Neonatal portal vein thrombosis: Diagnosis and management [629278]

Neonatal portal vein thrombosis: Diagnosis and management
Suzan Williamsa,*, Anthony K.C. Chanb
aDepartment of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
bDepartment of Hematology/Oncology, McMaster University, Hamilton, Ontario, Canada
Keywords:
AnticoagulationLiver lobe atrophyNeonatePortal hypertensionPortal vein thrombosissummary
Neonatal portal vein thrombosis (PVT) is an increasingly recognized event. Patients are generally
asymptomatic in the neonatal period. The diagnosis is made with Doppler ultrasound. Umbilical cath-
eterization, exchange transfusion and sepsis are risk factors for neonatal PVT. Thrombophilia is possiblya contributing risk factor. Although there are potential serious acute complications such as hepaticnecrosis, the outcome is good in the majority of cases, followed up to 8 years of age. Thrombus resolution
occurs in 30 e70% in days to months. Liver lobe atrophy may occur following PVT, and does not appear to
be associated with any impairment of liver function. Non-occlusive thrombosis is more likely to resolve
than non-occlusive thrombosis. A subset of patients without resolution is at risk for developing portal
hypertension over the next decade of life. There are no current de fining features present during the
neonatal period to enable identi fication of neonates at risk for portal hypertension. There is no evidence
that anticoagulation therapy improves time to resolution or decreases the likelihood of portal hyper-tension. Anticoagulation therapy may be considered. A management algorithm is proposed.
/C2112011 Elsevier Ltd. All rights reserved.
1. Introduction
Neonatal portal vein thrombosis (PVT) has been described as
a rare event, but is becoming more commonly recognized. Esti-
mates range from 1 in 100,000 live births1to 36 per 1000 neonatal
intensive care unit admissions.2Because portal venous thrombosis
rarely causes clinical problems during the neonatal period, histor-
ically the majority of cases remained unrecognized in the neonatalperiod and were found later in childhood.
3,4This led to the
supposition that neonatal PVT was as described by Thompson andSherlock: exceedingly rare.
5
By contrast with the reported rarity in the neonatal setting, PVT is
the major cause of extrahepatic portal hypertension and gastroin-
testinal bleeding in children.3Prehepatic or extrahepatic portal
hypertension is most commonly the result of an organizedthrombus in the portal vein. Portal vein fibrosis, stenosis, or web
may also lead to elevations in portal venous pressure.
6Occlusion of
the portal vein associated with small periportal collaterals is known
as cavernous transformation of the portal vein (CTPV).7
The etiology of neonatal PVT is different from that in children and
adults. In adults PVT is most frequently secondary to cirrhosis.8In
older children, PVT is related to liver transplantation, intra-abdominal sepsis, splenectomy, sickle cell anemia, and anti-phospholipid antibodies.
8e14Inw50% of children with PVT, an
underlying etiology is not identi fied.10,15PVT in neonates commonly
occurs secondary to the placement of an umbilical vein catheter
(UVC), with or without infection.16e18
2. Historical aspects
Historically, the etiology of portal vein occlusion in children has
been attributed to a variety of causes from congenital malformationsto thrombosis associated with infection and most recently to
thrombosis as a potential complication from trauma or vessel
catheterization. Prenatal onset of PVT and in association with
umbilical vein thrombosis has also been reported.
19e21
Cavernomatous transformation of the portal vein was histori-
cally described as a congenital or tumour-associated formation. In
initial reports, a congenital malformation22or hamartoma23were
presumed.
In 1928, Klemperer reviewed previously reported cases and
suggested that thrombosis was responsible for the changes in the
portal vein.24Wallgren in 1927 had postulated PVT as a complica-
tion of previous intra-abdominal infection, citing umbilical sepsis25
and appendicitis as possible causes. The possibility of umbilical
infection without sepsis having more disseminated complications
was described in a case of severe umbilical infection with cellulitis
of the anterior abdominal wall in 1957.26Neonatal sepsis and*Corresponding author. Department of Hematology/Oncology, The Hospital for
Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: ț14 1 6
813 8997; fax: ț1 416 813 5327.
E-mail address: suzan.williams@sickkids.ca (S. Williams).
Contents lists available at SciVerse ScienceDirect
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doi:10.1016/j.siny.2011.08.005Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339

umbilical sepsis leading to PVT was described in case series.27,28
Shaldon and Sherlock in 1962 reported 16 children with PVT; 11
had a history of sepsis.29Acute appendicitis, omphalitis, and biliary
infections were then all cited as a source of infected thrombileading directly to portal thrombophlebitis. PVT, therefore, may be
either secondary to portal pyemia with the site of infection some-
where in the portal venous system, or due to local spread of
infection from a site adjacent to the portal vein.
Later, cavernomatous lesion in the portal vein was more strongly
connected as secondary to PVT and represented attempts at
a collateral circulation to carry portal blood to the liver.
30,31It is
now established that a PVT may completely resolve or it maytransform into a cavernoma with dilated pancreatico-duodenal and
prebiliary veins, secondary to portal hypertension.
2,32,33
Despite umbilical infection and sepsis being common in the case
series initially describing PVT in children ( Table 1 ), a signi ficant
proportion of cases did not have infection. Exchange transfusion viathe umbilical vein was postulated as an etiological factor in case
reports.
34,35In a case series, Oski et al. in 1963 reported four cases of
PVT; three having trauma and prolonged umbilical catheterization,with three out of four (75%) having no evidence of infection.
36
3. Umbilical vein catheterization
The transition from fetal to neonatal life causes major changes in
hepatic vascular anatomy. As blood flow from the umbilical vein to
the portal vein ends, the portal vein will take on its adult function of
carrying nutrients and toxins from the stomach and intestine to the
liver for processing in hepatic capillary-like vessel sinusoids. In
adults, the portal vein supplies 70 e75% of liver blood flow, and
50e55% of the oxygen requirement.
In neonates, the umbilical vein is available as a site for central
venous access for the first week of life. The umbilical vein joins the
left portal vein in the liver. There is a direct communication formed
between the umbilical vein and the ductus venosus, which
bypasses the liver and joins the inferior vena cava. The umbil-
icoportal con fluence is the area at which the portal vein is traversed
by the junction of the umbilical vein and the ductus venosus(Fig. 1 ).
37The normal umbilical venous catheter traverses through
the umbilical vein past the left branch of the portal vein, into theductus venosus, which lies at the cephalic aspect of the left portal
vein and ends in the right or middle hepatic vein close to their
entrance into the inferior vena cava.
38The ductus venosus is nar-
rowed at its origin, and is not always perfectly aligned to theumbilical vein. Therefore, the left branch of the portal vein may be
the recipient of the umbilical venous catheter tip during
placement.
39,40
The catheterization of the umbilical vein has now long been
implicated as a cause for PVT presenting in childhood.3,4,36,41 e43
There are several mechanisms by which umbilical venouscatheters may cause thrombosis; including damage to vessel walls,disrupted blood flow, the infusion of substances such as total
parenteral nutrition that damage endothelial cells, and thrombo-genic catheter materials.
44,45
4. Variable incidence of PVT with umbilical veincatheterization
There is a variable reported incidence of umbilical venous
catheter-related PVT in infants and children from zero to 43%(Table 2 ).
17,37,42,46 e50A number of explanations have been put forth.
Table 1
Portal vein thrombosis (PVT) following neonatal umbilical catheterization, septi-cemia and umbilical sepsis.
Author Year Total
patientsSepticemia Umbilical
sepsisPVT
Thompson et al.
51964 493 (470)a51 (10%) 37 (8%)b0
Yadav et al.461993 47 7 (15%) 4 (8.5%) 0
Schwartz et al.171997 173 (100)aee 1 (1%)
Guimaraes et al.471998 40 ee 0
Kim et al.372001 100 5 (5%) e 43 (43%)
Sakha et al.552007 50 11 (22%) e 17 (34%)
Gharehbaghi et al.542011 164 10 (6%) 2 (1%)c5 (3%)
aPatients followed.
bUmbilical infections.
cPeri-umbilical erythema.
Fig. 1. Anatomy of neonatal portal vein. RPV, right portal vein; RHV, right hepatic vein;
IVC, inferior vena cava; LHV, left hepatic vein; LPV, left portal vein; SV, splenic vein;SMV, superior mesenteric vein; PV, portal vein (Published with permission from Kim etal.
110).
Table 2
Portal vein thrombosis (PVT) following umbilical venous catheterization (UVC)
imaging.
