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[66,8284]. An occluded splenic vein, the presence of ascites, and delay in initiating anticoagulation were associ-
ated with failure of portal vein recanalization
[65,66]. Complication of anticoagulation therapy did not apparently
differ from those expected from natural history
[65]. Mortality rate was 2% after a median follow-up of 8 months
after diagnosis and was unrelated to NCPVT or anticoagulation therapy
[65]. In summary, anticoagulation
should be maintained for at least 6 months duration but probably better, for 12 months. After 12 months, no fur-
ther recanalization is expected to occur. Doppler ultrasound, or the appropriate imaging study if ultrasound does
not adequately assess the thrombosed vessel (anatomy of the patients, gas distribution ...), is recommended at
3- and 6-month interval to assess recanalization during anticoagulation treatment.
A few cases of treatment of recent NCPVT using DOACs have been reported recently
[8587]. This group of
drugs includes orally available direct factor Xa inhibitors (rivoraxaban, apixaban, edoxaban, betrixaban) and the
direct thrombin inhibitor dabigatran
[88]. A recent study assessed 26 patients treated with DOACs and 23 treated
with enoxaparin for PVT
[87]. Although sample size was small and the tumoral setting may influence the resu lts,
the thrombosis recurrence, and major bleeding rates were not different between patients treated with DOACs or
with enoxaparin.
Interventional treatment
If there is progression of thrombus despite anticoagulation therapy, thrombolysis (local or systemic) could be
considered as an adjunct to anticoagulation. Hollingshead et al. retrospectively assessed local thrombolysis in 20
patients with acute or subacute PVT with severe symptoms, deteriorating clinical condition, and/or persistent
symptoms despite anticoagulation
[89]. Three patients had complete recanalization, 12 had partial recanalization,
and five had no resolution. Seventeen patients (85%) had resolution of symptoms and major complications
including blee ding occurred in 60% patients. Severe procedure-related complications and mortality have also
been reported in other studies, with similar recanalization rates compared with anticoagulation alone
[48,8991].
It was suggested that thrombolysis combined with TIPS might result in a better outcome [9294]. However, cur-
rent data on the risk-benefit ratio of these invasive procedures are scare. It might be useful in selected patients
with extensive thrombosis of the portal venous system, clinical deterioration despite adequate anticoagulation, or
with a low likelihood of recanalization following therapeutic anticoagulation.
Surgery
Given the low rate of resolution, the favorable outcome acquired using only anticoagulation, and the invasive-
ness of the procedure leading to morbidity and mortality, surgical thrombectomy is not recommended for
NCPVT
[34]. Surgery was only considered for treating a local factor responsible for NCPVT or suspicion of the
presence of mesenteric infarction
[95].
Treatment of underlying causes
Rapid identification and treatment of underlying risk factors for NCPVT might favorably influence NCPVT
outcome. Antibiotics are given in patients with NCPVT driven by an abdominal infection
[34]. In patients with
acute mesenteric ischemia, oral antibiotics should be given to reduce the risk of irreversible transmural intestinal
necrosis
[96]. Although specific data on NCPVT are scare, etiological treatment in combination with anticoagula-
tion therapy, such as corticosteroids and/or immunosuppressive therapy in Behcet’s disease, or eculizumab in
PNH, improves patients’ outcome
[97,98].
Treatment of chronic nontumoral portal vein thrombosis
Management of complications of portal hypertension
Generally, the current recommendation is to treat and prevent complications of portal hypertension as it is
recommended for patients with cirrhosis
[34,44], esophageal, and gastric varices.
In a recent prospective study that included 178 patients with NCPVT from two referral centers, the natural his-
tory of esophageal varices appeared similar to that observed in patients with cirrhosis
[60]. The risk of develop-
ing new varices in patients without them at inclusion was 2% at 1 year and 22% at 3 years. Progression from
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small varices to medium-large ones was 13% at 1 year and 54% at 5 years. In patients with medium-large varices
given adequate prophylaxis, the risk of bleeding was 9% at 1 year and 32% at 5 years. Currently, high-quality
evidence regarding the impact of prophylaxis in the natural history of NCPVT is lacking
[34]. However, it has
been suggested that the use of nonselective beta-blockers was associated with a decreased risk of bleeding and
improved survival, and that incid ence of bleeding was similar using beta-blockers or endoscopic band ligation
(32% and 25%, respectively)
[60,99101]. The same consensus guiding the treatment of portal hypertension-
related complications for patients with cirrhosis should also be applied in patients with NCVPT [44].
Anticoagulation
The aim for long-term anticoagulant therapy in patients with chronic NCPVT is to prevent thrombosis exten-
sion/recurrence. Therefore the main indication is in those patients with a recognized underlying prothrombotic
condition that are at higher risk of recurrent thrombosis. However, either because of the severity of the initial epi-
sode or an estimated high risk of new thrombotic events, long-term anticoagulation is also indicated in patients
with chronic NCPVT that had severe intestinal ischemia or previous history of other thrombotic events at extra-
splanchnic sites or high familiar history of thrombosis. Anticoagulants have been associated with decreased risk
of thrombosis extension or recurrence and improved survival
[99,100,102,103]. Recurrence of thrombosis was
associated with the presence of a prothrombotic condition. No change, or a mild increased risk of gastrointestinal
bleeding in patients under anticoagulation treatment, has been reported, however, without increasing bleeding
severity nor mortality
[99,104].
