Optimizing Diagnosis of Splanchic Vein Thrombosis With MR Direct Thrombus Imaging, the Rhea Study
Conditions: Splanchnic Vein Thrombosis
Sponsor: Leiden University Medical Center

Rhea study, version 1.7, 2024-03-26, P18.089 
 
 
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Optimizing diagnosis of splanchnic vein 
thrombosis with MR Direct Thrombus Imaging 
The Rhea-study 
 
Version: 1.7, 2024-03-26 
Sponsor trial code: P18.089 
ABR research file number: NL65303.058.18 
NTR code: 7061 
 
 
Coordinating investigator:  
Drs. S.N.M. ter Haar  
Email:  
 
 
s.n.m.ter_haar@lumc.nl  
Telephone: 
 
 
0031-71-5298096 
Address: 
Leiden University Medical Center, Department of Thrombosis and 
Hemostasis, Room C-07-068, Albinusdreef 2, PO Box 9600, 2300 RC, 
Leiden, The Netherlands 
Principal investigators:  
Prof. F.A. Klok, Dr. L.J.M. Kroft, Prof. M.V. Huisman, Dr. M.E. 
Tushuizen, Prof. W. Ageno, Prof. F. Leebeek 
Participating centers: 
Leiden University Medical Center (Leiden, the Netherlands), Varese 
University Hospital (Varese, Italy), Erasmus Medisch Centrum 
(Rotterdam, the Netherlands), Gemelli Hospital (Rome, Italy) 
Sponsor:  
Leiden University Medical Center 
Sponsor address: 
Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 
RC, Leiden, The Netherlands 
 
 
This protocol is confidential information and is intended solely for the guidance of the clinical study. This 
protocol may not be disclosed to third parties not associated with the clinical study or used for any other 
purpose without the prior written consent of the Principal investigators. 
 
 

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Study synopsis 
Title 
Optimizing diagnosis of splanchnic vein thrombosis with MR Direct Thrombus 
Imaging 
Short title 
Rhea study 
Dutch title 
De evaluatie van Magnetic Resonance Direct Thrombus Imaging (MRDTI) bij 
patiënten met een verdenking op buikvene trombose 
Sponsor trial code 
P18.089 
NTR code 
7061 
ABR research file number 
NL65303.058.18 
Background 
Splanchnic vein thrombosis (SVT) is one of the manifestations of unusual site 
venous thromboembolism (VTE). SVT includes portal vein thrombosis (PVT), 
mesenteric vein thrombosis (MVT), splenic vein thrombosis (SpVT) and the 
Budd-Chiairi syndrome (BCS).[1] There is no validated clinical algorithm for the 
diagnosis of SVT and there are no specific laboratory tests available to confirm 
or rule out the disease. Particularly, D-dimer tests do not have a role in the 
diagnosis of SVT, due to its low specificity and the high percentage of false 
positive results, especially in patients with cancer, liver cirrhosis or underlying 
inflammatory conditions, present in more than half of the total SVT 
population.[2] Thus the diagnosis of SVT relies on imaging tests alone. Whereas 
Doppler ultrasound is the imaging test of choice for most forms of SVT, its 
sensitivity is only 90%, as is the sensitivity of CT angiography (CTA).[3] MR 
angiography (MRA) has been reported to have 90-100% sensitivity for SVT, but 
this technique is limited by the need to administer a contrast agent. 
Furthermore, in studies evaluating the accuracy of MRA for the diagnose of SVT, 

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gold standard for SVT (surgical validation) was lacking[4, 5]  
Importantly, many of SVT diagnoses in clinical practice (up to 30%) are 
incidental findings, i.e. findings on imaging tests of the abdomen performed for 
another reason than suspected SVT. Whereas the diagnosis of symptomatic SVT 
is often challenging, the correct diagnosis of acute versus chronic SVT is even 
more difficult, as neither of the current available imaging tests is helpful in 
determination of the age and clinical relevance of the thrombus, especially in 
non-symptomatic patients. Due to this impossibility to determine whether the 
incidentally observed thrombosis is acute, chronic or even an imaging artefact, 
the vast majority of patients with incidental SVT are treated with -often lifelong- 
anticoagulants.[1, 6] It is widely acknowledged that this practice likely results in 
overdiagnosis and unjust exposure to anticoagulant therapy with associated risk 
of bleeding.  
An alternative imaging technique for more accurate diagnosis of SVT is MR 
Direct Thrombus Imaging (MRDTI). This technique is in an advanced stage of 
development (Theia study, NCT02262052, supported by TSN grant 2013-02) and 
is close to implementation in clinical practice. The method is based on the 
formation of methemoglobin in a fresh thrombus leading to shortening of the 
T1 signal. It does not require contrast dye. Both the diagnostic accuracy 
(sensitivity 97-100%, specificity 100%) as well as the inter-observer agreement 
of MRDTI for first and recurrent DVT of the leg were reported to be excellent 
(kappa 0.89-0.98). Moreover, it was shown to accurately differentiate acute 
from chronic thrombosis.  
There is an unquestionable need for improved diagnostic approaches for 
(incidental) SVT. We plan to evaluate the MRDTI technique, that has been 
shown to be accurate in other settings of difficult-to-diagnosis venous 

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thrombosis, for the notoriously challenging diagnosis of incidental SVT. This 
study targets an important unmet need and will provide the basis for precision 
medicine for patients with SVT in the near future, i.e. the possibility of 
assessment of the age of the thrombus in patients with incidental SVT, which is 
of utmost importance for determination of the indication for anticoagulant 
therapy. 
Primary objective 
To explore the diagnostic accuracy of MRDTI in the diagnostic management of 
acute and chronic SVT in a prospective diagnostic proof of concept study 
Secondary objectives 
1) To optimise MRDTI sequences for imaging SVT.  
2) To assess the interobserver agreement of the readers of MRDTI for 
suspected SVT.  
Study design 
This study is a prospective diagnostic proof of concept study to explore the 
diagnostic accuracy of MRDTI in the diagnostic management of acute and 
chronic SVT. This will be achieved by performing MRDTI scans to adjust and 
optimize the DTI scan sequence in 3-5 patients with confirmed, acute SVT. If a 
reproducible clearly positive DTI signal is achieved in all patients, the study can 
proceed with the inclusion of cohort 1 and 2, i.e. 35 patients with confirmed 
acute SVT and in 35 patients with confirmed, chronic SVT. All scans will be 
evaluated post-hoc by expert readers blinded for the final diagnosis. It is 
predetermined that at least five patients of each SVT site (PVT, SpVT and BCS 
and at least five patients of each SVT risk factor (oncologic, post-surgical and 
inflammatory/infectious) will be included. To make sure that cohort 1 is 
generally similar to cohort 2 frequency matching will be performed, in which all 
controls will be selected to get the same distribution according to  SVT site and 
risk factor as cases. 