Study Year UVC ( n) PVT N(%) Time to image
Thompson et al.51964 493 (470)a0bSchool age
Yadav et al.461993 47 0 22 newborns:
within 4 e8 weeks,
q3 months to age
12 months, 24 months.25 children at age1e5 years
Schwartz et al.
171997 173 (100)a1 (0.6%) 3 days to 5 months
Guimaraes et al.471998 40 0 8e9 years
Kim et al.372001 43 43 (43%) Within 1 week of UVC
q2e4 days till
UVC removalq2e7 days till
resolution
Sakha et al.
552007 50 17 (34%) 1 e2 weeks after
UVC removalq1e2 months until
clot resolution
Turebylu et al.
562007 28 2 (7%)c3, 5e7 days post UVC
Weekly while UVCin place3 days post UVC
Gharehbaghi et al.
542011 164 5 (3%) 24 e48 h of UVC
48e72 h post
UVC removal
Weekly till discharge
or resolution
aPatients followed.
bThree children died and had ‘suppurative thrombophlebitis ’in umbilical vein,
extending into ductus venosus, with no specifi c mention of portal vein on
postmortem.
cAdditional 4 (14%) had inferior vena cava clots.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 330

Differences between previous studies that contribute to the
difference in reported incidence of PVT with umbilical venous
catheter are: the prospective or retrospective nature of the study;
the diagnostic method used to study the thrombus; the time
schedule of examinations; and catheter variables such as size,
location, and duration.
Retrospective studies have shown that many infants and children
with extrahepatic portal hypertension have undergone catheteri-
zation of the umbilical vein during the newborn period.2e4,36,41,42
One of the more recent retrospective cohorts showed that five out
of seven (71%) patients with portal hypertension or splenomegaly in
a cohort of patients with PVT had a history of umbilical venous
catheterization.32
Autopsy studies have estimated the incidence of umbilical
venous catheter-related thrombosis at 20 e40% of neonates who die
with an umbilical venous catheter in place.42,48,50 e53Larroche
found that 40% of neonates having umbilical vein catheterization
developed portal venous thrombi after 25 e48 h. Thrombi and
fibrin rings around the catheter or adherent to the intimae were
seen in 13.7% after a period of 12 h, and in 100% after three days.48
Thompson and Sherlock described 470 of 493 neonates, who
had umbilical venous catheters placed for exchange transfusion,prospectively surveyed years later as children, as having no inci-
dences of PVT or portal hypertension.
5
Some more recent prospective studies of umbilical venous
catheters have also reported that properly inserted catheters are
not associated with PVT, with no reported incidences of PVT, when
ultrasound imaging was completed weeks to years after the
umbilical venous catheter placement.17,46,47However, the absence
of portal hypertension by school age or portal vein occlusion onimaging several weeks after the catheterization does not rule out
the possibility of a neonatal PVT.
Given the temporal evolution of thrombi, the timing and
frequency of ultrasound monitoring is relevant in determining the
incidence of PVT. More recent studies, with prospective ultrasound
examination starting hours to weeks after umbilical catheter
placement have described the incidence of PVT as 1.3e 43% in neo-
nates.
17,37,54 e56Kim et al. showed a 43% rate of neonatal PVT
following umbilical venous catheters when ultrasound examination
was completed every 5 e7 days while infants where in hospital. Most
of the small thrombi were attached to the catheter rather than thewall of the portal vein, supportive of the idea that a catheter in the
lumen is closely related to the initiation of thrombosis. There was
clot resolution occurring in more than half of the cases within 23
days after catheter removal. Schwartz et al. commented that
thrombi which developed during the early neonatal period and
resolved before ultrasound imaging, which was performed at
a median of 2 months, would not have been detected, contributing
to a lower incidence of 1.3 %.
17
Non-visualization of the portal vein is not considered as
representative of PVT in all reports. In the study by Yadav et al.,
there was an absence of splenoportal flow in at least seven (32%)
and possibly 12 (55%) of 22 neonates, which normalized by the ageof 2 years.
46The authors reported no PVT in this cohort. Guimaraes
et al. studied the late outcome of umbilical vein catheterization inschool-age patients (at age 8 years), and found intact portalcirculation by Doppler ultrasound in all 40 children except for two
with no portal vein visualized, one of which was associated with
small left hepatic lobe.
47Like Yadav et al., they reported no PVT in
their cohort of 40 patients with neonatal umbilical venous cathe-ters. In the one patient where the findings were persistent, the
authors postulated the non-visualization of the portal vein asa normal variant,
47as has been previously described.47,57However,
atrophy of the left hepatic lobe has been shown to be a potentialcomplication from neonatal PVT.
2The varying reported incidences of neonatal PVT following
umbilical vein catheterization reported by retrospective, prospec-tive, and autopsy studies are compatible with a few assumptions.
Thefirst is that the development of PVT is common in the newborn
period. The second is that the majority of thrombi resolve sponta-neously and therefore do not cause portal hypertension. Third, the
definition of PVT will in fluence the incidence. When de fined by
imaging, the incidence of PVT will be higher than when de fined by
clinical symptoms of portal hypertension.
4.1. Catheter size, duration, location
Catheter-related variables such as size, duration of placement and
location also have an impact on the incidence of line-associated
thrombosis. In Schwartz et al. ’s study there was control of a smaller
(uniformly 3.0 F) catheter, with respect to catheter position, so that itwas not allowed toterminate in the liver,
17potentiallycontributing to
lower incidence than studies reporting on all patients with umbilicalvenous catheters. Prolonged catheterization and transfusion through
the catheter were signi ficantly associated with PVT.
37The highest
rate of thrombosis ( five out of eight, 63%) was in neonates with
catheter placement in the portal vein, and the main site of throm-bosis was the umbilicoportal con fluence (the space of Rex).
37
Outside of placement in the portal vein, a particular umbilical
venous catheter position does not appear to be signi ficantly asso-
ciated with PVT. It has been suggested that PVT may occur lessfrequently if the umbilical venous catheter tip is present in the right
atrium or in the inferior vena cava (high placement). There is
greater blood flow in the right atrium and inferior vena cava
compared to the portal sinus or umbilical vein (low placement). Thegreater blood flow was thought to ensure adequate mixing of the
infusates with the neonate’ s blood and to avoid direct exposure of
the liver to unphysiologic stimuli. In addition, the mechanical
endothelial damage and altered blood flow caused by the catheter
traversing the umbilicoportal con fluence, serving as the initiating
thrombotic insult, would in fluence the incidence of thrombosis.
There was no statistically signi ficant difference in rates of PVT
related to catheter position in Kim et al. ’s study. However, high
placement actually had a higher rate of thrombosis 27/68 (42%)compared to low placement 4/15 (27%).
37In the Schwartz et al. ’s
study, the single infant with PVT had an umbilical vein catheterwhich terminated in the right atrium.
17In Morag et al. ’s study, 45%
of infants with PVT had the umbilical venous catheter placed in anappropriate high flow position.
2
4.2. Patient factors
Apart from endothelial damage during catheter placement and
composition of the infusate, other factors associated with theinitiation and propagation of thrombosis include patient charac-
teristics. Low birth weight, low flow state, hypercoagulability,
hypoxia, infection, sepsis, congenital malformations, and gesta-tional diabetes mellitus can contribute to complications caused by
umbilical catheterization.
42,53,58 e61The same variables that
contribute to complications necessitate the use of the catheter forsupportive care in critically ill infants.
In spite of the potential hazard of thrombus formation, the
umbilical venous catheter remains a practical and widely usedroute for the monitoring and treatment of critically ill infants.
62As
a result, neonatal PVT will continue to be a relevant clinical entity.
5. Outcome
There are potentially signi ficant complications which can occur
following neonatal PVT ( Table 3 ). Thrombosis of the umbilicalS. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 331

Table 3
Neonatal and childhood portal vein thrombosis: radiologic and clinical outcome.
Study Year N Diagnosis Treatment Complete
resolution (CR)Partialresolution (PR)No change Extension or
recurrenceTime toCR/PRLLA PHTN Death
Alvares et al.
31983 108 (1 months
to 15 years)104 AG
4U S3V L1M S
76 PS2
a
Schwartz et al.171997 1 US 100% 6 months
Kim et al.372001 43 neo US ( e)UVC 18/36 (50%) 2/36 (6%) 11/36
(30%)5/36 (9%) 2 e23 days
(e)UVC1/36 (3%)
Morag et al.22006 133
128/133 neo5/133 infUS ACT 59/133
(44%)81/133 (61%) 16/133 (12%) 2e626 days
mean: 63median: 2530/133(22.5%)6/133 (4.5%) 22/133 (16%)
b
Turebylu et al.562007 5 US 3/5 (60%) 3e6 weeks 2/5 (40%)
Sakha et al.552007 17 neo
16 nocc1 occUS None 13/13 (100%) 2e5 months NA NA 0
Demirel et al.
