Key Clinical Summary: Transforming Sickle Cell Disease Care

This is a micro-learning module summary of an expert roundtable session with Dr Nirmish Shah, Dr Biree Andemariam, Dr Enrico Novelli, and Dr Donnell Ivy, which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This program is supported through an independent educational grant from Novo Nordisk. It is intended exclusively for healthcare professionals in the United States.

Introduction
Sickle cell disease (SCD) is often approached through the lens of acute painful crises, yet it is fundamentally a chronic, progressive, systemic condition marked by cumulative organ damage driven by ongoing hemolysis and vaso-occlusion. Despite major gains in childhood survival, adult outcomes remain suboptimal, highlighting persistent gaps in longitudinal disease management.
This micro-learning module focuses on three core areas essential to improving care: proactive monitoring of progressive organ dysfunction, effective use of an evolving therapeutic landscape, and integration of patient-reported outcomes and patient priorities into clinical decision-making.

Pillar 1: Proactive Monitoring and Management of Progressive Organ Damage

• Cerebrovascular risk in adults
  Stroke risk persists into adulthood for individuals with sickle cell disease (SCD) after aging out of pediatric transcranial Doppler screening. Cerebrovascular injury is often silent; silent cerebral infarction may occur without overt neurologic events yet contribute to cognitive dysfunction and long-term morbidity.
  Current American guidance acknowledges this risk but relies on non-prescriptive recommendations. The American Society of Hematology suggests at least one screening brain MRI in adults with SCD, reflecting uncertainty around adult management strategies rather than lack of clinical importance. In practice, this has led to inconsistent surveillance and under-recognition of cerebrovascular disease.
  Adult care therefore requires a personalised, phenotype-driven approach. Brain MRI should be strongly considered in adults with HbSS disease, neurologic symptoms (including headaches or cognitive concerns), prior childhood stroke, elevated historical TCD velocities, or chronic exchange transfusion, and may be appropriate before initiating migraine-directed therapies to support safer prescribing.
  In HbSC disease, cerebrovascular assessment should prioritise aggressive management of conventional vascular risk factors, while recognising that risk is not absent. The absence of rigid adult screening algorithms should not be interpreted as reassurance but as a call for deliberate, individualised vigilance.

• Neurocognitive dysfunction
  Subtle neurocognitive impairment is a frequent but under-recognized complication of SCD. Executive dysfunction may not be apparent on routine clinical evaluation but can significantly affect medication adherence, appointment attendance, and the ability to navigate complex care plans.
  Neurocognitive assessment should be considered in adults with known or suspected cerebral infarction, functional decline, or patterns of missed care. Identifying impairment enables targeted interventions such as enhanced case management, simplified treatment regimens, and social or community-based support, even when disease-modifying neurologic interventions are limited.

• Pulmonary hypertension
  Pulmonary hypertension represents a major contributor to morbidity and mortality in adults with SCD. Tricuspid regurgitant (TR) jet velocity values that may be considered borderline in the general population warrant heightened attention in SCD, as even modest elevations can signal increased mortality risk.
  Echocardiographic assessment should be performed during clinical steady state, as TR jet velocity may be transiently elevated during vaso-occlusive crises or acute illness. Initial evaluation should focus on identifying and managing contributory pulmonary conditions such as asthma, airway hyperreactivity, or obstructive sleep apnea. In symptomatic individuals, functional testing and biomarker assessment can guide escalation to invasive hemodynamic evaluation.

• Renal disease
  Kidney disease in SCD develops insidiously and may be missed if clinicians rely solely on serum creatinine, which can remain deceptively normal due to hyperfiltration. Routine screening for albuminuria is essential for early detection.
  When albuminuria is present, early intervention with renin–angiotensin system blockade can slow progression. Referral to nephrology is appropriate, particularly for patients with progressive disease or additional risk factors. Counseling on avoidance of nephrotoxic exposures, including frequent NSAID use, is a critical component of early renal protection.

Section 2: Therapeutic Strategies Across the Disease Spectrum

• Disease-modifying therapies
  Hydroxyurea remains the foundation of pharmacologic management for SCD. Its benefits extend beyond reduction of vaso-occlusive crises to include broader disease modification through fetal hemoglobin induction and downstream effects on vascular and inflammatory pathways. Current practice supports offering hydroxyurea broadly across genotypes and ages, with dose optimization to achieve maximal tolerated benefit.
  Chronic transfusion therapy remains an important option for selected patients, particularly those with high-risk neurologic phenotypes or those who demonstrate sustained benefit without prohibitive alloimmunization.
  Other approved agents may play a role in selected individuals; however, their use should be individualized based on phenotype, response, and patient priorities.

• Curative-intent approaches
  Curative-intent therapies, including allogeneic stem cell transplantation and gene therapy, represent a paradigm shift in SCD management. These options should be discussed early in the disease course for patients with recurrent vaso-occlusive crises, recurrent acute chest syndrome, or progressive disease despite optimized medical therapy.
  Delayed referral may limit eligibility due to cumulative organ damage, iron overload, or alloantibody formation. Selection among curative strategies requires individualized assessment, taking into account donor availability, prior transfusion history, marrow health, and patient goals.

• Emerging therapies
  Multiple novel agents are in development, targeting diverse mechanisms such as red cell metabolism and fetal hemoglobin induction. Therapies capable of achieving robust, pancellular fetal hemoglobin expression are of particular interest, as incomplete cellular distribution may allow continued vaso-occlusive activity despite apparent laboratory improvement.
  Ensuring that clinical trials include diverse SCD genotypes and are conducted globally is essential to producing evidence that is generalizable and clinically actionable.

Section 3: Integrating the Patient Voice and Reducing Care Burden
As individuals with SCD live longer, care complexity increases. Effective management requires deliberate coordination across multiple subspecialties while minimizing the logistical burden placed on patients.
Strategies that support continuity include clustering appointments, consolidating diagnostic testing, and using digital tools for reminders and communication. Systems must also proactively identify and re-engage patients who miss appointments, particularly those with neurocognitive impairment or limited support. Community health workers and social services play a critical role in maintaining longitudinal engagement.
Adherence challenges are not unique to SCD and reflect broader issues seen across chronic diseases. Aligning treatment plans with patient priorities, addressing access and affordability barriers, and maintaining open, structured communication about daily function and quality of life are essential to sustaining long-term benefit.

Conclusion
Modern sickle cell disease care requires a shift from reactive, crisis-driven management to proactive, longitudinal disease control. Early identification of organ dysfunction, timely escalation of disease-modifying and curative-intent therapies, and intentional integration of the patient voice are central to improving outcomes. By addressing both biological progression and care delivery barriers, clinicians can better support individuals with SCD across the lifespan.

Content is accurate as of the date of release.