Original Research
Hemostatic Dysfunction With Acute Fatty
Liver of Pregnancy
David B. Nelson, MD, Nicole P. Yost, MD,
OBJECTIVE: To estimate the frequency of disseminated
intravascular coagulation (DIC); elucidate the genesis of
hemostatic dysfunction; and characterize associated
hemolysis in women with acute fatty liver of pregnancy.
METHODS: Hemostatic function was measured in 51
women. Disseminated intravascular coagulation was
assessed using the International Society of Thrombosis
and Haemostasis DIC score. Hepatic and hemostatic
function was quantified with measurement of fibrinogen,
fibrinfibrinogen split products, cholesterol, and coagu-
lation testing. As a comparison of fibrinogen synthesis,
these women were compared with 25 women with pla-
cental abruption. Hemolysis was assessed indirectly by
quantification of reticulocytosis and nucleated red blood
cells with determination of erythrocyte morphotypes.
RESULTS: Eighty-percent of women were classified as
having unequivocal DIC (mean score 5.961.8) at delivery,
which persisted 45 days postpartum. Fibrinogen regen-
eration with placental abruption was rapid, whereas it
remained depressed for 45 days with acute fatty liver
of pregnancy; fibrinfibrinogen split products were also
cleared more rapidly after abruption than women with
acute fatty liver (P,.001 for interaction for both using
random effects modeling). Kaplan-Meier survival analysis
of fibrinogen recovery to a set point of 280 mg/dL after
delivery was also different between the two cohorts
(median 1.7 compared with 4.2 days, P5.046). Continuing
hepatic dysfunction with acute fatty liver of pregnancy
was exemplified by diminished procoagulant production.
From the University of Texas Southwestern Medical Center at Dallas, Division of
Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Dallas,
Texas.
Corresponding author: David B. Nelson, MD, Division of Maternal-Fetal
Medicine, Department of Obstetrics and Gynecology, University of Texas
Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas,
TX 75390-9032; e-mail: DavidB.Nelson@UTSouthwestern.edu.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2014 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14
40 VOL. 124, NO. 1, JULY 2014
and F. Gary Cunningham, MD
Reticulocytosis, nucleated red blood cells, and elevated
serum bilirubin levels reflected ongoing hemolysis.
CONCLUSIONS: Hemostatic dysfunction with acute
fatty liver of pregnancy persists 45 days postpartum
and results from substantive ongoing DIC in concert with
reduced procoagulant synthesis and clinically significant
hemolysis.
(Obstet Gynecol 2014;124:406)
DOI: 10.1097/AOG.0000000000000296
LEVEL OF EVIDENCE: III
O
bstetric hemorrhage is a major cause of maternal
morbidity and mortality associated with acute
fatty liver of pregnancy.16 When the syndrome was
first described, the accompanying profuse obstetric
hemorrhage was attributed to the severe coagulopathy
caused by liver failure characteristic of acute fatty
liver of pregnancy.7,8 Later, however, disseminated
intravascular coagulation (DIC) was implicated as
a primary cause of the hemostatic derangement,9
a concept further propagated by Castro et al1,10 in their
description of 28 women with convincing evidence of
severe DIC. Meanwhile, our previous report of clini-
cal outcomes associated with acute fatty liver of preg-
nancy suggested that both mechanismsdiminished
production of procoagulants and increased use by
intravascular coagulationwere likely related to the
coagulopathy.6
There is also controversy related to whether
hemolysis is a clinically significant component in
women with acute fatty liver of pregnancy. Whereas
Sheehan11 concluded that there was no discernible
hemolysis, Burroughs and colleagues7 reported that
accelerated red cell destruction was a major facet of
acute fatty liver of pregnancy. In our previous clinical
observations of 51 women with acute fatty liver of
pregnancy, we reported that brisk ongoing hemolysis
was a common finding that contributed to hyperbilir-
ubinemia as well as the need for red cell transfusions.6
Because of these disparate observations, we de-
signed the present investigation with three principal
OBSTETRICS & GYNECOLOGY
