Association of Surgical Splenectomy and Venous Thromboembolism and Stroke in People with Sickle Cell Disease

A major complication for people with sickle cell disease (SCD) is acute splenic sequestration, which may cause rapid splenic enlargement and a marked decrease in hemoglobin levels. This can lead to recurrent complications, often necessitating splenectomy in early childhood. However, surgical splenectomy, especially in the context of hemolytic anemias, has been associated with increased thrombotic risks. Recent studies suggest that surgical splenectomy in people with SCD increases the risk of venous thromboembolism (VTE). However, the genotype-specific risks of thrombosis with splenectomy are unknown.

In this retrospective cohort study of people with SCD, we evaluated the association between surgical splenectomy and thrombotic events, comprised of VTE (defined as isolated deep vein thrombosis (DVT) or pulmonary embolism ± DVT (PE)) and/or stroke. Data were obtained from the Globin Research Network for Data and Discovery (GRNDaD) registry, which includes data from 58 sites. Our analysis was limited to people with an SCD genotype who were ≥18 years old and had minimum complete data. Logistic regression models were used to assess the association between history of splenectomy and thrombotic events as a composite outcome (VTE and/or stroke) and for each outcome individually, adjusting for age, sex, SCD genotype, and baseline hemoglobin levels. Subgroup analyses were also performed to investigate these relationships for different SCD genotypes.

The analysis included a total of 1,499 people with SCD (genotypes: SS/Sβ⁰ n= 1,027, SC n= 360, and Sβ⁺ n= 112). Of these, 348 (23%) people had a history of VTE (PE n=219 and isolated DVT n=129) and 213 (14%) people had a history of stroke. On multivariate analysis, surgical splenectomy was significantly associated with an increased risk of thrombotic events in people with SCD. Compared to their non-splenectomized counterparts, those who underwent surgical splenectomy had a 2.26-fold increased risk (95% confidence interval [CI] 1.65-3.08) for the composite outcome of VTE or stroke. On genotype-specific analysis, odds ratios (ORs) were 2.19 (CI 1.52-3.14) for the SS/Sβ⁰ cohort and 6.60 (CI 1.80-28.41) for the Sβ⁺ cohort. The OR for the SC cohort was not statistically significant (OR=1.74 [CI 0.78-3.76]).

For the individual outcome of VTE, surgical splenectomy was associated with a 1.82-fold increased risk (CI 1.29-2.55) among the entire SCD cohort. Splenectomy was associated with an increased risk of VTE in both the SS/Sβ⁰ (OR 1.76 [CI 1.17-2.60]) and Sβ⁺ cohorts (2.35-fold [CI 1.03-13.36]). This increased risk of VTE was explained predominantly by an increased risk of PE in both the SS/Sβ⁰ cohort (OR 1.88 [CI 1.15-3.00]) and the Sβ⁺ cohort (OR 7.24 [CI 1.92-28.85]), and there was a trend toward significance in the SC cohort (OR 2.10 [CI 0.85-4.82]). There was no statistically significant difference in isolated DVT risk between splenectomized and non-splenectomized patients in either the entire cohort or any specific genotype.

When investigating stroke risk, splenectomized patients with SCD demonstrated a 2.20-fold increased risk (CI 1.51-3.17) compared to non-splenectomized patients. On genotype analysis, the splenectomized SS/Sβ⁰ cohort demonstrated a 2.02-fold (CI 1.33-3.02) increased risk of stroke. The SC (OR=2.93 [CI 0.90-8.15]) and Sβ⁺ (OR=3.24 [CI 0.61-14.40]) cohorts demonstrated a trend toward increased risk of stroke with splenectomy, but these findings were not statistically significant.

In this large multi-institutional cohort of adults with SCD, we found that surgical splenectomy is associated with an increased risk of both VTE and stroke. Both the SS/Sβ⁰ and Sβ⁺ genotypes consistently demonstrated an increased risk of VTE in splenectomized individuals, with the highest risk in those with Sβ⁺ genotypes. The pattern of VTE is PE-predominant, which is similar to the pattern observed in prior studies of SCD. Because our study is cross-sectional, we were unable to assess the relative timing of events. However, for venous events specifically, splenectomy usually occurs in childhood and VTE in adulthood. In general, these findings suggest an association between thrombosis and surgical splenectomy in people with SCD and that this patient population may benefit from thrombotic risk evaluation.

Betensky:NHLBI K23: Research Funding; Abbot: Honoraria; Aziyo: Honoraria; Boston Scientific: Honoraria; Zoll: Honoraria. Boucher:Takeda Pharmaceuticals: Research Funding; CSL Behring: Research Funding. Desai:Novo Nordisk: Research Funding; Chiesi: Honoraria; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; NMDP: Other: Study Monitor . Gopal:Pfizer: Research Funding; Agios Pharmaceuticals, Inc.: Research Funding. Guarino:Novartis: Consultancy. Hsu:Nemours/DuPont Children's Hospital: Consultancy; Abt Assoc: Consultancy; DisperSol: Consultancy; Hilton HPC: Consultancy; Asklepion: Research Funding; Pfizer: Research Funding; GBT: Research Funding; Aruvant: Other: data safety monitoring, ended 2023. Idowu:Novartis: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Research Funding; Vertex: Consultancy; Forma: Research Funding; bluebird bio Pharmaceuticals: Consultancy; Novo Nordisk: Consultancy, Other: Advisory board or panel, Research Funding; GBT: Consultancy, Other: Advisory board or panel, Research Funding, Speakers Bureau. Kanter:Merck: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Research Funding; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Health Resources and Services Administration: Other: Federal Funding; Fulcrum: Consultancy; bluebird bio: Consultancy, Research Funding; Chiesi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; EcoR1: Consultancy; CDC: Other: Federal Funding; Guidepoint Global: Consultancy; NIH/NHLBI: Other: Federal Funding; Beam Tx: Consultancy, Research Funding; GLG Pharma: Consultancy; Takeda: Research Funding; Bioline Rx: Consultancy; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Optum United Health: Consultancy; Novartis: Consultancy; Bausch: Consultancy; Emerging Therapy Solutions: Honoraria; Sanofi: Consultancy; Affimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Watkins, Lourie, Roll & Chance: Consultancy. Lanzkron:PCORI: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Teva: Current holder of stock options in a privately-held company; Novartis: Consultancy, Research Funding; Merck: Consultancy; HRSA: Research Funding; Pfizer: Consultancy; Takeda: Research Funding; CSL-Behring: Research Funding; Glycomimetics: Consultancy; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Pfizer: Current holder of stock options in a privately-held company. Little:Novo-Nordisk: Other: Adjusications Committee; Pfizer: Other: Research support directly and indirectly (through NASCC); Novartis: Other: Research support directly and indirectly (through NASCC); Beam: Other: Research support directly and indirectly (through NASCC); NASCC: Membership on an entity's Board of Directors or advisory committees; ASH: Research Funding; NHLBI: Honoraria, Research Funding. Manwani:GBT: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy. Rivlin:Fulcrum: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Other: travel grant. Strouse:Takeda: Research Funding; GE Healthcare: Current equity holder in publicly-traded company; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Editas: Consultancy. Treadwell:Novo Nordisk: Consultancy; Global Blood Therapeutics: Consultancy.