The thrombotic burden of high-risk immune thrombocytopenia patients receiving second-line treatments: a systematic review

OBJECTIVE: Immune thrombocytopenia (ITP) carries an increased thrombotic risk, especially when associated with autoimmune conditions and/or antiphospholipid antibody (aPL) positivity. The burden of thrombotic events in patients treated with second-line therapies in these instances has not been systematically studied. METHODS: Medline and Embase were searched from 2010 to November 16th, 2025, for studies on high-risk ITP patients receiving eligible second-line treatments, including thrombopoietin receptor agonists (TPO-RAs), fostamatinib, rituximab, other immune suppressants (cyclosporine, cyclophosphamide, azathioprine and mycophenolate) and splenectomy. High-risk ITP was defined as (1) primary ITP (pITP) with aPL positivity or (2) secondary ITP (sITP) when associated to an autoimmune disease posing an increased thrombotic risk. The primary outcome was the frequency of any thrombotic event during follow-up. Secondary outcomes were the separate frequencies of arterial and venous thromboses, overall and stratified by treatment. RESULTS: We included 13 studies providing data of 308 high-risk ITP patients on at least one eligible second-line treatment. Thrombosis occurred in 40 patients (10%, 95% CI 5-19) over a median follow-up ranging from 6 to 42 months. Stratifying by treatment, thrombosis occurred in 30 patients on TPO-RAs (16%, 95% CI 11-22), in 3 on rituximab (14%, 95% CI 3-35), in 3 on immune suppressants (11%, 95% CI 2-28) and in 6 who underwent splenectomy (12%, 95% CI 4-24). CONCLUSION: We have found a consistent thrombotic burden in high-risk ITP patients on second-line therapy, evident across all examined treatment options, underscoring the pro-thrombotic immune milieu of this population and the need for tailored risk-mitigation strategies.