aims. First, we sought to expand our previous observa-
tions concerning the frequency and severity of DIC
complicating acute fatty liver of pregnancy. Second, we
wanted to elucidate the respective contributions to
hemostatic dysfunction from DIC and defective procoa-
gulant synthesis. Our final aim was to characterize the
cause and extent of associated hemolysis.
PATIENTS AND METHODS
From 1975 through 2012, one or more of the
investigators was involved in the care of women
admitted to Parkland Hospital and diagnosed with
acute fatty liver of pregnancy. With approval from the
institutional review boards at the University of Texas
Southwestern Medical Center at Dallas and Parkland
Hospital, clinical and laboratory data were extracted
from medical records of these women. These cases
were entered into a registry specific for acute fatty
liver of pregnancy as previously described.6 Patient
information was deidentified and stored in a comput-
erized database. Maternal demographic information,
clinical findings, laboratory results, management,
delivery and pregnancy outcomes, and recovery after
delivery were reviewed. Laboratory findings were
those determined by methods contemporaneously in
use for various biochemical, hematologic, and coagu-
lation tests. Additional hematologic and coagulation
studies were performed as available by certified med-
ical technologists in the Obstetrical Hematology
Research Laboratory.12 For clinical management,
hepatic tissue to confirm microvesicular fatty infiltra-
tion was obtained by liver biopsy in nine women
because of uncertain diagnosis and at autopsy in the
two who died. Clinical management was directed
using real-time results available contemporaneously
from the Parkland Hospital Clinical Laboratory.
For this observational study, women with acute
fatty liver of pregnancy were classified and analyzed
according to the International Society of Thrombosis
and Haemostasis DIC score (Box 1).13,14 Briefly, this
scoring system uses a combination of laboratory tests
to provide a five-step diagnostic algorithm to calculate
the DIC score. These tests include quantification of
platelets, fibrinogen, fibrin-related markers (fibrin
monomers and fibrin degradation products), and pro-
thrombin time in combination with the underlying
disorder known to be associated with DIC.13 Compos-
ite International Society of Thrombosis and Haemo-
stasis DIC scores 2 or greater are suggestive of DIC
and scores 5 or greater are considered to define
unequivocal DIC.13 This scoring system provides
a sensitivity and specificity of DIC with 93% and
98%, respectively.14 For the current study, a composite
VOL. 124, NO. 1, JULY 2014
Box 1. International Society of Thrombosis and
Haemostasis Disseminated Intravascular
Coagulation Scoring System
1. Risk assessment: Does the patient have an under-
lying disorder known to be associated with overt
DIC?
(yes=2; no=0)
If yes, proceed; if no, do not use this algorithm.
2. Order global coagulation tests (platelet count,
prothrombin time, fibrogen, soluble fibrin mono-
mers, or fibrin degradation products).
3. Score global coagulation test results.
 Platelet count (.100, 0; ,100, 1; ,50, 2)
 Elevated fibrin-related marker (eg, soluble
fibrin monomers/fibrin degradation products)
(no increase, 0; moderate increase, 2; strong
increase, 3)
 Prolonged prothrombin time (,3 secs, 0; .3
secs but ,6 secs, 1; .6 secs, 2)
 Fibrogen level (.1.0 g/L, 0; ,1.0 g/L, 1)
4. Calculate score
5. If $5, compatible with overt DIC; repeat scoring
daily. If ,5, suggestive (not affirmative) for non-
overt DIC; repeat next 12 days.
DIC, disseminated intravascular coagulation.
Reprinted from Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M;
Scientific Subcommittee on Disseminated Intravascular Coag-
ulation (DIC) of the International Society on Thrombosis and
Haemostasis (ISTH). Towards definition, clinical and laboratory
criteria, and a scoring system for disseminated intravascular
coagulation. Thromb Haemost 2001;86(5):132730. Copyright
2001 John Wiley and Sons.
International Society of Thrombosis and Haemostasis
DIC score was provided for each woman at 24 hours
epochs after delivery.
Studies of hepatic and hemostatic function
