Background and Objectives: Blood transfusion is a key component of sickle cell disease (SCD) management, and ABO and Rh compatibility is essential to minimize transfusion-related complications. This study investigated factors associated with blood transfusion history and examined the relationships of ABO and Rh blood groups with clinical and laboratory markers of disease severity. Materials and Methods: A cross-sectional study was conducted among 309 patients attending a hematology outpatient clinic in Saudi Arabia between October and December 2025. Clinical data were collected through patient interviews, and laboratory results were obtained from medical records. Results: Overall, 89.9% of patients had a history of blood transfusion. Older age, chronic disease, higher platelet count, MCV, MCH, and HbA2 levels were associated with blood transfusion history. In contrast, higher hemoglobin and HbF levels were associated with fewer transfusions. Patients with blood group O had lower odds of transfusion than those with non-O blood groups (OR = 0.340, 95% CI: 0.135-0.856; p = 0.022). Hydroxyurea use was associated with lower LDH levels, while G6PD deficiency and higher MCV were independently associated with higher LDH levels. ABO and Rh blood groups were not associated with acute chest syndrome or LDH levels. Conclusions: Blood transfusion history in SCD was associated with several clinical and hematological factors. These findings support further investigation of G6PD status and reinforce the known benefits of hydroxyurea. Further studies are needed to clarify the role of ABO and Rh blood groups in disease progression and transfusion practices.
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