-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

293 Biomarkers of Hemolysis, Hemostasis, and Endothelial Activation Are Associated with Clinical Outcomes in Children with Sickle Cell Disease: An 8-Year Prospective Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Tools and Biomarkers for Improving Sickle Cell Disease Treatments
Hematology Disease Topics & Pathways:
Research, Clinical trials, Sickle Cell Disease, Clinical Research, Hemoglobinopathies, Pediatric, Diseases, Study Population, Human
Saturday, December 7, 2024: 5:00 PM

Bushra Zucca, MD1*, Alina Ferster, MD2, Laurence Rozen, PharmD, PhD3*, Anne Demulder, MD, PhD3*, Laurence Dedeken, MD4*, Anna Vanderfaeillie, MD2*, Phu-Quoc Le, MD, PhD4,5, Denis Noubouossie, MD, PhD6* and Nicolas Lefèvre, MD, PhD1*

1Laboratory of Pediatrics, Université Libre de Bruxelles, Brussels, Belgium
2Department of Pediatrics, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium
3LHUB-ULB, Laboratory of Hematology, Université Libre de Bruxelles, Brussels, Belgium
4Department of Hematology-Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
5Department of Pediatrics, Centre Hospitalier Etterbeek-Ixelles, Brussels, Belgium
6Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN

Introduction

Sickle Cell Disease (SCD) is clinically variable. Biomarkers may enhance the prediction of disease complications, but prospective studies are scarce and early predictive biomarkers are lacking. We measured markers of inflammation, hemostasis, and endothelial dysfunction in SCD infants and followed them for 8 years to evaluate the association of these markers with disease-related complications.

Methods

In this prospective multicentric study, we measured endogenous thrombin potential, plasma levels of cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α), soluble adhesion molecules (sICAM-1, sVCAM-1, sP-selectin, sE-selectin), and vascular endothelial growth factors (VEGF-A, VEGF-D) in 36 SCD children at steady state at 6 months and annually until age 4. Biological and clinical data were collected prospectively until age 8, focusing on chronic organ damage and acute events. Chronic organ damage was defined by the presence of conditional and abnormal transcranial Doppler velocities, silent cerebral infarcts, stroke, transient ischemic attack, neuro-cognitive defect, left ventricular dysfunction, retinopathy, proteinuria, kidney dysfunction, sickle cell cholangiopathy, or osteonecrosis. Acute events included hospitalized pain crises, Acute Chest Syndrome (ACS), dactylitis, splenic sequestration, and other acute anemia (AA).

Results

Among the 36 subjects (26 SS, 10 SC/+), 15 developed chronic organ disease (11 SS, 4 SC/+) at a median age of 5 years. Cerebrovascular disease was the most prevalent (n=12), followed by non-proliferative retinopathy (n=3) and persistent proteinuria (n=1). The latter subject presented both cerebral and renal organ damage.

Among the 23 SS and 8 SC/Sß+ subjects who presented an acute event during follow-up (FU), median age at first event was 1.8 years (range: 0.3–7.3 years) and 4.2 years (range: 2–6.8 years), respectively. Twenty-six subjects had at least one hospitalized pain crisis, with a median age of 3.6 years (range: 0.8-8 years) at first event. Dactylitis was observed in 5 subjects and 16 developed ACS at a median age of 5.1 years (range: 1.1-7.2 years). Seven subjects had splenic sequestration at a median age of 1.3 years (range: 0.5-6.5 years) and 5 presented with AA at a median age of 4 years (range: 0.8-8 years).

Hydroxyurea (HU) was prescribed to 27 children, with initiation at a median age of 3 years. None of the children began HU therapy prior to age 1.

At age 1, the median hemoglobin (Hb) was 9.8 g/dL (range: 5.2–13.8 g/dL), median reticulocyte count was 22.95 x 10⁴/µL (range: 7.5–75 x 10⁴/µL), median fetal hemoglobin (HbF) was 23% (range: 11%–46%), and median LDH was 463 U/L (range: 295–1134 U/L).

Reticulocyte counts and sVCAM-1 levels at age 1 were significantly higher in subjects who developed organ damage than in those who did not (34.34±20.20 x 10⁴/µL vs. 21.09±8.78 x 10⁴/µL, p=0.011; 876.97±273.48 ng/L vs. 647.46±163.10 ng/L, p=0.003). Reduction of Endogenous Thrombin Potential (RETP) at age 1 was significantly lower in subjects who developed organ damage (8.51±9.64% vs. 16.63±8.57%, p=0.013).

When controlling for gender, genotype, and HU treatment, a 1% increase in Hb F or RETP at age 1 was associated with a 12.1% (p=0.031, OR: 0.879) or 11.8% (p=0.019, OR: 0.882) decrease in the odds of chronic organ damage, respectively. Conversely, an increase of 10⁴ reticulocytes/µL or 1 ng/L in sVCAM-1 at age 1 was associated with a 13.3% (p=0.0241, OR: 1.133) or 0.5% (p=0.0159, OR: 1.005) increase in the odds of organ damage, respectively.

When accounting for gender, genotype, and HU treatment, an increase of 1 g/dL in Hb or 1% in Hb F at age 1 was associated with a 24.2% (p=0.0092, OR: 0.758) or 4% (p=0.0107, OR: 0.960) decrease in the count of acute events by the end of FU, respectively.

No association was found between plasma levels of cytokines and clinical outcomes.

Conclusion

Certain biomarkers measured in SCD infants were associated with disease-related events, suggesting their potential to predict long-term outcomes. Specifically, higher reticulocyte counts and sVCAM-1 levels in infancy may indicate a greater risk of organ damage by the age of 8, while higher Hb F and RETP may be protective. Lower Hb levels in infancy appear to predict more frequent acute events. Larger cohort studies should validate these markers’ utility in the early detection of patients at risk of developing severe complications, thereby allowing specific management strategies.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH