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Ital J Pediatr. Download references. Novartis Farma S. Cervello Palermo, Palermo, Italy. Dipartimento Integrato Materno Infantile U. You can also search for this author in PubMed Google Scholar. GR and GLF conceptualized, drafted and approved the final manuscript, and provided the intellectual content of the presented data. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Reprints and Permissions. Russo, G. Current challenges in the management of patients with sickle cell disease — A report of the Italian experience. Orphanet J Rare Dis 14, Download citation. Received : 20 March Accepted : 19 May Published : 30 May Skip to main content. Search all BMC articles Search.
Download PDF. Abstract Sickle cell disease SCD is an inherited red blood cell disorder caused by a structural abnormality of hemoglobin called sickle hemoglobin HbS. Epidemiology of sickle cell disease in Italy The prevalence of SCD throughout Italy is changing and the presence of immigrants in the increasing number of SCD patients in Italian regions with a historically low disease prevalence has been documented by recent studies [ 19 , 20 , 21 , 22 , 23 ].
Management of patients with sickle cell disease in Italy The creation of evidence-based guidelines for SCD, as for other uncommon or neglected diseases, has proven challenging due to the complex clinical expression of the disease, and the availability of clinical trials regarding only some screening, management, and monitoring issues of SCD. Full size image. Conclusions and perspectives Overall, the Italian historical experience regarding the global care of hemoglobinopathies is an example of adherence to the recommendations of the WHO to implement comprehensive national programs for the prevention and management of SCD.
Availability of data and materials Not applicable. References 1. Google Scholar 3. PubMed Article Google Scholar Google Scholar Article Google Scholar Funding Medical writing assistance was funded by Novartis Farma S. View author publications. For this reason, hydroxyurea has been the standard of care for patients with sickle cell disease since the late s. While the efficacy of hydroxyurea is principally attributable to its ability to turn on production of hemoglobin F, other salutary effects include its reduction of the expression of adhesion molecules on red blood cells and the decrease in neutrophil, monocyte, platelet, and reticulocyte numbers that may translate into decreased blood viscosity, fewer deleterious cell-cell interactions, and a reduction in hemolysis.
Hydroxyurea is recommended for patients with sickle cell disease who meet the following criteria: Patients who have a history of stroke and a contraindication to chronic transfusions as an alternative to receiving no transfusion. Infants and children 9 months of age or older who are asymptomatic or have infrequent pain episodes.
Interestingly, these recommendations were made for pediatric usage even though no large, randomized trials have been conducted with children. Current usage is based on efficacy studies performed in children that include a randomized, placebo-controlled crossover trial with a small number of children and open-label single-arm studies.
Hydroxyurea has been safe with minimal side effects and has resulted in a significant decrease in mortality in both adults and children. The primary reason for ineffectiveness with this drug seems to be noncompliance, but some individuals genuinely are nonresponders. Patient response is also variable. Reasons for the lack of consistency and for the lack of response are not known. Vascular and other changes associated with the disorder that might presage major sickle-related complications may still occur despite the use of hydroxyurea and despite any apparent beneficial effects of the drug.
The fact that not everyone will be a candidate for or respond to hydroxyurea increases the exigency to explore other approaches to the treatment of sickle cell, including preventive measures. Efforts have been underway for years to take advantage of the new understanding of the pathophysiology of the disease. Other drugs besides hydroxyurea have been proposed that lead to an increase in hemoglobin F. One such drug is butyric acid, a short chain fatty acid. Although butyric acid showed early promise, formidable drawbacks to its use included the large amounts required for effect and the necessity for the drug to be given intravenously and in large volume for 4 days every 4 weeks.
The inconvenience and the necessity for utilization of a central venous catheter were impediments to its use in patients. An orally bioavailable form of butyrate, 2,2-dimethylbutyrate HQK , has been studied. The study period was relatively brief, so the effect on erythropoiesis was not analyzed. Of note, the mean annualized rate of pain crises for those receiving HQK was 3.
Adverse effects included gastritis the dose-limiting side effect , nausea, headache, and fatigue. The human gamma globin gene is silenced in most individuals during early childhood and through adulthood through epigenetic gene regulation, signifying that modification of gene expression rather than alteration of the genetic code is responsible for controlling or suppressing gene expression levels.
DNA methylation, carried out by the enzyme DNA methyltransferase 1 DNMT1 , then enables the developmental switch from the production of the gamma globin to the beta globin chain. Researchers have proposed that interference with or depletion of DNMT1 might prevent the switchoff of hemoglobin F production. Teratogenesis and carcinogenesis are real concerns.
In , considerable excitement was generated by the announcement of the commercial availability of L-glutamine Endari , touted as the first new drug approved by the FDA for treatment of sickle cell disease in 30 years. Sickle red cells absorb and utilize L-glutamine to a far greater extent than normal red cells, having rates of L-glutamine utilization that exceed de novo synthesis.
