The Physiotherapy Management of Thalassaemia and Sickle Cell Anaemia

Original Editors - Mariam Hashem

Top Contributors - Mariam Hashem and Kim Jackson 

Thalassaemia

IMAGE Thalassaemia Shutterstock License Download.jpg

Thalassaemia is one of the most common inherited diseases. It is defined as an autosomal recessive blood disorder that results from reduction or absence in the production of globin chains that make up the haemoglobin (Hb) leading to abnormal destruction of erythrocytes and consequently decreased oxygen delivery[1][2]. As a result, patients have a range of symptoms and complications that impose a large burden on individuals and the healthcare systems[3].

Thalassaemia is derived from the Greek word "Thalassa" which means ''sea''[4]. It's also referred to as ''Mediterranean Anaemia''. It mainly affects individuals originating from the Mediterranean area, Middle East, Transcaucasia, Central Asia, Indian subcontinent, and Southeast Asia[5].

There are two types of Thalassaemia: α- and β- depending on the type of the involved globin chain. Alpha Thalassaemia is developed when the alpha gene is affected and likewise, in beta-thalassemia, the globin chain that is affected or the abnormal haemoglobin involved is the beta-globin gen[6].

The prevalence rate is about 4.4 of every 10000 live births globally and approximately about 5% of all population[5]. It is estimated that there are 270 million carriers of Alpha thalassemia genes. More than 95% of children have alpha thalassemia are Asian, Indian, or Middle Eastern[7]. About 80 to 90 million people are carriers of β-thalassemia genes, that’s about 1% to 1.5% of the worldwide population[8]

It has been estimated that globally 9million carriers of Thalassaemia and Sickle cell anaemia become pregnant each year[9].

[10]

Clinically, Thalassemia is classified into three forms[6]:

  • Thalassemia major: this is a severe form of anaemia where patients need continuous blood transfusions throughout their lives.
  • Thalassemia intermedia: mild to moderate anaemia, patients occasionally need blood transfusions
  • Thalassemia minor or trait: patients have mild symptoms and they usually don’t need blood transfusions.

The Alpha haemoglobin chain is formed of four genes. Alpha Thalassaemia is classified according to the number of mutated genes[11][5]:

  • A person is a carrier when one gene is mutated
  • Alpha Thalassaemia Trait: when two genes are mutated leading to mild manifestations
  • Alpha Thalassaemia Major: when three genes are mutated leading to moderate to severe symptoms
  • Rarely,  four genes might be mutated leading to an early death.

Beta haemoglobin chain is formed of two genes[5]:

Beta Thalassaemia Minor develops when one gene is mutated. Patients experience mild symptoms

Cooley's Anaemia or Beta Thalassaemia Major develops when two genes are mutated leading to moderate to severe manifestation

Thalassaemia class 2.png

Symptoms & Complications

The severity of symptoms depends on the type and number of mutated genes. Thalassaemia has different symptoms[12][5]:

  • Pain
  • Fatigue
  • Brittle bones
  • Poor appetite
  • Liability to infection
  • Dark urine
  • Generalized body weakness

Complications[5]:

  • Anaemia due to the deficiency of haemoglobin.
  • Hepatosplenomegaly: abnormal enlargement of the abdomen.
  • Iron overload as a result of repeated blood transfusion. Consequently, a patient may develop further complications such as:
  1. Endocrine complications such as diabetes, glucose intolerance, decreased production of growth hormone and hypogonadism
  2. Cardiac disorders, for example, congestive heart failure or arrhythmias
  3. Hepatic disorders such as cirrhosis and liability to have HCV

Diagnosis[13]:

The diagnosis is based on the Red Blood Cells (RBC) count specifically the number of erythrocytes.

Another important blood marks in the diagnosis of Thalassaemia are genetic testing, Haemoglobin electrophoresis and reticulocyte count (the number of young RBCs formed from bone marrow)

Medical management[14]:

Although Thalassaemia has a wide range of symptoms and classifications, there are general principals of medical management.

