Towards understanding recurrent venous thromboembolism in clinical practice

<p dir="ltr">Introduction: Diagnostic evidence for recurrent venous thromboembolism (VTE) is weaker than for first-time events. Standard pathways combine clinical decision rules (CDRs) and D-dimer testing before imaging, most commonly using ultrasound for deep vein thrombosis (DVT) and computed tomography pulmonary angiography (CTPA) for pulmonary embolism (PE). In suspected ipsilateral recurrent DVT of the leg, ultrasound may fail to rule out DVT in over 30% of cases. This is often due to chronic thrombotic changes after previous DVT and symptoms that frequently overlap with those of the post-thrombotic syndrome (PTS). Magnetic resonance direct thrombus imaging (MRDTI), a method that does not require intravenous contrast, has been shown to accurately differentiate acute thrombi from chronic thrombotic remains. The primary objective of this thesis was to examine how standard diagnostic tests perform in the diagnosis of acute recurrent ipsilateral DVT, and to explore the potential contribution of MRDTI in enhancing diagnostic accuracy.</p><p dir="ltr">Methods: In the Theia study, a prospective international management study, we examined patients who presented with suspected acute ipsilateral recurrent DVT with MRDTI performed within 24 hours of clinical presentation. Treatment decisions were based on MRDTI results. Ultrasound examination, as a reference standard, was conducted in case of MRDTI negative for DVT but did not affect treatment decisions. Patient history and clinical parameters, including D-dimer and CDR (Wells score and modified Wells score for DVT), were obtained for all patients at baseline. All patients were followed for three months for recurrent DVT or PE, bleeding, and all-cause mortality. The primary outcome was the three-month incidence of VTE in patients with an MRDTI negative for DVT at baseline, defined by the failure rate. At one of the participating centers in the Theia study, ultrasound examinations were obtained for all patients with both positive and negative MRDTI results, without affecting treatment protocols. Additionally, prolonged follow-up of two years was conducted using standardized medical chart review. Furthermore, we reviewed the literature on diagnostic management of recurrent ipsilateral DVT and PTS, highlighting CDRs, D-dimer testing, imaging techniques, and surveillance strategies.</p><p dir="ltr">Results: A total of 305 consecutive patients were included in the Theia study, both with and without anticoagulant therapy at inclusion. The prevalence of DVT in this cohort was 38%. The failure rate in MRDTI-negative patients without anticoagulant therapy at inclusion was 1.1% (95% CI, 0.13%-3.8%), below the predefined safety threshold. Interobserver agreement for MRDTI readings was excellent, with a Cohen's kappa of 0.91. The sensitivity for the combination of an unlikely ruling by the Wells score and a negative D-dimer to rule out DVT was 97% and the specificity was 36%, leading to a failure rate of 6.1% (95% CI 1.3%- 1.8%). Using the modified Wells rule, the sensitivity level was maintained, and the specificity was reduced to 20% (95% CI 14-27%). In patients with a MRDTI negative for DVT at Danderyd Hospital, 41% (27/66; 95% CI: 30-53%) had ultrasound results where DVT was confirmed or could not be ruled out, suggesting that MRDTI may help in reducing potential overdiagnosis. Of patients with positive MRDTI results, ultrasound was positive in 92%. During a two-year follow-up, 5.5% (5/91, 95% CI 2.4%-12.2%) of patients included at Danderyd Hospital suffered VTE recurrence. MRDTI has been applied into routine clinical practice at several centers.</p><p dir="ltr">Conclusions: Our data do not support the use of the combination of an unlikely Wells rule or modified Wells rule score with a negative D-dimer to rule out recurrent ipsilateral DVT. MRDTI is a safe and reliable imaging modality for ruling out recurrent ipsilateral DVT and may be useful to prevent overdiagnosis, particularly when ultrasound findings are inconclusive.</p><h3>List of scientific papers</h3><p dir="ltr">This thesis is based on the following papers, which will be referenced by their corresponding Roman numerals:</p><p dir="ltr">I. van Dam LF*, Dronkers CEA*, <b>Gautam G*</b>, Eckerbom Å, Ghanima W, Gleditsch J, et al. Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis. Blood. 2020;135(16):1377-85. *Shared first authorship. <a href="https://doi.org/10.1182/blood.2019004114" rel="noreferrer" target="_blank">https://doi.org/10.1182/blood.2019004114</a></p><p dir="ltr">II. van Dam LF, <b>Gautam G,</b> Dronkers CEA, Ghanima W, Gleditsch J, von Heijne A, et al. Safety of using the combination of the Wells rule and D-dimer test for excluding acute recurrent ipsilateral deep vein thrombosis. J Thromb Haemost. 2020. <a href="https://doi.org/10.1111/jth.14986" rel="noreferrer" target="_blank">https://doi.org/10.1111/jth.14986</a></p><p dir="ltr">III. <b>Gautam G*</b>, Sebastian T<i>, Klok FA. How to Differentiate Recurrent Deep Vein Thrombosis from Postthrombotic Syndrome. Hamostaseologie. 2020;40(3):280-91. *</i>Shared first authorship. <a href="https://doi.org/10.1055/a-1171-0486" rel="noreferrer" target="_blank">https://doi.org/10.1055/a-1171-0486</a></p><p dir="ltr">IV. <b>Gautam G,</b> van Dam LF, Dronkers CEA, von Heijne A, Bröms G, Thålin C, Wallen H, Klok FA, Westerlund E. Role of magnetic resonance direct thrombus imaging in preventing overdiagnosis of ipsilateral recurrent deep vein thrombosis by ultrasonography. [Submitted]</p>