The most commonly used anticoagulants are LWMH and VKA. The clinical application of unfractionated hep-
arin has decreased due to the risk of heparin-induced thrombocytopenia
[105]. A small sized single center study
showed that in patients with NCPVT treated with anticoagulants, the incidence (7.4%) and severity of bleeding
after endoscopic band ligation were not significantly different compared to that observed in nonanticoagulated
patients
[106], suggesting that there is no need to stop or delay anticoagulation if a patient requires band ligation.
However, before a formal recommendation can be made, more studies are needed.
Transjugular intrahepatic portosystemic shunt
TIPS in patients with chronic PVT could be technically challenging. TIPS failure in these patients may be due
to lack of identification of the intrahepatic portal branches, failing to access the occluded main portal trunk, or
lack of a clear patent area of the mesenteric or splenic territories to be connected (also called “landing” zone)
[107]. Due to all these facts, in most centers extensive chronic PVT was considered a contraindication for TIPS.
However, improvement in interventional radiologic techniques using percutaneous transhepatic and/or more
recently transplenic approaches to the portal venous system have increased the number of successful procedures
achieving portal vein recanalization followed or not by TIPS (portal vein recanalization-TIPS) if it is necessary to
get adeq uate portal vein flow
[108,109]. Until now, portal vein recanalization-TIPS was mostly performed in
patients with cirrhosis and chronic PVT/cavernoma. A high technical success of portal vein recanalization-TIPS
(98%) was reported in a cohort of 61 patients with cirrhosis and chronic PVT
[109]. Recanalization of the portal
vein restoring physiological portal blood flow without the need of TIPS should always be the first procedure of
choice in patients with NCPVT. Recent studies show good results performing recanalization without the need of
TIPS in selected cases
[110,111]. Currently, the indications of portal vein recanalization or portal vein
recanalization-TIPS include recurrent variceal bleeding not manageable medically or endoscopically and refrac-
tory ascites.
Management of portal biliopathy
The recommendations for the treatment of portal biliopathy are mostly based on expert opinions [79,112].
Asymptomatic patients do not require any specific treatment. In patients with increased GGT and ALP, ursodeoxy-
colic acid has been shown to decrease or normalize these biochemical alterations but whether this translates to
some clinical benefit is unknown. Endoscopy is indicated for main bile duct stones or biliary stenosis; however, the
risk of bleeding is increased given the presence of peri ampullar collaterals. The use of ursodeoxycholic acid
(UDCA) may decrease the risk of recurrence of symptoms after endoscopic treatment
[80,81].Decompressionof
portal venous system, using TIPS or surgery, may also be required in some selected cases when other treatment
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modalities have failed. Surgical biliary-enteric anastomosis should only be considered in very selected cases
because it is associated with high morbidity/mortality due to the presence of multiple collaterals in the area.
Sinusoidal obstruction syndrome
SOS, previously known as hepatic veno-occlusive disease, is a relatively rare but potentially life-threatening
complication that was primarily associated with hematopoietic stem cell transplantation (HSCT) but can also
occur after chemotherapy, ingestion of pyrrolidine alkaloids, or high doses of radiotherapy in nontransplant
environments
[113118]. Most current knowledge about SOS comes from HSCT patients. However, the incidence
of SOS in this setting has markedly dec reased due to impro vement in HSCT technique.
Incidence
The incidence of SOS varies widely between studies depending on the type of transplant, the intensity of the
conditioning regimen, the presence of risk factors, and criteria used to make the diagnosis (Seattle or Baltimore
criteria). A retrospective review of 135 studies performed between 1979 and 2007 demonstrated that the overall
mean incidence of SOS was 13.7% (17.3% using the Seattle criteria and 9.6% using the Baltimore criteria)
[119].
More recently, two studies with large sample size found that the cumulative incidence of SOS was 1.66% in
Taiwan and 10.8% in Japan using the Seattle criteria
[120,121]. The reported incidence of SOS in pediatric patients
ranges from 11% to 25.6%, being higher than in adults
[122126].
Outside the transplant setting, SOS has been reported after chemotherapy, such as cyclophosphamide, cytara-
bine, vincristine, methotrexate, thioguanine, oxaliplatin, and especially with the calicheamicin-containing immu-
noconjugates inotuzumab and gemtuzumab ozogamicin among others
[117,127]. Previous studies reported a
nontransplant-associated SOS incidence of 7%12% following chemotherapy
[128,129].