Accurate diagnosis is crucial. The family history should be documented and studied to help assess relative risks and future decisions of the family. Medical management includes[5]:

  • Regular transfusions with observations to prevent unnecessary complications [15]
  • Folic acid supplements are also included in the long term management
  • Chelation therapy which refers to the extraction the iron excess to prevent iron overload.
  • STEM cell transplantation
  • Genetic therapy
  • Bone marrow transplantation.
  • Psychological therapy

Sickle Cell Anaemia

Sickle Cell block.jpg

Sickle cell anaemia is an autosomal recessive inherited group of blood disorders characterized by the presences of atypical haemoglobin molecules (haemoglobin S) leading to distortion of erythrocytes red blood cells into a sickle, or crescent, shape. It is characterized by the presences of abnormal haemoglobin, excessive erythrocytes destruction. The crescent or sickle-shaped erythrocytes are approximately 15 microns[16].

Sickle cell anaemia was diagnosed in 1910 by Dr Ernest who described the red blood cells of a patient with anaemia symptoms as “having the shape of a sickle”[17]

[18]

Sickle Cell Anemia is inherited in an autosomal recessive manner due to mutation of the HBB gene leading to Hemoglobin S production[19]

Sickle Cell Anemia inheritance model.jpg

Sickle Cell anaemia mainly affects people with African origins but it has spread globally. The estimated prevalence rate is 250,000 children are born annually with sickle cell anaemia worldwide[20]. Around  1% of all births in Africa are inheriting sickle cell disease, causing  6–15% of all deaths in children younger than 5 years[21].

SC prevelence.PNG

Classification

There are several types of sickle cell anaemia but the most common are: Sickle Cell Anemia (SS), Sickle Hemoglobin-C Disease (SC), Sickle Beta-Plus Thalassemia and Sickle Beta-Zero Thalassemia[22].

Sickle Hemoglobin-D Disease (Hemoglobin SD), Hemoglobin SE, And Sickle Hemoglobin-O Disease (Hemoglobin SO) are less common  and are usually less severe types[23]

Type Inheritance Population Characteristics Severity
Sickle Cell Anemia (SS), also known as Hemoglobin SS Disease The child inherits one substitution beta-globin genes (the sickle cell gene) from each parent. African and Indian descents. The most common type The most severe type
Sickle Hemoglobin- C Disease (SC) known as Hemoglobin SC Disease The child inherits haemoglobin beta S gene from one parent and the haemoglobin C gene from the other. West African, Mediterranean and Middle Eastern descents. It is the second most common sickle cell anaemia type. Some normal beta haemoglobin is produced but in reduced amounts. As there is a production of some normal haemoglobin, this leads to less severe form than haemoglobin SS disease.
Sickle Beta-Plus Thalassemia Known as Hemoglobin SB+ (Beta) Thalassemia The child inherits haemoglobin beta S gene from one parent and a haemoglobin beta plus thalassemia gene from the other parent. Mediterranean and Caribbean descents Some normal beta haemoglobin is produced but in reduced amounts. This is a less severe type than haemoglobin SS disease. Symptoms are milder than Sickle Cell Anemia (SS) and Sickle Hemoglobin- C Disease (SC) but complications can still be developed.
Sickle beta zero thalassemia Haemoglobin S is inherited from one parent and haemoglobin beta0 thalassemia gene mutation is inherited from the other parent Eastern Saudi Arabia It has similar symptoms Sickle Cell Anemia (SS) type. The body only produces haemoglobin S. Less severe

Manifestations

The severity of the sickle cell anaemia varies from person to another. People with sickle cell disease can experience acute and chronic signs, symptoms, and various complications[5].

