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RESEARCH ARTICLE

A JH

Pregnancy complications predict thrombotic events in young


women with essential thrombocythemia
Maria Luigia Randi,1* Irene Bertozzi,1 Elisa Rumi,2 Chiara Elena,2 Guido Finazzi,3 Nicola Vianelli,4 Nicola Polverelli,4
Marco Ruggeri,5 Alessandro Maria Vannucchi,6 Elisabetta Antonioli,6 Federico Lussana,3 Alessia Tieghi,7 Alessandra Iurlo,8
Elena Elli,9 Marco Ruella,10 Fabrizio Fabris,1 Mario Cazzola,2 and Tiziano Barbui11
Although Philadelphia-negative myeloproliferative neoplasms (MPNs) occur typically in middle to advanced age,
any age group may be affected, posing a challenge for their management during pregnancy when they occur in
young females. There is a high incidence of thromboembolic events and pregnancy complications in patients
with myeloproliferative neoplasms, and a possible relationship between these complications is a matter of
concern. The aim of this article was to correlate thrombosis and pregnancy outcome in 158 females with ET
experiencing 237 pregnancies. Seven patients had a thrombotic event before their first pregnancy, one of them
ended (14.3%) in a miscarriage. Among the 151 patients with no history of thrombosis before they became
pregnant, 40 (26.5%) had a miscarriage (P 5 NS). Eighteen patients (11.4%) developed major thrombotic
complications (12 splanchnic vein, 1 cerebral vein, 2 coronary syndromes, and 3 strokes) after at least one
pregnancy (4 uneventful and 14 complicated). The occurrence of thrombosis was significantly more frequent
(P < 0.001) in patients with a history of pregnancy complications (28%) than in those experiencing a normal
pregnancy and delivery (3.7%). Pregnancy complications in women with ET are associated with a higher risk of
subsequent thromboses, so pregnant women with this neoplasm who miscarry need to be carefully monitored.
C 2013 Wiley Periodicals, Inc.
Am. J. Hematol. 89:306309, 2014. V

Introduction
Myeloproliferative neoplasms (MPNs) are hematological diseases due to a stem-cell-derived clonal myeloproliferation. These diseases have many
clinical features including a predisposition to vascular events, and progression to myelofibrosis and acute myeloid leukemia. Thrombosis is the
main cause of morbidity and mortality: blood rheology, possibly relating to leukocyte adhesion, platelet activation and platelet-leukocyte aggregates
[1,2], is believed to have a leading role in the development of these complications.
MPNs have a peak incidence in the sixth and seventh decades of life, but they do occur in younger patients too, consequently posing a challenge for
their management in pregnancy [3]. The most common MPN in women of childbearing age is essential thrombocythemia (ET) [46], whereas polycythemia vera (PV) is unusual in young patients [3]. Key factors influencing pregnancy outcome include an adequate placental development and the
maintenance of a normal uterine blood flow. Thromboses can occur in any vessel in MPN patients, including the placental vessels, as documented in
patients with late fetal loss, preterm delivery [7], and intrauterine growth restriction (IUGR) [8]. As a higher incidence of thromboembolic events and
pregnancy complications are both associated with MPN, the possibility of a relationship between these complications is a matter of concern.
In this retrospective study, we correlated thrombotic events with pregnancy outcome in a large population of young women with ET.

Material and Methods


Eleven Italian hematology centers of the GIMEMA group (Bergamo, Bologna, Firenze, Padova, Milano S Paolo, Milano Policlinico, Monza, Pavia, Reggio Emilia, Torino, Vicenza) adopted an ad-hoc spreadsheet in which physicians collected clinical and laboratory data on their patients. The eligibility criteria for the study were: patients with a diagnosis
of ET established between 18 and 40 years. The diagnostic criteria were as recommended by the PVSG [9] and the WHO [10], in patients diagnosed before and after 2001, respectively. In most cases, older diagnosis were confirmed with WHO criteria. The study was approved by the institutional review boards at each institution.
This large dataset included 668 women with ET diagnosed between 1980 and 2009. For the purposes of the present study, we considered the 158 females (23.65%) who had at
least 1 pregnancy at diagnosis or during the follow-up of ET: 5 were pregnant when their MPN was diagnosed, and 153 became pregnant during their follow-up (median time
elapsing from ET diagnosis to first pregnancy: 2.8 years).