Pathology
The underlying pathogenesis of SOS has been broadly studied in animal models, but limited data are available
in humans. The first functional changes associated with SOS are thought to involve toxic injury to the sinusoidal
endothelial cells (SEC) and zone III hepatocytes
[130]. This damage can be caused by the chemotherapy or radio-
therapy included in the conditioning regimen, cytokines, and endogenous microbial products released from
injured tissue, drugs used during the HSCT procedure, and potentially alloreactivity associated with the engraft-
ment process itself
[131]. The resulting damage causes the SECs to round up, facilitating the egress of red blood
cells, leukocytes, and cellular and extracellular debris into the space of Disse beneath the endothelial cells, and
the dissection of the endothelial lining. The sloughed sinusoidal lining cells also embolize downstream and block
sinusoidal flow. These hemodynamic changes combined cause progressive postsinusoidal portal hypertension,
worsening liver dysfunction, ascites, and may eventually result in multiorgan dysfunction and death. The patho-
logical changes in human PA-related SOS are similar to those observed in rat models, including swelling, dam-
age, and shedding of hepatic sinusoid endothelial cells in zone III hepatocytes and significant dilation and
congestion of hepatic sinusoids
[132].
Risk factors
It is critical to identify patients at high risk of SOS to apply early prophylactic or therapeutic interventions to
improve their outcomes
[120,133,134]. This has been better defined in the setting of HSCT. In this setting, the risk
factors of SOS can be categorized into the pretransplant condition, the transplant itself, a preexisting hepatic con-
dition, the type of disease being transplanted, or individual patient characteristics and health (
Table 5.4).
Diagnosis
Clinical signs of SOS incorporated into the Baltimore and Seattle criteria include fluid retention and ascites,
edema, jaundice (serum bilirubin: .2 mg/dL), weight gain ( . 2% and $ 5%, respectively), and painful
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hepatomegaly before day 121 after HSCT [137,139,140]. The limitations of these criteria are that they are less
applicable in pediatric patients or to diagnose later onset SOS (beyond day 21) where hyperbilirubinemia is often
less obvious and could be a late event. A recent study in a large cohort of patients receiving HSCT found that in
the 7 days prior to the diagnosis, patients developing SOS had higher serum creatinine and trough serum tacroli-
mus levels, were more likely to develop acute kidney injury and experienced more refractoriness to platelet
transfusion compared to patients not developing SOS
[141].
Imaging studies
Several US and US-Doppler parameters have been evaluated, either in children [142] or in adults [143] with
SOS, suggesting that ultrasound may be a useful diagnostic tools for SOS and som e of those have been proposed,
together with other clinical criteria, to be incorporated in the context of a diagnosis of late onset SOS
[135].
However, the definitive benefits of ultrasound for SOS diagnosis remain inconclusive.
Elastography values are increased in SOS because of congestion
[144]. Elastography may be helpful in the dif-
ferential diagnosis in patients with suspected SOS, particularly in facilitating early diagnosis
[145,146]. It has
been shown that patients who develop SOS have increased liver stiffness compared to patients who do not, and
elastography changes occur before other imaging and clinical findings
[145] suggesting that elastography techni-
ques measuring liver stiffness maybe the most promising approach for an early diagnosis of SOS.
One study evaluating retrospectively 71 patients showed that finding of a patchy enhancement and heteroge-
neous hypoattenuation at enhanced CT-Scan was valuable features having a superior diagnostic performance
than Seattle criteria for PAs-induced SOS
[147]. Similarly, heterogeneous hypointensity on MRI scan was a
TABLE 5.4 Traditional risk factors for sinusoidal obstruction in HSCT.
Transplantation related Adult patient related
• Prior abdominal radiation [134]
•
Previous HSCT [134]
•
Prior treatment with gemtuzumab ozogamicin [134] or inotuzumab
ozogamicin
[135]
•
Impaired pulmonary function [134]
•
Infection/antibiotic/antiviral use [124,136,137]
•
Ferritin levels .1000 ng/mL [134]
•
Bilirubin .26 μmol/L [134]
•
Allogeneic HSCT . autologous HSCT [134,135]
•
Unrelated/HLA-mismatched donor [131,134,135]
•
High-dose busulfan with a second alkylator conditioning
[131,135,138]
•
High-dose total body irradiation conditioning [134]
•
GVHD including combinations of sirolimus, methotrexate and
cyclosporine
[134]
•
Non-T-cell-depleted graft [131,134]
•
Second myeloablative HSCT [131]
•
Older . younger [131,135,138]
•
Female receiving norethisterone [131,135]
•
Karnofsky score ,90% [131,135,138]
•
Gene polymorphism (GSTM1, GSMTT1, heparanase)
[131,135,138]
•
Advanced disease (beyond second CR or relapse) [131,135,138]
•
Metabolic syndrome [131,135]
•
Activated protein C resistance [131,135]
•
Thalassemia [131,135]
•
Deficit of AT III or t-PA [131]
•
Hemophagocytic lymphohistiocytosis [131]
•
Osteopetrosis [131]
•
Myelodysplastic syndrome [120]
•
Transaminase .2.5 3 ULN [131,135]
•
Cirrhosis [131,135]
•
Hepatic fibrosis [131,135]
•
History of viral hepatitis B or C [131]
•
Abdominal or hepatic irradiation [135]
•
Iron overload [135]
•
Use of hepatotoxic drugs (etc., chemotherapeutic agents,
thiopurines, PAs)
[135]
Pediatric patients related
• Hemophagocytic lymphohistiocytosis
a
, adrenoleukodystrophy,
osteopetrosis
[131]
•
High-dose chemotherapy and autologous HSCT in neuroblastoma
[131]
•
Young age (,12 years) [131]
•
Low weight [131]
•
Juvenile myelomonocytic chronic leukemia [131]
•
Interval between diagnosis of malignancy and transplantation .12
months
[134]
•
Deteriorated health status within 30 days before transplantation [134]
a
Can occur in adults.