Sings and Symptoms[24]:

Complications[24]:

  • Acute chest syndrome
  • Acute pain crisis
  • Brain complications eg. a clinical /silent stroke
  • Chronic pain
  • Delayed growth and puberty
  • Eye problems
  • Gallstones
  • Heart problems
  • Infections. 
  • Joint complications
  • Kidney complications
  • Leg ulcers. 
  • Liver complications
  • Pregnancy complications

Diagnosis

The most common blood tests used for Sickle cell Anemia diagnosis are [25]:

  • Haemoglobin electrophoresis
  • High-performance liquid chromatography (HPLC)
  • Deoxyribonucleic acid (DNA) testing

Medical Management 

Blood Transfusion and STEM cell transplantation are used in the management od Sickle Cell anaemia

Also, Medications are used mainly to reduce the frequency of pain crises in sickle cell anaemia[26]:

  • Hydroxyurea (Droxia, Hydrea, Siklos). 
  • L-glutamine oral powder (Endari). 
  • Crizanlizumab (Adakveo). 
  • Pain-relieving medications
  • Voxelotor (Oxbryta) -> Improves the anaemia

Role of Physiotherapy in the management of Thalassaemia and Sickle Cell Anaemia

Physiotherapy can help in the management of thalassemia and sickle cell anaemia symptoms [27] Thalassemia was proven to have a negative impact on pain, muscle strength, functional ability and quality of life in terms of physical, emotional, social and school functioning when compared to healthy children[28].

Benefits of Physical Activity

Children with thalassemia and sickle cell anaemia experience low physical activity. Low-to-moderate intensity exercises can be helpful in improving physical activity and improve bone strength[29].

The Center for Disease Control (CDC) recommends 60 minutes of physical activity per day with thalassemia and recommends a minimum of 150 minutes of moderate activity every week[30].

A study of sickle cell anaemia randomly allocated 40 patients into two groups. One group assigned to follow their normal daily routine and the second group was assigned 40-minute moderate-intensity stationary bicycle workouts three times a week. After eight weeks, biopsies were taken from the thigh muscles of participants. The samples showed that the exercises group had a significant increase in the capillaries density, increase in the number of capillaries around muscle fibre, and increase in the surface area through which oxygen and nutrients can flow between blood and muscle[29].

Eight weeks Aerobic exercise program was shown to reduce Ferritin and increase iron-binding capacity in girls with Thalassemia minor[31].

Pain Management

One of the most common problems affecting patients with thalassemia and sickle cell anaemia is pain.[32]. Physiotherapy can help patients to manage their pain using different techniques and strategies:

Breathing Exercises

Regular breathing can help in reducing catheter pain in children with thalassaemia[33]. Breathing exercises were also found to help with pain during Venipuncture due to its analgesic effect[34]. This effect can also be achieved when combined with spirometry[35].

Distraction techniques: such as breathing Exercises and bubble-making was proven to reduce catheter insertion pain in children with thalassemia[34][35].

Transcutaneous electrical nerve stimulation(TENS) has been used in a variety of acute and chronic painful conditions but has not been studied in Sickle Cell Disease pain crises yet[36].

Pulmonary Functions

Pulmonary functions and lung capacity were found to be reduced in patients with thalassemia and sickle cell anaemia such as forced vital capacity (FVC), forced expiratory flow in the first second (FEV 1) Functional capacity, anaerobic threshold and O2 pulse; indicating a restrictive pulmonary dysfunction[37][38]

Whole Body Vibration

A study of thirty-nine children with β-thalassemia major, Whole body vibration was shown to improve the bone mineral density and functional capacity[39].