712009 15 neo US ACT (LMWH
/UFH)13/15 (87%)c2/15 (13%)a
Morag et al.322011 70dUS 14/37 (38%)
normal20/37 (54%)2/20 (10%)
PHTN2/37 (5%)
6/133 prior PHTN
2/6 (33%) CR1/6 (17%) transplant
e
1/6 (17%) lost2/6 (33%) PCS
Gharehbaghi et al.
542011 5 occ US 3/5 (60%) 3e6 weeks 2/5 (40%)
LLA, liver lobe atrophy; PHTN, portal hypertension; AG, angiogram; US, ultrasound; VL, variceal ligation or gastric devascularization; MS, mesocaval shunt; PS, portosystemic shunt surgery; neo, neonates; inf, infants; PCS,portacaval shunt; lost, lost to follow-up; ( e)UVC, umbilical venous catheter removal; nocc, non-occlusive; occ, occlusive.
aDue to other causes.
b25/133 (22.5%) lost to follow-up.
cDescribed as recovered.
dFollow-up at 2 e8 years from prior cohort: 12/133 primary liver pathology, 22/133 deaths before 2 years, 29/99 (29%) lost to follow-up.
ePatient with primary liver disease.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 332

portal sinus can lead to adjacent liver necrosis, found on post-
mortem examination, with risk factors for necrosis including
placement of the umbilical catheter in the portal vein, infusion of
alkaline solution, sodium bicarbonate via the catheter, and
thrombocytopenia.63Cerebral infarct resulting from paradoxical
emboli, in which emboli from the PVT passing through the ductusvenosus and foramen ovale into systemic circulation, has been
reported.
64Hepatic hematoma with PVT related to malpositioned
umbilical venous catheter has been reported.49Bleeding diathesis
with hemorrhagic ascites, massive intrapulmonary bleeding, and
subsequent death in diffuse intrahepatic PVT with marked hepatic
necrosis con firmed by postmortem has been documented.20
5.1. Resolution
The long term sequelae and clinical importance of thrombosis
detected on ultrasound in asymptomatic neonates are not fullyunderstood. The spontaneous regression of catheter-related
thrombi detected on ultrasound has been reported.
17,65In fact,
early spontaneous resolution has been postulated as a reason whyPVT was diagnosed only relatively rarely in the clinical setting of theneonatal intensive care unit.
3,17,37The single detected PVT in the
Schwartz study had detection at 2 weeks and resolution at 6months.
17In the five PVT detected at 3 e12 days in the Gharehbaghi
et al. study, three (60%) resolved by 3 e6 weeks, whereas the two
other patients died before a second ultrasound.54Recanalization
(partial or complete resolution) occurs more frequently in caseswith partial thrombi than in cases with occlusive thrombi. Kim et al.
found a statistically signi ficant relationship between the initial size
of the thrombus (occlusive versus non-occlusive) and clot resolu-tion. Resolution occurred in 70% of neonates with non-occlusive
clots and 31% of neonates with occlusive clots. The time to detec-
tion of resolution after the removal of the catheter was at a mean of
10 days with a range of 2 e23 days.
37There were similar findings in
the Morag et al. study, in which there was a higher resolution rate innon-occlusive versus occlusive clots with 77% resolution for
non-occlusive clots and 48% for non-occlusive clots; mean time
detected to resolution of the thrombus was 63 days (range: 2 e626
days; median: 25 days). Although there was no association ofoutcome with presence of an umbilical venous catheter, in the
subset of patients with umbilical venous catheters, there were
higher resolution rates in infants with appropriate placement of
umbilical venous catheters compared to low or intrahepatic
placements.
2
5.2. Portal hypertension and cavernoma
If the PVT does not resolve, there may be long term implications.
It may transform into a cavernoma, with dilated pancreatico-duodenal and prebiliary veins, secondary to portal hyperten-
sion.
33,37,46,47,66Esophageal variceal bleeding, splenomegaly and
growth retardation are the most common clinical features in chil-dren with portal hypertension. Alveraz et al. found that portal
hypertension was diagnosed at a mean of 5.7 years after the acute
event. Eighty percent of patients with portal hypertension present
within the first 3 years of life.
3,33,41,67 e69Portal cavernomas and
portal hypertension were not seen in neonates with PVT followed
for 2e73 days (median: 8 days).37Portal hypertension occurred in
(6/133) 4.5% followed for a median of 79 days (range: 1 e1814 days).2
In the follow-up study of a subset of 70 of the neonatal cohort at
a median age of 5 years (range: 2 e8 years), two children with portal
hypertension diagnosed during neonatal period required portacavalshunting.
32
However, portal hypertension appears to be uncommon
following neonatal PVT. This may in part be due to the predominantleft portal vein involvement. If the thrombus does not propagate
into the main or right portal vein, the effect on portal obstruction is
limited. Periportal collateral circulation would minimize portal
obstruction. The presumption is that even in unresolved PVT;
clinically signi ficant portal hypertension would not develop,
provided the clot remained in left portal vein only. Althoughhepatic necrosis with PVT has been reported, even with extensive
PVT, signi ficant hepatic necrosis is not expected to occur, given the
compensatory blood flow from the hepatic artery.
20
5.3. Liver lobe atrophy
Liver lobe atrophy is more common than portal hypertension
following neonatal PVT. Liver lobe atrophy occurred in 1 of 36 (3%)
infants with follow-up imaging in the Kim et al. study.37Thirty out
of 133 (22.5%) of the infants in Morag et al. ’s study had lobar
atrophy, which was not demonstrated in early ultrasound exami-
nation but developed in later imaging.2Rates of liver lobe atrophy
did not change in the subset of patients reported at age 2 e8 years,
with left lobar atrophy noted in 20 (54%); in two associated with
splenomegaly, and in two associated with portal hypertension.32
Liver atrophy is more likely to occur with occlusive PVT than
non-occlusive PVT.2Similar to the recent pediatric studies,
a correlation between hepatic lobar atrophy and ipsilateral portalvein obstruction has been reported in adults.
70
6. Thrombophilia
There have been reports of thrombophilia associated with PVT
in neonates and children ( Table 4 ). Case series have reported factor
V Leiden, prothrombin gene mutation, protein C de ficiency, protein
Sd eficiency, antithrombin de ficiency, increased factor VIII, meth-
ylene tetrahydrofolate reductase (MTHFR) variants with elevated
homocysteine, and elevated lipoprotein (a).1,2,32,71 e77One case
report describes inherited dys fibroginemia presenting at age 15
years with PVT.78In case econtrol studies the odds ratio for children
with PVT having a thrombophilic defect compared to controls wasfrom 5.47 to 11.9.
1,77
One of the dif ficulties in interpreting the signi ficance of
thrombophilia findings with respect to inhibitor protein de fi-
ciencies (protein C, protein S and antithrombin) is teasing apartgenetic versus acquired de ficiencies. Testing is completed after the
thrombosis has occurred. Therefore, there is the possibility in theabsence of family studies with genetic testing, that the observed
deficiency may be secondary to elevated consumption from portal
hypertension-associated portosystemic shunts or reducedsynthesis caused by a reduction of hepatic blood flow as a result of
thrombosis.
Revel-Vilk et al. found that inherited prothrombotic coagulation
proteins do not contribute signi ficantly to the pathogenesis of
venous thromboembolic disease in neonates, concluding that the
most signi ficant etiologic risk factors are the presence of a central
venous line and other medical conditions.
79In a prospective study
of 53 infants with umbilical vessel catheterization, in which 28 had
umbilical venous catheters, factor V Leiden, prothrombin, and
MTHFR mutations were screened for and serial ultrasoundscompleted for detection of thrombosis. There was no statistically
significant difference in rates of thrombosis in neonates with the
mutations compared to the neonates without mutations.
80There-
fore, factor V Leiden, prothrombin gene mutations and MTHFR
mutations do not appear to add signi ficant risk for neonatal PVT.
The possibility remains that thrombophilia defects other than
factor V Leiden, prothrombin and MTHFR mutations may
contribute to the risk of neonatal PVT. As with other venous
thrombotic events in infants and children, thrombophilia may beS. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 333

one of multiple factors contributing to thrombotic risk. There is no
available data on how the presence of a prothrombotic state
impacts on the care of a neonate with PVT.
