Sickle Cell Anaemia

By: Ashleigh Robertson, Shannah del Rosario and Sharon Qiao (Xiaoxi)

LSB555: Principles and Practice of Clinical Haematology 

Case Study

  • A young 6 year old girl presented to ED with fever, tiredness, pallor and acute episodes of pain
  • Clinical examination: 
    • Icteric sclera
    • Splenomegaly
    • hand-foot syndrome (pain and swelling of fingers and toes)
  • Family immigrated from Nigeria 3 years ago
Empirical Dx: Sickle Cell Anaemia

Tests Requested: FBE and other relevant tests

What is Sickle Cell Anaemia?

  • Sickle cell anaemia is a haemoglobinopathy affecting normal haemoglobin production
  • Forms distinct sickle red blood cells

Genetics of Sickle Cell Disease

  • Sickle cell disease is autosomal recessive 
  • 25% chance of producing offspring with homozygous sickle cell disease - symptomatic phenotype
  • 50% chance of passing down sickle cell trait genotype [1]

Source: CDC Website [2]

What mutation causes Sickle Cell Disease?

HbA (normal Hb)

HbS

(Sickle cell Hb)

Source: BBC Website [3]

How does sickling occur?

• Glutamic acid has a net charge of -1 (polar)

• Polar glutamic acid would normally bind water molecules – soluble in cytosol

• Valine has a net charge of 0 (non-polar)

• Non-polar valine is hydrophobic [1]

Source: American Society of Hematology [4] 

How does sickling occur?

• Valine searches for hydrophobic niche to bind

• Oxygenated HbS has no hydrophobic niche – freely soluble

• Deoxygenated HbS creates hydrophobic pocket for valine from adjacent Hb to bind [1]

Source: New England Journal of Medicine [5] 

How does sickling occur?

• HbS molecules polymerise when deoxygenated

• Forming long, rigid fibres

• Sickling reversible by oxygenation of HbS molecules

• Extensive membrane damage can cause irreversible sickle cell formation [2]

Source: New England Journal of Medicine [5] 

Sickling manifestations

  • Chronic Haemolytic Anaemia
  • Microvascular occlusion
  • Tissue damage

Chronic Haemolytic Anaemia

• Sickle cells are fragile and more prone to haemolysis – shortened RBC lifespan

• Haemolysis of RBCs cause anaemia and hyperbilirubinaemia [6]

Empirical Dx:

Jaundice in sclera - hyperbilirubinaemia

Fatigue and pallor - haemolytic anaemia

 

Microvascular occlusion

• Occurs due to blockage of small vasculature by sickle cells

• Hypoxic injury to these vessels cause pain crisis

• Commonly occurs in the bones of the hands and feet

• Adhesion of sickle cells to endothelium promotes occlusion [6]

Empirical Dx:

Hand-Foot Syndrome - vaso-occlusive crises

Recurring episodes of acute pain - occlusion of microvasculature

 

Tissue damage

• Sickle cells commonly get trapped in the spleen 

• Can lead to splenic infarction, fibrosis, and progressive shrinkage – decreasing the functionality of the spleen

• Sickle cells can also cause infarctions in other tissues – causing organ failure [6]

Empirical Dx:

Splenomegaly - continuous screening and removal of sickle cells (Autosplenectomy)

 

Prevalence of Sickle Cell Anaemia

• Sickle Cell Anaemia is frequently found in West and Central Africa, as well as the Middle East and India [7]

Source: Encylopaedia Britannica Inc. [7] 

Occurrence of sickle cell anaemia parallels the incidence of endemic malaria – suggests protective adaptation with resistance against malaria parasite [7]

Source: Encylopaedia Britannica Inc. [7] 

Diagnosis of Sickle Cell Anaemia

Morphology on Peripheral Blood Smear

Peripheral Blood Smear [8]

Howell Jolly Bodies [10]

Sickle cell [8]

Target Cell [8]

Hypochromic Cell [9]

Polychromatic Cell [8]

Red Cell Fragment (Schistocyte) [11]

Full Blood Examination

   Patient Dx:
  • Hb - Decreased 
  • RCC - Decreased
  • Hct - Decreased
  • MCV - Normal
  • MCH - Normal
  • MCHC - Normal
  • RDW - Increased
  • WCC - Increased 
  • PLT - Increased

Source: [12],[13],[14]

Haemoglobin Electrophoresis

Source: American Society of Hematology [15]

Haemoglobin Electrophoresis

Source: Helena Laboratories [16]

High Performance Liquid Chromatography (HPLC)