Fluidotherapy

Fluidized therapy (Fluidotherapy) it is a high-intensity heat modality consisting of a dry whirlpool of finely divided solid particles suspended in a heated air stream. The mixture has the properties of liquids and provides tactile stimulation while allowing space for performing active range of motion[40]

Fluidotherapy® has shown to decrease hospitalization time and dependency on analgesics. It also improved joints range of motion and gait in patients with sickle cell anaemia[41]

[42]

Hydrotherapy

A study investigated a hydrotherapy program consisting of stretching, aerobics and relaxation exercises in warm water( 34°C ) for 45 minutes, twice a week, for 10 sessions. The study reported improvement in muscle strength, quality of life and decrease in pain[43]

References

  1. Medline Plus. Thalassemia [Internet]. US National Libraray of Medicine. 2020 [cited 2020 Jul 21]. Available from: https://medlineplus.gov/ency/article/000587.htm
  2. Cao A, Kan YW. The prevention of thalassemia. Cold Spring Harbor perspectives in medicine. 2013 Feb 1;3(2):a011775.
  3. Lai K, Huang G, Su L, He Y. The prevalence of thalassemia in mainland China: evidence from epidemiological surveys. Scientific reports. 2017 Apr 19;7(1):1-1.
  4. Saggar SA. Thalassemia: Cultural and Historical Perspectives [Internet]. Science Museum. 2019 [cited 2020 Jul 12]. Available from: https://blog.sciencemuseum.org.uk/thalassemia-cultural-and-historical-perspectives/
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Kora A. The Physiotherapy Management of Thalassaemia and Sickle Cell Anaemia. Physioplus Course 2020
  6. 6.0 6.1 Aszhari FR, Rustam Z, Subroto F, Semendawai AS. Classification of thalassemia data using random forest algorithm. InJournal of Physics: Conference Series 2020 Mar 1 (Vol. 1490, No. 1, p. 012050). IOP Publishing.
  7. Cheerva A. What is the global prevalence of alpha thalassemia syndromes? [Internet]. Medscape. 2018 [cited 2020 Jul 18]. Available from: https://www.medscape.com/answers/955496-156159/what-is-the-global-prevalence-of-alpha-thalassemia--thalassemia-syndromes
  8. Prevalence and Clinical Presentation of Beta Thalassemia [Internet]. HCPLive Network. 2020 [cited 2020 Jul 18]. Available from: https://rarediseases.org/rare-diseases/thalassemia-major/
  9. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bulletin of the World Health Organization. 2008;86:480-7.
  10. What is Thalassemia? . Available from:https://www.youtube.com/watch?v=JxuupecxHO8[last accessed 30/09/2020]
  11. Thalassemia [Internet]. Mayo Foundation for Medical Education and Research. 2020 [cited 2020 Jul 21]. Available from:https://www.mayoclinic.org/diseases-conditions/thalassemia/symptoms-causes/syc-20354995
  12. Nienhuis AW, Nathan DG. Pathophysiology and clinical manifestations of the β- thalassemias. Cold Spring Harb Perspect Med. 2012;2(12):1–13.
  13. Clevland Clinic. Thalassemias: Diagnosis and Tests [Internet]. 2020 [cited 2020 Jul 21].Available from: https://my.clevelandclinic.org/health/diseases/14508-thalassemias/diagnosis-and-tests
  14. Olivieri NF, Brittenham GM. Management of the thalassemias. Cold Spring Harb Perspect Med. 2013;3(6):1–14.
  15. Allen A, Fisher C, Premawardhena A, Peto T, Allen S, Arambepola M, Thayalsutha V, Olivieri N, Weatherall DBlood. 2010 Dec 9; 116(24):5368-70.
  16. Robinson IB, Sarnat BG. Roentgen Studies of the Maxillae and Mandible in Sickle-Cell Anemia. Radiology [Internet]. 1952 Apr 1;58(4):517–23. Available from: https://doi.org/10.1148/58.4.517
