Abstract Introduction An unprovoked thombotic event in a patient is cause for further evaluation of an underlying hypercoaguable state. The investigation should include a thorough search, including checking for a variety of known inherited and acquired hypercoaguble states (protein C or S deficiency, anti-phospholipid antibodies, and anti-thrombin III deficiency) and gene mutations that predispose patients to an increased risk of clotting (for example, prothrombin gene 20210 mutation, factor V Leiden, and the <it>JAK2 V617F </it>mutation). Case presentation We report the case of a 38-year-old Caucasian woman with spontaneous, unprovoked abdominal venous thrombosis and demonstrate how testing for the <it>JAK2 V617F </it>mutation was useful in unmasking an underlying hypercoaguable state. Conclusions <it>JAK2 V617F</it>-positive myeloproliferative neoplasm was diagnosed. This case illustrates the importance of testing for <it>JAK2 V617F </it>in patients presenting with Budd-Chiari syndrome, even in the absence of overt hematologic abnormalities, in order to establish a diagnosis of underlying myeloproliferative neoplasm.</p

A Carobbio

Alison R Moliterno

Andrew M Cameron

AR Moliterno

BL Stein

D Valla

E Zuckerman

EJ Baxter

James Peter Hamilton

JJ Kiladjian

JL Spivak

N Pemmaraju

Naveen Pemmaraju

RK Patel

S Darwish Murad

S Sozer

Stephen Sisson

English

PubMed

Springer - Publisher Connector

Abdominal venous thrombosis presenting in myeloproliferative neoplasm with JAK2 V617F mutation: a case report

Abstract Introduction An unprovoked thombotic event in a patient is cause for further evaluation of an underlying hypercoaguable state. The investigation should include a thorough search, including checking for a variety of known inherited and acquired hypercoaguble states (protein C or S deficiency, anti-phospholipid antibodies, and anti-thrombin III deficiency) and gene mutations that predispose patients to an increased risk of clotting (for example, prothrombin gene 20210 mutation, factor V Leiden, and the JAK2 V617F mutation). Case presentation We report the case of a 38-year-old Caucasian woman with spontaneous, unprovoked abdominal venous thrombosis and demonstrate how testing for the JAK2 V617F mutation was useful in unmasking an underlying hypercoaguable state. Conclusions JAK2 V617F-positive myeloproliferative neoplasm was diagnosed. This case illustrates the importance of testing for JAK2 V617F in patients presenting with Budd-Chiari syndrome, even in the absence of overt hematologic abnormalities, in order to establish a diagnosis of underlying myeloproliferative neoplasm.</p

Pemmaraju Naveen

Hamilton James

Cameron Andrew M

Sisson Stephen

Moliterno Alison R

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Journal of Medical Case Reports

Abdominal venous thrombosis presenting in myeloproliferative neoplasm with <it>JAK2 V617F </it>mutation: a case report