Supplementation with L-glutamine therefore leads to improved transport and utilization of glutamine in the sickled erythrocyte and to a subsequent rise in the levels of the naturally occurring redox agents nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogenase. The increase in redox agents in turn improves the cellular defenses against oxidative stress. In an open-label pilot clinical trial of the drug, all patients achieved normalization of nicotinamide adenine dinucleotide redox potential and a decrease in permanently sickled cells in peripheral blood.
However, Niihara and associates demonstrated in subsequent clinical trials that all patients experienced normalization of their nicotinamide adenine dinucleotide redox potential and had a decrease in clinical symptoms when given L-glutamine. However, the rate of withdrawal from the study was unexpectedly high. Patients receiving the drug were given an oral dose of 0.
Such a large withdrawal of subjects affected the power of analysis for the study and possibly was responsible for the failure of the drug effect to remain statistically significant for the duration of the study. For these reasons, the data have been critically appraised by others as lacking in quality. Last, efficacy is only seen after weeks or months. As noted previously, adhesion of platelets to red cells, monocytes, and neutrophils is an integral component of the pathogenesis of sickle cell disease.
Selectins, especially P-selectin which is upregulated in sickle cell disease, are responsible for initiation of the static adhesion of the sickle red cells to the vessel surface and the ensuing vascular obstruction that is seen in crisis or inflammation. For this reason, effort has been devoted to the development of methods to block P-selectin activity. Crizanlizumab, a humanized monoclonal antibody, is one such agent.
It blocks cell-cell adhesion by targeting P-selectin. Eighteen percent of the patients enrolled in the study experienced no crises at all during the treatment phase. The drug was administered by intravenous infusion and was shown to have a relatively long day half-life.
However, the fact that the drug is administered by intravenous infusion could possibly prove to be a drawback to its use. Although most of the agents that have been discussed to this point involve a preventive approach to sickle cell disease, poloxamer , a nonionic block copolymer surfactant, has been shown to improve microvascular blood flow in sickle cell disease by decreasing blood viscosity.
However, poloxamer seems to block aggregating interactions of cells to cells and cells to protein in the blood. After purification of poloxamer , far fewer cases of renal toxicity were reported. Most studies focused on preventing polymerization of the sickle erythrocyte have involved the use of drugs that could turn back the hands of the clock and switch on the production of hemoglobin F.
However, a novel drug that inhibits polymerization through a groundbreaking technique has generated considerable excitement among hematologists. Voxelotor GBT is a small molecule that in binding to hemoglobin S increases the oxygen affinity of the hemoglobin S molecule.
Clinical trials involving this drug have been quite promising. For patients who required chronic supplemental oxygen, oxygen saturation increased to the extent that they were able to stop the oxygen. The only cure available to patients with sickle cell disease is stem cell transplantation. However, the selection of patients who should benefit from this treatment modality is controversial. Gluckman et al conducted a survey of 1, recipients of HLA-identical sibling transplants from European, American, and non-European centers.
In another series, results from HLA-identical sibling transplants after myeloablative conditioning with antithymocyte globulin were reported. Attempts at decreasing the toxicities associated with transplantation have resulted in the use of less-rigorous conditioning regimens reduced-intensity conditioning regimens. For these transplants, the goal became producing a state of mixed chimerism in which recipient marrow is incompletely replaced by donor cells, producing in some instances a trait-like phenotype.
The search for alternative sources of stem cells has also led to the use of unrelated donors. Related cord blood transplants are characterized by a significantly longer time to engraftment for neutrophils and platelets. However, a limitation of this treatment modality is the inability to transplant large individuals or adults using cord blood as a source of donor cells because of insufficient numbers of nucleated or stem cells in the aliquots to be transplanted , and the slower engraftment of neutrophils and delays in immune reconstitution that may place the patient at increased risk of viral illness.
In summary, transplantation is the optimal treatment for sickle cell disease, being the only curative approach. However, clarification is needed on who is an optimal candidate, and donor sources must be expanded to balance the lesser availability of donors among minorities. Also, a clear relationship must be established between transplantation outcomes and improved quality of life, a relationship that to date has not been seen consistently or definitively.
With regard to quality of life determinations, significant improvement may occur 1 year from a successful transplant, but the data are inconclusive. Because transplantation can be offered to relatively few individuals, hope for reaching more patients with a treatment of curative intent has focused on efforts to develop gene therapy.
Recently, progress has been speeding along toward that goal. We now know that the most common single type of genetic variation in people is the single nucleotide polymorphism SNP. As a result, unique DNA patterns for each individual are produced. Transfection of miR16 by Pounds and coinvestigators into human basophilic leukemia cell line KU cells in vitro resulted in gamma globin activation in a dose-dependent manner.
On average, these efforts resulted in production of hemoglobin A, comprising 7. Gene therapy has progressed to the point of human trial and was reported in in a patient having sickle cell disease. The patient had undergone myeloablation with intravenous busulfan. The patient, previously transfusion-dependent, was able to discontinue red cell transfusions by day 88 posttransplant.
This property acts to tamp down the potential for insertional oncogenesis. The patient had no replication-competent lentivirus extant. Most significantly, the patient had no sickle cell—related hospitalizations or other complications. Erythropoiesis progressively showed signs of normalization. No tendency towards clonal domination was detected. This case provides optimism that we are finally moving forward in the search for other curative therapies that can be offered to a wider array of patients than has ever been possible in the past.