  17. Winter WP. A Brief History of Sickle Cell Disease [Internet]. Howard University Hospitals. 2020 [cited 2020 Aug 3]. Available from: http://www.sicklecell.howard.edu/ABriefHistoryofSickleCellDisease.htm
  18. 44,211 views•Nov 10, 2011 163 4 SHARE SAVE DNA Learning Center 36.3K subscribers Sickle cell anemia is a genetic disease that affects hemoglobin, the oxygen transport molecule in the blood. Originally created for DNA Interactive ( http://www.dnai.org ). TRANSCRIPT: Sickle cell anemia is a genetic disease that affects hemoglobin, the oxygen transport molecule in the blood. The disease gets its name from to the shape of the red blood cells under certain conditions. Some red blood cells become sickle-shaped and these elongated cells get stuck in small blood vessels so that parts of the body don't get the oxygen they need. Sickle cell anemia is caused by a single code letter change in the DNA. This in turn alters one of the amino acids in the hemoglobin protein. Valine sits in the position where glutamic acid should be. The valine makes the hemoglobin molecules stick together, forming long fibers that distort the shape of the red blood cells, and this brings on an attack. Up next AUTOPLAY 5:29 NOW PLAYING Sickle Cell Disease academiadeciencia 650K views 9 years ago 4:41 NOW PLAYING How this disease changes the shape of your cells - Amber M. Yates TED-Ed 486K views 1 year ago 8:55 NOW PLAYING Pathophysiology of Sickle Cell Anemia tootRN, LLC. 80K views 6 years ago 56:40 NOW PLAYING Yuval Noah Harari and Tristan Harris interviewed by Wired Yuval Noah Harari 99K views 1 year ago 5:34 NOW PLAYING Phenylketonuria - causes, symptoms, diagnosis, treatment, pathology Osmosis 60K views . Available from:https://www.youtube.com/watch?v=ZSpFVPBEeLk[last accessed 30/09/2020]
  19. Mumal I. Inheritance of Sickle Cell Disease [Internet]. Sickle Cell Disease News. 2020 [cited 2020 Aug 3]. Available from: https://sicklecellanemianews.com/inheritance-sickle-cell-anemia/
  20. Lervolino LG, Baldin PEA, Picado SM, Calil KB, Viel AA, Campos LAF. Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev Bras Hematol Hemoter. 2011;33(1):49–54. 
  21. Uyoga S, Macharia AW, Mochamah G, Ndila CM, Nyutu G, Makale J, et al. The epidemiology of sickle cell disease in children recruited in infancy in Kilifi, Kenya: a prospective cohort study. Lancet Glob Heal [Internet]. 2019;7(10):e1458–66. Available from: http://dx.doi.org/10.1016/S2214-109X(19)30328-6
  22. Types of Sickle Cell Disease [Internet]. Sickle Cell Association of the National Capital Area. 2017 [cited 2020 Aug 3]. Available from: http://scancainc.org/learn/types-of-sickle-cell-disease/
  23. Types of Sickle Cell Anemia [Internet]. Global Blood Therapeutics Inc. 2020 [cited 2020 Aug 3]. Available from: https://sicklecellspeaks.com/understanding-sickle-cell/types-of-sickle-cell/
  24. 24.0 24.1 Sickle Cell Disease [Internet]. National Heart, Lung and Blood Institute. 2020 [cited 2020 Aug 3]. Available from: https://www.nhlbi.nih.gov/health-topics/sickle-cell-disease
  25. Diagnostic Screening for Sickle Cell Disease [Internet]. St. Jude Children’s Research Hospital. 2020 [cited 2020 Aug 3]. Available from: https://www.stjude.org/treatment/disease/sickle-cell-disease/diagnosing-sickle-cell.html
  26. Sickle Cell Anemia [Internet]. Mayo Clinic. 2020 [cited 2020 Aug 3]. Available from: https://www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/diagnosis-treatment/drc-20355882