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CASE REPORT Open Access
Abdominal venous thrombosis presenting in
myeloproliferative neoplasm with JAK2 V617F
mutation: a case report
Naveen Pemmaraju1*, James Peter Hamilton2, Andrew M Cameron2, Stephen Sisson2 and Alison R Moliterno2
Abstract
Introduction: An unprovoked thombotic event in a patient is cause for further evaluation of an underlying
hypercoaguable state. The investigation should include a thorough search, including checking for a variety of
known inherited and acquired hypercoaguble states (protein C or S deficiency, anti-phospholipid antibodies, and
anti-thrombin III deficiency) and gene mutations that predispose patients to an increased risk of clotting (for
example, prothrombin gene 20210 mutation, factor V Leiden, and the JAK2 V617F mutation).
Case presentation: We report the case of a 38-year-old Caucasian woman with spontaneous, unprovoked
abdominal venous thrombosis and demonstrate how testing for the JAK2 V617F mutation was useful in unmasking
an underlying hypercoaguable state.
Conclusions: JAK2 V617F-positive myeloproliferative neoplasm was diagnosed. This case illustrates the importance
of testing for JAK2 V617F in patients presenting with Budd-Chiari syndrome, even in the absence of overt
hematologic abnormalities, in order to establish a diagnosis of underlying myeloproliferative neoplasm.
Introduction
An unprovoked thombotic event in a patient is cause for
further evaluation of an underlying hypercoaguable
state. The investigation should include a thorough
search, including checking for a variety of known inher-
ited and acquired hypercoaguble states and gene muta-
tions that predispose patients to an increased risk of
clotting. Therefore, the differential diagnosis of underly-
ing etiologies of Budd-Chiari syndrome (BCS) includes
the following: myeloproliferative neoplasm (MPN),
malignancy, paroxysmal nocturnal hemoglobinuria, anti-
phospholipid syndrome, sickle cell anemia, and inherited
hypercoaguable states, including factor V Leiden, pro-
thrombin 20210 mutation, and protein C and S and
anti-thrombin deficiencies [1].
The MPNs are a related group of diseases that have a
common origin of an acquired stem cell or progenitor
cell defect that leads to the development of overproli-
feration of the myeloid series, manifest as essential
thrombocytosis (ET), polycythemia vera (PV), or pri-
mary myelofibrosis (PMF). In 2005, it was demonstrated
that MPNs are connected by an acquired somatic muta-
tion of the JAK2 gene, JAK2 V617F [2], which is found
in approximately 95% of patients with PV and in 50% of
patients with ET or PMF.
Case presentation
A 38-year-old Caucasian woman presented to our hospi-
tal with two months of epigastric abdominal pain asso-
ciated with bloating. She denied nausea or vomiting,
history of acid reflux, constipation, or diarrhea. She had
no known trauma. She affirmed complaints of fatigue
and decreased appetite but denied fevers, chills, night
sweats, or weight loss. She denied a history of liver or
blood disorders.
The initial evaluation revealed a jaundiced young
woman with abdominal ascites and trace lower-extre-
mity edema. Laboratory studies revealed elevated levels
of gamma glutamyl transferase (GGT), total bilirubin,
and CA-125. A computed tomography (CT) scan with
oral and intravenous contrast of the abdomen and pelvis
was performed, demonstrating a heterogeneous
* Correspondence: npemmaraju@mdanderson.org
1MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX
77030, USA
Full list of author information is available at the end of the article
Pemmaraju et al. Journal of Medical Case Reports 2012, 6:102
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CASE REPORTS
© 2012 Pemmaraju et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
appearance of the liver and caudate lobe hypertrophy,
ascites, and a cystic mass in the right ovary. The liver
abnormalities described were thought to be consistent
with diffuse metastatic involvement of the liver, and the
ovaries were thought to be a possible primary source.
Our patient then underwent laparoscopic oopherectomy
and liver biopsy to evaluate for underlying malignancy.
No evidence of either ovarian or hepatic malignancy
was found, but the liver biopsy revealed fibrous oblitera-
tion of the central hepatic veins and patchy areas of
sinusoidal dilatation diagnostic of hepatic vein obstruc-
tion, or BCS. A triphasic CT scan of the liver with
three-dimensional reconstruction confirmed occlusion
of the hepatic veins and associated ascites, splenome-
galy, and abdominal varices.
Our patient’s medical history was notable for one epi-
sode of unexplained syncope one year prior and migraine
with aura. Medications included warfarin and aspirin.
Our patient was married and lived with her husband. She
worked as a busy executive, frequently taking interna-
tional flights. She had never smoked and she drank one
or two glasses of wine per week. The only family history
of a thrombosis was in a paternal aunt with a deep vein
thrombosis in the setting of a long car ride. Our patient
had no family history of cancer or other blood disorders.
Laboratory findings revealed a white blood cell count
of 3640 K/μL, hemoglobin of 11.1 g/dL, mean corpuscu-
lar volume (MCV) of 80fL, and a platelet count of