AT III, antithrombin III; BMT, bone marrow transplant; CR, complete response; HLA, human leukocyte antigen; GSTM1, glutathione S-transferase mu 1; GSTT1,
glutathione S-transferase theta 1; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; PA, pyrrolizidine alkaloid; SOS/VOD , sinusoidal
obstruction syndrome/veno-occlusive diseas e; t-PA, tissue plasminogen activator; ULN, upper limit of normal.
Adapted table.
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distinct sign, and the severity of heterogeneous hypointensity correlate d with liver function tests and with a non-
invasive marker of fibrosis in patients with PAs-induced SOS
[148]. Notwithstanding these intriguing data on the
diagnostic role of imaging studies, further studies with a larger cohort of patients with SOS are needed in order
to identify the role of imaging modalities in the early diagnosis of SOS and in differential diagnosis with other
liver disease.
Biopsy
Liver biopsy could be performed in patients in whom the diagnosis is unclear based on standard clinical diag-
nostic criteria
[149,150]. Compared with percutaneous liver biopsy, transjugular access can reduce the bleeding
risk associated with extensive ascites, coagulation disorders, and thrombocytopenia
[151] and will allow measure-
ment of Hepatic venous pressure gradient (HVPG) during the same procedure. However, transjugular liver
biopsy is not recommended for use in children
[152].
Hepatic venous pressure gradient
A HVPG measured by a transjugular or transfemoral approach, greater than 10 mmHg in the first 30 days
after HSCT had a high specificity for SOS diagnosis
[150,153]. Beside its diagnostic role, HVPG may also be used
as prognostic factor for SOS patients
[154]. However, measuring HVPG is a semi-invasive procedure that is not
routinely available in many centers.
Baltimore and Seattle criteria
The Baltimore, Seattle, and modified Seattle criteria are the most commonly used criteria for diagnosing SOS
(
Table 5.5) [136,137,139]. The three criteria differ in the number and magnitude of clinical features required for a
positive diagnosis and in the time of assessment after HSCT. The Baltimore criteria requires a bilirubin level
above 34.2 μmol/L (2 mg/dL) within 21 days of HSCT and two of hepatomegaly, ascites, and weight gain of
.5% from the baseline weight
[139]. The original Seattle criteria did not have special requirement of bilirubin
value or weight gain
[136]. The modified Seattle criteria require two of the following with in 20 days of HSCT: bil-
irubin .34.2 μmol/L, hepatomegaly or right upper quadrant pain and weight gain . 2% from the baseline
weight
[137]. Biopsy was not mandatory in these criteria.
TABLE 5.5 Sinusoidal obstruction syndrome criteria.
Baltimore
Serum bilirubin .34 μmol/L ( . 2 mg/dL) within 21 days of
transplantation and $ 2 of the three requirements
Painful hepatomegaly
5% weight gain from baseline
Ascites
Seattle
Development of $ 2 of the three requirements before day 30 after
transplantation
Jaundice
Hepatomegaly with right upper quadrant pain
Ascites and/or unexplained weight gain
Modified Seattle
Occurrence of $ 2 of the three requirements within 20 days of
transplantation
Serum bilirubin .34 μmol/L ( . 2 mg/dL)
Hepatomegaly with right upper quadrant pain
. 2% weight gain from baseline due to fluid retention
Nanjing
A definite history of PA-containing plant plus meeting the three
requirements or pathological evidence and rules out other known causes
of liver injury
Abdominal distention and/or pain in the hepatic region,
hepatomegaly, and ascites
Elevation of serum total bilirubin or abnormal liver
Typical features of enhanced CT or MRI
CT, computed tomography; MRI, magnetic resonance imaging; PA, pyrrolidine alkaloid; SOS, sinusoidal obstruction syndrome.
Adapted table.
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Nanjing criteria
Baltimore and Seattle criteria are based on the history of HSCT, which make them not suitable for the diagno-
sis of Pyrrolizidine Alkaloids-induced SOS. Indeed, these criteria were not validated in a cohort of Chinese
patients with acute Pyrrolizidine Alkaloids-induced SOS. Therefore the Committee of Hepatobiliary Diseases of
Chinese Society of Gastroenterology convened an expert consensus conference on the diagnosis and treatment of
PAs-induced SOS with the objective of evaluating current research in China and abroad. In light of the current
evidence, this consensus recommends the “Nanjing criteria” for PAs-induced SOS diagnosis (
Table 5.5) [132].