7. Diagnosis
There may be an absence of clinical and laboratory signs with
PVT in the neonate. Thrombocytopenia may be seen at the time of
diagnosis, but is not speci fic for PVT. Thrombocytopenia
(<100/C2109/L) has been reported in 26/133 infants (19.5%). In 13 of
these infants, the thrombocytopenia may have been secondary to
other conditions, including necrotizing enterocolitis (in two
infants) or sepsis (in 11 infants).2Consumption from the throm-
bosis or the concomitant clinical risk factors for thrombosis, such assepsis, may explain the low platelet count in the acute phase. In the
late chronic stage, a low platelet count would be most likelysecondary to hypersplenism with portal hypertension ( Table 5 ).
36
In contrast to adults, liver function is usually normal in children
presenting with PVT.8There can be mild liver biochemical abnor-
malities in children with PVT. The extent to which similar abnor-malities occur in neonates is less clear. Nine out of 133 (7%)
neonates had abnormal liver enzymes as the indication for ultra-
sound which identi fied the PVT.
2In the follow-up study in 2011 on
70 of the 133 neonates diagnosed with PVT, 25 had liver functionsassessed and mild abnormalities were detected in nine (36%)
children with a mean age of testing of 5.5 years (range: 1.5e 8
years). There were mild elevations of aspartate aminotransferase(AST) in three (12%) and alanine aminotransferase (ALT) in six (24%)
children, with normal albumin, direct bilirubin, and gamma-
glutamyl transferase levels.
32In a study on ultrasound imaging in
16 infants with abdominal thrombosis, the presence of main leftintrahepatic PVT in six infants was clinically unsuspected. In four of
the six infants (67%), there was an association with transitory
abnormalities of the liver function tests, with no other cause for the
elevation of AST and ALT found. Levels returned to normal with
thrombus resolution ( Table 6 ).
65
Investigational radiographic studies in the diagnosis of PVT
include abdominal ultrasound, computed tomography (CT), angi-
ography, and magnetic resonance imaging (MRI). Accurate inter-
pretation of the findings identi fied by each of these modalities can
be dif ficult, especially in the neonates. A CT scan accurately iden-
tifies PVT and the presence of collateral vessels but requires expo-
sure to radiation and the use of intravenous contrast materials.Similarly, angiogram requires exposure to radiation and intrave-
nous contrast material. MRI performs as least as well or better thanCT in diagnosing PVT, without the issues of ionizing radiation
exposure and intravenous contrast.
81In comparing the ef ficacy of
imaging techniques in identifying portal vein patency, Weinrebet al. found MRI superior to CT in visualizing hepatic architecture
and vascular anatomy and patency in 27 children undergoing
evaluation of suspected liver disease.
82Unfortunately MRI, like CT,
cannot be performed at the bedside of an ill neonate. Therefore,each of these modalities may have limited utility in the neonatal
population.
Table 5
Clinical presentation of neonatal portal vein thrombosis.
Study Year N Signs Symptoms Laboratory tests
Kim et al.372001 43 neonates None None
Morag et al.22006 128 neonates
5 infantsThrombocytopenia
26/133 (19.5%)
Sakha et al.552007 17 neonates
16 nocc1 occSepsis 11 (65%)
Demirel et al.
712009 15 neonates Hepatosplenomegaly
2 (13%)
Gharehbaghi et al.542011 5 neonates
5 occ2/5 (40%) [AST, ALT
nocc, non-occlusive; occ, occlusive; AST, aspartate aminotransferase; ALT, alanine aminotransferase.Table 4Thrombophilia and paediatric portal vein thrombosis.
Study N FVL PTG YPC YPS YAT MTHFR/ [
HomocysCombined/other OR (95% CI)
Heller et al.
124 4 (17%) 0 1 (4%) 0 1 (4%) 1 (4%) ACLA 2 (8%) 5.47 (1.7 /C617.6)
Demirel et al.7116 0 0 0 0 0 0 PTGțMTHFR 1 (7%)
[FVIII 0 (0%)
Morag et al.240 1 (2.5%) 0 0 0 1 (2.5%) NP [FVIII 11 (27.5%)
Morag et al.3225 2 (8%) 0 NP 3 (12%) 1 (4%) NP
El-Karaksy et al.7240 11 (27.5%) 5 (12.5%) 11 (27.5%) 0 0 NP 5 (12.5%)
YPCțYAT def 1 (2.5%)
YPCțFVLțAPCR 1 (2.5%)
YPCțPTG 1 (2.5%)
FVLțAPCR țPTG 2 (5%)6 for FVL
Pietrobattist et al.7731 2 (7%) 3 (10%) 4 (13%) 4 (13%) NP 16 (68%)
(13% homo)11.91 (1.41 /C6100.77)
Pinto et al.7314 0 1 (7%) 6 (43%) 3 (21%) 1 (7%) 4 hetero (28%)
3 homo (21%)No thrombophiliain control patients
Uttenreuther-
Fischer et al.
7523 2 (9%) NP NP NP NP NP
Dubuisson et al.7420 NP NP 9 (45%) 13 (65%) 10 (50%) NP
Seixas et al.10820 0 NP NP NP NP NP 1/64 control patient FVL
Schobess et al.1099 2 (22%) NP NP NP NP NP
FVL, factor V Leiden; PTG, prothrombin gene mutation; PC, protein C; PS, protein S; AT, antithrombin de ficiency; FVIII, factor 8; MTHFR, methylene tetrahydrofolate reductase
variant mutation; Homocys, homocysteine; APCR, activated protein C resistance; ACLA, anticardiolipin antibody; NP, not performed or not provided; homo, homozygous
mutation; hetero, heterozygous mutation.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 334

From a practical perspective, neonatal PVT is diagnosed via
Doppler ultrasound. Abdominal ultrasound with colour Doppler is
less invasive, less traumatic to the patient, and more economical
than CT or MRI.
Ultrasound is an operator-dependent modality and technical
factors (including the skill level of the sonographer, patient cooper-
ation, and the presence of abdominal gas and anatomic variations)
may prevent the identi fication of vascular structures. Despite this,
portal vein obstruction is well evaluated even by grey-scale sonog-raphy. The features of portal blood flow distinguishable from
systemic venous floware: (i) continuous flow, with little or no cardiac
or respiratory variation; (ii) relatively low mean and peak frequen-
cies compared to systemic veins, which generally have a ‘window ’
due to concentration of flow velocities in a narrow band near the
peak; and (iii) mild turbulence, visible as ‘roughness ’of the Doppler
spectrum envelope and audible as a distinct low-pitched rumble.
83
In a study comparing portal vein patency by Raby et al., the portal
vein was assessed in 115 patients (age range: 6 months to 75 years)
by ultrasound scanning and arterial portography over a 2-year
period.84Ultrasound scans correctly assessed portal vein patency
in 31/34 (90%) patients with diffuse liver disease, 47/52 (90%) withliver tumours and 6/6 (100%) with primary PVT. Ultrasound
assessment of portal vein patency or occlusion had an overall
accuracy of 87.5%, and was more reliable in demonstrating patency
(90% accuracy) than occlusion (68% accuracy). Ultrasound assess-
ment was con firmed as accurate by arterial portography in a subset
of 21 cases that underwent subsequent liver transplantation.Therefore, the accuracy of ultrasound is comparable to arterial
portography. Technical factors, however, may preclude the visuali-
zation of the portal vein and its collaterals and prevent establish-
ment of their patency.
Ultrasonography has been supplanted by Doppler ultrasound,
which improves assessment by providing information on portal
vein patency and blood flow characteristics.
85Doppler ultrasound
and especially color flow Doppler is useful for con firming the
changes in flow patterns around the thrombus and the resumption
of normal flow pattern in follow-up imaging as the thrombosis
resolves.65,83,86
A grading system for PVT based on ultrasound findings has been
suggested. Grade 1 PVT was de fined as non-occlusive PVT with
normal liver parenchyma; grade 2 as occlusive PVT with normalliver parenchyma; and grade 3 as occlusive PVT with ultrasono-
graphic abnormalities of the liver parenchyma.
2
The authors initially postulated an association between grade 3
PVT (occlusive PVT with parenchymal abnormalities) and pooroutcome; de fined as portal hypertension or left liver lobe atrophy.
In the follow-up paper on a cohort of children, representinga subset of the neonates in the original paper, this hypothesis was
contradicted. There did not appear to be an association between the
grade of thrombus and the risk of progressive splenomegaly. Of the
five children found to have splenomegaly, three (60%) had grade 1
PVT on neonatal imaging.
