Myelodysplastic syndromes (MDS)

MDS are a diverse and heterogeneous group of disorders characterised by ineffective haematopoiesis, dysplasia in haematopoietic cells, cytopenias and increased risk of progression to acute myeloid leukaemia.5,6 Over 80% of patients with MDS experience anaemia.7 Mutations involving signalling molecules, epigenetic regulators, splicing factors and transcription regulators are present in most cases of MDS.5

Thalassaemia (e.g. specific types of α- and β‑thalassaemias)

Thalassaemias are inherited genetic diseases caused by decreased or absent expression of one of the two globin chains of the haemoglobin molecule, α and β, resulting from mutations in, or deletion of, the encoding genes.8,9 The severity of the disease depends on the nature of the mutation or deletion, with symptoms ranging from no clinical symptoms to severe anaemia.10

Below are the four video clips of experts discussing the mechanisms involved in chronic anaemia associated with MDS and
β-thalassaemia

Parallels in ineffective erythropoiesis: MDS and β‑thalassaemia biology

Professor Clara Camaschella, Professor of Internal Medicine and Haematology, Vita-Salute San Raffaele University

In this video, Professor Camaschella discusses some of the growth factors and transcription factors involved in erythropoiesis. Professor Camaschella describes the role of GATA‑1 and the transforming growth factor (TBF‑β) superfamily in the erythropoiesis process and in the ineffective erythropoiesis that plays a key part in the chronic anaemia observed in MDS and β-thalassaemia.

6-minute video

Burden of anaemia and chronic transfusions

Professor Maria Domenica Cappellini, Professor of Internal Medicine, University of Milan

In this video, Professor Cappellini discusses the burden of chronic anaemia in patients with β-thalassaemia, including the varying impact of anaemia on transfusion-dependent and non-transfusion-dependent patients. Professor Cappellini also considers the impact of red blood cell transfusions on patients with β‑thalassaemia including the effect on their psychological wellbeing.

8-minute video

Chronic anaemia in MDS

Doctor David Valcárcel, University Hospital Vall d’Hebron

In this video, Dr Valcárcel outlines the incidence, symptoms and treatments of chronic anaemia in patients with MDS. Dr Valcárcel also describes the role of ineffective erythropoiesis in the pathogenesis of chronic anaemia in MDS.

3-minute video

Complications of ineffective erythropoiesis in
β-thalassaemia

Professor Olivier Hermine, Professor of Haematology, Paris Necker Children’s Hospital

In this video, Professor Hermine describes several complications associated with ineffective erythropoiesis in patients with β-thalassaemia. Professor Hermine also outlines the mechanisms of iron overload due to ineffective erythropoiesis and as a result of red blood cell transfusions, highlighting the resulting complications experienced by patients with β-thalassaemia.

5-minute video

Other haematological diseases

Aplastic anaemia

Aplastic anaemia is a blood disorder characterised by bone marrow failure causing an inability to produce blood cells and a deficit in haematopoietic stem cells and progenitor cells.11,12 This leads to pancytopenia and various symptoms such as fatal anaemia, bleeding and infection.11,12 The causes of aplastic anaemia include viral infection, environmental toxins and genetic mutations in genes affecting cellular mechanisms, which lead to bone marrow failure through physical or chemical damage, immune destruction or constitutional genetic defects.11

Myelofibrosis

Myelofibrosis is a myeloproliferative neoplasm characterised by ineffective stem cell-derived clonal haematopoiesis, bone marrow stromal reaction including reticulin fibrosis, abnormal cytokine expression, and extramedullary haematopoiesis.13 This leads to a vast array of symptoms including hepatosplenomegaly and severe anaemia.13 Ineffective erythropoiesis is the main cause of anaemia and it is thought that the aberrant cytokine production and host immune reaction contribute to this.13

Sickle cell anaemia

Sickle cell disease describes a group of inherited disorders characterised by abnormal haemoglobin molecules, haemoglobin S, which are caused by a point mutation in the β‑globin chain.14 In sickle cell anaemia, the most common form of sickle cell disease, both β-globin subunits of the haemoglobin molecule are replaced by haemoglobin S.15 This leads to intravascular vaso-occlusion, stroke, priapism, and acute chest syndrome.14 Symptoms vary from person to person with some experiencing mild symptoms and others encountering more serious complications.15

Congenital dyserythropoietic anaemias

Congenital dyserythropoietic anaemias belong to a group of inherited conditions characterised by anaemia due to ineffective erythropoiesis with distinct morphological abnormalities of erythroblasts.16 These disorders result in variable degrees of anaemia without additional cytopenias.17

Inherited sideroblastic anaemias

Sideroblastic anaemia includes a group of heterogeneous disorders, characterised by the accumulation of iron in immature erythroid cells, which are referred to as ringed sideroblasts.3 The ineffective erythropoiesis characteristic of patients with inherited sideroblastic anaemia is caused by mutations in the genes involved in the initial stages of haem synthesis. Reduced haemoglobin and iron overload cause disease symptoms that range from mild to severe.3,18

