Splenectomy as a treatment for relapsed or refractory immune thrombotic thrombocytopenic purpura: A systematic review

Abstract Background: Immune Thrombotic Thrombocytopenic Purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by acquired ADAMTS13 protein deficiency. First-line therapy consists of plasma exchange (PLEX) and, more recently, adjuncts such as rituximab and caplacizumab. Despite these advancements in therapy, 10-20% of patients experience relapsed/refractory disease, and adjunctive therapies may be inaccessible in resource-limited settings. Numerous cohort studies and case series have investigated the efficacy and safety of splenectomy in refractory and relapsing iTTP; however, as stated in the International Society on Thrombosis and Haemostasis (ISTH) 2025 TTP guidelines, splenectomy as a prophylactic/treatment strategy has not been systematically reviewed to date. Objective: We completed a systematic review assessing the safety and efficacy of splenectomy for relapsed/refractory iTTP. Methods: A comprehensive literature search was performed across MEDLINE, Embase, and Web of Science databases from inception to May 2025, and the American Society of Hematology and ISTH conference abstracts published since 2014. Studies were included if they enrolled adults with iTTP who relapsed or were refractory to PLEX as per study definition, underwent splenectomy, and reported remission rate as an outcome. Non-English studies and case reports with fewer than five patients were excluded. Studies were screened at title/abstract and full-text levels, and data were extracted independently and in duplicate. Baseline characteristics, relevant disease definitions, prior therapies, and operative details were extracted. Primary efficacy outcomes included remission and relapse/exacerbation rate as defined by the International Working Group or by study authors. Secondary outcomes included 90-day all-cause mortality, surgical mortality, and surgical complication rate. Given expected heterogeneity in data, inferential analysis was deferred. The study protocol was pre-registered in PROSPERO: CRD42024612298. Results: We identified 1781 studies, of which 91 were reviewed at full-text level, and 18 were ultimately included (n=171 patients): 1 prospective cohort study, 4 retrospective cohort studies, and 13 case series with a median follow-up of 30.8 months (IQR: 17.3 - 45.0). Studies were published between 1983 to 2020, with sample sizes ranging from 5 to 33 patients. From the total patient population, 132 (77%) were female with a median age of 42 years (IQR: 36.5 - 46.6). All patients received PLEX prior to splenectomy, often alongside corticosteroids, dextran, vincristine, and oral antiplatelet therapies. Rituximab was given to 10 patients in two studies published in 2012 and 2020, and no patients received caplacizumab. Splenectomy was performed on patients with an open (54%) and laparoscopic (46%) technique, but the surgical approach of splenectomy was only reported in 33% of studies. Definitions for relapse, remission, and response were highly variable. Per study definitions, 129 (75%) patients achieved long-term remission with splenectomy, and 29 (16.9%) had TTP relapse after splenectomy. Nineteen patients (11.1%) died at 90 days; 6 deaths (3.5%) were related to surgical complications, including infection. Other post-operative complications were reported in 11 of 18 studies involving a total of 21 patients. The most frequently reported events included infection, hematoma, and pulmonary embolism; less common complications were pancreatic injury, fistula, and fluid collections. Conclusion: Splenectomy leads to a high rate of iTTP remission and is associated with low mortality, suggesting that it may be a reasonable therapeutic option in resource-limited settings where other adjunctive therapies such as rituximab and caplacizumab are inaccessible. Conclusions are limited by heterogeneity with respect to disease and response definitions, and high risk of publication bias.