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Study population 
Inclusion criteria  
− Patients with confirmed acute SVT; definitions provided in paragraph 4.2 
(Cases, group 1) 
− Patients with confirmed non-symptomatic chronic SVT, defined by incident 
SVT with chronic thrombi on 2 serial imaging tests with at least 3 months 
interval (controls, group 2) 
− Aged 18 years and older 
− Willing and able to give informed consent 
 
Exclusion criteria  
− MRI contra-indication (including but not limited to a cardiac pacemaker or 
subcutaneous defibrillator; vascular clips in the cerebral vessels; metal 
splinter in the eye, a hearing aid that cannot be removed; a neurostimulator 
that cannot be removed; a hydrocephalus pump)  
− A medical condition, associated illness or co-morbid circumstances that 
precludes completion of the study procedures (MRI and 90-day follow-up 
assessment), including but not limited to life-expectancy less than 3 
months, inability to lie flat, morbid obesity preventing use of MR and 
claustrophobia. 
− Patients with decompensated liver disease with Child-Pugh class C cirrhosis 
(since MRDTI evaluation will be inadequate in these patients)  
− Patients with suspected tumour thrombus 
Number of subjects 
73-75 patients will be enrolled: 3-5 patients for the optimization of the scan 
sequence, 35 patients with confirmed acute SVT and finally 35 patients with 
confirmed, non-symptomatic chronic SVT. It is predetermined that at least five 

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patients of each  SVT site (PVT, SpVT and BCS) and at least five patients of each 
SVT risk factor (oncologic, post-surgical and inflammatoir/infectious) will be 
included. 
Primary endpoints 
The sensitivity and specificity of MRDTI for the diagnosis of acute SVT 
Secondary endpoints 
The secondary endpoints are  
1) optimized MRDTI scan sequences for SVT; 
2) the assessment of interobserver agreement between the reviewers.  
Study 
duration 
and 
planning 
The total duration of this study is expected to be 3 years.  
Number of sites 
4 
Sample size consideration 
A sample size of 35 patients in each of groups 1 and 2 was chosen because with 
this sample size and an expected sensitivity of greater than 90%, the 95% 
confidence intervals on the point estimates would have a bandwidth of 
approximately ±15%, ensuring that the point estimate was sufficiently accurate 
to make decisions about the appropriateness and safety of a future 
management study. To optimize the MRDTI scan sequences before the start of 
including patients in group 1 and 2, 3 patients with confirmed SVT will be 
included. If a reproducible clearly positive DTI signal is achieved in all three to 
five patients, the study can proceed with the inclusion of cohort 1 and 2. The 
final sample size is thus 73-75 patients. 
Statistical analysis 
Primary analysis  
A diagnosis (acute SVT, no signs of acute SVT, or non-diagnostic) for each arm of 
interest based on an aggregate reading of the MRDTI images will be made by 
two independent expert readers. A third reader will be involved to resolve any 
dispute. The sensitivity of MRDTI is determined by calculating the proportion of 

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scans that are read as "positive for acute SVT” in patients with a confirmed 
acute SVT and the specificity is determined by calculating the proportion of 
scans that are read as "no signs of acute SVT" in patients with chronic SVT. The 
corresponding exact 95% confidence interval for each of the point estimates will 
be calculated. In addition to these estimates, sensitivity and specificity 
estimates with corresponding 95% confidence intervals will be calculated for 
the initial independent assessment of each of the two readers participating. A 
point estimate of the sensitivity of >90% will be acceptable for initiating a future 
management study. 
 
Secondary analyses 
For the optimization of the MRDTI scan sequences 3-5 pilot patients will be 
tested. The final sequences will be used in the 2 study groups when the study 
PI’s all agree that the accuracy and quality of the sequences is adequate 
 
For the interobserver agreement between the two reviewers a kappa statistic 
will be assessed. According to established criteria, a kappa score above 0.8 is 
considered excellent reliability, a score between 0.6 and 0.8 is considered good 
reliability, a score between 0.4 and 0.6 is considered moderate reliability and a 
score below 0.4 is considered poor reliability. 
 
 

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Study schedule 
 
Visit 0: 
Clinical 
assessment 
Visit 1: 
Enrolment 
Visit 2: 
MRDTI (within 48 
hours of visit 1 in 
acute SVT)  
Visit 3: 
90-day follow-up 
Check for inclusion/exclusion criteria 
 
X 
 
 
Obtain informed consent 
 
X 
 
 
Medical history 
 
X 
 
 
Demographic data 
 
X 
 
 
Clinical examination 
 
X 
 
 
Laboratory 
test 
(D-dimer, 
renal 
function) 
 
X* 
 
 
Doppler ultrasound, CT or MRI of the 
abdomen 
 X* 
 
 
 
Treatment decision  
 X 
 
 
 
MRDTI of abdomen 
 
 
X 
 
Recording of 
 
 
 
 
Death 
 
 
 
X 
Major bleeding 
 
 
 
X 
Hospital admission 
 
 
 
X 
Symptomatic SVT or VTE 
 
 
 
X 
*Part of clinical practice, no study proceedings 
 
 

