COAGULATION STUDIES IN ABRUPTIO PLACENTAE
COMPLICATED BY HYPOFIBRINOGENEMIA
TIBOR J. CREENWALT, M.D., AND DEMETRIOS C.
TRIANTAPHYLLOPOULOS, M.D.
The Laboratories of the Milwaukee Blood Center, Inc., Milwaukee, Wisconsin
Acquired hypofibrinogenemia complicating abruptio placentae was first demonstrated by Dieckmann 1 in 1936. This observation has been amply confirmed.2' 10, 16 Low fibrinogen levels and hemorrhagic manifestations also may
occur in amniotic fluid embolism8 or associated with prolonged intra-uterine retention of a dead fetus.9 The escape of thromboplastin-rich material into the
maternal circulation causing defibrination in vivo may be the pathogenesis common to all these syndromes. Activation of fibrinolytic systems has also been
suggested as the mechanism.16
It is not our purpose to review the rapidly expanding literature covering this
subject. Relatively few studies of coagulation factors other than fibrinogen have
been recorded. 3 ' 4 ' "• 1 2 ' 1 6 We are reporting some limited observations concerning
the disturbance of the coagulation mechanism in 4 cases of abruptio placentae
complicated by hemorrhagic diathesis.
METHODS
Levels of fibrinogen and labile factor (Ac-globulin) and the prothrombin consumption and thromboplastinogen activity time7 were performed according to
the procedures described by Quick.6
The adsorption and elution technic of Quick6 was used for measuring prothrombin levels whenever feasible because it was not possible to obtain accurate results
with the 1-stage technic in the presence of low levels of labile factor and fibrinogen. In this procedure the prothrombin was adsorbed on tricalcium phosphate
and then eluted with a measured volume of 0.2 M sodium citrate. The prothrombin content of the eluate was determined, using deprothrombinized rabbit
plasma to supply fibrinogen and labile factor to the system. The same results
were obtained when the fibrinogen and labile factor deficiencies of the plasma
under test were corrected directly by adding an equal volume of deprothrombinized rabbit plasma.
The presence of fibrinolysin (plasmin) was demonstrated by keeping 2 ml.
of clotted blood in a 37 C. waterbath for 24 hours. The test was regarded as
positive, if the clot dissolved in that time.
R E S U L T S AND DISCUSSION
The results are presented in Table 1. All 4 patients had premature separation
of the placenta. The prothrombin times performed by Quick's 1-stage method
Received for publication August 20, 1954.
Dr. Green wait is Medical Director, Milwaukee Blood Center, and Assistant Clinical
Professor of Medicine, Marquette University School of Medicine, Milwaukee, Wisconsin;
Dr. Triantaphyllopoulos is Research Associate, Milwaukee Blood Center.
1246
NOV. 1 9 5 4
ABRTJPTIO PLACENTAE AND HYPOFIBRINOGENEMIA
1247
TABLE 1
SUMMARY OP COAGULATION S T U D I E S *
Time
Therapy
Fibrinogen
(mg. %)
Prothrombin!
Time
(seconds)
Labile
Factor
(seconds)
Thrombo- Prothromplastin
bin ConTime
sumption
(seconds) (seconds)
Fibrinolysis
P a t i e n t 1 (ER) delivered 5:52 P.M., December 20, 1953
6:20 P.M.
8:15 P.M.
9:00 P . M .
144.41
3 pints bank
278.3
blood
1 pint bank blood
1800 mg. Frac- 315.6
tion I
12-21-53
9:15 A.M.
433.3
No clot
Partial
27.5
—
—
—
16.0
Good clot
Good clot
P a t i e n t 2 (HH) delivered 2:50 A.M., J a n u a r y 1, 1954
2:50 A.M.
7:00-7:45
A.M.
1-4-54
5 % glucose
96.3{ 23.0(12.0)
D e x t r a n 500 ml.
2 pints b a n k
blood
2100 mg. Frac- 187.3
tion I
3 pints bank
428.0
12.0
blood
12.5
—
—
Partial
Good clot
23.0
Good clot
11.0
No clot
P a t i e n t 3 (VB) delivered (cesarean) 11:32 P.M., March 17, 1954
9:00 P . M .
