Sickle cell disease is the most common hemoglobinopathy affecting about 100,000 Americans mostly of African descent and 20 million worldwide. It was first discovered in the 1900s, but its molecular and clinical manifestations were inconclusive. It was not until Dr. Linus Pauling, who was a renowned scientist, carried out a landmark study in 1949 where he concluded that sickle cell disease is caused by abnormal hemoglobin that sickles once exposed to a low oxygen environment. This sickle-shaped hemoglobin is due to a single amino acid mutation which forms abnormal hemoglobin called hemoglobin S.
Sickle cell disease (SCD) is an autosomal recessive genetic disorder that is caused by a mutation in the beta-globin chain genes leading to what we know as hemoglobin S. This mutation of the sixth amino acid in the hemoglobin Beta-chain induces polymerization of the hemoglobin, causes deformation of red blood cells and ischemia leading to multiple organ damage. In sickle cell disease, glutamic acid is converted to valine. The valine formed hemoglobin causes polymerization and is the primary cause of sickle cell disease. The normal Hb A is found in adult but when this mutation occurs it allows for Hb S to form. Because sickle cell disease is an autosomal recessive disorder, it requires two carriers of HbS to have full disease symptoms. A patient with only the HbS is known to have sickle cell trait. Sickle cell trait is usually benign, but patients may have sickled cells when they are exposed to very low pressures of oxygen.
Since 1949, scientists have understood the molecular manifestations. However, there had been no cure for this genetic disorder until about two decades ago when the first bone marrow stem cell transplant was carried out. This procedure offered a cure for the disease. According to Dr. Mary T Basset, a physician during the American civil rights movement, sickle cell disease research, screening, and treatment received little to no funding and was neglected because patients were of mostly African American descent. As a result, one achievement of the civil right movement in the 1970s was to create the Sickle Cell Disease Association of America which led to the establishment of the Sickle Cell Anemia Act of 1972. Since then, there has been more public awareness of the genetic disorder and it has led to more funding towards finding a cure for the disease.
Since the Sickle Cell Anemia Act, there has been progress in the screening and treatment of sickle cell disease. For instance, in most parts of the United States, sickle cell screening is done before babies are discharged from the hospital. As a result, parents know the status of their baby, leading to early medical intervention at a young age, and reducing morbidity and mortality. Treatment of sickle cell disease has also improved, including the use of penicillin prophylaxis for patients <5 years old, the use of hydroxyurea for increasing the number of fetal hemoglobin, blood transfusions, and pain medications including opioids. Most of these treatments are palliative and unfortunately, patients still have a poor quality of life because of extreme pain episodes, end-organ damage, and also a reduced life expectancy.
In September 2018, the National Heart, Lung and Blood Institute (NHLBI) launched the Cure Sickle Cell Initiative. Advancement in new gene therapy has shown a promising result in both preclinical and clinical trials. This new technology will entail removing the patient’s stem cells from the bone marrow and then adding a therapeutic gene to those cells which will then lead to the production of anti-sickling cells.
Not all sickle cell patients are eligible for HSCT because of the significant associated toxicity. Hematopoietic stem cell transplant is only for patients with severe sickle cell disease who have complications including stroke, acute chest syndrome, recurrent pain crisis and exchange transfusions, nephropathy, retinopathy, osteonecrosis of multiple joints, and priapism. Transplant is only performed when benefits outweigh the risk of the procedure.
A bone marrow transplant is a complicated process that involves several tests and personnel. Routine labs including CBC, CMP, and 24-hour urine creatinine are performed. A brain MRI/MRA inspects for the extension of brain infarcts and vascular abnormalities. An echocardiogram is performed to estimate pulmonary pressures. Dental clearance and pulmonary function tests are also a part of pre-transplant testing. Most importantly, HLA- typing is performed to find a donor for the transplant. Red cell phenotype of both the recipients and the donor is obtained. Screening for donor-directed antibodies is also undertaken because of the risk of pure red cell aplasia post-transplant.
