Hematology - Red Cell Disorders

1. E-Learning Modules – machealth.ca/programs/hemoglobinopathy/

• Module 1: Andrea, 19-year old female with fatigue

• Module 2: Katrina, 28-year old female with sickle cell anemia and thigh pain

• Module 3: A Day in the Hematology Lab

• Module 4: Hany, 3-year-old boy with recurrent pain

• Module 5: Stephen, a 30 year old man with sickle cell disease

• Module 6: Rafail, an 11-year-old boy with beta thalassemia major

• Module 7: A Day At The Hematology Lab: Part 2

• Module 8: Akuba, a 32-year-old pregnant woman with HbSC

• Module 9: Emmanuel, a 16-year-old male with HbSS presenting for routine follow-up

• Module 10: Jenny, a 49-year-old woman with thalassemia and fatigue

• Module 11: Andre, a 48-year-old man with sickle cell disease for pre-op of total hip arthroplasty

• Module 12: Teresa, an 18-year-old woman with beta thalassemia major and cardiac complications of iron overload

2. Global Burden of Anemia

• Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood J 2015; 123: 615–25.

3. Introduction to Sickle Cell Disease and Thalassemia

• SCD Introduction

  • Ware RE, de Montalembert M, Tshilolo L, et al. Sickle cell disease. The Lancet 2017. 390(10091): 311-323.

  • Ezenwa MO, Yao Y, Molokie RE, et al. Coping with Pain in the Face of Healthcare Injustice in Patients with Sickle Cell Disease. J Immigr Minor Heal 2017. 19: 1449–56.

  • P. Goddu A, O’Conor KJ, Lanzkron S, et al. Do Words Matter? Stigmatizing Language and the Transmission of Bias in the Medical Record. J Gen Intern Med 2018. 33: 685–91.

• Thalassemia Introduction

  • Galanello R, Origa R. Beta-thalassemia. Orphanet Journal of Rare Diseases. 2010. 5: 11.

  • Harteveld C, Higgs D. Alpha-thalassemia. Orphanet Journal of Rare Diseases. 2010. 5: 13.

  • Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2009. 118(13): 3479-88.

  • Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassemias. Haematologica. 2013. 98(6): 833-44.

• Hemoglobin SC

  • Gualandro SFM, Fonseca GHH, Yokomizo IK, Gualandro DM, Suganuma LM. Cohort study of adult patients with haemoglobin SC disease: Clinical characteristics and predictors of mortality. Br J Haematol. 2015. 171: 631–7.

  • Naessens V, Ward R, Kuo KHM. A proposed treatment algorithm for adults with Haemoglobin SC disease. Br J Haematol 2018. 182: 607–9.

• Hypoxia

  • Machogu EM, Machado RF. How I treat hypoxia in adults with hemoglobinopathies and hemolytic disorders. Blood. 2018. 132: 1770–80.

• Introduction to Gene Therapy

  • Lidonnici MR, Ferrari G. Gene therapy and gene editing strategies for hemoglobinopathies. Blood Cells, Mol Dis 2018. 70: 87–101.

4. Transfusional Iron Overload and Chelation

• Wood JC. Estimating tissue iron burden: current status and future prospects. Br J Haematol 2015. DOI:10.1111/bjh.13374.

• Brittenham GM. Iron-chelating therapy for transfusional iron overload. NEJM. 2011. 364; 146-56.

• Fernandes JL. Iron chelation therapy in the management of transfusion-related cardiac iron overload.  Transfusion. 2012. 52(10): 2256-69.

• Hider RC, Hoffbrand AV. The role of deferiprone in iron chelation. N Engl J Med. 2018. 379: 2140–50.

• Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol. 2017. 178: 676–88.

5. Sickle Cell Disease – Prevention and Treatment of Specific Complications

• Stroke

  • Overview

    • Mack AK, & Thompson AA. Primary and secondary stroke prevention in children with sickle cell disease. Journal of Pediatric Health Care. 2017. 31(2): 145-154.

  • STOP trial

  • Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler Ultrasonography. NEJM 1998. 339(1): 5.

  • STOP2 trial

  • Adams RJ, et al. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. NEJM. 2005. 353 :2769-78.

  • SWITCH

    • Ware RE,  & Helms RW. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012. 119(17); 3925-3932.