32Although the grading system may not
be useful for prognosis, it may be of value in data collection for
prospective studies.Table 6
Clinical presentation of childhood portal vein thrombosis.
Study Year Patients Symptoms Signs Laboratory tests
Alvares et al.31983 108 children
Mean age:
5 years 7 monthsRange: 1 monthto 15 years86 GI bleeds (80%)Hematemesis 58 (53%)Melena 19 (17.5%)Hemorrhoidbleeding 5 (4.6%)
Diarrhea 5 (4.6%)
Abdominaldistension 5 (4.6%)Splenectomy 5 (4.6%)Abdominal pain 2 (2%)Splenomegaly 101 (94%)Hepatomegaly 13 (12%)Ascites 9 (8.3%)Liver function tests (106 tested)[serum transaminase 11 (10%)
(11 previous blood transfusions, 6
hepatitis B surface antigen positive)Hypoalbuminemia (2.5 to 3.5 g/dL) 12 (11%)
[serum unconjugated bilirubin 5 (4.7%)
Thrombocytopenia (40 000 e150 000) 64 (63%)
Lymphopenia ( <1000 lymphocytes) in 25/96 (26%)
Neutropenia ( <1500 neutrophils) 8/98 (8%)
Anemia 4 (4%)
Yfactor II 7 (7%)
Yfactor I 5/104 (5%)
[high fibrin split product 2 (2%)
Yfactor V
El-Karaksy et al.
722004 40 children
PHTN 2/C14
to PVTHematemesis țmelena
15 (37.5%)
Hematemesis 7 (17.5%)Melena 1 (2.5%)Abdominal distension11 (27.5%)Abdominal pain 3 (7.5%)
Neonatal sepsis 2 (10%)
Umbilical sepsis 3 (5%)Splenomegaly 35 (87.5%)Splenectomy 5 (12.5%)Incidental splenomegaly3 (7.5%)Endoscopy findings:
Esophageal varices 40 (100%)Gastric varices 10 (25%)Congestive gastropathy 3 (7.5%)
Pietrobattist et al.
772010 31 children Umbilical sepsis (6%)
Gastroenteritis andDehydration (6%)Family history ofVTE (3%)Parental consanguinity
(1%)
Peter et al.
1072003 86 children
EHPVOUGI bleeding
53 (61.6%)JaundiceAscites 2 (2.3%)Splenomegaly 11 (12.8%)Normal liver serum biochemistry81 (94.2%)
Morag et al.
322011 70 children
Median age:55 months
Range:
24e96 monthsSplenomegaly 3/37 (8%)
GI, gastrointestinal; PHTN, portal hypertension; PVT, portal vein thrombosis; UGI, upper gastrointestinal; VTE, venous thromboembolism; EHPVO, extrahepatic portal veinocclusion.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 335

8. Treatment
8.1. Impact of anticoagulation
The role of anticoagulation in PVT management is unclear. Given
that there is often rapid resolution eand even in the absence of
resolution, there may be no clinical sequelae from the liver lobe
atrophy ethe question of whether anticoagulation therapy would
lead to a decrease in the rates of portal hypertension in childhoodremains unanswered.
There is an absence of prospective data on anticoagulation in the
literature. Multiple strategies have been reported in the literature
from observation, anticoagulation, and thrombolysis. In the retro-
spective Morag et al. study with reported resolution rates of 81/133
(61%) with complete or partial resolution and 16/133 (12%) with no
change, and no infants with extension described, anticoagulation
treatment was given to 59 infants. The authors describe no asso-
ciation of outcome with the use of anticoagulation. The indications
for anticoagulation treatment included the presence of a second,
occlusive thrombus with liver parenchymal changes or involving
two branches of the portal vein, post cardiac surgery. Dosages andlengths of treatment varied signi ficantly.
2
8.2. Absence of guidelines
There are no evidence-based guidelines on treatment of
neonatal PVT. The American College of Chest Physicians have beenunable to develop speci fic guidelines due to insuf ficient data. The
literature on neonatal PVT consists largely of case reports, and theinfrequency of the diagnosis hinders obtaining evidence that would
permit informed pediatric guidelines for therapy. Differences in
etiology and pathophysiology reduce the usefulness of the
extrapolation of therapeutic guidelines for adults with PVT to
children, much less neonates.
87
Although there are insuf ficient data to make strong recom-
mendations regarding anticoagulation therapy for neonatal PVT,
the options include conventional anticoagulation therapy in age-
appropriate doses, short term anticoagulation therapy, or closemonitoring of the thrombus with objective tests and the use of
anticoagulation therapy if thrombus extension occurs. The treat-
ment in each neonate should be individualized with consideration
of the risk:bene fit ratio. Importantly, there is no current evidence
that anticoagulation therapy would lead to improved outcomefollowing neonatal PVT, namely reduction in the incidence of portal
hypertension.
8.3. Current recommendations for anticoagulation in neonates
There are several Grade 2C or weak treatment recommenda-
tions based on low quality evidence.
88The guiding principles in
light of the lack of evidence would be to avoid anticoagulation if
possible and treat for the minimum duration possible. Anti-
coagulation treatment with unfractionated heparin (UFH) or lowmolecular weight heparin (LMWH) can be initiated. Alternatively,
radiographic monitoring with anticoagulation therapy if extension
occurs can be considered. Initial anticoagulation would be appro-
priate in the absence of contraindications such as bleeding, coa-
gulopathy, intracranial hemorrhage or cerebral infarct. If
anticoagulation is selected, initial administration would be in the
form of UFH or LMWH, and subsequent LMWH for 10 days to 3
months.
87
If no therapy is chosen, interval imaging to rule out an extending
thrombosis would be appropriate. Imaging at the end of the initial
phase of therapy would be prudent to decide on need for furthertherapy. Imaging should be repeated after completion of anti-
coagulation therapy to rule out extension when off therapy.
Treatment of symptomatic acute PVT, extending to the main
portal vein, by means of regional streptokinase infusion has been
reported.89However, aggressive therapy is not likely warranted in
the majority of cases. Thrombolytic therapy should be reserved formajor vessel occlusion with organ compromise. In contrast to the
ischemic symptoms caused by thromboembolism of the arteries,
PVT seldom causes clinical problems during the neonatal period,
may resolve without any intervention, and even unresolved
thrombosis is expected to remain silent if it does not propagate into
other branches. Therefore unless the PVT extends into the adjacent
vessels einferior vena cava, renal veins or right atrium ewith
clinical symptoms, the risk of thrombolysis likely outweighs thebenefit. In order to ensure adequate plasminogen to maximize
efficacy of thrombolytic therapy, supplementation with plasmin-
ogen via the use of fresh frozen plasma should occur immediately
prior to thrombolysis.
8.4. Considerations for anticoagulation
After initial treatment with UFH or LMWH, vitamin K antago-
nists (VKA) with a target INR of 2 e3 could theoretically be used to
continue anticoagulation therapy. However, the use of warfarin in
the neonatal period is problematic. Formula-fed infants will receive
large amounts of vitamin K, and will be warfarin resistant. Dosing
becomes dif ficult as there is no commercially available liquid
formulation of warfarin.
90Given the anticipated dif ficulties, anti-
coagulation with warfarin would not be recommended in the
neonatal period.
LMWH may be preferable to UFH if anticoagulation therapy is
used to treat neonatal PVT, given the predictable pharmacokinetics,
reduced monitoring requirements, and possibly decreased rate of
major bleeding. In a randomized, controlled trial of therapeutic
anticoagulation in children, LMWH therapy was compared with
UFH and VKA for the treatment of venous thromboembolic events
in children. There was a major bleeding rate of 12.5% in the UFH/
VKA versus 5.6% in the LMWH arm.91A major bleeding rate of 0.7%
of children treated with the low molecular weight heparin, enox-aparin, has been reported.
92The rate of major bleeding in children
aged<3 months receiving enoxaparin has been reported as 3%.93
Neonates have an increased dose requirement compared to
older infants and children. Increased dose requirement in neonatesis multifactorial. Anticoagulant proteins are decreased in the
neonate when compared to adult levels.
94,95The levels of natural
anticoagulants such as antithrombin and protein C are decreased to35e50% of adult levels during the neonatal period.
95,96Neonates
also have an increased volume of distribution which will accentuatethe volume of distribution for hydrophilic drugs such as the
commonly used low molecular weight heparin, enoxaparin.
97
Preterm infants tend also to have higher dose requirements thanterm infants.
98,99Therefore, a higher low molecular weight heparin
dosing than in older children should be considered to facilitatefaster time to therapeutic levels, and to decrease the number ofvenipunctures required for monitoring.
