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THE EFFECTIVENESS OF LAPAROSCOPIC MANAGEMENT AND ITS OUTCOMES IN NON-PALPABLE INTRA-ABDOMINAL TESTIS: ...
Section 1. Clinical Medicine
https://doi.org/10.29013/ELBLS-20-4-3-5
Alatrash Yehya Ahmad, 6th year student, Faculty of Medicine 2 of SUMPh, "Nicolae Testemitanu", Chisinau, Republic of Moldova E-mail: yahia0alatrash@gmail.com Buruiana Sanda,
Associate Professor of the Department of Hematology SUMPh,"Nicolae Testemitanu" Chisinau, Republic of Moldova E-mail: sandaburuiana69@gmail.com
THERAPEUTIC APPROCHES OF ^-THALASSEMIA
Abstract. ^-thalassemia is an inherited disorder of haemoglobin associated with ineffective erythropoiesis and anemia. During the last 40 years, in addition to the considerable progress made in prevention and treatment of thalassemias, there have also been major advances in their symptomatic management, at least in wealthier countries where appropriate facilities are available. Therapeutic management depends on the severity of the disease.
Keywords: Thalassemia, treatment, erythropoiesis.
1. Background North America and Central and North Europe, are
Thalassemias are characterized by compro- rapidly increasing in number [3]. mised red blood cell survival due to mutations in During the last 40 years, in addition to the consid-the genes encoding a- and/or ^-globins. Imbal- erable progress made in prevention and treatment of anced globin chain production results in excess thalassemias, there have also been major advances in P - or a -globin precipitation, reduced red blood their symptomatic management, at least in wealthier cell fitness, and ineffective erythropoiesis and countries where appropriate facilities are available [4]. hemolysis [1]. ^-thalassemia is an inherited dis- 2. Study methods
order of haemoglobin associated with ineffective Electronic searches using Google scholar, erythropoiesis and anemia [2]. The incidence PubMed, Cochrane Library were performed for of thalassemia carriers is high in regions such as studies published in English and Romanian between Mediterranean, Indian subcontinent, Middle East, 2010-2020. South China and Southeast Asia [3]. In the past 3. Results
few decades, migrants from the thalassemia preva- Therapeutic management depends on the se-lent countries to non-prevalent countries, mainly verity of the disease. The most severe clinical form
Section 1. Clinical Medicine
is thalassemia major. The treatment depends on whether the patient is transfusion-dependent patients, frequent and lifelong red blood cell transfusions or is without blood transfusion [5].
Depending on the pathogenetic dysfunctions, we distinguish different treatment methods: blood transfusions, stimulation of Hb F production, correcting dyserythropoiesis, antioxidative treatment, gene therapy, allogeneic hematopoietic stem cell transplantation and prophylaxis of possible complications removal of excess iron, infections and other [5].
Blood transfusion is a symptomatic method of compensating for low erythrocyte counts in the blood. In the 1960 s and 1970 s, the only effective treatment for thalassemia was blood transfusion [6]. Transfusions temporarily relieve anemia, but do not restore normal erythropoiesis and secondarily various complications can be induced such:
• increased rate oftransfusion infections (viral B, C hepatitis, human immunodeficiency virus);
• increased rate of allergic reactions to blood components;
• increasing the level of iron in the body with its accumulation in various organs.
Stimulation of Hb F production because high levels of Hb F ameliorate the severity of the disease, mainly by reducing the surplus of a-globin chains [5]. Currently, the only compound in clinical use is hydroxyurea, an S-phase cell cycle inhibitor. However, its mechanism of action on Hb F remains elusive, a subset of patients is resistant, and being myelosup-pressive necessitates careful monitoring of patients. Hydroxyurea can attain transfusion independency among patients with certain primary and secondary genetic modifiers from the time of diagnosis [5; 7].
New agents include those that affect chromatin regulators (such as decitabine on DNA methyla-tion and histone deacetylase inhibitors) and others that affect DNA-binding transcription factors [5]. Increased production of y-globin has been accomplished using lentiviral vectors that express a zinc finger protein. Have been identified BCL11A and
ZBTB7A, two potent transcriptional repressors of 7-globin [5]. They act with additional trans-acting epigenetic repressive complexes, lineage-defining factors, and developmental programs the 7-globin genes by working on cis-acting sequences at the globin gene loci. Inhibition of these repressors could reactivate 7-globin production in adult patients [5].