European society for blood and marrow transplantation
New diagnostic and severity criteria for SOS were proposed by the European society for blood and marrow
transplantation (EBMT) for adults in 2016 [135] and for children in 2018 [126]. In adults, the EBMT has estab-
lished new diagnostic criteria for SOS in the first 21 days after HSCT and for late-onset SOS (
Table 5.6) in which
the presence of hyperbilirubinemia is no longer mandatory. Besides, pathological and imaging findings are incor-
porated into the diagnostic criteria.
The EBMT set new criteria for diagnosing SOS in children (
Table 5.7), as it differs significantly between chil-
dren and adults in terms of incidence, clinical presentation, and outcomes
[126]. There are challenges in the diag-
nosis of SOS in children. As hyperbilirubinemia in children is frequently either absent, preexisting related to the
underlying disease, or found in advanced-stage severe SOS, bilirubin .2 mg/dL is not a mandatory requirement
in EBMT diagnostic criteria for SOS in children
[126]. Myers et al. reported that up to 30% of pediatric patients
have an absence of elevated bilirubin at the time of SOS diagnosis
[155]. The Baltimore criteria may not applica-
ble to anicteric SOS in children; as patients without hyperbilirubinemia are excluded. In contrast, the Seattle crite-
ria may lead to early or overdiagnosed SOS in the presence of fluid overload
[126,156]. Instead, the EBMT criteria
TABLE 5.6 2016 New EBMT diagnostic criteria for SOS/VOD in adults.
a
Classic SOS Late-onset SOS
# 21 days post-HSCT . 21 days post-HSCT
Bilirubin $ 2 mg/dL and two of the following criteria
must be present:
• Painful hepatomegaly
b
• Weight gain .5%
• Ascites
b
Classic SOS beyond day 21 or histologically proven SOS or two or more of the
following criteria must be present:
• Bilirubin $ 2 mg/dL (or 34 μmol/L)
• Painful hepatomegaly
b
• Weight gain .5%
• Ascites
b
and hemodynamic or/and ultrasound evidence of SOS
a
After the exclusion of competing causes.
b
Suggested: imaging (ultrasonography, computed tomography, or magnetic resonance imaging) immediately before HSCT to determine baseline value for both hepatomegaly and
ascites.
EBMT, European Society for Blood and Marrow Transplantation; HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
Adapted from Mohty M., Malard F., Abecassis M., Aerts E., Alaskar A.S., Aljurf M., et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-
occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transpl. 2016;51(7):906912.
TABLE 5.7 2018 EBMT diagnostic criteria for sinusoidal obstruction syndrome in children.
The presence of two or more of the following with the exclusion of other potential diagnoses:
• Unexplained consumptive and transfusion-refractory thrombocytopenia ($1 weight-adjusted platelet substitution/day to maintain
institutional transfusion guidelines)
• Otherwise unexplained weight gain on three consecutive days despite the use of diuretics or a weight gain .5% above baseline value
• Hepatomegaly (best if confirmed by imaging) above baseline value
a
• Ascites (best if confirmed by imaging) above baseline value
a
• Rising bilirubin from a baseline value on three consecutive days or bilirubin $ 2 mg/dL within 72 h
a
Suggested: imaging (ultrasonography, computed tomography, or magnetic resonance imaging) immediately before HSCT to determine baseline value for both hepatomegaly and
ascites.
EBMT, European Society for Blood and Marrow Transplantation; SOS, sinusoidal obstruction syndrome.
Adapted from Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive
disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transpl. 2018;53(2):138145.
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use a rising bilirubin value from baseline on three consecutive days or bilirubin $ 2 mg/dL within 72 hours, after
excluding the plausible causes, as a criterion. The pediatric EBMT also require a weight gain on three consecutive
days in spite of diuretic treatment or .5% above baseline. US seems to be the most appropriate diagnostic imag-
ing tool to assess as cites and hepatomegaly in children, because it is radiation-free, reproducible, and objective.
Assessing severity
The EBMT proposed a new criteria for grading SOS severity and to guide therapy decisions, based on the level
of bilirubin and its rate of change, the level of transaminase, weight gain, renal function, and the kinetic of their
onset (
Table 5.8) [135]. This grading system is divided into five categories, as in the Common Terminology
Criteria for Adverse Events: grade 15 mild; grade 2 5 moderate; grade 3 5 severe; grade 45 very severe; and
grade 5 5 death. These severity criteria should be analyzed at the same time that the diagnosis of SOS is estab-
lished using the clinical criteria mentioned above.
The EBMT criteria for assessing severity in children are tailored to signs and symptoms noted in children. In
addition, liver and pulmonary function, coagulation, central nervous system, ascites, and persistent refractory
thrombocytopenia also are assessed (
Table 5.9) [126].