The burden of chronic anaemia in haematological diseases

Chronic anaemia is associated with symptoms such as fatigue, dyspnoea, tachycardia, hypotension, low body temperature and enlarged spleen.19,20 If left untreated chronic anaemia can cause many health problems such as heart complications and failure, due to a rapid or irregular heartbeat, cognitive impairment, renal failure and even death from life-threatening complications.21

The impact of anaemia on health-related quality of life has been studied in different populations of patients with a range of haematological disorders. In these studies, anaemia was associated with a reduced health-related quality of life with severe fatigue being the main symptom affecting a patient.22-25 Patients with chronic anaemia may also experience depression and have increasing reliance on caregivers.26

The production of haemoglobin is frequently reduced in haematological diseases. Since the majority of iron transported into erythroblasts is normally incorporated into haem, reduced production of haem can lead to a build-up of excess iron in the erythroid cells.18 Additionally, haemoglobin shortage in the body is compensated for by increased intestinal iron uptake. The combination of reduced haemoglobin levels and build-up of iron leads to iron overload. Iron overload may cause deposition of excess iron in organs resulting in endocrinopathies, diabetes, and liver and cardiac damage.27,28

Please see Normal and ineffective erythropoiesis for further details

References

  1. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet 2018;391:155-67.
  2. Raj K, Mufti GJ, Hoffbrand VA, Higgs DR, Keeling DM, Mehta AB. The myelodysplastic syndromes. Postgraduate haematology, seventh edition: John Wiley & Sons Ltd.; 2016:438-73.
  3. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. BJH 2016;172:512-23.
  4. Gupta R, Musallam KM, Taher AT, Rivella S. Ineffective erythropoiesis: Anemia and iron overload. Hematol Oncol Clin North Am 2018;32:213-21.
  5. Fenaux P, Ades L. How we treat lower-risk myelodysplastic syndromes. Blood 2013;121:4280-6.
  6. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.
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  8. Sabath DE. Molecular diagnosis of thalassemias and hemoglobinopathies: An ACLPS critical review. Am J Clin Pathol 2017;148:6-15.
  9. Barrera-Reyes PK, Tejero ME. Genetic variation influencing hemoglobin levels and risk for anemia across populations. Ann N Y Acad Sci 2019;1450:32-46.
  10. Muncie HL, Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician 2009;80:339-44.
  11. Young NS. Aplastic anemia. N Engl J Med 2018;379:1643-56.
  12. Dong X, Han Y, Abeysekera IR, Shao Z, Wang H. GDF11 is increased in patients with aplastic anemia. Hematology 2019;24:331-6.
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  16. Iolascon A, Esposito MR, Russo R. Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: From morphology to molecular approach. Haematologica 2012;97:1786-94.
  17. Renella R, Hall G, Ferguson D, Wood W. Chapter 15. Congenital dyserythropoietic anemias. In: Porwit A, McCullough J, Erber WN, eds. Blood and bone marrow pathology. Second Edition. Churchill Livingstone; 2011:235-44.
  18. National Library of Medicine (US). Genetics Home Reference. X-linked sideroblastic anemia. Reviewed Apr 2009. (Accessed Dec 2019, Available at: https://ghr.nlm.nih.gov/condition/x-linked-sideroblastic-anemia#.)
  19. Lambert J-F, Beris P. Pathophysiology and differential diagnosis of anaemia. In: Beaumont C, Beris P, Beuzard Y, Brugnara C, eds. The handbook disorders of erythropoiesis, erythrocytes, and iron metabolism. Chapter 4. 2009:108-41.
  20. Prochaska MT, Newcomb R, Block G, Park B, Meltzer DO. Association between anemia and fatigue in hospitalized patients: Does the measure of anemia matter? J Hosp Med 2017;12:898-904.
  21. Badireddy M, Baradhi KM. Chronic anemia. Statpearls. Treasure Island (FL)2019.
  22. Escalante CP, Chisolm S, Song J, et al. Fatigue, symptom burden, and health-related quality of life in patients with myelodysplastic syndrome, aplastic anemia, and paroxysmal nocturnal hemoglobinuria. Cancer Med 2019;8:543-53.
  23. Merli F, Bertini M, Luminari S, et al. Quality of life assessment in elderly patients with aggressive non-Hodgkin’s Lymphoma treated with anthracycline-containing regimens. Report of a prospective study by the Intergruppo Italiano Linfomi. Haematologica 2004;89:973-8.
  24. Koutsavlis I. Transfusion thresholds, quality of life, and current approaches in myelodysplastic syndromes. Anemia 2016;2016:8494738.
  25. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): An international internet-based survey of 1179 MPD patients. Cancer 2007;109:68-76.
  26. The MDS Foundation, Bennett J, Greenberg P, Komrokji R, Kurtin S, List A. Building blocks of hope: Strategies for patients & caregivers living with MDS. (Accessed Jan 2020, Available at: https://www.mds-foundation.org/bboh/.)
  27. Lyle L, Hirose A. Iron overload in myelodysplastic syndromes: Pathophysiology, consequences, diagnosis, and treatment. J Adv Pract Oncol 2018;9:392-405.
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