1
Dept of Medicine -DIMED, Internal Medicine, University of Padua, Padua, Italy; 2Department of Hematology, University of Pavia, IRCCS Policlinico S Matteo, Pavia,
Italy; 3Hematology Division, Ospedale Papa Giovanni XXII, Bergamo, Italy; 4Institute of Hematology Lorenzo e Ariosto Seragnoli, Department of Hematology and
Oncology, Bologna, Italy; 5Department of Hematology, Ospedale di Vicenza, Vicenza, Italy; 6Division of Hematology, University of Florence, Florence, Italy; 7Hematology
Unit, Department of Oncology, Arcispedale Santa Maria NuovaIRCCS, Reggio Emilia, Italy; 8Hematology Division, Fondazione Ca Granda IRCCS, Ospedale Policlinico, Milan, Italy; 9Hematology Division, San Gerardo Hospital, Monza (Milan), Italy; 10Department of Hematology and Cell Therapy, University of Torino, Torino,
Italy; 11Hematology Division, Research Foundation, Ospedale Papa Giovanni XXII, Bergamo, Italy.

Conflict of interest: The authors declare no competing financial interests.


*Correspondence to: Maria Luigia Randi, Department of Medicine DIMED, University of Padua, 35128 Padua, Italy. E-mail: marialuigia.randi@unipd.it
Contract grant sponsor: Ministero dellIstruzione, dellUniversita e della Ricerca; Contract grant numbers: MIUR; PRIN; 2010.
Contract grant sponsor: Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano); AIRC-Gruppo Italiano Malattie Mieloproliferative; project #1005..
Received for publication: 15 November 2013; Accepted: 18 November 2013
Am. J. Hematol. 89:306309, 2014.
Published online: 22 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.23635
C 2013 Wiley Periodicals, Inc.
V

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American Journal of Hematology, Vol. 89, No. 3, March 2014

doi:10.1002/ajh.23635

RESEARCH ARTICLE

Pregnancies in patients with essential thrombocythemia

TABLE I. Demographic, Hematological Characteristics, and Pregnancies


Outcomes and Complications of 158 Pregnant Women With ET
No. of patients
Median age years (range)
Median leukocyte count 3 109/L (range)
No. of pats with WBC > 10 3 109/L
Median hemoglobin g/dL21 (range)
Median platelet count 3 109/L (range)
No. of patients with platelets >1,500 3 109/L
No. of patients with at least 1 abortion risk factora
No. of patients with thrombophilia and/or
cardiovascular risk factorsb
Pregnancies
Uneventful
Total pregnancies events
Fetal loss
First trimester abortion
Second/third trimester abortion
Stillbirth
Maternal complications
Pre-eclampsia (resolved after delivery)
Arterial hypertension (resolved after delivery)

158
28 (1740)
10.9 (3.2427.1)
46 (29%)
14 (8.515)
1093 (5003140)
17 (10.7%)
29 (18%)
10 (6.3%)
237
152
85 (36%)
69 (29%)
60 (87%)
8 (11.5%)
1 (1.5%)
16 (7%)
9 (56%)
7 (44%)

Age, smoking, diabetes, hypertension, hyperlipidemia, thrombophilia.


Smoking, diabetes, hypertension, hyperlipidemia, oral contraception,
lupus anticoagulant, congenital thrombophilia.

