro para iv, gravida vii, 37 years of age, was first. seen at thr. Sort,lL (~‘arolina in laltor, having hali no prwatal wre Memorial Hospital on June 17, 1954, \t-hen rhr. arrived of any kind. She gave an essentially unrevealiug history YBW for haviug wwived a blood transfusion at the time of delivery 4 years previously. On this admission the blood pressurfa ranged from 200/90 to 16OJlOO. Ocular fundi and urine were normal. One hour after ~11~ mission she was spontaneously delivered of a liviug 4 pound 101/b ounce, female infant. Slw was discharged from the hospital on the fourth postpartum day and failed to keep any rrt IJ~‘JI appointments. She was next seen at 3:30 p.Ir. on May 3U, 1955. The last menstrual period had bwri in October, 1954, the estimated date of confinement July, 1955. Again she had JIO~ swn a At 5:00 L.V. on the day of admission she ha11 first physician throughout her pregnancy. Harly in the afternoon she began passing clots noted vaginal bleeding and stomach cramps. and came to the hospital. Physical examination at this time showed a slightly pale Negro woman who appeawl to The temperature was 99” F., pulse 96, respiratious Z!, be iu discomfort but not seriously ill. and blood pressure 170/100. Positiw findings were a term-sized rigid, tender, gravid uterus National

*Supported in part by a research grant from the Division of Research Institutes of Health, United States Public Health Service(H 1510). **Present address, Department of Medicine, University of Pittsburgh. 418

Grants

uf

thl

l?IBBlNOLYTIC

419

FIBBINOWNOPENTA

with absenceof fetal he& sonnd~ or fetal mov~~d~ and moderately profuse w

Bleed-

ing. Laboratory flndiigs were : hematoerit 26 ; hemoglobin 7.0 Gm. 4 leukocyte count 18,766; polymorphonuolear leukocytes 74; lymphocytes 25; eosinophil 1. There was 2 plus albumin in the urine. The blood type was 0, Bh positive. Intravenous glucose was begun while blood was being grouped and matobed. Softtissue films of the abdomen revealed a large outline of the uterus with a small fetal skeleton noted in the inferior portion. Above the fetal skeleton, between it and the outline of the could conceivably represent a tremendous fundus, was a large soft-tissue density “which placenta such as occurs in placental apoplexy due to infarction or hemorrhage. ”

%

BLOOD w RBFtlNOGEN

CLOT

II &id

47

LYSIS 140 loo

00

0

II

0

II 1 1

:q

j DELIVERY

BLOOD

0

EXPLCdQATlON

,

UTERINE FL?CKING

LOSS .M.

TIME

Fig. l.-Patient

C. J.

Fibrinogk,

during

parturition,

proaccelerin, and platelet levels (as per cent’.oi complicated by abruptio placentae.

norm&i)

She was t.ransferred to the operating room and at 4:30 P.M. blood was drawn for the special studies which are the subject of this report. The administration of whole blood was begun, and sterile vaginal examination was performed with a double set-up, under nitrous oxide analgesia. Examination disclosed about 200 cc. of clots in the vagina. The cervix was soft, effaced, 4 cm. dilated, with the membranes bulging. The vertex was presenting in left occipitotransverse position at the spines. No placenta could be felt. The membranes were ruptured artificiaJly and irrtravenous Pitocin was begun. Labor progres+ed ra@idly aud at 6:OO P.M., without anesthesia, the patient was spontaneously delivered of: a 2,100 gram stillborn female infant. The placenta and membranes followed immediately ,with about, &Do0 cc. of blood and old clots. The fundus contracted well. Pitocin and bload .were continued. Clotting studies were repeated at 7:00 P.M. The patient continued to bleed in amounts that were considered exceqive ah&or@ not dramatic, and at 8:00 P.M., under Xylocaine pudendal block supplemented I with interm$tent nitrous oxide and cyclopropane, exploration of the uterus, cervix, and vagina was carried out, revealing nothing except a few small fragments of placental tissue in the fundus, which

420

LEWIS

ET

Am. J. Oh. & Gynec. Februarv. 1958

AL.