100
Apart from bleeding, there are other potential side-effects of
anticoagulation. Heparin-induced thrombocytopenia (HIT) is an
immune-mediated thrombocytopenia accompanied by a paradox-
ical prothrombotic state, occurring after heparin exposure.101The
incidence of HIT in pediatric intensive care units is 1.5e 2.3%.102The
incidence of HIT in neonates is reportedly lower. In 108 neonates
receiving heparin for more than 5 days, none developed HIT.103HIT
occurs less frequently following LMWH exposure than UFH expo-sure.
104However, HIT has been reported in children following the
use of enoxaparin.105Heparin use has also been associated withS. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 336

osteopenia and osteoporosis. There is evidence that prolonged
heparin therapy is associated with osteopenia and therefore pro-
longed therapy should be avoided.106
8.5. Prevention of neonatal PVT
Reducing the risk factors for PVT in an attempt to prevent PVT
may not be feasible in a neonate with a need for central venous
access. Nevertheless, prevention strategies would include place-
ment of the umbilical venous catheter in initial correct position,
removal of the umbilical venous catheter within one week, and
avoidance of transfusion through the umbilical venous catheter.
Given the lack of evidence for anticoagulation, preventive strategies
would be prudent.
9. Summary
Neonatal PVT is an increasingly recognized event. There may be
no symptoms or laboratory abnormalities on bloodwork. Somepatients may have accompanying thrombocytopenia or liver serum
biochemical abnormalities. As a result of the lack of symptoms, the
diagnosis may not be suspected. Diagnosis is via Doppler ultra-
sound. Umbilical catheterization and sepsis are risk factors for
neonatal PVT. Thrombophilia is possibly a contributing risk factor.
However, neonatal PVT may still occur in the absence of risk factors.
From the available literature, there appears to be a good outcome in
the majority of cases followed up to 8 years of age. Non-occlusive
thrombosis is more likely to resolve than occlusive thrombosis.
Most patients likely do not require treatment, as resolution occurs
without speci fic treatment. There is a mean time to resolution of
days to months, dependent on how frequently imaging iscompleted. Approximately 40% of patients with PVT in the neonatal
period do not have rapid resolution, but the vast majority will not
have clinically signi ficant sequelae. Liver atrophy is common
following PVT, and appears to be of little clinical signi ficance in the
childhood years. However, there is a subset of patients ( w5%) that
will go on to develop the more serious complication of portalhypertension in childhood. Unfortunately, there are no current
Remove UVC,
HUS, INR,
aPTT, FBN,
PLT, LFTs PVT
Thrombophilia work-up 6-12 mos
US to R/O PHTN yearly X 5 ACT LMWH
US @ 5-7 days No ACT
Stable/smaller
on
3 images ExtensionResolution Stable/Smaller US @ 10 da ys
Ensure adequate ACT
↑ACTExtension
IVC/RA/RV
with
symptoms
ACT X 3 mos
LMWH Stop ACT
US @ 5-7 days Coagulopathy No Coagulopathy
ACT UFH
ResolutionExtension
Consider tPA
No PVT PVT
Fig. 2. Neonatal portal vein thrombosis management. PVT, portal vein thrombosis; ACT, anticoagulation therapy; aPTT, activated partial thromboplastin time; FBN, fibrinogen; HUS,
head ultrasound to rule out hemorrhage; INR, international normalized ratio; IVC/RA/RV, inferior vena cava/right atrial/right ventricular; LFT, liver function tests; LMWH, low
molecular weight heparin; PHTN, portal hypertension; PLT, platelets; PVT, portal vein thrombosis; tPA, tissue plasminogen activator; US, ultrasound; UFH, unfractionated heparin;UVC, umbilical vein catheter; mos, months.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 337

defining features present during the neonatal period to identify and
define neonates at risk for portal hypertension. There is no current
evidence that anticoagulation therapy makes a difference to reso-
lution rates or incidence of portal hypertension. However, given the
potential morbidity of portal hypertension, it may be prudent to
consider anticoagulation therapy in the absence of coagulopathy
(Fig. 2 ). Neonates should be followed for at least 5 years after PVT to
monitor for the development of portal hypertension in an attemptto avoid presentation with gastrointestinal hemorrhage in
childhood.
Conflict of interest statement
None declared.
Funding sources
None.
References
1. Heller C, Schobess R, Kurnik K, et al. Abdominal venous thrombosis in
neonates and infants: role of prothrombotic risk factors ea multicentre
caseecontrol study. For the Childhood Thrombophilia Study Group. Br J
Haematol 2000; 111:534e9.
2. Morag I, Epelman M, Daneman A, et al. Portal vein thrombosis in the neonate:
risk factors, course, and outcome. J Pediatr 2006; 148:735e9.
3. Alvarez F, Bernard O, Brunelle F, Hadchouel P, Odievre M, Alagille D. Portal
obstruction in children. I. Clinical investigation and hemorrhage risk. J Pediatr
1983; 103:696e702.
4. O ’Donnell B, Moloney MA. Development and course of extrahepatic portal
obstruction in children. Lancet 1968; 1:789e91.
5. Thompson EN, Sherlock S. The aetiology of portal vein thrombosis with
particular reference to the role of infection and exchange transfusion. QJM e d
1964; 33:465e80.
6. Glassman MS, Klein SA, Spivak W. Evaluation of cavernous transformation of
the portal vein by magnetic resonance imaging. Clin Pediatr (Phila)
1993; 32:77e80.
7. Fisher MR, Wall SD, Hricak H, McCarthy S, Kerlan RK. Hepatic vascular
anatomy on magnetic resonance imaging. Am J Roentgenol 1985; 144:739e46.
8. Wilson KW, Robinson DC, Hacking PM. Portal hypertension in childhood. Br J
Surg 1969; 56:13e22.
9. Brady L, Magilavy D, Black DD. Portal vein thrombosis associated with anti-
phospholipid antibodies in a child. J Pediatr Gastroenterol Nutr
1996; 23:470e3.
10. Arav-Boger R, Reif S, Bujanover Y. Portal vein thrombosis caused by protein C
and protein S de ficiency associated with cytomegalovirus infection. J Pediatr
1995; 126:586e8.
11. Skarsgard E, Doski J, Jaksic T, et al. Thrombosis of the portal venous system
after splenectomy for pediatric hematologic disease. J Pediatr Surg
1993; 28:1109e12.
12. Laishram H, Cramer B, Kennedy R. Idiopathic acute portal vein thrombosis:
a case report. J Pediatr Surg 1993; 28:1106e8.
13.
Arnold KE, Char G, Serjeant GR. Portal vein thrombosis in a child with
homozygous sickle-cell disease. West Indian Med J 1993; 42:27e8.14. Kowal-Vern A, Radhakrishnan J, Goldman J, Hutchins W, Blank J. Mesenteric
and portal vein thrombosis after splenectomy for autoimmune hemolytic
anemia. J Clin Gastroenterol 1988; 10:108e10.
15. Pinkerton JA, Holcomb Jr GW, Foster JH. Portal hypertension in childhood. Ann
Surg 1972; 175:870e86.
16. Rehan V, Seshia MM. Complications of umbilical vein catheter. Eur J Pediatr
1994; 153:141.
17. Schwartz DS, Gettner PA, Konstantino MM, et al. Umbilical venous catheter-
ization and the risk of portal vein thrombosis. J Pediatr 1997; 131:760e2.
18. Kooiman AM, Kootstra G, Zwierstra RP. Portal hypertension in children due to
thrombosis of the portal vein. Neth J Surg 1982; 34:97e103.
19. Stiller RJ, Neale D, Schwartz D, Laifer S, Kleinman G. Prenatal diagnosis of
portal vein thrombosis by ultrasound. Ultrasound Obstet Gynecol
2003; 22:295e8.
20. Ries M, Zenker M, Kandler C, Rauch R, Fischer E. Severe bleeding diathesis in
a premature baby with extensive hepatic necrosis due to portal vein throm-bosis of prenatal onset. Ann Hematol 1999; 78:339e40.
21. Rubabaza P, Persadie RJ. Two cases of umbilical vein thrombosis, one with
associated portal vein thrombosis. J Obstet Gynaecol Can 2008; 30:338e43.
22. Balfour QW, Stewart TG. Case of enlarged spleen complicated with ascites
both depending upon varicose dilatation and thrombosis of the portal vein.Edinb Med J 1869; 14:589e98.
23. Pick L. Total hemangiomatous obliteration of the portal vein. Virchows Arch ;
1909:197.