In each patients clinical and laboratory data were collected at diagnosis (Table
I). Before pregnancies, 23.4% patients received low-dose-aspirin and 17.7% cytoreductive drugs (14 hydroxyurea, 3 anagrelide, 9 interferon-a, and 2 alkylating
agents). Each physician treated pregnant ET in agreement with guide-lines available
at the time of pregnancy.
A total of 237 pregnancies in patients with ET (median age at conception 32,
range 1840 years) were followed up. Pregnancy outcomes, risk factors for miscarriage (age, smoking, diabetes, hypertension, hyperlipidemia, thrombophilia), cardiovascular events, cardiovascular risk factors (smoking, diabetes, hypertension,
hyperlipidemia), and prothrombotic conditions (oral contraception, lupus anticoagulant, congenital thrombophilia) were assessed. Fetal outcome was classified as live
birth, spontaneous first-trimester abortion, or advanced fetal loss (2nd- and 3rdtrimester abortions or stillbirths).
Pregnancy risk was stratified according to Griesshammer et al. [11]: low-risk
pregnancies were those occurring in patients with no prior MPN-related complications, no hereditary thrombophilia factors, age under 35 years, and a platelet count
below 1000 3 109/L. When these criteria were not met, or severe complications had
occurred in a previous pregnancy, the pregnancy risk was considered high. The
highest risk was associated with recent acute thromboembolic events and previous
major thrombotic or hemorrhagic complications in the mother.

Statistical analysis
All the statistical analyses were run considering the parameters at the time of the
patients MPN diagnosis. Patient groups with nominal variables were compared with the
X2 test. Thrombosis-free survival curves were prepared using the KaplanMeier method,
and were compared with the log-rank test. Coxs proportional hazards regression model
was used for multivariate analyses. P values of <0.05 were considered significant.

Results
Pregnancy outcome
Within our 158 females with ET, 95 females (60.1%) had one, 50
had two, 10 had three, and 3 had four or more pregnancies.
Overall, 69 pregnancies in ET patients (29%) ended in fetal loss. The
live birth rate was 71%. Complications for the mother were recorded in
16 women; they all regressed rapidly after delivery (Table I).
The impact of several pregnancies was investigated in 50 women
who had two pregnancies with no differences in managing. The outcome of their two pregnancies was concordant, i.e., both pregnancies
were either complicated or uncomplicated, in 29 cases (58%), while it
was discordant in 21 (42%). Pregnancy outcome was not significantly
influenced by the outcome of a previous pregnancy.

doi:10.1002/ajh.23635

TABLE II. Risk Stratification of 228 Pregnancies in Patients With ET


According to Griesshammers Criteria [11]

Low risk (n 5 87)


Livebirth
1st trim abortion
late fetal loss
High risk (n 5 128)
Livebirth
1st trim abortion
late fetal loss
Highest risk (n 5 13)
Livebirth
1st trim abortion
late fetal loss

1st
preg

2nd
preg

3rd
preg

4th
preg

49
16
3

10
5
.

.
3
.

1
.
.

64
15
2
3
.
3
.

27
10
2
6
4
2
.

5
2
.
3
2
1
.

.
1
.
1
1
.
.

Pregnancy and JAK2 status


One hundred and forty two ET patients had been tested for the
JAK2V617F mutation, with a positive result in 69 (48.6%).
Among 110 pregnancies in 69 patients carrying JAK2 mutations,
72 were uneventful and 38 had miscarriages, while among 105 pregnancies in 73 JAK2 wild-type (JAK2-WT) women, 77 pregnancies
ended in normal delivery and 28 in fetal loss (P 5 NS). Among the
13 patients who had 3 or more pregnancies, 8 were JAK2V617F and
5 were JAK2-WT; there were complications in 16 (64%) of the 25
pregnancies in the JAK2V617F cases, and 8 (47%) of the 17 pregnancies in the JAK2-WT patients were complicated (P 5 NS). Among 23
patients who had complications during all their pregnancies, 12 carried a JAK2 mutation and 11 were JAK2-WT (P 5 NS).

Pregnancy outcome according to Griesshammers


criteria
For 228 pregnancies stratified by pregnancy risk according to
Griesshammers criteria (Table II), we found no difference in pregnancy outcome between the low, high and highest risk groups.

Hemorrhagic complications
Hemorrhagic complications were recorded in 23 women (14.5%),
15 minor hemorrhages and 8 gastro-intestinal bleedings. No postpartum bleeding was observed. No relationship emerged between platelet count and bleeding complications. In particular, only 4 of the 17
ET patients with >1,500 3 109/L platelets had minor bleeding episodes, a proportion statistically no different from the hemorrhage episodes occurring in patients with lower platelet counts.