Preventive measures
Nonpharmacologic prevention
Considering the outcome of severe SO S and the limited treatment options, any possible preventive measure
that could reduce its incidence and/or severity should be considered. Nonpharmacologic preventive measures
mostly rely on the reduction of SOS risk factors. However, most relevant risk factors are usually impossible to
reverse, such as undergoing a second HSCT, having previous liver disease or radiation, or treatment with gemtu-
zumab ozogamicin
[138]. However, it may be reasonable to consider delaying the HSCT, when feasible according
to the disease status, until resolution or treatment of these factors (such as iron overload or acute hepatitis).
Furthermore, concomitant treatment with hepatotoxic drugs must be avoided whenever possible.
It may be easier to modify transplant-related risk factors through optimization of the conditioning regimen.
The use of reduced-intensity conditioning may decrease the incidence of SOS and shou ld be considered in elderly
patients and in heavily pretreated adult patients or those with comorbidities
[157160]. The risk of alloreactive
TABLE 5.8 2016 EBMT criteria for severity grading of a suspected SOS in adults.
a
Mild
b
Moderate
b
Severe Very severe-MOD/MOF
c
Time since first clinical
symptoms of SOS
d
.7 days 5 to 7 days ,4 days Anytime
Bilirubin (mg/dL) $ 2 and ,3 $ 3 and ,5 $ 5 and ,8 $ 8
Bilirubin (μmol/L) $ 34 and ,51 $ 51 and ,85 $ 85 and ,136 $ 136
Bilirubin kinetics Doubling within 48 h
Transaminases # 2 3 normal .2 and # 5 3 normal .5 and # 8 3 normal .8 3 normal
Weight increase ,5% $ 5% and ,10% $ 5% and ,10% $ 10%
Renal function ,1.2 3 baseline at
transplant
$ 1.2 and ,1.5 3 baseline
at transplant
$ 1.5 and ,2 3 baseline
at transplant
$ 2 3 baseline at transplant or other
signs of MOD/MOF
a
Patients belong to the category that fulfills two or more criteria. If patients fulfill two or more criteria in two different categories, they must be classified in the most severe
category. Patients with weight increase $ 5% and ,10% are considered by default as having severe SOS;s however, if patients do not fulfill other criteria for severe SOS, weight
increase $ 5% and ,10% is therefore considered as a criterion for moderate SOS.
b
In the case of presence of two or more risk factors for SOS, patients should be in the upper grade.
c
Patients with multiorgan dysfunction must be classified as very severe.
d
Time from the date when the first signs/symptoms of SOS began to appear (retrospectively determined) and the date when the symptoms fulfilled SOS diagnostic criteria.
EBMT, European Society for Blood and Marrow Transplantation; MOD, multiorgan dysfunction; MOF, multiorgan failure; SOS , sinusoidal obstruction syndrome.
Adapted from Mohty M., Malard F., Abecassis M., Aerts E., Alaskar A.S., Aljurf M., et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-
occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transpl. 2016;51(7):906912.
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phenomena should also be evaluated. To prevent these, the use of donors with the maximum degree of human
leukocyte antigen (HLA) compatibility, or the use of T-cell depleted grafts, especially in the case of HLA-
mismatched donors, is recommended
[161,162]. Finally, it is necessary to consider the nature of the graft versus
host disease (GVHD) prophyl axis. In particular, the combination of sirolimus with a calcineurin inhibitor is asso-
ciated with higher incidence of SOS after allogeneic HSCT and especially when used together with tacrolimus
and methotrexate
[163,164].
Pharmacologic prevention
There are currently no pharmacologic agents approved for the prophylaxis of SOS. Several candidate pharma-
cologic prophylaxes have been reported to be beneficial, including UDCA, defibrotide, heparin, LMWH, anti-
thrombin III, prostaglandin E1, pentoxifylline, and recombinant thrombomodulin
[122,138,165168]. In spite of
the data for prophylactic use of UDCA being inconclusive, it is generally recommended in patients following
HSCT, as all studies show a lower liver toxicity, GVHD incidence and severity, and treatment-related mortality
among patients receiving this prophylaxis
[165,169172]. Moreover, as a drug with virtually no side effects, its
potential risk/benefit ratio is very high.
Prophylactic use of defibrotide with or without heparin has also shown reduced incidence of SOS
[166,173].In
a prospective Phase 3 study, the prophylactic use of defibrotide seemed to reduce the incidence of SOS 30 days
after HSCT (12% vs 20%)
[122]. Results from prophylactic anticoagulation using heparin, LMWH, or antithrom-
bin III are inconclusive
[138]. Furthermore, bleeding was reported as an adverse event in 7 of the 12 studies
under the meta-analysis (2782 patients)
[167]. Recently, the efficacy of using recombinant thrombomodulin to pre-
vent post-HSCT SOS in high-risk pediatric patients was evaluated in a retrospective study by Yamamoto et al.