24. Klemperer P. Cavernous transformation of the portal vein. Arch Pathol
1928; 6:353e77.
25. Wallgren A. Contribution to the study of the splenomegalies of childhood.
Acta Paediatr 1927; 6:1.
26. Somers K. Cavernous transformation of the portal vein following umbilical
sepsis. Br
Med J 1957; 2:335e6.
27. Hsia DY, Gellis SS. Portal hypertension in infants and children. Am J Dis Child
1955; 90:290e1.
28. Clatworthy Jr HW, Boles Jr ET. Extrahepatic portal bed block in children:
pathogenesis and treatment. Ann Surg 1959; 150:371e83.
29. Shaldon S. The investigation of portal hypertension in childhood. Proc R Soc
Med 1962; 55:769e70.
30. Gibson JB, Richards RL. Cavernous transformation of the portal vein. J Pathol
Bacteriol 1955; 70:81e96.
31. Parker RA, Seal RM. Cavernous transformation of the portal vein. J Pathol
Bacteriol 1955; 70:97e103.
32. Morag I, Shah PS, Epelman M, Daneman A, Strauss T, Moore AM. Childhood
outcomes of neonates diagnosed with portal vein thrombosis. J Paediatr Child
Health ; 2011.
33. Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin Liver Dis
2002; 22:43e58.
34. Habif DV. Treatment of esophageal varices by partial esophagogastrectomy
and interposed jejunal segment. Surgery 1959; 46:212e37.
35. Tizard JP. Portal hypertension following exchange transfusion through the
umbilical vein. Proc R Soc Med 1962; 55:772.
36. Oski FA, Allen DM, Diamond LK. Portal hypertension ea complication of
umbilical vein catheterization. Pediatrics 1963; 31:297e302.
37. Kim JH, Lee YS, Kim SH, Lee SK, Lim MK, Kim HS. Does umbilical vein cath-
eterization lead to portal venous thrombosis? Prospective US evaluation in
100 neonates. Radiology 2001; 219:645e50.
38. Ades A, Sable C, Cummings S, Cross R, Markle B, Martin G. Echocardio-
graphic evaluation of umbilical venous catheter placement. J Perinatol
2003; 23:24e8.
39. Kunad T. On diffi culties and dangers in catheterization of the umbilical vein.
Kinderarztl
Prax 1967; 35:293e300.
40. Rosen MS, Reich SB. Umbilical venous catheterization in the newborn: iden-
tification of correct positioning. Radiology 1970; 95:335e40.
41. Junker P, Egeblad M, Nielsen O, Kamper J. Umbilical vein catheterization and
portal hypertension. Acta Paediatr Scand 1976; 65:499e504.
42. Scott JM. Iatrogenic lesions in babies following umbilical vein catheterization.
Arch Dis Child 1965; 40:426e9.
43. Alvarez F. Risk of portal obstruction in newborns. J Pediatr 2006; 148:715e6.
44. Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured
human endothelial cells. Thromb Res 1978; 12:773e82.
45. Pottecher T, Forrler M, Picardat P, Krause D, Bellocq JP, Otteni JC. Thrombo-
genicity of central venous catheters: prospective study of polyethylene, sili-cone and polyurethane catheters with phlebography or post-mortemexamination. Eur J Anaesthesiol 1984; 1:361e5.
46. Yadav S, Dutta AK, Sarin SK. Do umbilical vein catheterization and sepsis lead
to portal vein thrombosis? A prospective, clinical, and sonographic evaluation.
J Pediatr Gastroenterol Nutr 1993; 17:392e6.
47. Guimaraes H, Castelo L, Guimaraes J, et al. Does umbilical vein catheterization
to exchange transfusion lead to portal vein thrombosis? Eur J Pediatr
1998; 157:461e3.
48. Larroche JC. Umbilical catheterization: its complications. Anatomical study.
Biol Neonate 1970; 16:101e16.
49. Image interpretation session: 1995. Case 7. Hepatic hematoma and left portal
vein thrombosis due to an inappropriately placed umbilical vein catheter.
Radiographics 1996; 16:230e2.
50. Tanke RB, van Megen R, Daniels O. Thrombus detection on central venous
catheters in the neonatal intensive care unit. Angiology 1994; 45:477e80.Practice points
/C15Neonatal PVT is increasingly recognized.
/C15Neonatal PVT may have no signs or symptoms.
/C15Diagnosis of neonatal PVT is via colour Doppler
ultrasound.
/C15Umbilical venous catheters and sepsis are risk factorsfor neonatal PVT.
/C1560e70% of neonatal PVT may have spontaneous reso-
lution in the neonatal period.
/C15Non-occlusive PVT are more likely to resolve thanocclusive PVT.
/C15Non-resolving neonatal PVT are associated with liverlobe atrophy, which may be of no clinical significance.
/C15A small subset of neonates with PVT will develop portalhypertension in childhood.
/C15The role of anticoagulation in the management ofneonatal PVT is unclear.
/C15The role of thrombophilia in neonatal PVT is unclear.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 338

51. Khilnani P, Goldstein B, Todres ID. Double lumen umbilical venous catheters
in critically ill neonates: a randomized prospective study. Crit Care Med
1991; 19:1348e51.
52. Schmidt B, Zipursky A. Thrombotic disease in newborn infants. Clin Perinatol
1984; 11:461e88.
53. Wigger HJ, Bransilver BR, Blanc WA. Thromboses due to catheterization in
infants and children. J Pediatr 1970; 76:1e11.
54. Gharehbaghi MM, Nemati M, Hosseinpour SS, Taei R, Ghargharechi R.
Umbilical vascular catheter associated portal vein thrombosis detected by
ultrasound. Indian J Pediatr 2011; 78:161e4.
55. Sakha SH, Rafeey M, Tarzamani MK. Portal venous thrombosis after umbilical
vein catheterization. Indian J Gastroenterol 2007; 26:283e4.
56. Tchuenbou J, Bacq Y, Fimbel B, Metman EH. [Portal vein thrombosis associated
with factor V Leiden mutation in a woman who underwent exchange trans-fusion at birth]. Gastroenterol Clin Biol 2003; 27:645e7.
57. Fraser-Hill MA, Atri M, Bret PM, Aldis AE, Illescas FF, Herschorn SD. Intra-
hepatic portal venous system: variations demonstrated with duplex and color
Doppler US. Radiology 1990; 177:523e6.
58. Seibert JJ, Taylor BJ, Williamson SL, Williams BJ, Szabo JS, Corbitt SL. Sono-
graphic detection of neonatal umbilical-artery thrombosis: clinical correla-tion. Am J Roentgenol 1987; 148:965e8.
59. Colburn MD, Gelabert HA, Quinones-Baldrich W. Neonatal aortic thrombosis.
Surgery 1992; 111:21e8.
60. Tooley WH. What is the risk of an umbilical artery catheter? Pediatrics
1972; 50:1e2.
61. Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheter-related thrombosis in
critically ill children: comparison of catheters with and without heparinbonding. J Pediatr 1995; 126:50e4.
62. Butler-O ’Hara M, Buzzard CJ, Reubens L, McDermott MP, DiGrazio W,
D’Angio CT. A randomized trial comparing long-term and short-term use of
umbilical venous catheters in premature infants with birth weights of less
than 1251 grams. Pediatrics 2006; 118:e25e35.
63.
Devlieger H, Snoeys R, Wyndaele L, et al. Liver necrosis in the new-borninfant: analysis of some precipitating factors in neonatal care. Eur J Pediatr
1982; 138:113e9.
64. Parker MJ, Joubert GI, Levin SD. Portal vein thrombosis causing neonatal
cerebral infarction. Arch Dis Child Fetal Neonatal Ed 2002; 87:F125e7.
65. Stringer DA, Krysl J, Manson D, Babiak C, Daneman A, Liu P. The value of
Doppler sonography in the detection of major vessel thrombosis in the
neonatal abdomen. Pediatr Radiol 1990; 21:30e3.
66. Mitra SK, Kumar V, Datta DV, et al. Extrahepatic portal hypertension: a review
of 70 cases. J Pediatr Surg 1978; 13:51e7.
67. Schettino GC, Fagundes ED, Roquete ML, Ferreira AR, Penna FJ. Portal vein
thrombosis in children and adolescents. J Pediatr (Rio J) 2006; 82:171e8.
68. Webb LJ, Sherlock S. The aetiology, presentation and natural history of extra-
hepatic portal venous obstruction. Q J Med 1979; 48:627e39.
