Transfusion · 2025
Clinics and genetics of hyperhemolysis syndrome in patients with sickle cell disease.
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Malta Barbara, Cintho Ozahata Mina, Gomes Moura Isabel Cristina, Amorim Luiz, Ferraz Alessandra, Belisário André Rolim, Miranda Carolina, Kelly Shannon, Custer Brian, Sabino Ester C, Dinardo Carla L, International Component of the NHLBI Recipient Epidemiology and Donor Evaluation Study (REDS‐III) and for the TOPMed (NHLBI TransOmics for Precision Medicine) SCD working
Аннотация
BACKGROUND: Hyperhemolysis syndrome (HHS) is a severe transfusion-related complication with a complex immune pathophysiology, primarily affecting individuals with sickle cell disease (SCD). Limited research has investigated the clinical and molecular risk factors for HHS, which could help identify at-risk patients. This study aimed to assess clinical factors associated with HHS and identify genetic variations that increase susceptibility using a candidate-gene approach.
METHODS: Data were obtained from the REDS-III SCD cohort, comprising 2793 patients who underwent whole-genome sequencing as part of the Trans-Omics for Precision Medicine (TOPMed) program. Clinical and laboratory data were retrospectively collected. Patients with HHS were compared to matched controls (1:4) based on clinical variables and the frequency of single nucleotide variations (SNVs) associated with HHS, autoimmunity, and red blood cell (RBC) alloimmunization.
RESULTS: HHS was identified in 13 patients (prevalence: 1.13%), the majority of whom had the HbSS genotype (69.2%). The most affected age group was 11-20 years (46.2%), and 61.5% of patients had RBC alloantibodies. Pain crisis was the most common indication for transfusion leading to HHS (41.7%). Three significant genetic variants were identified: rs10748663 (C > T) on chromosome 10 (BLNK gene), rs936469 (G > A) on chromosome 11 (PHRF1 gene), and rs6503691 (C > T) on chromosome 17 (STAT5B gene).
CONCLUSION: HHS primarily affects adolescents and young adults with RBC alloantibodies, often following episodic transfusions. Genetic variations in STAT5B and the IRF7-PHRF1 region suggest that the B-cell receptor signaling pathway, which is essential for B-cell differentiation, may play a critical role in HHS pathophysiology.
METHODS: Data were obtained from the REDS-III SCD cohort, comprising 2793 patients who underwent whole-genome sequencing as part of the Trans-Omics for Precision Medicine (TOPMed) program. Clinical and laboratory data were retrospectively collected. Patients with HHS were compared to matched controls (1:4) based on clinical variables and the frequency of single nucleotide variations (SNVs) associated with HHS, autoimmunity, and red blood cell (RBC) alloimmunization.
RESULTS: HHS was identified in 13 patients (prevalence: 1.13%), the majority of whom had the HbSS genotype (69.2%). The most affected age group was 11-20 years (46.2%), and 61.5% of patients had RBC alloantibodies. Pain crisis was the most common indication for transfusion leading to HHS (41.7%). Three significant genetic variants were identified: rs10748663 (C > T) on chromosome 10 (BLNK gene), rs936469 (G > A) on chromosome 11 (PHRF1 gene), and rs6503691 (C > T) on chromosome 17 (STAT5B gene).
CONCLUSION: HHS primarily affects adolescents and young adults with RBC alloantibodies, often following episodic transfusions. Genetic variations in STAT5B and the IRF7-PHRF1 region suggest that the B-cell receptor signaling pathway, which is essential for B-cell differentiation, may play a critical role in HHS pathophysiology.