Correcting dyserythropoiesis can be performed with the help of:
- Activin receptor-II trap ligands [2]. Luspater-cept, is a first-in-class erythroid maturation agent approved for adult transfusion-dependent patients with (3 -thalassemia who require regular red blood cells transfusions, binds several TGF- (3 superfam-ily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis [2; 5]. Efficacy and safety of Luspatercept in adult patients dependent on transfusion with-^ thalassemia requiring regular transfusions of red blood cells has been demonstrated in phase 3 of BELIEVE double-blind randomized, placebo-controlled study [2].
- JAK2 inhibitors: ^-thalassemia mice have elevated erythropoietin levels associated with increased JAK2 phosphorylation, resulting in ineffective erythropoiesis and extramedullary hematopoiesis. JAK2 inhibitors could be for non-transfusion-dependent patients with splenomegaly, because these drugs effectively reduce splenomegaly in such mice [5].
- Induction of the heat shock protein 70 (Hsp70) chaperone machinery and is needed for normal termination of erythropoiesis. Factors that control the nucleocytoplasmic trafficking of proteins and RNAs, inhibitors of erythroid progenitors from ^-thalassemia major patients, demonstrated induction of HSP70 nuclear localization, and improved terminal erythroid differentiation [5].
Antioxidative treatment: exogenous antioxidants, activation of endogenous antioxidant proteins
[5].
Gene therapy. Studies of gene therapy have utilized mainly lentivirus vectors in experimental systems, including cultured CD34 from ^-thalassemia
THERAPEUTIC APPROCHES OF ^-THALASSEMIA
patients and ^-thalassemia mouse models. Yet the safety profile of such technologies is still uncertain
[5].
Allogeneic hematopoietic stem cell transplantation is a treatment for patients with ^-thalassemia major, with good risk features have a > 90% chance of a successful outcome but this type of transplantation in high-risk patients is challenging because of graft rejection and transplant-related mortality. Stem cell transplantation is not practical due to a variety of factors like financial costs, donor unavailability and scarcity of transplantation facilities [5; 8].
Removal of excess iron. Chronic transfusion therapy leads to iron overload and, if untreated, usually results in severe organ damage. Removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia
patients, has become an essential therapy to prolong life [6; 9]. Due to the early start of iron chelation therapy, a profound knowledge of efficacy and safety in young patients is essential [6; 9]. There are several possibilities for reducing iron in the human body:
- Iron chelators. There are three iron chelators licensed: deferoxamine, deferiprone and deferasirox;
- Modulation of iron absorption (administration of hepcidin);
- Stimulating its expression (inhibition of negative regulators, inhibition of erythroferrone) [6; 9].
4. Conclusion
Based on the results of the literature review we can say that the therapeutic management depends on the severity of the disease, by the development of pharmaceutical technologies and last but not least by the socio-economic possibilities of the country.
References:
1. Kuo K., Layton D. et.al. 7 proof of concept for the oral pyruvate kinase activator mitapivat in adults with non-transfusiondependent thalassemia: interim results from an ongoing, phase 2, open-label, multicenter study. Hema Sphere. Abstract book. 2020; 4(S1): 109.
2. Taher A., Viprakasit V., Cappellini M. Assessment of longer-term efficace and the fase 3 believe trial of lus-patercept to treat anemia in in patients with B-Thalassemia. HemaSphere. Abstract book. 2020; 4(S1): 108.
3. Li C. K. New trend in the epidemiology of thalassemia. Best Practice & Research Clinical Obstetrics & Gynaecology. 2017; 39:16-26.
4. Olivieri N., Brittenham G. Management of the Thalassemia. Cold Spring Harb Perspect Med. 2013; 3(6): a011767.
5. Fibach E., Rachmilewitz E. Pathophysiology and treatment of patients with beta-thalassemia-an update. F 1000 Research. 2017; 6: 2156.
6. Crichton R., Ward R., Hider R. et. al. The efficacy of iron chelators for removing iron from specific brain regions and the pituitary-ironing out the brain. Pharmaceuticals. 2019; 12(3): 138.
7. Hussain S., Munzir S., Ali S. Effectivness of Hydroxyurea therapy: a 15 year experience of Thalassemia management without blood transfusion. HemaSphere. Abstract book. 2020; 4(S1): 720.
8. Yu U., Wang X., Zhang X. Outcomes of haplo-cord transplantation in children with beta thalassemia major. HemaSphere. Abstract book. 2020; 4(S1): 718.
9. Botzenhardt S., Li N., Chan E. et. al. Safety profiles of iron chelators in young patients with haemoglo-binopathies. European Journal of Haematology. 2016; 98: 198-217.