  27. Jadhav D, Agrawal P, Fernandes S, Mathur R, Vishwakarma U, HN R, et al. Thalassemia: Impact of Physiotherapy. Pediatr Hematol Oncol J [Internet]. 2018;3(3):S38. Available from: https://doi.org/10.1016/j.phoj.2018.11.108
  28. Hakeem GLA, Mousa SO, Moustafa AN, Mahgoob MH, Hassan EE. Health-related quality of life in pediatric and adolescent patients with transfusion-dependent ß-thalassemia in upper Egypt (single center study). Health Qual Life Outcomes. 2018;16
  29. 29.0 29.1 Preidt R. Time to Rethink Ideas About Exercise, Sickle Cell Disease? [Internet]. HealthDay. 2019 [cited 2020 Jul 22]. Available from: https://www.usnews.com/news/health-news/articles/2019-11-19/time-to-rethink-ideas-about-exercise-sickle-cell-disease
  30. Goldberg E, Fung E, Gaine S. The Benefits of Exercise [Internet]. Northern California Comprehensive Thalassemia Center. 2017 [cited 2020 Jul 22]. Available from: https://thalassemia.com/exercise-and-thalassemia.aspx#gsc.tab=0
  31. Heidary H, Bijeh N, Javahery SAAH, Abrishami F. The Effect of eight weeks of Aerobic Training on Hematological Indices in β-Thalassemia Minor Patients in Kermanshah. QHMS [Internet]. 2011 Oct 1;17(3):20–8. Available from: http://hms.gmu.ac.ir/article-1-1281-en.html
  32. Ballas SK, Darbari DS. Review/overview of pain in sickle cell disease. Complement Ther Med [Internet]. 2020;49:102327. Available from: https://doi.org/10.1016/j.ctim.2020.102327
  33. Bagheriyan S, Borhani F, Abbaszadeh A, Ranjbar H. The effects of regular breathing exercise and making bubbles on the pain of catheter insertion in school age children. Iran J Nurs Midwifery Res [Internet]. 2011;16(2):174–80. Available from: https://pubmed.ncbi.nlm.nih.gov/22224103
  34. 34.0 34.1 Bagheriyan S, Borhani F, Abbaszadeh A, Miri S, Mohsepour M, Zafarnia N. Analgesic effect of regular breathing exercise with the aim of distraction during venipuncture in school aged thalassemic children. Irian J Pediactric Hematol Oncol. 2012;12(3):116–22. 
  35. 35.0 35.1 Matthie N, Brewer CA, Moura VL, Jenerette CM. Breathing exercises for inpatients with sickle cell disease. MEDSURG Nurs. 2015;24(1):35–8. 
  36. Al-Jafar H. Non-Conventional Pain Management for Sickle Cell Disease. Ann Hematol Oncol. 2017;4(7).
  37. El-tagui M, Salama K, Salama HM, Mahmoud MM, Massoud HH, El-batanony M, et al. Spirometry and Cardiopulmonary Exercise Performance in Patients with Thalassemia Major. Med J Ca. 2009;77(1):523–8. 
  38. Vieira AK, Alvim CG, Carneiro MCM, Ibiapina C da C. Pulmonary function in children and adolescents with sickle cell disease: Have we paid proper attention to this problem? J Bras Pneumol. 2016;42(6):409–15. 
  39. Eid MA, Aly SM. Effect of whole body vibration training on bone mineral density and functional capacity in children with thalassemia. Physiother Theory Pract [Internet]. 2019 Jun 10;1–8. Available from: https://doi.org/10.1080/09593985.2019.1625089
  40. aetna. Fluidized Therapy (Fluidotherapy) [Internet]. 2019 [cited 2020 Jul 27]. Available from: http://www.aetna.com/cpb/medical/data/400_499/0450.html
  41. Alcorn R, Bowser B, Henley EJ, Holloway V. Fluidotherapy® and Exercise in the Management of Sickle Cell Anemia: A Clinical Report. Phys Ther [Internet]. 1984 Oct 1;64(10):1520–2. Available from: https://doi.org/10.1093/ptj/64.10.1520
  42. fluidotherapy. Available from:https://www.youtube.com/watch?v=_NAYuPgfgp0[last accessed 30/09/2020]
  43. Tinti G, Somera R, Valente FM, Domingos CR. Benefits of kinesiotherapy and aquatic rehabilitation on sickle cell anemia. A case report. Genet Mol Res. 2010;9(1):360–4.