Optimizing diagnosis of splanchnic vein thrombosis with MR Direct Thrombus Imaging.

Splanchnic vein thrombosis (SVT) includes portal vein thrombosis, mesenteric
vein thrombosis, splenic vein thrombosis and the Budd-Chiari syndrome (Riva et
al, Thromb Res 2017). There is no validated clinical algorithm for the
diagnosis of SVT and there are no specific laboratory tests. D-dimer cannot be
used due to the high rate of false positive results, especially in patients
with cirrhosis, cancer, or underlying inflammatory conditions, present in more
than half of the total SVT population (Dai et al, Int J Clin Exp Med 2015).
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 (Riva et
al, Thromb Res 2017; Garcia-Pagán et al, J Hepatol 2015). MR angiography has
been reported to have 90-100% sensitivity for SVT, but this technique is
limited by the need to administer a contrast agent. Moreover, it may take >60
minutes to complete the scan.
Importantly, many of SVT diagnoses in clinical practice (up to 30%) are
incidental findings in asymptomatic patients (Thatipelli et al, Clin
Gastroenterol Hepatol 2010). Whereas the diagnosis of symptomatic SVT is often
challenging, the correct diagnosis of acute versus chronic incidental SVT is
even more difficult, as neither of the current available imaging tests is
helpful in determination of the age of the clot. 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.
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) (Fraser et al, Ann Intern Med 2002; Tan et al, Blood 2014).
Moreover, it was shown to accurately differentiate acute from chronic
thrombosis (Tan et al, Blood 2014).

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. The secondary objectives include optimizing
MRDTI sequences for imaging of SVT and assessing the interobserver agreement of
the readers of MRDTI for suspected SVT.

This study is a prospective diagnostic proof of concept study to explore the
diagnostic accuracy of MRDTI in the diagnostic management of incidental SVT.
This will be achieved by performing MRDTI scans to adjust and optimize the DTI
scan sequence in 3 patients with confirmed, symptomatic SVT. 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, i.e. 35 patients with confirmed
acute SVT (cases) and in 35 patients with confirmed, non-symptomatic chronic
SVT remains (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, MVT, 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,
the last 10 patients with acute SVT will be included by matching with the last
10 included controls, according SVT site and risk factor.
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 processto change this. When At the moment 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.

This is an observational study; patients do not have direct benefits of
participating in this study other than helping in
increasing our knowledge of the subject under study. The burden of the study is
limited and includes a MRDTI test, which is a non-invasive imaging test,
without the use of ionizing radiations and iodinated contrast agents and a
telephonic follow up. The MRDTI scan will only take a few minutes, as will the
90-day telephonic follow up. Patients are not expected to experience harm from
study participation.