Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy characterized by the polymerization of Hemoglobin S (HbS), which results from a point mutation in the β-globin gene. The clinical heterogeneity of the disease is dictated by a complex interplay of three core pathophysiological mechanisms: vaso-occlusion (VOC), driven by erythrocyte rigidity secondary to deoxy-HbS polymerization; chronic hemolytic anemia, resulting from a shortened erythrocyte lifespan; and a state of chronic sterile inflammation and ischemia-reperfusion injury, triggered by the scavenging of nitric oxide (NO) by cell-free hemoglobin. While HbSS and HbS/β⁰-thalassemia genotypes constitute the most severe phenotypes, therapeutic algorithms are designed to target these fundamental molecular underpinnings.

The cornerstone of modern SCD management is rooted in proactive and preventive medicine. Early diagnosis through newborn screening programs facilitates the immediate initiation of penicillin prophylaxis (from 2 months to 5 years of age) and comprehensive vaccinations (against Pneumococcus, Meningococcus, and H. influenzae), which dramatically reduce the risk of invasive pneumococcal disease secondary to functional asplenia. Primary stroke prevention in the pediatric population (ages 2-16) relies on annual Transcranial Doppler (TCD) screening. A time-averaged mean of maximum velocity exceeding 200 cm/sec is an absolute indication for initiating a chronic transfusion program, a measure proven to reduce stroke risk by over 90%. Hydroxyurea remains the cornerstone of this foundational care, recommended for all patients with severe genotypes over the age of 9 months. When titrated to the maximum tolerated dose (MTD), its pleiotropic effects—including the induction of fetal hemoglobin (HbF) and its anti-inflammatory and anti-adhesive properties—significantly modify the disease course.

Acute complications warrant standardized and aggressive intervention. The management of vaso-occlusive crises (VOCs) necessitates rapid, multimodal analgesia, featuring the administration of parenteral opioids and non-steroidal anti-inflammatory drugs (NSAIDs) within 30 to 60 minutes of presentation. Acute Chest Syndrome (ACS), a leading cause of mortality, is managed with broad-spectrum antibiotics, supplemental oxygen, and transfusion support. In cases of severe ACS, the 2020 American Society of Hematology (ASH) guidelines recommend exchange transfusion over simple transfusion to rapidly decrease the HbS fraction to less than 30%. Similarly, acute ischemic stroke constitutes a hematologic emergency that mandates immediate exchange transfusion to reduce the HbS level to below 30%.

For patients with a suboptimal response to or intolerance of hydroxyurea, therapy is personalized with phenotype-specific agents. In the vaso-occlusive-dominant phenotype, options include the P-selectin inhibitor crizanlizumab and the oxidative stress-targeting agent L-glutamine. However, the role of crizanlizumab in the treatment algorithm has become contentious following the failure of its post-approval STAND study to meet its primary endpoint. For the hemolysis-dominant phenotype, voxelotor, a direct inhibitor of HbS polymerization, is effective in increasing hemoglobin levels. Nevertheless, its use has become debatable following the non-renewal of its marketing authorization by the European Medicines Agency (EMA) due to insufficient evidence of clinical benefit and the company's subsequent global withdrawal decision.

Chronic transfusion therapy is a life-saving intervention, particularly for stroke prophylaxis, but inevitably leads to iron overload. Iron chelation therapy should be initiated when serum ferritin levels exceed 1000-1500 ng/mL. The gold standard for monitoring chelation efficacy is the quantitative assessment of hepatic and cardiac iron burden via T2* MRI. To minimize iron accumulation and more precisely achieve target HbS levels, the 2020 ASH guidelines advocate for automated red cell exchange (RCE) over simple transfusions for patients on chronic transfusion regimens.

The management paradigm for SCD has evolved from reactive care to a multi-faceted approach encompassing proactive foundational therapies, phenotype-specific treatments, and curative strategies. Allogeneic hematopoietic stem cell transplantation and the recently approved gene therapies based on CRISPR-Cas9 (Exa-cel) and lentiviral vectors (Lovo-cel) have ushered in a new era, offering curative potential for eligible patients. The future therapeutic algorithm is anticipated to become even more personalized through the integration of these revolutionary treatments.