252,000 K/μL. Erythropoietin level was 22 mIU/mL
(normal is 4.1 to 19.5), international normalized ratio
was 1.4 on warfarin therapy, ammonia 45 Umol/L (10 to
47 Umol/L), total bilirubin 3.1 mg/dL, direct bilirubin
0.6, albumin 3.7 g/dL, and alkaline phosphate 158 IU/L.
Alanine aminotransferase and aspartate aminotransfer-
ase were normal. GGT was elevated to 120 U/L (12 to
48 U/L). CA-125 was 55 U/mL (normal is less than 35
U/mL). Liver biopsy results showed central hepatic veins
with pericentral fibrosis and mild portal fibrosis and pat-
chy areas of moderate sinusoidal dilatation consistent
with chronic BCS.
Our patient was evaluated for a hypercoaguable state,
including tests for lupus anticoagulant and anti-phos-
pholipid antibodies, factor V Leiden, and prothombin
20210 mutation. The results of these tests were negative.
Levels of anti-thrombin and protein C and S were nor-
mal. The result of one test was found from the hyper-
coaguable workup to be positive: JAK2 V617F mutation
with an allele percentage of 36%. Complete blood counts
obtained in the five years prior to her diagnosis were
notable for thrombocytosis (Table 1).
Discussion
On the basis of the new-onset BCS combined with the
finding of the JAK2 V617F mutation, our patient’s con-
dition was diagnosed as an underlying chronic MPN.
Thromboses, including abdominal vein thromboses,
constitute a major etiology of morbidity and mortality in
MPN [3]. MPN now constitutes the most common
cause of abdominal venous thromboses, accounting for
approximately 50% of BCS cases and 25% of portal vein
thromboses [4]. A recent study demonstrated MPN to
be the most prevalent underlying condition (49%) in a
series of 163 incident cases of BCS [1]. In most of these
patients, portal hypertension was a typical feature. This
becomes important because it may help to explain the
surprisingly low or normal blood counts observed in
BCS JAK2 V617F-positive patients; the subsequent
hemodilution and hypersplenism resulting from the por-
tal hypertension may decrease the actual hemoglobin
and other blood cell counts, making the diagnosis of
MPN quite challenging in many cases [4]. Masking of
the MPN by subsequent hemodilution from portal
hypertension or even from hepatic dysfunction is evi-
dent in our patient, in whom the platelet count
Table 1 Complete blood counts in a patient with JAK2 V617F-associated Budd-Chiari syndrome
Date Hemoglobin, g/dL WBCs, K/μL Platelets, K/μL Clinical events
Dec. 9, 2002 11.3 4.1 349
Dec. 19, 2002 12.9 6.6 416
Jan. 10, 2006 13.8 8.6 522
Dec. 27, 2007 13.9 6.9 354 Symptoms of BCS
Jan. 7, 2008 12.5 5.5 379 Post-oophorectomy
March 25, 2008 13.5 4.7 261 Post-TIPS
April 29, 2008 11.1 3.6 252 Follow-up visit
July 29, 2008 12.5 3.5 239 Follow-up visit
Sept. 15, 2009 13.2 4.7 287 Follow-up visit
May 4, 2010 14.1 5.4 293 Follow-up visit
June 3, 2011 13.3 5.2 285 Follow-up visit
Normal ranges of hemoglobin, white blood cells (WBCs), and platelets are 12 to 15 g/dL, 4.5 to 11 K/μL, and 150 to 450 K/μL, respectively. BCS, Budd-Chiari
syndrome; TIPS, transjugular intrahepatic porto-systemic shunt.
Pemmaraju et al. Journal of Medical Case Reports 2012, 6:102
http://www.jmedicalcasereports.com/content/6/1/102
Page 2 of 4
normalized from the previously mild elevation evident in
the years before her BCS diagnosis (Table 1). Several
groups have hypothesized that endothelial cell (EC) dys-
function may contribute to the prothrombotic state in
MPN. In a seminal study, Sozer and colleagues [5]
demonstrated that the JAK2 V617F mutation was pre-
sent in the ECs from venules of liver biopsy specimens
obtained from two patients with BCS and PV, suggest-
ing that ECs in PV are involved in the malignant pro-
cess and contribute to the prothrombotic state found in
this disorder.
It has been suspected for decades that primary, occult
MPN may play a role in the prevalence of BCS, espe-
cially in young women. One study demonstrated that
erythroid colony formation in the absence of erythro-
poietin, a reliable indicator of MPN in the pre-JAK2
V617F era, was present in 16 out of 20 patients with
BCS, most of whom were young women (18 to 45 years
old) [6]. The authors concluded, some 20 years prior to
the elucidation of the JAK2 V617F mutation, that pri-
mary MPN is a major cause of BCS in young women.
Many cases labeled as idiopathic BCS have been subse-
quently found to be secondary to underlying myeloproli-
ferative disease upon JAK2 V617F testing [7]. In the
literature reported to date, the largest series relating
JAK2 V617F mutation status to abdominal venous
thrombosis showed that JAK2 V617F-associated BCS
was predominantly a disease of young women, that it
was associated with relatively low JAK2 V617F allele
burdens, and that the majority of the patients did not
have additional identified hypercoagulable risk factors,
all features common to our patient [4]. Also, the most
common risks for thrombotic disease in MPN are older
age (> 60 years), elevated white cell count, and prior
thrombotic events [8], none of which applies to either
our patient or the MPN BCS patients at large [4]. The
discrepancy between the absence of traditional MPN
thrombotic risk factors and the low JAK2 V617F allele
burdens in the patients with BCS indicates that other