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Table of contents 
 
Study synopsis ......................................................................................................................................... 3 
Study schedule ........................................................................................................................................ 9 
Table of contents ................................................................................................................................... 10 
List of abbreviations .............................................................................................................................. 13 
1. Introduction and hypothesis ............................................................................................................. 14 
2. Background and rationale ................................................................................................................. 14 
2.1 Epidemiology of splanchnic vein thrombosis .............................................................................. 14 
2.2 Available Methods for the Diagnosis of splanchnic vein thrombosis ......................................... 16 
2.2.1. Biomarkers........................................................................................................................... 16 
2.2.2. Doppler ultrasonography .................................................................................................... 16 
2.2.3. CT angiography .................................................................................................................... 17 
2.2.4. MR imaging .......................................................................................................................... 18 
2.3 Acute versus chronic SVT ............................................................................................................ 18 
2.4 Magnetic Resonance Direct Thrombus Imaging as a Promising Alternative .............................. 19 
2.4.1. MRDTI for the lower extremity ........................................................................................... 19 
2.4.2. MRDTI for splanchnic vein thrombosis ............................................................................... 20 
3. Objectives .......................................................................................................................................... 21 
3.1 Primary objective......................................................................................................................... 21 
3.2 Secondary objectives ................................................................................................................... 21 
4. Methods ............................................................................................................................................ 21 
4.1 Study design ................................................................................................................................ 21 
4.2 Definition of SVT .......................................................................................................................... 22 
4.2.1. Acute Splanchnic vein thrombosis ...................................................................................... 22 

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4.2.2. Chronic Splanchnic vein thrombosis ................................................................................... 23 
4.3. MRDTI ......................................................................................................................................... 23 
4.4. Therapeutic management .......................................................................................................... 23 
5. Subjects ............................................................................................................................................. 23 
5.1 Population base ........................................................................................................................... 23 
5.2 Inclusion criteria .......................................................................................................................... 24 
5.3 Exclusion criteria ......................................................................................................................... 24 
6. Study endpoints ................................................................................................................................. 25 
6.1. Primary endpoint ........................................................................................................................ 25 
6.2. Secondary endpoints .................................................................................................................. 25 
7. Data analysis ...................................................................................................................................... 25 
7.1 Sample size calculation ................................................................................................................ 25 
7.2 Data analysis ................................................................................................................................ 26 
7.2.1. Primary endpoint ................................................................................................................. 26 
7.2.2. Secondary analyses ............................................................................................................. 26 
7.3 Data management ....................................................................................................................... 27 
7.3.1. Data collection ..................................................................................................................... 27 
7.3.2. Data handling ...................................................................................................................... 27 
7.3.3. Storage and Archiving of Data ............................................................................................. 28 
7.3.4. Withdrawing consent .......................................................................................................... 28 
7.3.5. Processing data .................................................................................................................... 28 
8. Ethical considerations........................................................................................................................ 29 
8.1 Regulatory statement .................................................................................................................. 29 
8.2 Inclusion and consent .................................................................................................................. 29 
8.3 Confidentiality ............................................................................................................................. 30 

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8.4 Responsibilities of principal investigators ................................................................................... 30 
8.5 Approval of Study Protocol ......................................................................................................... 31 
8.6 Ongoing information for independent ethics committee ........................................................... 31 
8.6.1. Amendments ....................................................................................................................... 31 
8.6.2. Annual progress report ....................................................................................................... 31 
8.6.3. End of study report .............................................................................................................. 32 
8.6.4. Public disclosure and publication policy ............................................................................. 32 
8.7 Insurance ..................................................................................................................................... 32 
9. 
Safety reporting ............................................................................................................................. 33 
9.1 Section 10 WMO event ............................................................................................................... 33 
9.2 Adverse events ............................................................................................................................ 33 
9.3 Serious adverse events ................................................................................................................ 34 
9.4 Follow-up of adverse events ....................................................................................................... 34 
10. Agreements ..................................................................................................................................... 34 
10.1 Financing of the study ............................................................................................................... 34 
10.2 Publication ................................................................................................................................. 34 
11. Reference List .................................................................................................................................. 36 
 
 
 

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List of abbreviations 
AE 
 
Adverse events 
BCS 
 
Budd-Chiairi syndrome 
CTA 
 
Computed tomography angiography 
DUS 
 
Doppler ultrasonography 
DVT 
 
Deep vein thrombosis 
INR 
 
International normalized ratio  
IRB 
 
Institutional Review Board 
MRA 
 
Magnetic resonance angiography 
MRDTI  
Magnetic resonance direct thrombus imaging 
MRP 
 
Magnetic resonance portography 
MVT 
 
Mesenteric vein thrombosis 
PTT 
 
Partial thromboplastin time  
PVT  
 
Portal vein thrombosis 
SAE 
 
Serious adverse events 
SVT 
 
Splanchnic vein thrombosis 
SpVT 
 
Splenic vein thrombosis 
VTE  
 
Venous thromboembolis 
 
 
 
 
 
 
 

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1. Introduction and hypothesis 
Compared to lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE), very little 
research has focused on the diagnostic management of splanchnic vein thrombosis (SVT).[3] The 
tests that are currently used to diagnose SVT, doppler ultrasound (DUS) and computed tomography 
angiography (CTA), have a number of limitations, particularly related to patient safety. For example, 
CT angiography involves the use of ionizing radiations and iodinated contrast agent, with potential 
renal toxicity or allergic reactions. DUS has the advantage of being relatively inexpensive and widely 
available. It is however operator-dependent and the accuracy can be limited by body habitus and the 
presence of intestinal gas.[3] Importantly, whereas the diagnosis of symptomatic SVT is often 
challenging, the correct diagnosis of acute versus chronic SVT is even more difficult, as neither of the 
current available imaging tests is helpful in determination of the age of the thrombus or its clinical 
relevance. Due to this impossibility to determine whether the incidentally observed thrombosis is 
acute, chronic or even an imaging artefact, the vast majority of patients with incidental SVT are 
treated with -often lifelong- anticoagulants. It is widely acknowledged that this practice likely results 
in overdiagnosis and unjust exposure to anticoagulant therapy with associated risk of bleeding. In the 
proposed study we will evaluate whether magnetic resonance direct thrombus imaging (MRDTI) is a 
valid, reliable, safe and effective alternative for the diagnosis of acute and chronic SVT. Our primary 
hypothesis is that MRDTI will demonstrate acceptable sensitivity and specificity for the diagnosis of 
acute SVT and the differentiation between acute and chronic SVT.  
 