were removed. The fundus remained firm but bleeding continued. At 8:30 P.M. clotting studies were repeated. At 9:15 P.M., since bleeding continued to be excessive, the uterus was packed with gauze and at 9:45 PX. 3 Gm. of fibrinogen was given intravenously. In retrospect it seems fair to say that bleeding had significantly deereased after 8:30 P.M. and by 1O:OO P.M. was within normal limits. At no time was she in clinical shock although one blood pressure reading at 8:45 P.M. was 110/80 with a pulse of 100. Between 4:30 and 7:OO P.M. the patient received 750 C.C. of whole blood and between 7:00 P.Y. and 9:45 P.M. she received 1,750 C.C. of whole blood. From 9:45 to 11:30 P.M. she received 500 cc. and on May 31, during the day, she received 500 c.c. Rer total estimated blood loss while under observation was 2,300 C.C. and total replacement 3,500 C.C. The pack was removed at 6:00 P.&L, May 31, without any bleeding. The postpartum course was essentially uneventful and she was afebrile on procaine penicillin. The urinary output, which was 100 C.C. on the day of admission, rose to 2,525, 4,830, and 3,150 on the three following days. The blood urea nitrogen, which was 19 on May 31, rose to 52 on June 2, and dropped back to 21 on June 6. Electrolyte studies showed no alteration. The hematocrit on May 31 was 39.5 and hemoglobin 9.7 Gm. Albuminuria decreased to a faint trace in a voided specimen. The blood pressure, by June 6, had dropped to 130/80 and on June 12. when she was seen at home, it was 120/80. She was discharged in good condition on thn seventh postpartum day and again has failed to keep any return appointments. Method&-All of the methods employed are either standard procedures or have beer! previously described-a, 6 Blood samples were collected in siliconed syringes and transferred immediately to a water bath at 37” C. (clotting time, whole blood fibrinolysis) or to iced containers. Assays were carried out as rapidly as possible to prevent any in vitro effects oL’ fibrinolysin. TABLE

i Clotting time (Glass) (min.) Clot retraction Lysis time Prothrombin consumption % Platelet count x 1.000 per cubic millimkter Prothrombin time* Proaccelerin* Prothrombin” Proconvertin Plasma thromboplastin component,* Antihemophilic factor* Fibrinogen” *As

I.

BLOOD ------e-.--

4:30

7:oo

P.M.

P.M.

8 47 min.

CLOTTING 8:30 / P.M. -----------.._.

hr.

>24

__I.._... TIME "p;-kd$

73

34

+++t++

TESTS

+r+++ >2’4hr.

/ 3m.5

1 lm.0

6

ffii >?4hr.

1 -If

7

t++t >Y-lhr.

4;

++++ >%hr.

(i ?

++i 7 >~‘ahr.

30

45

50

92

62

73

OU

395

217

12-t

47

41 40

86 1ooi

146 76

7":

135 88

It' 1 100

700+

lOO+

lOO+

lOOr

63 62

65 73

67 59

58 56

78 68

90 77

lOO+ 100

lOO+ 75

1 oo+ SO

lOO+ 100

l@O+

1 oo+

100

100

li)O+ 100

35

34

20

29

44

54

90

49 84 77

TO normal.

Laboratory &u&%.-These studies are shown in Table I and Fig. 1. The first blood sample, taken some llyz hours after bleeding had commenced but before transfusion, showed normal clotting, following by the rapid (47 min.) and complete disappearance of the clot. A sample taken some 21/2 hours later clotted rapidly, giving a soft rather friable clot which Subsequent samples retracted to a very small nubbin but never completely dissolved. showed no evidence of lysis. Assays of the various coagulation proteins (Table I) showed that on the initial examination only fibrinogen (35 per cent = 116 mg. per cent) and proaecelerin were depressed. The prothrombin time paralled the proaceelerin value. Following The fibrinogen rose only after the bleeding whole blood infusions these rose to normal levels. ceased, in spite of many transfusions and 3 Gm. fibrinogen (Cutter). The other remarkable finding on the initial examination was a low prothrombin consumption (normal z greater