included fibrinogen, fibrinfibrinogen split products,
coagulation studies, and cholesterol. Fibrinogen in
plasma and fibrinogenfibrin split products in serum
were measured using methods previously described
by Pritchard et al.12 Briefly, plasma was collected in
citrate-Trasylol tubes and fibrinogen was quantified
using the thrombin-clottable protein method of Ratn-
off and Menzie.15 Serum obtained after thrombin clot-
ting was assayed for fibrinfibrinogen split products
using the Thrombo-Wellcotest immunologic particle
agglutination method.
To portray normal fibrinogen synthesis after
acute defibrination in women with normal hepatic
function, serial plasma fibrinogen and serum fibrin-
degradation product concentrations were determined
in a cohort of 25 women with placental abruption and
hypofibrinogenemia. These women were identified
from a repository of women with fetal demise and
Nelson et al Acute Fatty Liver of Pregnancy 41
placental abruption confirmed at delivery.16 Compar-
isons among fibrinogen and fibrin-degradation prod-
uct measurements for those women with acute fatty
liver of pregnancy compared with women with severe
placental abruption were made using mixed-effect
modeling with interaction and within-subjects model-
ing, log likelihood x2 test for goodness of fit, and
Kaplan-Meier analysis for length of time for recovery
to specified fibrinogen values. Statistical analysis was
accomplished using SAS 9.2. P values ,.05 were con-
sidered statistically significant.
Concomitant with another ongoing study,17 in
some of these women, erythrocyte morphology was
quantified using scanning electron microscopy.
Briefly, these methods included preparation of eryth-
rocytes from peripheral blood collected into ethylene-
diamine tetraacetic acid-containing tubes was fixed in
1.25% glutaraldehyde, and 1,000 erythrocytes in con-
tiguous fields were scanned using a JEOL JSM-35
electron microscope. Red cells were classified as nor-
mal discocytes or as abnormal schizocytes, echino-
cytes, or spherocytes according to Bessis.18
RESULTS
Between 1975 and 2012, there were 51 women with
acute fatty liver of pregnancy cared for at our institution.
The clinical outcomes of this cohort have been pre-
viously described,6 and briefly, the frequency of acute
fatty liver of pregnancy was 1 per 10,000 births and
distribution over this time period was relatively homo-
geneous, mean maternal age was 27.467.3 years (range
1542 years), and 41% were nulliparous. Their overall
6
ISTH-DIC score
5 disseminated intravascular coagula-
4 more represent unequivocal DIC
3 mean (6SEM).
0 1 2 3 4 5
Days following delivery
42 Nelson et al Acute Fatty Liver of Pregnancy
demographic characteristics were similar to those of
women from our general obstetric population. Blood
or component transfusions were required in 28 of 51
women, and seven (14%) required platelet transfusions.
Importantly, 12 (42%) of the women were given addi-
tional red cell transfusions beyond 48 hours after deliv-
ery with indications being persistent, severe anemia.
Aside from obstetric hemorrhage associated with coa-
gulopathy and acute fatty liver of pregnancy, we found
only 5 of 51 women might have had an associated event
that contributed to the hematologic aberrations; specific
comorbid conditions included three abruptions, one
uterine rupture, and one subcapsular hematoma.
As shown in Figure 1, for the entire cohort,
the mean International Society of Thrombosis and
Haemostasis DIC score was 5.961.8 at the time of
delivery, confirming that 80% of these women had
unequivocal DIC defined as composite score of 5 or
greater. As discussed, inherent in this scoring system
is the presence of an underlying disorder known to
be associated with overt DIC, scored as yes or no.
As evidenced by the clinical hemostatic dysfunction,
a score of 2 was applied to all members of the cohort
on the day of delivery. Global coagulation tests were
then serially scored on days after delivery, and the
most influential marker scored was elevated fibrin-
split products that were present in all cases studied
during the first 48 hours after delivery. Importantly,
composite International Society of Thrombosis and
Haemostasis DIC scores remained elevated for up to
