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ORIGINAL ARTICLE
To cite this article: Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, Sibony O, Mahieu-Caputo D, Hurtaud-Roux MF, Huisse MG,
Denninger MH, de Prost D, for the PPH Study Group. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.
J Thromb Haemost 2007; 5: 26673.
Introduction
Summary. Background: Postpartum hemorrhage (PPH) is a
major source of maternal morbidity. Objectives: This studys
objective was to determine whether changes in hemostasis
markers during the course of PPH are predictive of its
severity. Patients and methods: We enrolled 128 women with
PPH requiring uterotonic prostaglandin E2 (sulprostone)
infusion. Two groups were dened (severe and non-severe
PPH) according to the outcome during the rst 24 hours.
According to our criteria, 50 of the 128 women had severe PPH.
Serial coagulation tests were performed at enrollment (H0), and
1, 2, 4 and 24 hours thereafter. Results: At H0, and through
H4, women with severe PPH had signicantly lower brinogen,
factor V, antithrombin activity, protein C antigen, prolonged
prothrombin time, and higher D-dimer and TAT complexes
than women with non-severe PPH. In multivariate analysis,
from H0 to H4, brinogen was the only marker associated with
the occurence of severe PPH. At H0, the risk for severe PPH was
2.63-fold higher for each 1 gL)1 decrease of brinogen. The
negative predictive value of a brinogen concentration
>4 gL)1 was 79% and the positive predictive value of a
concentration 2 gL)1 was 100%. Conclusion: These ndings
indicate that a simple brinogen measurement can anticipate
the risk of severe bleeding in PPH.
Keywords: brinogen, postpartum hemorrhage.
Correspondence: Dominique de Prost, Service dHematologie
Biologique, Immunologie et Transfusion, Hopital Louis Mourier,
178 rue des Renouillers, 92701 Colombes cedex, France.
Tel.: +33 14760 6113; fax: +33 14760 6278; e-mail: dominique.
de-prost@lmr.aphp.fr
This work is attributed to: AP-HP, Hopital Louis Mourier, Colombes,
France; University Paris 7 Denis Diderot, Paris, France.
Received 27 June 2006, accepted 23 October 2006
recorded prospectively and serial blood samples were collected at H0 and after 1, 2, 4 and 24 h. Importantly, no patient
received RBC units, FFP or platelet transfusion before the
H0 time-point.
The study protocol dened two groups of patients
according to the course of bleeding over the 24 h after H0.
The severe group included women meeting at least one of
the following criteria: peripartum decrease of Hb 4 g dL)1
(last Hb value before delivery considered as the reference);
transfusion of at least 4 RBC units; hemostatic intervention
(angiographic embolization, surgical arterial ligation or
hysterectomy); or death. The median (interquartile) time
period between the last predelivery Hb value and H0 was 0
(0;1) days. All women who did not meet any of these criteria,
over the rst 24 h postpartum, were assigned to the nonsevere group. Consequences of blood loss were assessed by
calculation of the organ dysfunction or infection (ODIN)
score [13].
Data on demographics, medical history, pregnancy and
delivery were collected, as was the last Hb level before labor or
Cesarean section.
Laboratory assays
268 B. Charbit et al
presence of soluble brin monomer complexes was semiquantitatively evaluated using the FS test (Diagnostica Stago).
Plasma levels of TAT (Dade Behring), PAP (Montes et al. [14])
and soluble thrombomodulin (Asserachrom Thrombomodulin, Diagnostica Stago) were measured by enzyme-linked
immunoassay.
Statistical analysis
one uterine rupture; all were in the severe group. In the two
groups, we analyzed the incidence of factors previously
described as being associated with PPH [15]: body mass index
> 30; age > 38 years; parity > 4; Cesarean section; premature delivery; birthweight > 4,000g; twin pregnancy; polyhydramnios; previous PPH; labor duration > 12 h; third stage of
labor > 30 min; abnormal placental insertion; and pre-existent
coagulation disturbances. Forty per cent, 31%, 16% and 13%
of all patients had no, one, two, and three or more PPH risk
factors, respectively. The incidence of these risk factors did not
differ between the two groups (P 0.8).
Clinical history of hemorrhage
Clinical characteristics
Results
Severe group n 50
Non-severe group n 78
P-value
28 [26; 33]
56 [50; 66]
40 [39; 41]
2 [1; 2]
40
4
4
3
4.0
4
62
18
18
2
6 [3; 9]
11.9 11.9
12.5
65.5
25.0
87 [40; 150]
12.1 [11.0; 13.0]
2.5 [)0.4; 5.3]
30 [26; 34]
62 [56; 72]
40 [38; 41]
2 [1; 3]
61
7
5
7
2.6
11
67
17
9
8
6 [4; 9]
11.1 9.1
32.3
46.2
21.5
60 [35; 125]
11.3 [10.7; 12.4]
1.9 [)1.1; 4.3]
0.34
0.01
0.29
0.20
0.9
0.65
0.06
0.27
0.94
0.24
0.07
0.08
0.04
0.46
Table 2 Laboratory values at enrollment (H0) in the severe and non-severe groups
Severe group n 50
Non-severe group n 78
P-value
AUC
173
81
1.16
1.0
3.3
83
72
9
72
69
55
39
26
304
9
63
142
181
88
1.10
1.0
4.4
93
90
6
79
75
36
20
19
199
9
69
145
0.40
0.02
0.02
0.05
< 0.0001
0.005
0.004
0.007
0.005
0.038
0.04
0.014
0.36
0.22
0.83
0.13
0.57
0.544
0.625
0.625
0.601
0.753
0.653
0.655
0.648
0.656
0.615
0.639
0.430
0.468
0.462
[141;209]
[70;90]
[1.08;1.30]
[1.0;1.2]
[2.5;4.2]
[72;94]
[60;94]
[5;22]
[62;79]
[57;83]
[40;69]
[19;57]
[15;41]
[162;803]
[9;20]
[48;74]
[112;166]
[139;231]
[80;96]
[1.04;1.18]
[0.9;1.1]
[3.7;5.1]
[83;102]
[75;109]
[3;9]
[71;84]
[66;85]
[24;48]
[13;38]
[11;31]
[94;645]
[9;20]
[60;79]
[113;193]
Results are given as median [25th percentile; 75th percentile] or percentage [95% condence interval]. AUC is the area under ROC curve used to
test the predictive power of each laboratory parameter for the severity of bleeding.
270 B. Charbit et al
Table 3 Multivariate logistic regression of laboratory parameters associated with severe PPH
Time
Laboratory
parameter
H0*
H1*
H2
H4
brinogen
brinogen
brinogen
brinogen
(g
(g
(g
(g
L)1)
L)1)
L)1)
L)1)
Number of
patients
OR [95% CI]
P-value
113
114
114
115
2.63
2.70
3.70
5.00
<
<
<
<
[1.664.16]
[1.754.16]
[2.176.25]
[2.639.09]
0.0001
0.0001
0.0001
0.0001
For brinogen, odds ratios (OR) were calculated for each 1 g L)1
decrease in its plasma concentration. *data introduced in the model:
INR, APTT, brinogen, factor II, factor V, D-dimer, antithrombin,
protein C and TAT. data introduced in the model: INR, APTT,
brinogen, factor II, factor V, D-dimer, antithrombin and protein C.
272 B. Charbit et al