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Introduction Acute non-malignant portomesenteric venous thrombosis (PMVT) is associated with high morbidity and mortality, with no prospective interventional studies assessing therapeutic options when anticoagulation alone has failed. We report the largest series of patients presenting with this condition who received a stepwise therapeutic protocol. It adopts an initial infusion of systemic low-dose tissue plasminogen activator (L-tPa) for 72 hours. Depending on the clinical and radiological response, the treatment is escalated to Transjugular Intrahepatic PortoSystemic Shunt (TIPSS) followed by thrombectomy and Catheter-Directed Thrombolysis (CDT) when indicated.Method We conducted a retrospective analysis of clinical records of patients with acute PMVT transferred to a tertiary centre (Royal Free Hospital) for stepwise management between 2014 – 2024.Results 106 patients were included; 65(61%) were males. The mean age was 47years(SD=15). There was a known thrombophilia diagnosed in 37 patients. 2 had a recent COVID-19 infection and 3 received the ChAdOx1 vaccine. 8 patients had underlying chronic liver disease. All patients had thrombosis of the superior mesenteric vein on imaging. Main portal vein thrombosis was found in 93(88%) patients. All patients had persistent abdominal pain despite standard anticoagulation prior to the initiation of L-tPa. The median time to initiation of L-tPa(n99) was 12(IQR=13) days of symptoms and the median duration of L-tPa infusion was 80 (IQR=57) hours. TIPSS was inserted in 48 patients(45%) and remained patent at discharge in 41/48 (85%). CDT was undertaken in all TIPSS patients, of whom, 30/48 had the local therapy delivered through EKOS™ endovascular system. Overall, a degree of recanalization was observed in 73(69%). At discharge 93% were pain free and 85% had intact gut with oral nutrition. 16 patients required small bowel resection (mean length 71cm [SD=51cm]). 1 patient was discharged with a stoma requiring parenteral nutrition. Minor bleeding occurred in 57 patients. One death was recorded (due to bowel ischemia). 1 patient had intracranial haemorrhage attributed to L-tPa. 65/107 patients were followed up at 3 months, 40/65(61.5%) had complete symptom resolution – this further improved as length of follow up increased. 4/65 required further IR intervention and 5 patients occluded their TIPSS stent.Abstract P136 Figure 1Stepwise protocol for treatment of PMVTConclusion Our protocol achieved good recanalization rates and sustained symptom control in the majority of patients. While some patients inevitably required surgical intervention, bowel continuity was eventually achieved in almost all cases. Serious adverse events are a concern. Prospective, randomised studies are required to expand the justification for using this approach in the future.