45 days suggesting persistent hemostatic dysfunction
after delivery (Fig. 1).
Fig. 1. International Society of
Thrombosis and Haemostasis (ISTH)
tion (DIC) composite scores after
delivery in women with acute fatty
liver of pregnancy. Scores of 5 or
(dashed line). Mean score observed
after delivery listed with error bars
representing standard errors of the
6 7
Nelson. Acute Fatty Liver of Pregnancy.
Obstet Gynecol 2014.
OBSTETRICS & GYNECOLOGY
 To demonstrate the effect of liver dysfunction on
procoagulant synthesis, serial plasma fibrinogen and
fibrin-degradation products were plotted and com-
pared for the two cohorts of women. For the 25 women
with placental abruption, hypofibrinogenemia, and
normal hepatic function, the mean age was 22.664.6
years (range 1631 years), 20% were nulliparous, and
mean gestational age and birth weight of their stillborn
neonates was 3561.5 weeks and 2,2906740 g, respec-
tively. In Figure 2, their serial values are compared
with women with acute fatty liver of pregnancy.
The initial mean fibrinogen level (6standard error of
mean) for women with acute fatty liver of pregnancy
were 188624 mg/dL compared with that of 153610
mg/dL for women with an abruption. As can be seen in
Figure 2, fibrinogen recovery for women with an
abruption was rapid, linear, and returned to near nor-
mal levels within 36 hours of delivery. For women
with acute fatty liver, however, several days were
required to reach similar levels. Random effects mod-
eling for both linear and quadratic regression curves
were significantly different for days after delivery
(P,.001 for interaction). Kaplan-Meier survival analy-
sis of fibrinogen recovery to a set point of 280 mg/dL
after delivery was also statistically different between
the two groups with median times to recovery for
acute fatty liver of pregnancy and abruption being
4.2 and 1.7 days, respectively (P5.046 using log-
rank test). The groups of women with acute fatty liver
of pregnancy and abruption were also compared for
fibrin-degradation product clearance, and as shown
Fibrinogen (mg/dL)
Fig. 2. Plasma fibrinogen levels after
delivery for 51 cases of acute fatty
liver of pregnancy (AFLP) compared
with 25 cases of placental abruption.
Random effects modeling for both
linear and quadratic regression curves
for days after delivery, P,.001 for
interaction. Mean fibrinogen values
(6standard error of mean) for all
patients available at each data point
listed.
Nelson. Acute Fatty Liver of Pregnancy.
Obstet Gynecol 2014.
VOL. 124, NO. 1, JULY 2014
in Figure 3, these differences were also significant
using random effects modeling for both linear and
quadratic regression curves for days after delivery
(P,.001 for interaction). Although we have previ-
ously described continuing hepatic dysfunction for
days after delivery, it was not possible to accurately
quantify the contribution of decreased synthesis ver-
sus continuing consumption of fibrinogenonly that
both were present.
Reticulocytosis, nucleated red blood cells, and
serum bilirubin levels together are indicative of
ongoing hemolysis in the cases of acute fatty liver of
pregnancy. As shown in Figure 4, levels of serum
bilirubin remained increased after delivery in women
with acute fatty liver of pregnancy in conjunction with
elevated reticulocyte counts. Nucleated red blood
cells were identified in 40% of women at delivery with
acute fatty liver of pregnancy (Fig. 5). The median
(quartile1, quartile3) nucleated red blood cells at deliv-
ery was 4 (2, 11)/100 white blood cells, and these cells
were present for up to 45 days postpartum. In three
women, erythrocyte morphology was determined
using scanning electron microscopy. Echinocytes
were the predominant abnormal form (Fig. 6), and
these women initially had 2239% echinocytes at the
time of delivery. This proportion compares with nor-
mally pregnant women whose mean value ranges
from 0.5 to 1.9%. In these women, normal discocyte
forms were present within 23 days. During this same
time, schizocyte proportions were less than 2% and
spherocytes were negligible.
350
300
250
200
150
100
AFLP
50
Abruption
0
0 1 2 3 4 5 6
Days following delivery
Nelson et al Acute Fatty Liver of Pregnancy 43
 140

120
Fibrin split products (Thrombo-Wellcotest)

100

AFLP
80
Abruption Fig. 3. Levels of fibrin-split products
after delivery for 51 cases of acute
60
fatty liver of pregnancy (AFLP) com-
pared with 25 cases of placental
40 abruption. Random effects modeling
for both linear and quadratic regres-
sion curves for days after delivery,
20 P,.001 for interaction. Mean fibrin-
split products values (6standard error
of mean) for all patients available at
0 each data point listed.
0 1 2 3 4 5 6
Nelson. Acute Fatty Liver of Pregnancy.
Days following delivery Obstet Gynecol 2014.

DISCUSSION twofold and the result of a combination of procoagulant

Our observations in these 51 women with acute fatty deficiency from liver failure as well as procoagulant
liver of pregnancy confirm that profound hemostatic consumption from continuing DIC. Another observation
dysfunction commonly exacerbates obstetric hemor- was that brisk hemolysis in these women substantively
rhage and contributes to the need for blood and adds to the requirement for continued transfusions well
component transfusions. At the time of delivery, half of beyond the immediate time of delivery.
these women now reported had a plasma fibrinogen level We have previously presented evidence for
less than 150 mg/dL, and 12 (48%) of these required continuing hemostatic dysfunction in these women
either fresh-frozen plasma or cryoprecipitate to achieve manifest by prolongation of the thrombin and partial
hemostasis because of dangerously depressed fibrinogen thromboplastin times for 46 days after delivery.6
concentrations in the setting of active bleeding. We also When we plotted the time course of plasma, fibrino-
found that the cause of hemostatic dysfunction was gen concentrations and fibrin degradation products

12

10

8
Bilirubin (mg/dL)

4
Fig. 4. Serum total bilirubin levels
after delivery with reticulocyte indi-
ces in women with acute fatty liver of
2
pregnancy. Mean total bilirubin and
Total bilirubin (mg/dL)
reticulocyte indices values (6stan-
Reticulocyte index dard error of mean) for all patients
0 available at each data point listed.
0 1 2 3 4 5 6 7 8
Nelson. Acute Fatty Liver of Pregnancy.
Days following delivery Obstet Gynecol 2014.