[168]. No case of SOS developed in eight patients who received recombinant thrombomodulin with UDCA and
LMWH, while three cases developed in the control group (n 5 11) who received UDCA and LMWH.
TABLE 5.9 2018 EBMT criteria for severity grading of suspected sinusoidal obstruction syndrome in children.
a
Mild 1 Moderate 2 Severe 3 Very severe MOD/MOF 4
LFT
b
(ALT, AST,
GLDH)
# 2 3 normal .2 and # 5 3 normal .5 .5
Persistent RT
b
,3 days 37 days .7 days .7 days
Bilirubin
b,c
(mg/dL; μmol/L)
,2; ,34 ,2; ,34 $ 2; $ 34 $ 2; $ 34
Ascites
b
Minimal Moderate Necessity for paracentesis
(external drainage)
Necessity for paracentesis (external
drainage)
Bilirubin kinetics Doubling within 48 h.
Coagulation Normal Normal Impaired coagulation Impaired coagulation with need for
replacement of coagulation factors
Renal function GFR
(mL/min)
8960 5930 2915 ,15 (renal failure)
Pulmonary function
(oxygen requirement)
,2 L/min .2 L/min Invasive pulmonary
ventilation (including CPAP)
Invasive pulmonary ventilation
(including CPAP)
CNS Normal Normal Normal New onset cognitive impairment
a
If patient fulfills criteria in different categories they must be classified in the most severe category. In addition, the kinetics of the evolution of cumulative symptoms within 48 h
predicts severe disease.
b
Presence of $ 2 of these criteria qualifies for an upgrade to level 4 (very severe SOS).
c
Excluding pre-existent hyperbilirubinemia due to primary disease.
ALT, alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CPAP, continuous positive airway pressure; GFR, glomerular filtration
rate; GLDH, glutamate dehydrogenase; LFT, liver function test; MOD/ MOF, multiorgan dysfunction/multiorgan failure; RT, refractory thrombocytopenia; SOS,
sinusoidal obstruction syndrome.
Adapted from Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive
disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transpl. 2018;53(2):138145.
81Preventive measures
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Treatment
Supportive therapy
Supportive therapy must be initiated as soon as possible, and includes minimizing fluid overload, closely
monitoring daily weight, and minimizing extracellular fluid while maintaining intravascular fluid volume with-
out worsening renal function
[174,175]. The use of colloids, such as albumin or red cells, may help to preserve
intravascular volume
[138,176]. Avoidance of hepato- and nephrotoxic drugs should be introduced at the first
suspicion of SOS
[174]. Oxygen supplementation to minimize liver ischemia, analgesia, therapeutic paracentesis,
thoracentesis, and hemodialysis/hemofiltration may be required to achieve comfort, alleviate volume overload,
and temporize complications of acute renal dysfunction
[138,172]. Finally, SOS with multiorgan dysfunction often
requires transfer to an intensive care unit and hemodialysis may become necessary
[134].
General
Recombinant tissue plasminogen activator is no longer recommended for the treatment of SOS because of the
high incidence of hemorrhagic complications, especially in patients with multiorgan failure [177]. Both unfractio-
nated heparin and LMWH have been studied in SOS treatment; however, the results were conflicting and incon-
clusive. High or low dose of methylprednisolone may be beneficial in adults with mild to moderate SOS
[178,179]. Despite the supporting evidence being weak, methylprednisolone could still be considered with appro-
priate caution regarding infections. Other treatment options used with limited evidence of success include prosta-
glandin E1 and antithrombin III
[138]. A very recent study found similar efficacy rates between recombinant
thrombomodulin and defibrotide.
Defibrotide
So far there is no specific treatment for SOS. However, recent data suggest that defibrotide might be a promising
agent. Defibrotide is approved to treat severe hepatic SOS post-HSCT in patients aged .1 month in the European
Union and hepatic SOS with renal or pulmonary dysfunction post-HSCT in the United States
[129]. The mechanism
of action of defibrotide is not fully determined. It has been shown to maintain endothelial cell integrity and has
antithrombotic, thrombolytic, antiinflammatory, and antiischemic properties
[180182]. Defibrotide can bind to
heparin-binding proteins (e.g., basic fibroblast growth factors) and promote endothelial cell mitogenesis, and then
aid in the partial revascularization of an injured, hypoxic hepatic parenchyma
[183]. It also reduces platelet adhe-
sion and aggregate formation in humans and inhibits platelet activation in vitro
[184,185].