10:30 P . M .
3-18-54
3-19-54
25.0(12.0) 30.0
500 ml. liquid
plasma
192.6
J-3 pint bank
blood
2100 mg. Fraction I
4.5 pints bank
blood
2 pints bank
blood
19.0
9.0
Good clot
31.0
11.0
Good clot
49.0
19.0
Good clot
46.5
11.5
17.5
No clot
Partial
P a t i e n t 4 (LJ) delivered 9:42 P.M., M a r c h 30, 1954
8:00 P . M .
10:00 P . M .
None
% pint bank
blood
165.0
31(12.0)
41.0
* T h e normal values of the tests used a r e : Prothrombin time 12 seconds, labile factor
20 seconds or less, T A T and P C over 15 seconds.
t Figures in parentheses represent values obtained by the adsorption-elution technic.
{ Fibrin threads t h a t could be wrapped on a glass rod were not formed. Flecks t h a t
appeared after the addition of thrombin had to be centrifuged in order to perform the
determination.
1248
GREENWALT & TRIANTAPHYLLOPOULOS
VOL. 2 4
were all prolonged. Whenever these results were checked by the adsorption
and elution technic, the prothrombin values were found to be normal. The
prolonged prothrombin time given by the 1-stage method was also corrected by
adding 1 volume of deprothrombinized rabbit plasma to 1 volume of the patient's plasma.
Hypofibnnogenemia was present in all the cases. In this laboratory, the mean
fibrinogen level of 25 patients studied during the last trimester of pregnancy
was found to be 503 mg. per 100 ml. (range 294-685).14
Labile factor (Ac-globulin) was found to be deficient in the 2 patients tested.
The prolonged prothrombin time in Case 1 (ER) was also presumably the result
of labile factor deficiency. Repeated determination of labile factor was done in
Case 3 (VB) and was found to become normal within 12 hours after the uterus
was emptied.
Prothrombin consumption was considerably impaired in the 3 cases tested.
Abnormally low consumption of prothrombin13 during clotting may be caused by:
1. Deficiency of
a. thromboplastinogen (antihemophilic globulin, AHG),
b. plasma thromboplastin component (PTC),
c. plasma thromboplastin antecedent (PTA);
2. Thrombocytopenia and/or thrombasthenia;
3. Deficiency of labile factor; and
4. Circulating anticoagulants.
The data presented are not sufficient to allow definitive interpretation. In
patient 3 (VB) the discrepancy between the thromboplastinogen activity time
(TAT) and the prothrombin consumption (PC) values suggests a deficiency of
platelet factor (thrombocytopenia). The increase in the TAT reading after 24
hours correlated with a simultaneous return of the PC value to normal may be
interpreted as indicating a rise in plasma thromboplastinogen. This can be taken
to mean that originally thromboplastinogen was decreased. I t is possible that
the increase in the TAT was due to natural fluctuation.
Depletion of labile factor can cause impairment of prothrombin consumption.
In Case 3 it does not appear to be the determining factor because the labile factor
was normal in the sample with decreased PC.
There was increased fibrinolytic activity in all 4 patients. It is impossibe to
state whether this is part of the primary mechanism or a secondary phenomenon.
Seegers and Loomis11 demonstrated the destruction of purified prothrombin
preparations by plasma fibrinolysin in vitro. Stefanini12 has found that the fibrinolysin that occurs in disseminated prostatic carcinoma seems to destroy all
coagulation factors. The identity of the fibrinolytic mechanisms that have
been described is questionable. We' have not studied this aspect of the problem.
Our observations confirm the finding by Johnson and his associates3 that there
is deficiency of labile factor (Ac-globulin) as well as hypofibnnogenemia in the
hemorrhagic syndrome complicating premature separation of the placenta. Our
data point to the presence of deficiencies in additional coagulation factors.
The major components of plasma Fraction I of Cohn are fibrinogen and anti-
NOV. 1954
ABRUPTIO PLACENTAE AND HYPOFIBRINOGENEM1A
1.249
hemophilic globulin. Its therapeutic effectiveness in the syndrome under discussion is well established. I t may owe its corrective action in part to components other than fibrinogen. I t would be of interest to determine if "pure"
fibrinogen15 preparations are as effective as Fraction I.