69. Lykavieris P, Gauthier F, Hadchouel P, Duche M, Bernard O. Risk of gastroin-
testinal bleeding during adolescence and early adulthood in children with
portal vein obstruction. J Pediatr 2000; 136:805e8.
70. Hann LE, Getrajdman GI, Brown KT, et al. Hepatic lobar atrophy: association
with ipsilateral portal vein obstruction. Am J Roentgenol 1996; 167:1017e21.
71. Demirel N, Aydin M, Zenciroglu A, et al. Neonatal thrombo-embolism: risk
factors, clinical features and outcome. Ann Trop Paediatr 2009; 29:271e9.
72. El-Karaksy H, El-Koofy N, El-Hawary M, et al. Prevalence of factor V Leiden
mutation and other hereditary thrombophilic factors in Egyptian childrenwith portal vein thrombosis: results of a single-center case econtrol study.
Ann Hematol 2004; 83:712e5.
73. Pinto RB, Silveira TR, Rosling L, Bandinelli E. [Thrombophilic disorders in
children and adolescents with portal vein thrombosis.]. J Pediatr (Rio J)
2003; 79:165e72.
74. Dubuisson C, Boyer-Neumann C, Wolf M, Meyer D, Bernard O. Protein C, protein S
and antithrombin III in children with portal vein obstruction. J Hepatol
1997; 27:132e5.
75.
Uttenreuther-Fischer MM, Vetter B, Hellmann C, et al. Paediatric thrombo-embolism: the in fluence of non-genetic factors and the role of activated
protein C resistance and protein C de ficiency. Eur J Pediatr 1997; 156:277e81.
76. Uttenreuther-Fischer MM, Ziemer S, Gaedicke G. Resistance to activated
protein C (APCR): reference values of APC-ratios for children. Thromb Haemost
1996; 76:813e4.
77. Pietrobattista A, Luciani M, Abraldes JG, et al. Extrahepatic portal vein
thrombosis in children and adolescents: in fluence of genetic thrombophilic
disorders. World J Gastroenterol 2010; 16:6123e7.
78. Bandyopadhyay R, Bandyopadhyay SK, Chatterjee U. Inherited dys fi-
brinogenaemia presenting with portal vein thrombosis. J Indian Med Assoc
2010; 108:180e2.
79. Revel-Vilk S, Chan A, Bauman M, Massicotte P. Prothrombotic conditions in an
unselected cohort of children with venous thromboembolic disease. J Thromb
Haemost 2003; 1:915e21.
80. Turebylu R, Salis R, Erbe R, Martin D, Lakshminrusimha S, Ryan RM. Genetic
prothrombotic mutations are common in neonates but are not associated
with umbilical catheter-associated thrombosis. J Perinatol 2007; 27:490e5.
81. Zirinsky K, Markisz JA, Rubenstein WA, et al. MR imaging of portal venous
thrombosis: correlation with CT and sonography. Am J Roentgenol
1988; 150:283e8.82. Weinreb JC, Cohen JM, Armstrong E, Smith T. Imaging the pediatric liver: MRI
and CT. Am J Roentgenol 1986; 147:785e90.
83. Weltin G, Taylor KJ, Carter AR, Taylor CR. Duplex Doppler: identi fication of
cavernous transformation of the portal vein. Am J Roentgenol
1985; 144:999e1001.
84. Raby N, Karani J, Powell-Jackson P, Meire H, Williams R. Assessment of portal
vein patency: comparison of arterial portography and ultrasound scanning.
Clin Radiol 1988; 39:381e5.
85. Niederau C, Sonnenberg A, Muller JE, Erckenbrecht JF, Scholten T, Fritsch WP.
Sonographic measurements of the normal liver, spleen, pancreas, and portal
vein. Radiology 1983; 149:537e40.
86.
Berland LL, Lawson TL, Foley WD. Porta hepatis: sonographic discrimination ofbile ducts from arteries with pulsed Doppler with new anatomic criteria. Am J
Roentgenol 1982; 138:833e40.
87. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and
children: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th edition). Chest 2008; 133:887Se968S.
88. Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schunemann HJ. Grades of
recommendation for antithrombotic agents: American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
2008; 133:123Se31S.
89. Rehan VK, Cronin CM, Bowman JM. Neonatal portal vein thrombosis
successfully treated by regional streptokinase infusion. Eur J Pediatr
1994; 153:456e9.
90. Veldman A, Nold MF, Michel-Behnke I. Thrombosis in the critically ill
neonate: incidence, diagnosis, and management. Vasc Health Risk Manag
2008; 4:1337e48.
91. Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled
trial of low molecular weight heparin compared to heparin and coumadin for
the treatment of venous thromboembolic events in children: the REVIVE trial.Thromb Res 2003; 109:85e92.
92. Ignjatovic V, Najid S, Newall F, Summerhayes R, Monagle P. Dosing and
monitoring of enoxaparin (low molecular weight heparin) therapy in chil-
dren. Br J Haematol 2010; 149:734e8.
93. Bauman ME, Belletrutti MJ, Bajzar L, et al. Evaluation of enoxaparin dosing
requirements in infants and children. Better dosing to achieve therapeuticlevels. Thromb Haemost 2009; 101:86e92.
94. Andrew M, Paes B, Milner R, et al. Development of the human coagulation
system in the healthy premature infant. Blood 1988; 72:1651e7.
95. Kuhle SMM. Maturation of the coagulation system during childhood. Prog
Pediatr Cardiol 2005; 21:3e7.
96. Kuhle S, Male C, Mitchell L. Developmental hemostasis: pro- and anticoagu-
lant systems during childhood. Semin Thromb Hemost 2003; 29:329e38.
97. Reiter P. Neonatal pharmacology and pharmacokinetics. Neoreviews
2002; 3:e229e36.
98.
Malowany JI, Knoppert DC, Chan AK, Pepelassis D, Lee DS. Enoxaparin use in
the neonatal intensive care unit: experience over 8 years. Pharmacotherapy
2007; 27:1263e71.
99. Streif W, Goebel G, Chan AK, Massicotte MP. Use of low molecular mass
heparin (enoxaparin) in newborn infants: a prospective cohort study of 62
patients. Arch Dis Child Fetal Neonatal Ed 2003; 88:F365e70.
100. Belletrutti M, Mitchell L, Massicotte MP. Does increasing the starting dose
of enoxaparin result in better treatment of children requiring thrombo-
prophylaxis? A retrospective cohort study [abstract]. E-PAS 2007; 61.
6316e11.
101. Dager WE, White RH. Pharmacotherapy of heparin-induced thrombocyto-
penia. Expert Opin Pharmacother 2003; 4:919e40.
102. Schmugge M, Risch L, Huber AR, Benn A, Fischer JE. Heparin-induced
thrombocytopenia-associated thrombosis in pediatric intensive care patients.Pediatrics 2002; 109:E10.
103. Klenner AF, Fusch C, Rakow A, et al. Bene fit and risk of heparin for main-
taining peripheral venous catheters in neonates: a placebo-controlled trial.
J Pediatr 2003; 143:741e5.
104. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia
in patients treated with low-molecular-weight heparin or unfractionated
heparin. N Engl J Med 1995; 332:1330e5.
105. Dager WE, White RH. Low-molecular-weight heparin-induced thrombocyto-
penia in a child. Ann Pharmacother 2004; 38:247e50.
106. Newall F, Johnston L, Ignjatovic V, Monagle P. Unfractionated heparin therapy
in infants and children. Pediatrics 2009; 123:e510e8.
107. Peter L, Dadhich SK, Yachha SK. Clinical and laboratory differentiation of
cirrhosis and extrahepatic portal venous obstruction in children.
J Gastroenterol Hepatol 2003; 18:185e9.
108. Seixas CA, Hessel G, Ribeiro CC, Arruda VR, Annichino-Bizzacchi JM. Factor V
Leiden is not common in children with portal vein thrombosis. Thromb
Haemost 1997; 77:258e61.
109. Schobess R, Junker R, Auberger K, Munchow N, Burdach S, Nowak-Göttl U.
Factor V G1691A and prothrombin G20210A in childhood spontaneous
venous thrombosis eevidence of an age-dependent thrombotic onset in
carriers of factor V G1691A and prothrombin G20210A mutation. Eur
J Pediatr
1999; 158(Suppl. 3):S105 e8.
110. Kim JH, Lee YS, Kim SH, et al. Does umbilical vein catheterization lead to
portal venous thrombosis? Prospective US evaluation in 100 neonates. Radi-
ology 2001; 219:645e50.S. Williams, A.K.C. Chan / Seminars in Fetal & Neonatal Medicine 16 (2011) 329 e339 339