  • TWITCH

    • Ware RE,  Davis  BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial Doppler flow velocities in children with sickle cell anaemia-TCD with transfusions changing to hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial. The Lancet. 2016. 387(10019): 661-670.

  • SIT

    • DeBaun MR, Gordon M, McKinstry RC, et al. Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia. N Engl J Med 2014. 371: 699-710.

• Penicillin Prophylaxis

  • Gaston MH, et al. Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. NEJM 1986. 314(25): 1593.

  • Faletta JM, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. J Pediatr 1995. 127(5): 685.

• VTE

  • Shet AS, Wun T. How I diagnose and treat venous thromboembolism in sickle cell disease. Blood. 2018. 132: 1761–9.

• Pre-operative transfusion in SCD

  • Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: A randomised, controlled, multicentre clinical trial. Lancet. 2013. 381: 930–8.

• Pregnancy

  • Canadian Haemoglobinopathy Association. Contraception, pre-conception counseling, and pregnancy in: Consensus statement on the care of Patients with sickle cell disease in Canada. Ottawa. 2015. 88-

  • Malinowski A, Shehata N, et al. Prophylactic transfusion for pregnant women with sickle cell disease: a systematic review and meta-analysis. Blood. 2015. 126(21): 2424

6. Sickle Cell Disease

• Treatments

  • Thein SL, Howard J. How I treat the older adult with sickle cell disease. Blood. 2018. 132: 1750–60.

• Hydroxyurea

  • MSH Trial - Charache S, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. NEJM 1995. 332(20); 1317.

  • BABY-HUG trial - Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: A multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011. 377: 1663–72.

  • Tshilolo L, Tomlinson G, Williams TN, et al. Hydroxyurea for children with sickle cell anemia in Sub-Saharan Africa. N Engl J Med 2019. 380: 121–31.

• Transfusion

  • Rees DC, Robinson S, Howard J. How I manage red cell transfusions in patients with sickle cell disease. Br J Haematol. 2018. 80(4): 607-617.

  • Biller E, Zhao Y, Berg M, et al. Red blood cell exchange in patients with sickle cell disease—indications and management: a review and consensus report by the therapeutic apheresis subsection of the AABB. Transfusion. 2018. 58: 1965–72.

• Targeted Therapies

  • Overview

    • Torres L, Conran N. Emerging pharmacotherapeutic approaches for the management of sickle cell disease. Expert Opin Pharmacother. 2019. 20: 173–86.

  • L-glutamine

    •  Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med. 2018.  379: 226–35.

  • Crizanlizumab

    • Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017.  376: 429–39.

  • Voxelotor

    • Vichinsky E, Hoppe CC, Kenneth I, et al. N Engl J Med. 2019. 381(6): 509-519.

7. Thalassemia Treatment – Transfusion, HSCT, Gene Therapy and Targeted Therapies

• Cazzola M, et al. Relationship between transfusion regimen and suppression of erythropoiesis in beta thalassemia major. British J Haematol 1995. 89; 473-478.

• Taher AT, Cappellini MD. How I manage medical complications of b-thalassemia in adults. Blood. 2018. 132: 1781–91.

• Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018. 378: 1479–93.

• Luspatercept

  • Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289

 Clinical Readings and e-Modules: Weeks 1 -4

Lab Learning: Weeks 5 - 8

1. Identification of hemoglobin variants and thalassemias (Beta variant, Alpha variant, beta thal, alpha thal etc. and combinations)

• 1 to 2 teaching sessions

Post-session mandatory readings:

1. Sickle cell haemoglobin and its interactions with other variant haemoglobins and with thalassemias (Chapter 4, Haemoglobinopathy Diagnosis book)

2. Other significant haemoglobinopathies (Chapter 5, Haemoglobinopathy Diagnosis book)

2. Reporting of Hemoglobinopathy and Hemolytic Screens 

• Several teaching sessions

Mandatory readings:

1. Organization of a haemoglobinopathy diagnostic service (Chapter 7, Haemoglobinopathy Diagnosis book)

2. Self-assessment test cases (Chapter 8, Haemoglobinopathy Diagnosis book)

3. Review of testing for rare hemoglobin variants (Unstable Hb testing, oxygen affinity testing (P50), Hb M spectral scan)

• Teaching session and lab instructional videos:

  • P50

  • Unstable

  • P5N

4. Molecular diagnosis of hemoglobin variants

• Teaching session with Barry Eng