SUMMARY
The coagulation mechanism Avas studied in 4 patients with abruptio placentae
complicated by hemorrhage. All the patients had fibrinogenopenia. The prolonged prothrombin times by the 1-stage method were shown to be due to deficiency of labile factor. Studies of prothrombin consumption and thromboplastinogen activity suggest the presence of platelet factor deficiency and perhaps
also lowthromboplastiiiogen levels. The latter data are insufficient for any definite
conclusions, however.
Acknowledgment. T h e fibrinogen used was supplied through t h e courtesy of D r . Sam
T . Gibson, Associate Director, Blood Program, T h e American National R e d Cross, N a tional Headquarters, Washington 13, D . C.
REFERENCES
1. DIECKMANN, W. J . : Blood chemistry and renal function in abruptio placentae. Am. J .
Obst. & G y n e c , 3 1 : 734-745, 1936.
2. H O D G K I N S O N , C . P . , M A R G U L I S , R . R., AND L U Z A D R E , J . H . : Etiology a n d m a n a g e m e n t
of hypofibrinogenemia of pregnancy. J.A.M.A., 154: 557-561, 1954.
3. JOHNSON, J . F . , S E E G E R S , W. H . , AND B R A D E N , R . G.: Plasma Ac-globulin changes in
placenta abruptio. Am. J . Clin. P a t h . , 22: 322-326, 1952.
4. K A E S E R , 0 . : Fibrinolyse dans certain cas de decollemcnt premature du placenta. R e v .
d'h6mat., 7: 55-59, 1952.
5. MOLONEY, W. C , E G A N , W. J., AND GORMAN, A. J . : Acquired afibrinogenemia in preg-
nancy. New England J . Med., 240: 596-598, 1949.
6. QUICK, A. J . : T h e Physiology and Pathology of Hemostasis. Philadelphia: Lea & Fobiger, 1951, 1SS p p .
7. QUICK, A. J., STAPP, W. F . , AND H U S S E Y , C. V . : T h e effect of heating on t h e t h r o m b o -
plastic activity of rabbit brain extract, a new test for t h e diagnosis of hemophilia.
J. L a b . & Clin. Med., 39: 142-147, 1952.
8. R E I D , D . E . , W E I N E R , A. E . , AND R O B Y , C. C : I. I n t r a v a s c u l a r clotting and afibrino-
genemia, the presumptive lethal factors in the syndrome of amniotic fluid embolism.
Am. J . Obst. & Gynec., 66: 465-474, 1953.
9. R E I D , D . E . , W E I N E R , A. E . , R O B Y , C. C , AND D I A M O N D , L . K . : I I I . M a t e r n a l afibrino-
genemia associated with long-standing intrauterine fetal death. Am. J . Obst. &
Gynec., 66: 500-506, 1953.
10. SCHNEIDER, C . L . : R u p t u r e of t h e basal (decidual) plate in abruptio placentae: A
pathway of autoextraction from t h e decidua into t h e maternal circulation. Am. J .
Obst. & G y n e c , 63: 1078-1090, 1952.
11. SEEGERS, W. H . , AND LOOMIS, E . C : Prothrombin and fibrinolysin. Science, 104: 461462, 1946.
12. S T E F A N I N I , M . , C A M P B E L L , E . W., P L I T M A N , G. I., AND SALOMON, L . : C o a g u l a t i o n
13.
14.
15.
16.
defects due to acquired anticoagulants and fibrinolysis; their detection a n d treatment. Bull. N . England M . Center, 15: 23-31, 1953. '
SYMPOSIUM: What is Hemophilia? Blood, 9: 244-293, 1954.
TIUANTAPHYLLOPOULOS, D. C : Unpublished observations.
W A R E , A. G., G U E S T , M . M., AND SEEGERS, W. H . : Fibrinogen: With special reference
to its preparation and certain properties of t h e product. Arch. Biochem., 13: 231-236,
1947.
W E I N E R , A. E . , R E I D , D . E . , AND R O B Y , C. C : I I . Incoagulable blood in severe prem a t u r e separation of t h e placenta: A method of management. Am. J . Obst. & G y n e c ,
66: 475-499, 1953.