2. Background and rationale 
2.1 Epidemiology of splanchnic vein thrombosis  
Splanchnic vein thrombosis (SVT) includes portal vein thrombosis (PVT), mesenteric vein thrombosis 
(MVT), splenic vein thrombosis (SpVT) and the Budd-Chiari syndrome (BCS). SVT is underdiagnosed, 

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given the heterogeneous clinical presentations and the non-negligible rate of asymptomatic 
incidental findings.[1] In a retrospective review of computed tomography (CT) scans of the abdomen 
performed for reasons other than the search for suspected SVT, the prevalence of unsuspected 
abdominal vein thrombosis was 1.7%.[7] Furthermore, 18-30% of the patients with SVT are 
incidentally detected.[8, 9]  
PVT is the most frequent manifestation of SVT, with a yearly incidence of 3.8 cases in males 
and 1.7 cases in females per 100.000 individuals.[1] BCS is the least frequent manifestation of SVT 
with a gender-specific incidence of 2.0 cases and 2.2 cases per million individuals, respectively.[1] 
MVT has an incidence of 2.7 per 100,000 persons per year, with a peak incidence in the age category 
70–79 years.[3] There are no precise data available on the incidence of SpVT, other than a 10% 
prevalence among patients with pancreatitis.[3] 
The diagnosis of SVT is often difficult to establish due to the anatomical heterogeneity, with 
different clinical manifestations according to the site of thrombosis.[3] Abdominal pain is the most 
frequent symptom and is reported in 60% of the patients with MVT or BCS, and in 40% of the 
patients with PVT. Hypersplenism, thrombocytopenia, ascites and portal hypertension are frequently 
reported in PVT and BCS. Other nonspecific symptoms include fever, nausea or vomiting, diarrhea 
and anorexia.[9] 
 
In at least one-third of the patients with SVT a precipitating risk factor is identified, which 
include liver cirrhosis, inflammatory, infectious and autoimmune diseases, abdominal surgery, 
malignancy, inherited and acquired thrombophilia, pregnancy-post-partum periods, hormonal 
therapy, JAK2 positive myeloproliferative neoplasms (MPN) and paroxysmal nocturnal 
hemoglobinuria (PNH).[10] The leading cause of BCS is myeloproliferative neoplasm (MPN). In 50% of 
the patients with BCS a MPN is reported.[11] In patients with PVT, abdominal cancer 
(gastrointestinal, pancreatic and hepatobiliary system) and livercirrhosis were the most commonly 
reported acquired risk factors. Isolated SpVT is most commonly associated with underlying acute 
pancreatitis.[12] 

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2.2 Available Methods for the Diagnosis of splanchnic vein thrombosis  
2.2.1. Biomarkers 
There is no clinical algorithm for the diagnosis of SVT and there are no specific laboratory tests. D-
dimer does not have a role in the diagnosis, due to its low specificity and the high percentage of false 
positive results, especially in patients with cancer, liver cirrhosis or underlying inflammatory 
conditions, present in more than half of the total SVT population.[2] Liver function tests are usually 
normal or may be elevated in case of an underlying hepatic disease and thus non diagnostic for SVT. 
Mildly prolonged international normalized ratio (INR) and partial thromboplastin time (PTT) can be 
seen in patients with PVT in absence of clinical evidence of liver diseases.[3] The diagnosis of SVT 
thus relies on different imaging tests. 
 
2.2.2. Doppler ultrasonography 
Doppler ultrasound (DUS) is the current imaging of choice for the diagnosis of PVT and BCS. Previous 
studies evaluating the accuracy of DUS for the diagnosis of PVT compared to angiographic or surgical-
pathologic findings, found a sensitivity of 89-93% and specificity of 92-99%.[13, 14] 
In BCS, DUS is usually the first choice imaging, since it is very accurate when performed by an 
experienced technician.[1] In a small study, a sensitivity of DUS for the diagnosis of BCS of 87,5% was 
found. The diagnosis of BCS was confirmed by histopathologic findings or by cavography with hepatic 
vein catheterisation.[15] However in a recent study, contrast enhanced US is found to be more 
accurate than colour DUS for the diagnosis of PVT and BCS in patients with cancer, with a sensitivity 
and specificity of >90% and 100%, respectively.[16] For the diagnosis of MVT DUS showed good 
specificity of 100% at cost of low sensitivity of 79-90%, due to operator-dependent differences. 
Overlying bowel gas can hinder the visualization of mesenteric veins and make it impossible to 
visualize the smaller mesenteric vessels.[5] DUS is usually a first-line non-invasive diagnostic test in 

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SpVT. However, the location of the splenic vein is a disadvantage for DUS, since collateral veins near 
the splenic hilum can be confused with the splenic vein.  
 
2.2.3. CT angiography 
In the diagnosis of PVT CT angiography compared to intraoperative findings as gold standard, showed 
a sensitivity of 90% and a specificity of 99%.[13] Furthermore, CT and MR are superior to DUS for 
providing information about the cause of thrombosis, such as infection, inflammation and cancer.[1] 
CT and MR are confirmatory diagnostic tests when DUS is non diagnostic in patients with a 
clinical suspicion of BCS.[17] Furthermore, CT and MR are superior for assessing the liver perfusion 
and liver parenchyma and showing indirect signs of BCS (hypertrophy of caudate lobe) and causes for 
secondary BCS.[18] 
For the diagnosis of MVT, CTA and MRA are considered the diagnostic tests of choice. They 
are more sensitive than DUS, since visualization of mesenteric veins with DUS is often very 
challenging.[17] Furthermore, the advantage of CT over DUS is the ability to visualise the mesentery 
and the bowel walls, since thickening of the bowel wall is the most common sign of intestinal 
infarction due to MVT.[19] Previous small studies evaluating diagnostic accuracy of MVT compared to 
angiography, intraoperative findings or autopsy found a sensitivity and specificity of 91-91% and 94-
100%, respectively.[20, 21] 
  
SpVT is most commonly diagnosed by abdominal contrast-enhanced CT, since SpVT is usually 
an incidental finding in the evaluation of patients with complicated pancreatic disorders or pre-
operative patients with chronic pancreatitis, the two most common situations that accompany 
SpVT.[22] For the diagnosis of SpVT, dynamic contrast-enhanced CT showed a sensitivity of 71% 
compared to angiography.[3] 
 
