Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoietic cell transplantation (HCT) has been used for more 30 years for the treatment of selected malignant and nonmalignant diseases. Traditionally, HCT for hematological disorders has relied on myeloablative conditioning before HLA-identical sibling bone marrow transplantation to correct the underlying hematological defect. Most children with hematological diseases who are referred to HCT have features that portend significant morbidity and early mortality. Among SAA patients who have HLA-identical sibling donors, younger patients with profound pancytopenia might be considered early for HCT. For others who lack sibling donors, patients who receive HCT from alternate sources have generally failed one or more courses of intensive immunosuppressive therapy and remain transfusion-dependent, some with hemosiderosis, red cell alloimmunization, and platelet transfusion refractoriness [44,46,48]. Currently, HCT for SCD is generally restricted to those who have experienced a significant sickle-related complication such as stroke, recurrent acute chest syndrome, or recurrent painful episodes [7,13]. In contrast, most reserve HCT in thalassemia for younger, Lucarelli class I, good-risk patients who have HLA-identical sibling donors, and veer away from older, high-risk thalassemics for whom transplantation is a riskier clinical intervention. For groups such as young adults with thalassemia major, HCT might become more widely applicable if its toxicity was reduced. Several approaches undergoing development include reduced-intensity conditioning and attempts to prevent GVHD. New methods to reduce the intensity and toxicity of conditioning as well as to use highly purified stem cells with the reduction in graft versus host disease may allow for the use of matched unrelated donors or haploidentical donors. This would serve to provide potentially more children who could benefit from stem cell transplantation with donors. These advances will hopefully lead to benefits for the majority of children who lack HLA-identical donors.
 ...
PMID:New approaches to hematopoietic cell transplantation for hematological diseases in children. 1243 Jun 22

Children with sickle cell anemia (SCA) carry a 200-fold increased risk for cerebral infarction. Stroke can be the result of small-vessel (SV) or large-vessel (LV) disease. However, it is unknown whether these subtypes result from the same pathophysiologic processes. Complete HLA genotyping was performed on 231 eligible children previously enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cerebral infarction on magnetic resonance imaging (MRI) was documented in 71 patients, and 160 patients had negative findings on MRI. Based on MRI/magnetic resonance angiography (MRA) findings, infarct size, and location, 36 patients were classified as having LV stroke and 35 as having SV stroke. When comparing the total MRI+ group with the MRI- group, HLA DPB1*0401 was associated with increased stroke risk (P =.01), whereas DPB1*1701 (P =.02) conferred protection from stroke. These DPB1 associations with stroke were attributed to the SV stroke group, in whom DPB1*0401 was associated with susceptibility (P =.003) and DPB1*1701 with protection from stroke (P =.06). In the LV stroke subgroup, HLA-A*0102 (P =.02) and -A*2612 (P =.007) conferred susceptibility, whereas -A*3301(P =.04) protected from stroke. These results suggest that specific HLA alleles influence stroke risk and appear to contribute differently to SV and LV stroke subtypes. The distinct HLA associations with SV and LV stroke suggest that different pathologic processes may be involved in the development of stroke in children with SCA. If these results are confirmed in a larger study, HLA type may serve as a useful marker for the early identification of SCA patients at high risk for stroke.
 ...
PMID:Distinct HLA associations by stroke subtype in children with sickle cell anemia. 1251 10

Although hematopoietic stem cell transplantation has curative potential for selected patients with sickle cell disease (SCD), most patients who are eligible for transplantation do not have a suitable donor. Cord blood (CB) from a sibling could provide an alternative stem cell source that, while not as well established as marrow, may offer certain advantages for selected families. These potential advantages include low risk to the infant donor, the possibility that mismatched CB units from sibling donors may be acceptable for transplantation, prompt availability of a stored CB unit for transplant, and decreased risk of clinically significant graft-versus-host disease. When families with SCD (or other transplant-treatable condition) conceive a sibling, no comprehensive research resource exists to assist the family in collecting the new infant's CB. With support from the National Heart Lung and Blood Institute, we are developing a noncommercial research-based CB Banking Program specifically for medically indicated sibling donations. In preliminary experience, we have collected CB from 52 SCD families across 19 states. Of these, 2 CB units have thus far been used for transplantation and 9 others are HLA-identical. We conclude that a CB bank focusing on sibling-donations may be feasible, but further study is required to determine whether such a bank can collect CB units of sufficient quantity and quality to support controlled trials of sibling CB transplantation. Families with a specific medical need, such as those already caring for a child with SCD, should consider collecting sibling CB as part of comprehensive care if the opportunity becomes available.
 ...
PMID:Sibling donor cord blood banking for children with sickle cell disease. 1267 40

Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with hemoglobinopathies. However, fewer than 30% of individuals will have an HLA-identical sibling. Improvement in outcomes after HSCT using unrelated donors (URD), and the development of novel nontoxic preparative regimens may make URD HSCT an option for hemoglobinopathy patients who do not have an HLA-identical sibling donor. The National Marrow Donor Program (NMDP) maintains a Registry of 4 million volunteer donors, and facilitates URD HSCT for patients with life-threatening blood diseases. In light of the increased representation of minorities in the NMDP registry, donor searches were run in April 2001 for a cohort of 272 thalassemia patients and 77 sickle cell disease (SCD) patients for whom searches had been submitted between 1989 and 2001 in order to determine the current likelihood of finding a potential donor of hematopoietic stem cells for hemoglobinopathy patients. About 59.7% SCD patients 80.2% thalassemia patients will find at least one potential 6/6 HLA matched donor or umbilical cord blood (UCB) unit. All patients will find at least one donor or UCB that is a potential 5/6 HLA match. In conclusion the majority of hemoglobinopathy patients will find at least one potential HLA matched unrelated bone marrow donor or UCB.
 ...
PMID:Availability of unrelated donors for hematopoietic stem cell transplantation for hemoglobinopathies. 1269 19

Since the first report of a young girl affected by sickle cell anemia, treated successfully by bone marrow transplantation (BMT) for acute myeloid leukemia, more than 200 patients have been transplanted worldwide for sickle cell anemia. The disease-free survival (DFS) is good (80-85% in several series), even though many children who received allografts had already significant sickle-related complications. The best results are obtained in young children who have HLA-identical sibling donors and are transplanted early in the course of the disease (DFS: 93%). Future directions in the field of stem cell transplantation of sickle cell anemia include (1) the establishment of new protocols with less toxicity, but still effective, (2) adapted conditioning regimen for adult patients, and (3) new sources of stem cells for broader application: umbilical cord blood and volunteer unrelated donors.
 ...
PMID:Hematopoietic stem cell transplantation in sickle cell disease. 1281 26

We describe previously transfused patients with sickle cell disease (n = 6) and thalassemia (n = 1) who received nonmyeloablative hematopoietic stem cell transplantation (HCT) to induce stable (full or partial) donor engraftment. Patients were 3 to 20 years (median, 9 years) old. All 7 received pretransplantation fludarabine and 200 cGy of total body irradiation; 2 patients also received horse antithymocyte globulin. Patients received bone marrow (n = 6) or peripheral blood stem cells (n = 1) from HLA-identical siblings, followed by a combination of mycophenolate mofetil and cyclosporine or tacrolimus for postgrafting immunosuppression. After nonmyeloablative HCT, absolute neutrophil counts were <0.5 x 10(9)/L and <0.2 x 10(9)/L for a median of 5 days (range, 0-13 days) and 0 days (range 0-13 days), respectively. A median of 0 (range, 0-9) platelet transfusions were administered. No grade IV nonhematologic toxicities were observed. One patient experienced grade II acute graft-versus-host disease. Two months after transplantation, 6 of 7 patients had evidence of donor chimerism (range, 25%-85%). Independent of red blood cell transfusions, these 6 patients initially had increased total hemoglobin and hemoglobin A concentrations and a reduction of reticulocytosis and transfusion requirements. There were no complications attributable to sickle cell disease during the interval of transient mixed chimerism. However, after posttransplantation immunosuppression was tapered, there was loss of the donor graft, and all patients experienced autologous hematopoietic recovery and disease recurrence. One patient did not engraft. The duration of transient mixed chimerism ranged from 97 to 441 days after transplantation in patients 4 and 6, respectively, and persisted until immunosuppressive drugs were discontinued after transplantation. In summary, the nonmyeloablative HCT regimens described here produced minimal toxicity and resulted in transient donor engraftment in 6 of 7 patients with hemoglobinopathies. Although complications from the underlying hemoglobinopathies did not occur during the period of mixed chimerism, these results suggest that stable (full or partial) donor engraftment after nonmyeloablative HCT is more difficult to achieve among immunocompetent pediatric patients with hemoglobinopathies than among adults with hematologic malignancies, perhaps in part because recipients may have been sensitized to minor histocompatibility antigens of their donor by preceding blood transfusions.
 ...
PMID:Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. 1293 Nov 21