Thrombotic events
Twenty-five patients developed thrombosis at or after their ET was
diagnosed, at a median 28 (range 2347) years old. We recorded: 2
myocardial infarctions, 3 strokes, 6 peripheral vein thromboses with or
without pulmonary embolism, 13 splanchnic vein thromboses, and 1
cerebral vein thrombosis. No correlation was found between WBC
counts and thrombosis. In particular, only 6 (14.3%) of the 42 patients
with PMN >10 3 109/L had thrombotic complications, a proportion
statistically much the same as in for patients with lower WBC counts.

Relationship between pregnancy and thrombosis


Seven patients had a thrombotic event before their first pregnancy,
one of them (14.3%) ended in a miscarriage; 85% were under lowdose aspirin when became pregnant and 28% received anagrelide that
was stopped 3 years before pregnancy. Among the 151 patients with
no history of thrombosis before they became pregnant, 40 (26.5%)

American Journal of Hematology, Vol. 89, No. 3, March 2014

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RESEARCH ARTICLE

Randi et al.

TABLE III. Multivariate Analysis for Risk Factors Predicting Thrombotic


Events After Pregnancy in ET Females
Thrombosis (n 5 18)
Parameters at diagnosis
WBC > 10 3 109/L
Platelets > 1,000 3 109/L
JAK2 V617F/WT
Hemoglobin <120 g/dL21
Hematocrit > 45%
Previous miscarriage yes/no
Age at diagnosis
CV risk factorsa

HR (95% CI)

1.12 (0.841.5)
0.99 (0.991)
0.64 (0.152.46)
0.92 (0.312.7)
1.0 (6.91.45)
9.33 (2.3536.97)
1.0 (0.941.2)
6.57 (1.4230.25)

0.434
0.074
0.554
0.890
0.976
0.001
0.301
0.016

CV indicates presence of at least 1 cardiovascular risk factor.


a
Smoking, diabetes, hypertension, hyperlipemia, thrombophilia.

Figure 1. Thrombosis-free survival data of 158 females with ET stratified


by pregnancy outcome: the 108 patients whose pregnancy(ies) were
uneventful had significantly lower incidence of subsequent thrombosis
than the 50 patients with at least one miscarriage.

had a miscarriage. No statistically significant difference emerged on


comparing the percentage of miscarriages in patients with or without
a history of thrombosis (P 5 0.7).
Eighteen patients (11.4%) developed major thrombotic complications after at least one pregnancy (4 uneventful, 14 complicated):
63.6% of them were under low-dose aspirin at time of thrombosis
while 27.2% were untreated. Only one patient was under hydroxyurea. Thirteen venous thrombosis (12 splanchnic and one cerebral)
occurred in the early post-partum period (within 6 months) or within
2 years after delivery (mean age at thrombosis 37.1 6 4.1 years). Five
arterial thromboses (two coronary syndromes and three strokes)
occurred a median 12 years (319 years) after delivery at a mean age
of 43.2 6 5.1 years (P 5 0.017 compared to patients with venous
events). The occurrence of thrombosis was significantly more frequent (P < 0.001) in patients who had experienced complications in
previous pregnancies (28%) than in those with a history of uneventful
pregnancy and delivery (3.7%) (Fig. 1).

Multivariate analysis
Multivariate analysis on the patients thrombosis-free survival was
conducted on data for all 158 ET patients and included several covariates of potential prognostic relevance, i.e. age, WBC and platelet
counts, hemoglobin level, JAK2V617F mutation, one or more cardiovascular risk factor(s), and history of abortion. The presence of at
least one cardiovascular risk factor (P 5 0.016) and a history of miscarriage (P 5 0.001) emerged as independent risk factors for the onset
of a thrombotic event (Table III).