important risk factors for this devastating presentation,
particularly relevant to young women with MPN, remain
undefined [9]. It is interesting to note that our patient’s
JAK2 V617 allele burden at diagnosis measured only
36%. JAK2 V617F allele burdens are lower in women in
comparison with men, suggesting that gender is an
important modifier of disease phenotype and may in
part account for differences in disease presentation and
complications between men and women with JAK2
V617F-positive MPNs [3,10].
It is important to note that, because JAK2 V617F is
present in 95% of patients with PV but only in approxi-
mately 50% of patients with ET or PMF, a negative
JAK2 V617F study should not by itself preclude the
diagnosis of an underlying MPN. In such cases, further
investigation, including a bone marrow biopsy, should
be sought as part of a complete workup.
Conclusions
Our patient’s condition was diagnosed as JAK2 V617F-
positive MPN, most consistent with ET (Table 1). She
subsequently underwent a transjugular intrahepatic
porto-systemic shunt (TIPS) placement to decompress
her hepatic obstruction and this was followed by indefi-
nite warfarin-based anticoagulation. Her clinical status
and blood counts have been stable in the three years
since her TIPS procedure (Table 1), and her hepatic
function remains excellent. This case illustrates the
importance of testing for JAK2 V617F in patients pre-
senting with BCS, even in the absence of overt hemato-
logic abnormalities, in order to establish a diagnosis of
underlying MPN. Although molecular testing with JAK2
is rather specific to the MPN classification, it alone can-
not specify which MPN the patient harbors [11,12].
Therefore, further studies, including red cell mass, regu-
lar complete blood cell counts, and assessment of the
JAK2 V617F allele percentage over time, may be indi-
cated to further aid in the individual MPN diagnosis of
our patient [10]. It is important to recognize that CA-
125 is not a reliable screening test for the diagnosis of
ovarian cancer in pre-menopausal woman. In addition,
as in this case, CA-125 can be elevated in the presence
of liver disease and can be a sensitive marker of ascites
[13]. Finally, non-invasive imaging is of critical impor-
tance in the diagnostic evaluation of abdominal vein
thrombosis, and the majority of cases are identified by
Doppler ultrasound. In some instances, high-quality
multi-phasic examinations of the liver are often needed
to confirm the diagnosis of BCS.
Consent
Written informed consent was obtained from the patient
for publication of this manuscript and accompanying
images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.
Abbreviations
BCS: Budd-Chiari syndrome; CT: computed tomography; EC: endothelial cell;
ET: essential thrombocytosis; GGT: gamma glutamyl transferase; MPN:
myeloproliferative neoplasm; PMF: primary myelofibrosis; PV: polycythemia
vera; TIPS: transjugular intrahepatic porto-systemic shunt.
Author details
1MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX
77030, USA. 2Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD
21287, USA.
Authors’ contributions
NP and ARM helped to design and write the manuscript and to analyze and
interpret the hematologic and internal medicine aspects of the patient data
from this case. SS helped to analyze and interpret the hematologic and
internal medicine aspects of the patient data from this case. JPH and AMC
Pemmaraju et al. Journal of Medical Case Reports 2012, 6:102
http://www.jmedicalcasereports.com/content/6/1/102
Page 3 of 4
analyzed and assisted with the gastrointestinal and hepatologic
interpretation of data from this case. All authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 14 October 2011 Accepted: 5 April 2012
Published: 5 April 2012
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case report. Journal of Medical Case Reports 2012 6:102.
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AR: Gender and vascular complications in the JAK2 V617F-positive myeloproliferative neoplasms. Thrombosis

Cancer Genome Project: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet

DC: The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood

Eldar S: Cancer antigen 125: a sensitive marker of ascites in patients with liver cirrhosis.

et al: Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with BuddChiari syndrome. Ann Intern Med

HL, EN-Vie (European Network for Vascular Disorders of the Liver): Etiology, management, and outcome of the BuddChiari syndrome. Ann Intern Med

JL: Phenotypic variability within the JAK2 V617F-positive MPD: roles of progenitor cell and neutrophil allele burdens. Exp Hematol

Moliterno AR: Sex differences in the JAK2 V617F allele burden in chronic myeloproliferative disorders. Haematologica

R: The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood

RT: Case 15-2006: the Budd-Chiari syndrome and V617F mutation in JAK2.

T: Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia. Blood

The quantitative JAK2 V617F neutrophil allele burden does not correlate with thrombotic risk in essential thrombocytosis. Leukemia

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Abdominal venous thrombosis presenting in myeloproliferative neoplasm with JAK2 V617F mutation: a case report

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