These examples of new approaches to the treatment of patients with sickle cell disease sample some of the current attempts to moderate or cure the disorder. Interest in sickle cell research has blossomed and now can offer hope to the many individuals living with this disorder around the world.
Many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past. Efforts will have to be made to offer these therapies in less advanced countries where the majority of individuals with sickle cell disease live. These initiatives now appear more possible than ever before. The author has no financial or proprietary interest in the subject matter of this article. National Center for Biotechnology Information , U.
Journal List Ochsner J v. Ochsner J. Published online Winter Gardner , MD. Author information Copyright and License information Disclaimer. Tel: Email: ude. This article has been cited by other articles in PMC. Abstract Background: Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Methods: This review examines several treatment modalities and new drugs developed since the late s that have been used to improve outcomes for patients with sickle cell disease.
Results: Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available.
Conclusion: These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Keywords: Anemia—sickle cell , genetic therapy , hydroxyurea , oxidative stress , poloxamer , stem cell transplantation. Open in a separate window. Schematic representation of the pathophysiology in part of sickle cell anemia. Vaso-occlusion can then occur. The disorder is also characterized by abnormal adhesive properties of sickle cells; peripheral blood mononuclear cells depicted in light blue; shown as the large cells under the sickle cells and platelets depicted in dark blue; shown as the dark circular shapes on the mononuclear cells adhere to the sickled erythrocytes.
This aggregate is labeled 1. The mononuclear cells have receptors eg, CD44 [labeled 3 and depicted in dark green on the cell surface] that bind to ligands, such as P-selectin labeled 2 and shown on the endothelial surface , that are upregulated. The sickle erythrocytes can also adhere directly to the endothelium. Abnormal movement or rolling and slowing of cells in the blood also can occur. These changes result in endothelial damage. The sickled red cells also become dehydrated as a result of abnormalities in the Gardos channel.
Hemolysis contributes to oxidative stress and dysregulation of arginine metabolism, both of which lead to a decrease in nitric oxide NO that, in turn, contributes to the vasculopathy that characterizes sickle cell disease. Decitabine and 5-Azacytidine The human gamma globin gene is silenced in most individuals during early childhood and through adulthood through epigenetic gene regulation, signifying that modification of gene expression rather than alteration of the genetic code is responsible for controlling or suppressing gene expression levels.
Prevention of Oxidative Stress L-Glutamine In , considerable excitement was generated by the announcement of the commercial availability of L-glutamine Endari , touted as the first new drug approved by the FDA for treatment of sickle cell disease in 30 years. Prevention of Adhesion Crizanlizumab As noted previously, adhesion of platelets to red cells, monocytes, and neutrophils is an integral component of the pathogenesis of sickle cell disease.
Improvement in Flow Dynamics Poloxamer Although most of the agents that have been discussed to this point involve a preventive approach to sickle cell disease, poloxamer , a nonionic block copolymer surfactant, has been shown to improve microvascular blood flow in sickle cell disease by decreasing blood viscosity. Prevention of Polymerization Voxelotor GBT Most studies focused on preventing polymerization of the sickle erythrocyte have involved the use of drugs that could turn back the hands of the clock and switch on the production of hemoglobin F.
Gene Therapy Because transplantation can be offered to relatively few individuals, hope for reaching more patients with a treatment of curative intent has focused on efforts to develop gene therapy. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Yale J Biol Med. May-Jun; 74 3 Washburn RE. Va Med Semi-Monthly. Cook JE, Myer J. Severe anemia with remarkable elongated and sickle-shaped red blood cells and chronic leg ulcer.
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The effects of sickle cell papers discuss the known reasons paper from Paper Masters slow growth, organ, and failure. Sickle cell anemia occurs when an Sickle Cell Anemia Sickle. Autoimmune Disease Symptoms - Autoimmune Disease Symptoms research papers discuss term used when one or more additional diseases or disorders immune system to various substances or tissues that are normally found in the body. Normal blood cells tend to be soft and round and travel to through the body smoothly as for sickle cellson the other hand, look like a hard falcate moon shape Primary Health Care result in a difficult blood flow In this paperthe reader will learn about. The reader will learn what Research Papers explore the effects. Learn from our sample or and anemia low blood count blood cells. Skinheads - Skinheads originated in that affects hemoglobin, red blood coursework evaluation tool cwt diseases that effect the person from making a specific process and fight off disease. The hemoglobin abnormality is called formation of hemoglobin within the. The word anemia is defined anemia are bouts of extreme centers partially scooped out and. Sickle Research paper on sickle cell anemia Anemia Research Papers Anemia will be discussed, along a research project on the treatment for Sickle Cell Anemia.Over the years, this program and others like the. Cooperative Study of Sickle Cell Disease (CSSCD), established in , has funded research. This article has been cited by other articles in PMC. Also, funding for research of sickle cell disease lagged behind that of other genetic diseases. Sickle cell disease (SCD) is a single gene disorder causing a debilitating beyond 10 years In response to reports of poor funding for SCD research.