 

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2.2.4. MR imaging 
In the diagnosis of PVT, contrast enhanced MRA is able to evaluate the patency of the portal venous 
system and flow direction. In a previous study evaluating the diagnostic accuracy of MR portography 
(MRP) versus DUS, MRP was more accurate in the diagnosis of PVT with a sensitivity and specificity of 
90% and 99%, respectively.[4] In another small study evaluating contrast enhanced MRA compared 
to reference standard, defined as surgical evaluation in the majority of patients and other imaging 
tests (DUS or CT) in the remaining, had a sensitivity of 100% and specificity of 98%.[5] 
In the diagnosis of BCS, MR angiography is better for the visualisation of liver perfusion and 
liver parenchym compared to DUS.[3] MR is usually performed when CTA is contra-indicated in 
patients with suspected MVT. Small studies evaluating the diagnostic accuracy of MR found a 
sensitivity and specificity close to 100% for the detection of MVT confirmed by surgical procedures, 
DUS or CT scan.[5, 23] Conventional angiography is rarely performed nowadays, because of its 
invasive nature. In patients with high clinical suspicion of SVT and non-diagnostic CT or MR findings, 
or in patients in need of endovascular therapeutic procedures, angiography may still be 
considered.[19]  
 
2.3 Acute versus chronic SVT  
Acute SVT has a poor short- and long-term prognosis [24] and a worse survival rate than usual site 
VTE (lower extremity deep vein thrombosis and/or pulmonary embolism).[9] Therefore, a timely 
diagnosis is crucial, in order to establish the appropriate anticoagulant treatment. Every 
manifestation of SVT has a risk of potentially life-threatening thrombotic complications, such as the 
development of bowel ischemia and the risk of hemorrhagic complications.[1] BCS has a high 
mortality rate of 10% at 6 months, 13% at 1 year and 18% at 2 years.[25] In one-third of the patients 
with acute MVT intestinal ischemia is reported and has a mortality rate of 20% at 30 days.[26] 
Usually, depending on the site of thrombosis, anticoagulant treatment should be started as soon as 

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possible after diagnosis to prevent progressive and/or recurrent thrombosis. The 2012 guidelines of 
the American College of Chest Physicians (ACCP) indeed recommend anticoagulation in all patients 
with symptomatic SVT.[27] 
 
Importantly, since many patients with SVT are at high risk of bleeding, some SVT patients are 
not treated with anticoagulants. In one study, 25% of the patients with acute PVT or SpVT suffered 
gastrointestinal bleeding shortly after initiation of anticoagulant therapy, mainly from 
gastroeosophageal varices due to portal hypertension.[9] As a consequence, the ACCP guidelines 
suggest no anticoagulation in patients with asymptomatic, incidentally detected SVT.[27] However, it 
is often challenging to diagnose acute SVT as neither of the current available imaging tests is helpful 
in determination of the age of the thrombus or its clinical relevance. A clear differentiation between 
acute or chronic thrombotic is therefore often impossible. With an ever increasing incidence of 
incidentally detected SVT due to the extensive use of CT imaging, especially in patients with liver 
cirrhosis or solid cancer, the lack of a decisive diagnostic test to differentiate acute from chronic SVT 
is clearly an unmet clinical need.[3] This illustrates the relevance of the current research proposal. 
 
2.4 Magnetic Resonance Direct Thrombus Imaging as a Promising Alternative  
2.4.1. MRDTI for the lower extremity  
Magnetic Resonance Direct Thrombus Imaging (MRDTI) has been shown to be a highly accurate 
diagnostic method for a first deep vein thrombosis of the legs.[28, 29] The method is based on 
measurement of the T1 signal which shortens as a result of the formation of methemoglobin in a 
fresh thrombus.[30] This technique does not require the administration of gadolinium contrast and 
the acquisition time is short, making it a safe and patient-friendly test. MRDTI was found to have a 
high sensitivity of 95% and specificity of 91% for a first venography proven symptomatic DVT of the 
legs [31]. Moreover, interobserver agreement was excellent with a kappa-statistic of 0.89-0.98. A 
second study found even higher diagnostic accuracy with a sensitivity of 95% and a specificity of 

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100% [32]. Moreover, the positive signal disappeared in all patients after a period of six months.[32] 
In the subsequently performed Return-study, it was shown that MRDTI differentiated accurately 
between patients with confirmed recurrent ipsilateral DVT and those with asymptomatic residual 
intravascular clots and a normal D-dimer level with a sensitivity of 95% (95%CI 83-99) and a 
specificity of 100% (95%CI 92-100). This study additionally confirmed the high interobserver 
agreement with a kappa-value of 0.98.[28]  
 
2.4.2. MRDTI for splanchnic vein thrombosis  
Only few reports are available on non-contrast enhanced MRDTI for diagnosis of SVT. In one small 
study evaluating non-contrast and gadolinium enhanced MR imaging for diagnosis of BCS results 
suggested that MR imaging may be a useful diagnostic modality for detection and classification 
(acute versus subacute/chronic) of BCS, but correlation with the gold standard (histopathologic 
findings) was missing.[33] Moreover, two small and outdated studies suggested that in acute SVT and 
PVT, the clot may be detected inside the lumen of the veins as isointense material on T1-weighted 
images and hyperintens material on T2-weighted images.[34, 35] However, in both studies the gold 
standard for SVT/PVT diagnosis was lacking and the differentiation between acute versus chronic 
thrombus was not validated.  
With MRDTI shown to be a valuable diagnostic test for arm vein thrombosis and sinus 
thrombosis in recent studies, the investigators hypothesize that MRDTI will also proof to be an 
accurate diagnostic test for acute SVT and for the distinction between acute and chronic SVT since 
formation of methemoglobin in a thrombus is common to all venous thromboses.[36, 37]  
 
 

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3. Objectives  
3.1 Primary objective 
The primary objective of this study is to explore the diagnostic accuracy of MRDTI in the diagnostic 
management of acute and chronic SVT in a prospective diagnostic proof of concept study. 
 
