Topics-in-Focus is a new EHA program that aims to raise awareness, provide education, stimulate further research and build a network of experts high-impact hematology issues. One of the topics chosen for 2018-2019 is hemoglobinopathies with a focus on sickle cell disease.
The kick-off session for this project was held at the 23rd Congress of EHA in Stockholm, on June 16.
As part of the launch, three experts on hemoglobinopathies focused on sickle cell disease (SCD) during the kick-off session on June 16.
SCD is characterized by abnormally shaped, non-pliable erythrocytes and increased blood viscosity. According to Dr Stefan Eber (Munich, Germany), screening for SDC is necessary to avoid morbidity and mortality from infection and acute anemia and to initiate preventive measures like penicillin prophylaxis and vaccination. Newborns defined ‘at risk’ for SCD should be screened based on ethnic origin, but not without a disease management program.
“Demonstrate the absence of hemoglobin (Hb) A together with the presence of HbS (and HbVar). Carriers should be reported to increase awareness and identify families at risk.” Patients heterozygous for both hemoglobin S and C (HbSC) are most prevalent in West Africa, USA, Caribbean and France. When a patient presents with tinnitus or acute hearing loss, Eber advised first to try a phlebotomy instead of prednisone. “HbSC is not a mild type of SCD. 90% of adult HbSC patients have Hb>10g/dL, with major otological and ophthalmic problems, and (a low incidence of) strokes, pulmonary hypertension, leg ulcers and nephropathy.”
There are about 15 different SCD genotypes, ranging from mild to severe, but the dominant defect is a point mutation in the beta globin gene. The resulting HbS forms fibers that initiate SCD pathology. “HbS polymer formation is a complex, two-stage process,” explained Dr David Rees (King's College London, UK). “Thereafter, erythrocytes dehydrate, become rigid, and enhance expression of adhesion molecules. This leads to vaso-occlusion and from there to a cascade of inter-related pathological events.”
The mean Hb in sickle cell anemia (HbSS) is 70-80g/dL; lower Hb is associated with generally poor prognosis (e.g. stroke and premature death).
Patients are often hypoxic and low overnight oxygen saturation is linked to increased frequency of acute pain and neurological events in children.
There is increased hemolysis in SCD. Free plasma hemoglobin binds nitric oxide (NO) and functional NO deficiency causes vascular dysfunction, but according to Rees, the contribution to pathophysiology is uncertain.
“Acute events leading to admission of SCD-patients to the emergency department (ED) are pain crisis, coronary syndrome, abdominal pain, pneumonia and septicemia,” said Prof Dr Lucia De Franceschi (University of Verona, Spain). “There is continuous pain, with breakthrough pain episodes that make life terrible.” Barriers to effective pain management include sociocultural factors and reluctance in prescribing opioids. “In the ED, management of acute vaso-occlusive crisis is improved by guidelines and we developed a triage algorithm for acute pain crisis in adults and children1, including a pharmacological flow chart2.” A recent development is the use of rapid-onset fentanyl against breakthrough pain.3
Available treatments are hydroxyurea, transfusion regimens and HSCT, but erythrocyte dehydration, free Hb, inflammation and vasculopathy are only partially controlled. Hydroxyurea is a multimodal therapy, but only 35-50% of the patients achieve high adherence and there are ongoing studies to improve this.4 Plasma of SCD patients is increased in endothelial cell adhesion molecule P-selectin. De Franceschi mentioned promising studies on P-selectin-blocking crizalizumab.5,6 Also GBT440, a small-molecule agent that delays HbS polymerization and sickling,7 is now in clinical trials.
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