The lack of healthy HLA-identical sibs limits the use of allogeneic hematopoietic cell transplantation in children with high-risk sickle cell disease (SCD). We evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with SCD who had cerebrovascular accidents (CVAs) and did not have HLA-matched sib donors. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. Neutrophil levels above 0.5 x 10(9)/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 x 10(9)/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease (GVHD; two grade II, one grade III), and one developed extensive chronic GVHD. One patient had graft failure and autologous hematopoietic recovery. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD at 40 and 61 months, respectively, after UPBCT. These observations demonstrate the feasibility of UPBCT in children with SCD. Further studies of UPBCT for SCD are needed but, because of risks of procedure-related morbidity and graft rejection, should be restricted to pediatric patients with high-risk manifestations of SCD.
 ...
PMID:Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. 1524 29

Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed. At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. These results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies and that new approaches will need to be developed before wider application of this transplantation method for hemoglobinopathies.
 ...
PMID:Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. 1553 1

Hypoxia, hemolysis and infection are more or less associated in patients affected with sickle cell disease. Treatment is based on a programme including regular lifestyle, hydration, folic acid supply, prevention of pneumococcal infections and cerebrovascular events in children, regular follow-up in specialised centres allowing precocious screening and treatment of organ deficiency. Some patients exhibit a severe form and need intensive preventive care, such as chronic transfusion, hydroxyurea or bone marrow transplantation for children and adolescent with an HLA-identical sibling. The choice between these strategies is multifactorial, excepted in patients with a severe cerebral vasculopathy, for whom chronic transfusion or bone marrow transplantation are preferable. We usually propose hydroxyurea as a first line treatment to patients with recurrent pain crises or acute chest syndromes. In cases of refusal, initial or secondary failure (which occur more frequently in adults), or intolerance of hydroxyurea, patients with a severe disease are chronically transfused, which leads them most of the time to necessitate iron chelation.
 ...
PMID:[Management of sickle cell disease]. 1555 66

Strong associations have been established between various HLA alleles and different complications of sickle cell disease (SCD). Recently, the HLA-DRB1*03 allele was shown to be associated with susceptibility to stroke while the HLA-DRB1*02 allele may be protective. While stroke and silent brain infarcts (SBI) are unusual in Kuwaiti children with SCD, avascular necrosis of the femoral head (AVNFH) is quite common. The modulatory association factors must still be elucidated. An investigation of HLA-DRB1 alleles was carried out in a group of 68 Kuwaiti SS patients, of age 7-44 years, of whom 20 (29.4%) had AVNFH, confirmed by magnetic resonance imaging. A group of 167 apparently healthy age- and sex-matched individuals served as controls. Comparison of the HLA alleles between the whole SS group and the controls showed a significant over-representation of DRB1*01 (P < 0.01) and DRB1*10 (P < 0.05) in the patient group. No significant differences in the allele frequencies in the SS patients with or without AVNFH were observed. It therefore appears that the HLA-DRB1 locus does not play a significant role in the pathogenesis of AVNFH Kuwaiti patients.
 ...
PMID:HLA-DRB1 alleles in Hb SS patients with avascular necrosis of the femoral head. 1584 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>