3.2 Secondary objectives 
The secondary objectives of this study are:  
1)  
To optimise MRDTI sequences for imaging of SVT 
2) 
To assess the interobserver agreement of the readers of MRDTI for suspected SVT  
 
4. Methods 
4.1 Study design 
This study is a prospective diagnostic proof of concept study to explore the diagnostic accuracy of 
MRDTI in the diagnostic management of acute and chronic SVT. This will be achieved by performing 
MRDTI scans to adjust and optimize the DTI scan sequence in 3-5 patients with confirmed, 
symptomatic SVT. If a reproducible clearly positive DTI signal is achieved in all patients, the study can 
proceed with the inclusion of cohort 1 and 2, i.e. 35 patients with confirmed acute SVT (cases) and in 
35 patients with confirmed, non-symptomatic chronic SVT (controls). All scans will be evaluated post-
hoc by expert readers blinded for the final diagnosis. It is predetermined that at least five patients of 
each SVT site (PVT, SpVT and BCS) and at least five patients of each SVT risk factor (oncologic, post-
surgical and inflammatoir/infectious) will be included. To make sure that cohort 1 is generally similar 

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to cohort 2 frequency matching will be performed, in which all controls will be selected to get the 
same distribution according to  SVT site and risk factor as cases. 
 
4.2 Definition of SVT 
4.2.1. Acute Splanchnic vein thrombosis 
Acute splanchnic vein thrombosis is defined as acute symptomatic or acute incidental asymptomatic 
thrombosis in the mesenteric, splenic, portal or hepatic veins.  
Acute symptomatic thrombosis refers to acute onset (< 2 week existent) of symptoms 
characteristic for SVT thrombosis (including but not limited to abdominal pain) with SVT confirmed 
with DUS, CTA or MRA, dependent on the anatomical location. Acute incidental asymptomatic 
thrombosis refers to an incidentally detected SVT with DUS, CTA or MRA, absent on previous 
diagnostic tests performed in the last 2 weeks before the new incidental finding, in patients without 
symptoms characteristic of SVT.  
The diagnosis of SVT can be made with DUS, CTA and MRA. The diagnosis SVT is defined as 
the absence of flow in the involved vein (mesenteric, splenic, portal or hepatic vein) as well as the 
hyperechogenic thrombus inside the lumen seen on DUS. Acute SVT on CTA is defined as a non-
enhancing filling defect in the lumen of the involved vein and possibly increased enhancement of 
hepatic ischemic areas during the arterial phase and decreased enhancement in portal phase. At MR 
imaging, acute SVT is isointense on T1-weighted images and hyperintense on T2-weighted images.[1] 
DUS is the current first line imaging test of choice for the diagnosis of PVT and BCS. However, 
when DUS is inconclusive MRA/MRP or CTA serves as reference test for the diagnosis of both PVT 
and BCS. For the diagnosis of SpVT, DUS is the first choice imaging test, however in a non-diagnostic 
test result, contrast enhanced CT will serve as the reference test.  
 

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4.2.2. Chronic Splanchnic vein thrombosis 
Chronic Splanchnic vein thrombosis is defined by incident SVT with chronic thrombi on 2 serial 
imaging tests with an at least 3 months interval. 
 
4.3. MRDTI 
MRDTI will be performed as described before with a 1.5 or 3.0 Tesla unit using a T1-weighted 
magnetisation prepared three-dimensional gradient-echo sequence. The sequence includes a water-
only excitation radiofrequency pulse to abolish the fat signal, and the effective inversion time is 
chosen to nullify the blood signal. Imaging will be performed of the affected veins in two imaging 
blocks with a total acquisition time of 8-12 minutes by using a 55-cm body coil. 
 
4.4. Therapeutic management 
This is not a management study: before inclusion in the study, a final diagnosis and management 
plan, i.e. initiation of anticoagulant treatment or not, is made and discussed with the patients. The 
MRDTI findings are not used for this decision process. When venous thrombosis at any anatomical 
site is diagnosed during follow-up, treatment with therapeutically dosed anticoagulants will be 
initiated without delay, according to current guidelines. 
 
5. Subjects 
5.1 Population base  
Consecutive patients with confirmed acute symptomatic SVT, who fulfil all the inclusion criteria and 
meet none of the exclusion criteria, are eligible for inclusion, as are patients with confirmed chronic 

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SVT. It is planned to enrol 73-75 subjects in the Rhea study (see paragraph 8.1 for detailed sample 
size considerations). 
 
5.2 Inclusion criteria  
1. Patients with confirmed acute SVT; definitions provided in paragraph 4.2 (Cases, group 1) 
2. Patients with confirmed non-symptomatic chronic SVT defined by incident SVT with chronic 
thrombi on 2 serial imaging tests with at least 3 months interval (controls, group 2) 
3. Aged 18 years and older 
4. Willing and able to give informed consent 
 
5.3 Exclusion criteria  
1. MRI contra-indication (including but not limited to a cardiac pacemaker or subcutaneous 
defibrillator; vascular clips in the cerebral vessels; metal splinter in the eye, a hearing aid that 
cannot be removed; a neurostimulator that cannot be removed; a hydrocephalus pump)  
2. A medical condition, associated illness or co-morbid circumstances that precludes completion of 
the study procedures (MRI and 90-day follow-up assessment), including but not limited to life-
expectancy less than 3 months, inability to lie flat, morbid obesity preventing use of MR and 
claustrophobia.  
3. Patients with decompensated liver disease with Child-Pugh class C cirrhosis (since MRDTI 
evaluation will be inadequate in these patients)  
4. Patients with suspected tumour thrombus  
 
 

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6. Study endpoints 
6.1. Primary endpoint 
 
The primary endpoint of this study is the sensitivity and specificity of MRDTI for the diagnosis of 
acute and chronic SVT. 
 
6.2. Secondary endpoints 
 
The secondary endpoints of this study are:  
1) optimized MRDTI scan sequences for SVT; 
2) the assessment of interobserver agreement between the reviewers. 
 
7. Data analysis  
7.1 Sample size calculation  
A sample size of 35 patients in each of groups 1 and 2 was chosen because with this sample size and 
an expected sensitivity of greater than 90%, the 95% confidence intervals on the point estimates 
would have a bandwidth of approximately ±15%, ensuring that the point estimate was sufficiently 
accurate to make decisions about the appropriateness and safety of a future management study. To 
optimize the MRDTI scan sequences before the start of including patients in group 1 and 2, 3-5 
patients with confirmed SVT will be included. If a reproducible clearly positive DTI signal is achieved 
in all three patients, the study can proceed with the inclusion of cohort 1 and 2. The final sample size 
is thus 73-75 patients. It is predetermined that at least five patients of each group (PVT, SpVT and 
BCS) will be included. 

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We expect that the required sample size is met within a time frame of three years. This 
expectation is based on the actual number of cases of acute SVT being diagnosed in the two study 
sites and considering that the number of chronic SVT diagnosis exceeds that of acute SVT. The Varese 
University Hospital is a tertiary referral center for SVT, and the LUMC is home to both a large 
oncology as well as organ transplantation departments where the diagnosis of SVT is made 
frequently. 
 
7.2 Data analysis 
7.2.1. Primary endpoint 
A diagnosis (acute SVT, no signs of acute SVT, or non-diagnostic) for each arm of interest based on an 
aggregate reading of the MRDTI images will be made by two independent expert readers. A third 
reader will be involved to resolve any dispute. The sensitivity of MRDTI is determined by calculating 
the proportion of scans that are read as "positive for acute SVT” in patients with a confirmed acute 
SVT and the specificity is determined by calculating the proportion of scans that are read as "no signs 
of acute SVT" in patients with chronic SVT. The corresponding exact 95% confidence interval for each 
of the point estimates will be calculated. In addition to these estimates, sensitivity and specificity 
estimates with corresponding 95% confidence intervals will be calculated for the initial independent 
assessment of each of the two readers participating. A point estimate of the sensitivity of >90% will 
be acceptable for initiating a future management study. 
 
7.2.2. Secondary analyses 
For the optimization of the MRDTI scan sequences 3 pilot patients will be tested. The final sequences 
will be used in the 2 study groups when the study PI’s all agree that the accuracy and quality of the 
sequences is adequate.  

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For the interobserver agreement between the reviewers a kappa statistic will be assessed. According 
to established criteria, a kappa score above 0.8 is considered excellent reliability, a score between 
0.6 and 0.8 is considered good reliability, a score between 0.4 and 0.6 is considered moderate 
reliability and a score below 0.4 is considered poor reliability. 
 
7.3 Data management 
7.3.1. Data collection 
Data will be collected, used and stored, which concerns data such as name, address, date of birth and 
medical information. Diligent efforts will be made to ensure the study data are stored securely and 
confidential information is protected. The handling of personal data will comply with the General 
Data Protection Regulation (GDPR).  
 
All study participants will receive a study number which is a unique identifier (not based on patient 
initials and birth date). The key to the code will be safely stored in the local research institute and 
safeguarded by the principal investigator. The unique studynumber will be used on the CRF and with 
the MR images stored in the radiology database. The data that will be sent to the sponsor will only 
contain the code and not names or other data that can identify study participants. All electronic data 
and records will be saved under their unique study number and stored in a secured file on the 
computer. Access to study files and electronic records will be restricted to authorized study 
personnel. The local investigators are responsible for ensuring that all sections of the eCRF are 
completed correctly, and that entries can be verified against source data. 
 
7.3.2. Data handling 
The electronic data entry system allows the principle investigators to control the entry process with 
the help of the built-in review functions. Any missing data or inconsistencies will be reported back to 

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the respective site and clarified by the responsible investigator. The principle investigators are 
authorized, in the case of discrepancies or correction of data errors, to directly contact the 
responsible person at the study site. After completion of data entry and if no further corrections are 
to be made in the database, the access rights will be withdrawn, and the database will be declared 
closed and used for statistical analyses. 
 
7.3.3. Storage and Archiving of Data 
The principle investigators will archive all study data (subject identification code list, source data, and 
investigator's files) and relevant correspondence in the Investigator Site File and this is archived in a 
closed storage cabinet. Only the principle investigator has access to the subject identification code 
list and source data. The monitor which has been hired by the sponsor of the study and the 
Healthcare and Youth Inspectorate also have access to the data in case of safety reviewing. The 
Investigator Site File, all source data, and other pertinent documents will be archived for 15 years at 
the research location. 
 
7.3.4. Withdrawing consent  
Study participants can withdraw their consent to the use of the personal data at any time. The study 
data collected until the moment of the withdraw can be used in the study.  
 
7.3.5. Processing data  
The principle investigator and coordinating investigator of the study in  the LUMC are responsible for 
the processing of personal data of the study participants. For questions about rights concerning 
processing data study participants can contact the principal and coordinating investigators or Data 
Protection Officer of the LUMC or the Dutch Data Protection Authority. 
 
 

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8. Ethical considerations 
8.1 Regulatory statement  
The study protocol and consent forms will be submitted to the Research Ethics Committee. Patient 
recruitment will not commence before formal approval has been granted. The study will be 
conducted according to the principles of the "Declaration of Helsinki" (as amended in Tokyo, Venice 
and Hong Kong, Somerset West and Edinburgh) and in accordance with the Guidelines for Good 
Clinical Practice (CPMP/ICH/135/95 - 17th July 1996). The study will be carried out in keeping with 
local legal and regulatory requirements. 
  
8.2 Inclusion and consent  
Before being admitted to the study, the subject must consent to participate after being fully 
informed about the nature, scope, and possible consequences of participation. The consent 
documents must be in a language understandable to the subject and must specify who informed the 
subject. After reading the informed consent document, the subject must give consent in writing. The 
subject's consent must be confirmed by the personally dated signature of the subject and by the 
personally dated signature of the person conducting the informed consent discussions. A copy of the 
signed informed consent document must be given to the subject. The original signed consent 
document will be retained by the investigator.  
 
The investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained. All participants will be told that participation is voluntary 
and they are free to leave the study at any time. Because the timeframe for patient recruitment and 
imaging are critical to the success of the study, research personnel will maintain regular 
communication with staff in clinical areas where eligible patients are likely to be recruited. After they 

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have given written acknowledgement of informed consent to participate, a medical screening will 
take place. Through patient interview and review of medical records, it will be confirmed that they 
satisfy all inclusion criteria and do not meet any of the exclusion criteria. 
 
