Kwaku Ohene-Frempong, MD
Children’s Hospital of Philadelphia; Sickle Cell Foundation of Ghana
Sickle cell disease (SCD) is a complex, multi-system disease, however, its clinical expression is derived first from its monogenic origin as a single nucleotide beta-globin mutation resulting in the production of sickle hemoglobin (Hb S). Fundamentally, SCD is a disease of red blood cells (RBC) because the globin gene clusters are expressed only in erythroid cells. The direct consequences of the hemoglobin abnormality in SCD, polymerization of deoxy-Hb S, sickling of S-cells, and resultant chronic hemolytic anemia of variable severity, are potentially serious but relatively simple pathophysiologically. Most of the major clinical manifestations of SCD, including the hallmark vasoocclusive pain, are secondary to the RBC defect and largely disappear when the RBC are healthy or replaced with non-sickling cells.
Red cells that contain mostly Hb S can behave normally in vivo in the presence of a modest amount of fetal hemoglobin (Hb F). Under such circumstances, as seen in beta-S/pancellular HPFH Types 1 or 2 (Hb F in range of 25-20% and Hb S in the 70-75% range), hemolytic anemia and acute vasoocclusive manifestations disappear. Hematopoietic stem cell transplantation cures SCD through a constant supply of healthy RBC. In a less dramatic fashion, hydroxyurea increases Hb F unevenly in most but not all RBC yet, it can reduce hemolytic anemia and frequency of vasoocclusive complications of SCD.
In the long history of clinical management of SCD one mode of therapy, transfusion of healthy RBC, has repeated served as a dependable resort when patients encounter or need prevention of serious complications. Children with history of primary stroke or abnormal blood flow velocity in major cerebral vessels, as measured by transcranial Doppler ultrasonography, benefit from chronic RBC transfusion not only in the prevention of stroke but in many other ways. At sickle cell centers where modern transfusion services are available, 15 to 20% of children with SCD-SS are on chronic transfusion therapy. This number will increase if the Silent Cerebral Infarct Trial, currently underway, shows that transfusions reduce the frequency of stroke in children with silent cerebral infarcts.
As amply demonstrated in severe beta-thalassemia, chronic RBC transfusions, as a preventive mode of therapy, can completely change the clinical course of a devastating disease and greatly improve the quality of life of those affected. Likewise the management of severe hemophilia has shifted from treatment of acute bleeding with its devastating consequences to its prevention through prophylactic factor replacement.
Improvements in blood safety, red cell typing and donor matching, erythrocytapheresis and iron chelation therapy have all combined to make modern RBC transfusion a viable preventive therapy in SCD. Very few clinicians familiar with the impact of chronic transfusion therapy on clinical course and quality of life of children with SCD, would doubt that if all children with severe SCD were placed on chronic transfusion, they would not be healthier