44 Nelson et al Acute Fatty Liver of Pregnancy OBSTETRICS & GYNECOLOGY


Percentage
Fig. 5. Percentage of 51 cases of
women with nucleated red blood
cells present on peripheral smear after
delivery for women with acute fatty
liver of pregnancy. Data represent
only observed values for each day
after delivery.
Nelson. Acute Fatty Liver of Pregnancy.
Obstet Gynecol 2014.
found that continuing fibrinogen deficiency is caused by
diminished production as well as increased use (Figs. 2
and 3). Evidence for decreased production was seen
with abnormally low plasma fibrinogen concentrations
persisting for the first several days after delivery along
with only mild to moderately elevated fibrin-
degradation products. By way of comparison, in the
same figures, fibrinogen values are plotted for 25
women who sustained a placental abruption severe
enough to kill the fetus. These women with hypofibri-
nogenemia who had normal hepatic function exhibited
the anticipated response with a rapid return within
24 hours to a normal plasma fibrinogen concentration
along with simultaneous clearance of fibrin degradation
products. This was in contrast to the women with
Fig. 6. Scanning electron microscope displaying echinocytes
present in a woman with acute fatty liver of pregnancy.
Nelson. Acute Fatty Liver of Pregnancy. Obstet Gynecol 2014.
VOL. 124, NO. 1, JULY 2014
40
30
20
10
0
0 1 2 3 4 5 6
Days following delivery
hepatic dysfunction from acute fatty liver of pregnancy
whose plasma fibrinogen levels remained static over
a period of several days after delivery.
At the same time, there is also evidence for
continuing increased procoagulant consumption caused
by ongoing DIC. As shown in Figure 1, most of these
women had evidence for persistent consumptive coa-
gulopathy as assessed by the DIC score of the Interna-
tional Society of Thrombosis and Haemostasis.13,14 As
shown in Figure 3, evidence for ongoing consumptive
coagulopathy is provided by the modestly elevated lev-
els of fibrin degradation products in the face of
depressed plasma fibrinogen concentrations. Although
this provides evidence of ongoing DIC, we cannot
exclude the possibility that elevated fibrin degradation
product levels are at least partially related to their
diminished clearance because of hepatic dysfunction.
We also found that these women with fatty liver
of pregnancy had brisk hemolysis that continued for
several days after delivery. This was of clinical
significance because of the frequent need for ongoing
red cell transfusions after delivery and at a time after
which surgical and obstetric hemostasis was secured.
Specifically, one-fourth of these women required
additional erythrocyte transfusions for persistent
severe anemia without evidence of ongoing hemor-
rhage. There are at least three other findings that
document hemolysis. One marker is the increasing
serum bilirubin levels that continued to rise at a time
when there is improving, albeit impaired, hepatic
bilirubin clearance. As shown in Figure 4, bilirubin
concentrations peaked at 57 days after delivery at
a time when reticulocytosis was also maximal.
Another potent marker for accelerated hemolysis with
Nelson et al Acute Fatty Liver of Pregnancy 45
hemopoiesis is the appearance of remarkably elevated
levels of nucleated red blood cells (Fig. 5), which are
seldom encountered in adults except with massive
hemolysis or hypoxia.1921 The third marker indica-
tive of hemolysis is the remarkably high proportion of
echinocytes in the three women studied. This cell
morphotype may be induced by abnormal plasma
and red cell membrane levels of cholesterol and other
blood lipids. Echinocytes either undergo premature
hemolysis or they can revert back to normal disco-
cytes. At the same time, the paucity of schizocytes
supports the observations by Burroughs et al7 that
there is negligible microangiopathic hemolysis.
Our study has several limitations. First, because of
the observational design, we could have missed some
women with acute fatty liver of pregnancy. Second, some
of these women may have been incorrectly diagnosed to
have hepatocellular steatosis. However, as we have
previously described,6 the criteria for diagnosis of acute
fatty liver of pregnancy included evidence of acute liver
failure with characteristic clinical findings accompanied
by laboratory evidence that confirmed hepatic dysfunc-
tion along with collateral multiorgan system aberrations.
We also applied both the Swansea criteria proposed by
Chng et al22 and the acute fatty liver of pregnancy triad
of Vigil-de Gracia et al5 to confirm the diagnoses.
Another drawback is that observations from this study
provide only circumstantial evidence of the hemostatic
dysfunction associated with acute fatty liver of pregnancy
as related to substantive ongoing DIC in concert with
reduced procoagulant synthesis.
In summary, our findings support the hypothesis
that a combination of substantive DIC and procoagu-
lant deficiency from hepatic dysfunction both con-
tribute significantly to hemostatic dysfunction that
characterizes acute fatty liver of pregnancy. To com-
pound the issue, this syndrome includes an element of
clinically significant hemolysis. Because prolonged
persistence of coagulopathy occurs in some women,
it seems prudent to monitor coagulation studies until
clinical recovery and derangements normalize.
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