8.3 Confidentiality 
The name of the subjects and other confidential information are subject to medical professional 
secrecy. For the primary and secondary analysis, only anonymized information that is included in the 
standardized paper CRF forms can be used. This information is depersonalized and stored under an 
individual identification code that is assigned to each patient at inclusion after signing informed 
consent. The study patients will declare in the written consent to release the investigator from the 
medical professional secrecy to allow identification of subject’s name and/or inspection of original 
data for monitoring purposes by health authorities and authorized persons (monitors).  
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. Study findings stored on a 
computer will be kept safe in accordance with local data protection laws and will be handled in 
strictest confidence. For protection of these data, organizational procedures are implemented to 
prevent distribution of data to unauthorized persons. The appropriate regulations of data legislation 
will be fulfilled in its entirety. 
 
8.4 Responsibilities of principal investigators 
The principal investigators will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, and their study-related duties and 
functions. The principal investigators will maintain a list of sub-investigators and other appropriately 
qualified persons to whom they have delegated significant study-related duties. 

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8.5 Approval of Study Protocol 
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the independent ethics committee/institutional review 
board of the LUMC in Leiden. The document of final approval by the independent ethics committee 
should mention the title of the study, the study code, all study sites, the documents they reviewed, 
and the date of decision. Before the first subject is enrolled in the study, all ethical and legal 
requirements must be met. The investigator must keep a record of all communications with the 
independent ethics committee and the competent authorities. 
 
8.6 Ongoing information for independent ethics committee 
8.6.1. Amendments 
The competent authorities including the independent ethics committee must be informed of all 
subsequent protocol amendments and administrative changes, in accordance with the respective 
local legal requirements. Amendments must be evaluated to determine whether formal approval 
should be sought and whether the informed consent document should also be revised. The 
independent ethics committee must be informed of all subsequent protocol amendments which 
require formal approval in accordance with the legal requirements. 
 
8.6.2. Annual progress report 
The coordinating investigator will submit a summary of the progress of the study to the accredited 
institutional review board (IRB) once a year. Information will be provided on the date of inclusion of 
the first subject, numbers of subjects included and numbers of subjects that have completed the 
study, serious adverse events/ serious adverse reactions, other problems, and amendments. 
 

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8.6.3. End of study report 
The investigator will notify the accredited IRB of the end of the study within a period of 8 weeks. The 
end of the study is defined as the last patient’s last follow-up visit. In case the study is ended 
prematurely, the investigator will notify the accredited IRB within 15 days, including the reasons for 
the premature termination. Within one year after the end of the study, the investigator/sponsor will 
submit a final study report with the results of the study, including any publications/abstracts of the 
study, to the accredited IRB. 
 
8.6.4. Public disclosure and publication policy 
The results of this study will be disclosed unreservedly according to the Central Committee on 
Research 
Involving 
Human 
Subjects 
(CCMO) 
statement 
on 
publication 
policy 
(http://www.ccmo.nl/attachments/files/ccmo-statement-publicatiebeleid-3-02-en.pdf). 
 
8.6.5. Monitoring and Quality Assurance 
Monitoring in all sites in the Netherlands will be executed by (internal) monitors of the LUMC 
according to the monitor plan. 
 
8.7 Insurance 
The sponsor has a liability insurance which is in accordance with article 7 of the WMO. The sponsor 
(also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 
7 WMO and the Measure regarding Compulsory Insurance for Clinical 
Research in Humans of 2015).. This insurance provides cover for damage to research subjects 
through injury or death caused by the study: 

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1) € 650.000,-- (i.e. six hundred and fifty thousand Euro) for death or injury for each subject who 
participates in the Research; 
2) € 5.000.000,-- (i.e. five million Euro) for death or injury for all subjects who participate in the 
Research; 
3) € 7.500.000,-- (i.e. seven million five hundred thousend Euro) for the total damage incurred by 
the organisation for all damage disclosed by scientific research for the Sponsor as ‘verrichter’ in 
the meaning of said Act in each year of insurance coverage. The insurance applies to the damage 
that becomes apparent during the study or within 4 years after the end of the study. 
 
9. Safety reporting  
9.1 Section 10 WMO event  
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and 
the reviewing accredited METC if anything occurs, on the basis of which it appears that the 
disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited METC, except insofar 
as suspension would jeopardise the subjects’ health. The investigator will take care that all subjects 
are kept informed.  
 
9.2 Adverse events 
Adverse events are defined as any suspected recurrent venous thromboembolism occurring to a 
subject during the study. All adverse events reported spontaneously by the subject or observed by 
the investigator or his staff will be recorded. 
 

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9.3 Serious adverse events  
A serious adverse event is an objectively proven (fatal) PE or death. The investigator will report all 
(fatal) PEs and deaths to the sponsor without undue delay after obtaining knowledge of the events.  
 
The sponsor will report the (fatal) PEs and deaths through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for the (fatal) PE and 
deaths followed by a period of maximum of 8 days to complete the initial preliminary report.  
 
 
9.4 Follow-up of adverse events  
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as indicated, 
and/or referral to the general physician or a medical specialist. SAEs need to be reported till end of 
study within the Netherlands, as defined in the protocol. 
 
10. Agreements 
10.1 Financing of the study 
This study is supported by an unrestricted grant from the International Society on Thrombosis and 
Haemostasis (ISTH). 
 
10.2 Publication 
Any publication of the results, either in part or in total (articles in journals or newspapers, oral 
presentation, etc.) by the investigators or their representatives, shall require the approval of the 

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principal investigators. It is planned to publish the results of the study as an original article in an 
appropriate medical journal as well as to present the results at international congresses. The choice 
of the journal for the publication will be made by the principal investigators in agreement with the 
co-authors. Besides the principal investigators, further authors of this article must meet the following 
criteria: 
• 
Substantial contribution to the recruitment of subjects, i.e. inclusion of at least 5 study subjects; 
• 
Substantial contribution to the interpretation of the data; 
• 
Substantial contribution to drafting the article or revising it for intellectual content 
 
 

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