Researchers have developed and improved the bone marrow transplant technique since the first transplant done in 1984. The technique entails using chemotherapy for conditioning to remove the recipient's cells and later replacing it with the donor cells free of sickling. The first transplantation in 1984 used cyclophosphamide at 120mg/kg and fractionated total body irradiation to destroy the patient's bone marrow and replaced it with matched donor stem cells. The patient then received GVHD prophylaxis consisting of a short course of methotrexate and methylprednisolone for 28 days.
There has been an improvement in the chemotherapy including the use of busulfan which was found to sustain engraftment in patients who receive the bone marrow transplant. Various conditioning regimens, as well as post-transplant cyclophosphamide, have improved outcomes in bone marrow transplant.
Since the first transplant in 1984, over 1200 cases have been reported. Major problems limiting the transplant to all patients include finding a matched donor, the risk associated with the procedure including graft vs. host disease and cost. If there is transplant mismatch, there is a high risk of morbidity and mortality. HSCT is safest when a matched donor is available, but unfortunately, only a few transplant candidates have such donors. Even with this, there is still a 9 percent risk of graft rejection and a 15 percent risk of chronic graft-versus-host disease. As a result, scientists are looking for various ways to reduce these complications including the use of less toxic medications and finding other stem cell sources like related and unrelated cord blood, haploidentical transplant and myeloablative allogeneic transplant. The unrelated cord blood stem cell transplant and haploidentical stem cell have been found to be less successful due to an increase in graft vs. host disease.
Many of the medications used as immunosuppressives are toxic and can cause infertility. These agents can also induce secondary malignancy in these patients. A good example is a case study on a patient who developed a Sertoli-Leydig tumor reported after stem cell transplantation.
Bone marrow donors are unlikely to get severe complications from donating their marrow cells. However, there has been a report of chronic pain in these patients. In a prospective study by Shaw et al., they found that 11% of teenage females around the age of 13-17-years-old reported Grade 2-4 pain compared to 3% in males in the same age group. Therefore, these patients should also be followed carefully to address pain-crisis syndrome.
Sickle cell anemia is a persistent chronic disorder with no cure. Patients develop recurrent vaso-occlusive crisis because of the clogging of tiny capillary vessels most especially in the bones. Apart from the sickling of the cells, other cells interact to cause more adhesion of the red blood cells including inflammatory cells, and platelets. This phenomenon also occurs in multiple organs in the body including the chest, heart, lungs, abdomen, kidneys, and extremities. Because of the repeated attacks, organ damage can occur due to the ischemia. The first presentation of sickle cell crisis in an infant is usually dactylitis with swelling of both the hand and foot, hence the name hand-foot syndrome. The dorsum of the hands and foot are very painful and swollen. Infants may also show signs of anemia such as conjunctiva pallor, jaundice, and poor capillary bed refill.
The only cure for this disorder is a hematopoietic stem cell transplant. This curative therapy, unfortunately, can lead to some complications and sometimes death, so it is only available for severe sickle cell patients who have complications including stroke, recurrent vaso-occlusive crisis, recurrent transfusion, renal damage, and other complications. To reduce these complications and increase the availability of stem cell transplant to sickle cell patients, researchers are now working on gene therapy. Bone marrow transplant in sickle cell patients has been around for over two decades, and it has helped improve the quality of life of patients. Although this intervention is not yet perfect because of the post-transplant complications, it should still be offered to patients to cure this debilitating disease.
Sickle cell disease was discovered more than a century ago as a genetic disorder. Approximately 8% of the population has this disease. There have been advances in how we screen and treat these patients, but there is still more to do regarding management. Apart from helping to improve patients’ quality of life, finding a definitive cure can help reduce the costs spent annually on the management of patients with sickle cell disease. An estimated $900,000,000 is spent annually on healthcare expenditure. Finding a cure would also help reduce the opioid epidemic caused by the over-prescription of opioid medications for pain control. Bone marrow transplantation is an excellent start to finding this cure. The newer gene therapy studies in pre-clinical and clinical trials have shown favorable outcomes in sickle cell patients. Although bone marrow transplantation is not yet perfect because of complications involved, it still serves as a hope for patients with severe sickle cell disease as the benefit outweighs the risks.
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