Richardson et al. first described the use of defibrotide in 19 patients with severe SOS and multiorgan dysfunc-
tion
[186]. Thereafter, several retrospective and prospective studies without control arms support the efficacy and
safety of defibrotide with overall response rates ranging 30%76%
[182,187189]. Richardson et al. conducted a
randomized study to compare the efficacy of lower-dose (25 mg/kg/day) and higher-dose (40 mg/kg/day) defi-
brotide in 149 pediatric or adult patients with SOS
[190]. There was no significant difference in the treatment
response or the incidence of adverse events; therefore the lower dose was recommended. In a Phase 3 trial of
patients with SOS and advanced multiorgan failure, defibrotide treatment was associated with a complete resolu-
tion in 25.5% of patients compared with 12.5% of the historical controls
[191]. In a retrospective analysis includ-
ing 45 pediatric patients with SOS, the average interval from diagnosis to treatment was significantly shorter in
the patients with complete response compared to nonresponses (1.3 vs 5.5 days), suggesting that treating earlier
in the course of SOS may improve outcome
[182]. This finding was supported by a more recent study, which
demonstrated that earlier defibrotide initiation was associated with higher Day 1 100 survival
[192]. A most
recent systematic review including 2598 patients with SOS revealed that among those patients treated with
B25 mg/kg/day, estimated Day 1 100 survival was 44% among patients with multiorgan dysfunction and 71%
in patients without multiorgan dysfunction
[193]. Although the current evidence show a possible benefit of defi-
brotide, there is a critical need for further research and well-designed RCTs comparing it with placebo.
Transjugular intrahepatic portosystemic shunt
Several small studies have reported varied outcomes of TIPS in the treatment of SOS following HSCT
[194197]. In a Chinese cohort of 23 PA-induced SOS patients who had not responded well to supportive
82 5. Obstruction of the liver circulation
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treatment, a significant reduction of ascites 1 week after TIPS was observed in 22 patients who survived during
the follow-up period
[198]. However, no established recommendation for the application of TIPS in the treatment
of SOS can be made based on current evidence. Future studies with a large sample size and longer follow-up are
required to determine whether TIPS can improve patient prognosis.
Hepatic artery thrombosis
Hepatic artery thrombosis is defined as a thrombotic occlusion of the hepatic artery that occurs mainly after LT
[199]. It is one of the most severe vascular complications of LT, which may lead to increased morbidity, graft loss,
and recipient death
[200202]. With improvements of perioperative care, the hepatic artery thrombosis incidence
has decreased over the last decade, with an overall incidence that varies from 2.5% to 11% in adults
[203205].The
hepatic artery thrombosis secondary to LT was usually divided into two categories depending on the time of onset:
early (within the first 30 days of LT) or late (after 30 days of LT)
[206]. Transcatheter arterial chemoembolization
(TACE), transcatheter arterial infusion, systemic thrombophilic disorders, and iatrogenic injury leading to hepatic
artery thrombosis in nontransplantation settings has also been described in case reports
[207209].
Etiology and risk factors
Surgical cause
The surgical causes of hepatic artery thrombosis include vascular endothelium injuries (e.g., intimal tears, dissec-
tion, and hematoma), technical problems with stenosis or kinking of the anastomosis, vascular graft interposition, and
small or multiple arteries
[210]. Hepatic artery reconstruction during LT is complicated and could be a potential risk
factor of hepatic artery thrombosis. The use of arterial conduits, a previous history of hepatic artery thrombosis or his-
tory of upper abdominal surgery, is also associated with a higher risk of developing hepatic artery thrombosis.
Portal vein thrombosis
Stine et al. identified 662 patients who had early hepatic artery thrombosis out of 63,182 (1.1%) recipients and
found that patients with pretransplant PVT had a higher incidence of hepatic artery thrombosis compared with
patients without PVT (13.8 vs 7.5%)
[211]. Pretransplant PVT was independently associated with hepatic artery
thrombosis, while heparin use at cross clamp, INR, and male donors were all significantly associated with lower
risk
[211]. This could be partly explained by the high levels of von Willebrand factor and fibrinogen and low
levels of ADAMTS13 and protein C in the post-LT period
[212,213].
Infections
A positive association between the use of a cytomegalovirus (CMV)-seropositive donor liver in a seronegative
recipient and the high incidence of early hepatic artery thrombosis has been reported by Madalosso et al.
[214].
The fact that most of the adult population has been infected by CMV may partly explain its high incidence in
CMV seronegative children receiving seropositive adult donor livers
[215]. Furthermore, latent CMV infection may
become activated and promote a procoagulant response
[216]. Other virus, bacterial, or fungal infection have also
been reported to be associated with the occurrence of hepatic artery thrombosis
[217219].
Intra-arterial liver-directed therapy
Intra-arterial liver-directed therapy is a current standard treatment option for nonresectable HCC and widely
used to bridge or downsize HCC to transplant eligibility
[220,221]. Common types of intra-arterial liver-directed
therapy are TACE, transcatheter arterial infusion, and transcatheter arterial radioembolization (TARE). Whether
pretransplant intra-arterial liver-directed therapy could increase the risk of hepatic artery thrombosis during and
after LT has not been fully determined. One study found that pretransplant TACE was associated with sixfold
increase of the probability to develop early hepatic artery thrombosis
[222]. On the contrary, neither TACE or
TARE was found to increase the risk of peri-transplant hepatic arterial complications in other study,
[223].
83Etiology and risk factors
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