Discussion
Although ET occurs typically in middle-aged and older adults, a small
but significant number of patients are women of childbearing age, and
the disease poses a challenge when it comes to managing pregnancy [3].
A number of studies have shown that women with ET are at
higher risk of developing pregnancy complications [35,11] and placental thrombosis has been documented in cases complicated by late
fetal loss [7], preterm delivery [7], and IUGR [8].
Both venous and arterial thrombotic events are typical of the clinical phenotype of patients with ET, and are considered significant
prognostic indicators [12]. These events may occur at any time leading to severe morbidities [13]. Although young ET patients with no

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American Journal of Hematology, Vol. 89, No. 3, March 2014

previous vascular events are considered at low thrombotic risk [14],


they can develop vascular events during their follow-up, and at least
some of the mechanisms considered as risk factors for fetal loss coincide with those implicated in thrombotic complications.
In the present study, we retrospectively analyzed a large cohort of
females with ET who were already pregnant when their disease was
diagnosed or became pregnant during their follow-up. Consistently
with other reports [4,5], about one in three of their pregnancies
ended in fetal loss, while maternal complications were rare [4,5,15].
We could identify no influence of parity on pregnancy outcome [4,5],
nor any relationship between JAK2 mutation status, or platelet or
WBC counts or hemoglobin levels, and pregnancy outcome [6]. These
results are not consistent with the findings of 2 previous studies [4,5]
reporting a higher incidence of miscarriages in JAK2V617F patients
with ET than in JAK2-WT cases, while are in agreement with the
Mayo Clinical study [6] in which the rate of pregnancy loss was similar between JAK2 mutated and nonmutated patients. The relevance of
JAK2V617F mutation as a thrombotic risk factor is still debated [16
19], as well as the role of platelet and WBC counts. It is worth nothing that the recently developed prognostic model to predict survival
in ET (IPSET) considers the leukocyte count but not the platelet
number to distinguish prognostic categories [20].
The main goal of the present study was to correlate thrombotic complications and pregnancy outcome in our sample of women with ET.
First we considered the occurrence of miscarriages among patients
who had experienced a thrombotic event before becoming pregnant,
finding their pregnancy outcomes no worse than for women with no
history of thrombotic complications. Then, when our patients were
stratified according to Griesshammers criteria [11], which attribute
great relevance to previous thrombotic events as a very high risk factor for miscarriage, we again failed to find any difference in pregnancy outcomes between the different risk groups.
In contrast, thrombotic events usually occurred within a few weeks
or months after delivery, and pregnancy outcome correlated significantly with postdelivery thrombosis: miscarriages were frequently followed by a venous thrombotic event, often in the splanchnic veins.
On multivariate analysis for risk factors predicting thrombotic events
(age, WBC count, hemoglobin, platelet count, previous miscarriage,
cardiovascular risk factors, and JAK2 mutation status), previous fetal
loss again retained its significance.
The rate of venous thromboembolism (VTE), with or without pulmonary embolism, in the general pregnant population is highest in
the first 3 weeks after delivery if the pregnancy ended in a live birth
[21]. Consistently, the only case with VTE and pulmonary embolism
in our series occurred in the early postpartum period.
An influence of female sex hormones on the risk of BuddChiari
syndrome (BCS) has long been recognized, on the grounds of a higher

doi:10.1002/ajh.23635

RESEARCH ARTICLE

Pregnancies in patients with essential thrombocythemia

risk of BCS among oral contraceptive users [22,23], and 647% of


reported cases of BCS involve women presenting in pregnancy or postpartum [24]. Most post-partum thrombotic events in our cohort were
cases of splanchnic vein thrombosis too. A large French study [25]
showed that pregnancy is unlikely to cause BCS in the absence of other
thrombotic risk factors, and MPNs were found in 56% of the reported
cases, which goes to show the prothrombotic role of MPNs. The high
percentage of placental infarctions found in patients with advanced fetal
loss [7,8] supports the suspicion of a fundamental role for thrombotic/
ischemic events in the pathogenesis of pregnancy failures. The occurrence of thrombotic events with a similar frequency all over the followup and not only in the postpartum period suggests that females with ET
and pregnancy failure may have a disease characterized by a higher
tendency to develop thrombotic complications.
Although prospective studies are needed to confirm our hypothesis, we conclude that pregnancy complications in patients with ET
should be considered as risk factors for subsequent thrombosis. Preg-

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Acknowledgment
A detailed description of the AGIMM project is available at http://
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