Clinics and genetics of hyperhemolysis syndrome in patients with sickle cell disease

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.

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.

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).

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.