Volume 75 Number 2

FIBRINOLYTIC

FIBRINOGENOPEMIA

421

than 90 per cent). As the bleeding and blood repkement continued, a marked f&l in platelet count and very slight falls in prothrombin, proeonvertin, and antihemopbilic fa&or were observed. Additional studies of the fibrinolytic enzyme system were nut very satisfactary. The initial sampie showed lysis of the recaleifled pIasma clot. Subsequent samples did not. Antilysin titers carried out against a fully a&ive dog serum enzyme showed a slight inereaee in a&l the patients specimens as compared to those of 2 normal controls. Streptokinacse activation did not differ signi&a&ly from that observed in the normal subjects, but this test is subject to error as the fibrin substrate employed (bovine Fraction I) contained plasminogen.

com?nent

It was fortunate that the initial specimen in this patient was taken before therapy and at the critical time when whole blood clot lysis could be demonstrated. Thus, it seems justified to relate the accompanying coagulation abnormalities to the presence of active fibrinolysin. In vitro tests have demonst&ed the ability of fibrinolysin to destroy fibrinogen and proaeeelerin7 the two proteins found to be depressed. Lack of intravascular coagulation is evidenced by the normal platelet count and antihemophilic factor levels, as both of these might be expected to be depressed in the presence of even traces of thrombin. Subsequent changes, in particular the fall in platelets, may perhaps be attributed to simple dilution by the 3,000 C.C. of blood which the patient received. Most of this was moderately fresh (less than 48 hours old) but was not taken with any special precautions. After the disappearance of the active fibrinolysin the infused blood may have simply replaced the lost blood. Thus, if release from tissue sto$es or production of new protein or platelets did not ensue, the levels of clotting factors might be expected to be dependent upon levels in the infwd blood. Proaccelerin and fibrinogen reacted in different ways, which the data are insuiE&ent to explain, Fibrinogen showed no rise until bleeding cea~d, which was coincident with fibrinogen administration and packing of the uterus. The observed rise in plasma fibrinogen would suggest that the infused fib contained far less than the stated concentration or that it was immedi&ely removed from the circulation. The cause of the abnormal protbrombin consumption, i.e., the high serum Prothrombin consumption is normal prothrombin level, remains a mystery. in afibrinogenemia,8 and may be slightly depressed in hypoproaeceleri.8 If it were due to the latter, the consumption would be expected to return to normal as the proaccelerin level rose, which it did not. IPerhaps one of the thromboplastic factors, other than platelets, antihemophilic factor, and plasma tbromboplastin component, has been depressed.

A case of abruptio placentae in a 37-year-old multipara has been presented. Initial blood study showed the presence of active fibrinolysin and dep levels of fibrinogen and proaccelerin. Bleeding was controlled with 3,000 C.C. whole blood, 3 Gm. fibrinogen, and uterine packing.

References 1. Jackson, 1). P., Hartmann, R. C., and Busby, T.: Obst. 8; Gynec. 5: 223, 1955. 2. Ratnoff, 0. D., Pritchard, J. A., and Colopy, J. E.: New England J. Med. 253: 63, 19%. 3. Phillips, L. L., Montgomery, CT., Jr., and Taylor, H. C., Jr.: Xix. J. Oss’r. & GYNw. 73: 43, 1957. 4. Johnson, J. F., Seegers, W. II., and Braden, R. 0.: dm. J. Clin. Path 22: 322, I%?. 5. Fresh, J. W., Ferguson, J. I-I., and Lewis, J. H.: Obst. & Gynec. 7: 117, 1956. 6, Lewis, J. H., Ferguson, J. H., Fresh, .I. IV.! and Zncktbr. M. B. : .I. I,:lh. C C’liu. Utvl. 49:

211,

1957.

7. Lewis, J. H., Howe, A. C., and Fergusou, .I. H.: J. Clin. L~irest. 28: 1507, 1949. 8. Lewis, J. H., and Fergnson, J. H.: A. M. A. iam. J. Dis. Child. 88: 71 I? 1954.