Source: Universite Libre de Bruxelles [17]

Isoelectric Focusing (IEF)

Source: Universite Libre de Bruxelles [17]

Sickle Solubility Test - Sickledex

Source: Streck [18]

Negative

Positive

Treatment of Sickle Cell Anaemia

Treatment

  • Blood and Bone Marrow Transplantation
  • Hydroxyurea 
  • Treatment of complications

Blood and Bone Marrow Stem Cell Transplantation 

  • Sickle cell anaemia has no universal cure yet
  • A small number of people are cured by blood and bone marrow transplants [19]
  • Transplant aims to replace defective stem cells with normally functioning ones 
  • Normal function? Reject reaction? 
Before and after procedure:
  • HLA tissue typing
  • Chemotherapy
  • Side effect:
    • ​Infection
    • Graft-vs-Host Disease
    • Graft Failure

What's Next?

  • Slow recovery [19]
    • Takes 6-12 months to recover normal RBC levels and immune function
    • Monitor risk of infection
    • Some patients may need regular blood transfusion
Patient Rx:
  • Routine health care every 6 months
  • Eye check up
  • Ultrasound scan of brain
  • Penicillin and Folate acid
  • Parental education: learn to manage symptoms
  • Genetic counselling

Hydroxyurea

  • For severe sickle cell anaemia [19]
  • Increases production of Foetal Haemoglobin (HbF) 
  • Prevents RBC from sickling
  • Improve anaemia
  • Reduces painful sensation from sickle cell crises
  • Reduces chances of blocking small vessels
  • Reduces visits to hospital
​Hydroxyurea will manage patient's:
Fatigue and Pallor
Recurrent pain crises
Hand-Foot Syndrome

Management of complications

Source: National Institute of Health [19]

Any Questions?

References

[1] Keohane EM, Smith LJ, Walenga JM. Rodak’s Hematology: Clinical Principles and Application. 5th Edition. Elsevier Inc: 2012. Chapter 27, Hemoglobinopathies (Structural Defects in Hemoglobin); p. 431-6.

[2] CDC: Centers for Disease Control and Prevention. Sickle cell trait [Internet]. 2013 [cited 2015 Apr 24]. Available from: http://www.cdc.gov/ncbddd/sicklecell/traits.html

[3] BBC. Gene mutations [Internet]. 2014 [cited 2015 Apr 24]. Available from: http://www.bbc.co.uk/bitesize/higher/biology/genetics_adaptation/mutations/revision/1/

[4] Schechter A. Hemoglobin research and origins of molecular medicine [Internet]. American Society of Hematology. 2008 [cited 2015 Apr 24]. Available from: http://www.bloodjournal.org/content/112/10/3927?sso-checked=true

[5] Bunn FH. Pathogenesis and Treatment of Sickle Cell Disease. The New England Journal of Medicine, Vol 337. 1997 [cited 2015 Apr 24].

[6] Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran: Pathologic Basis of Disease. 8th edition. Elsevier Inc: 2010. Chapter 14, Anemias.

[7] Encyclopaedia Britannica Online. “Malaria and sickle cell anemia, distribution of” Map [Internet]. [cited 2015 Apr 24]. Available from: http://www.britannica.com/Ebchecked/topic/556001/South-Asia/images-videos/160694/malaria-and-sickle-cell-anemia-distribution-of

 [8] Chambers K. Blood smears from patients with sickle cell disease – part 3 [internet] Leicester, UK: De Montfort University; August 23, 2011 [cited 2015, April 26] available from: http://www.sicklecellanaemia.org/OER/article.php?id=68

[9] Maslak P. Hypochromic erythrocytes – 1 [internet] Washinton DC, USA: American Society of Hematology (ASH) ; March 04, 2009 [cited 2015, April 27] available from: http://imagebank.hematology.org/AssetDetail.aspx?AssetID=3901

[10] Maslak P. Howell-Jolly bodies– 1 [internet] Washinton DC, USA: American Society of Hematology (ASH) ; January 10, 2008 [cited 2015, April 27] available from: http://imagebank.hematology.org/AssetDetail.aspx?AssetID=3677

[11] Maslak P. Schistocytes – 1 [internet] Washinton DC, USA: American Society of Hematology (ASH) ; January 10, 2008 [cited 2015, April 27] available from http://imagebank.hematology.org/AssetDetail.aspx?AssetID=3718&AssetType=Asset

[12]  Valavi E, Ansari, M-J A, Zandian K, How to Reach Rapid Diagnosis in Sickle cell Disease? [internet] Iran J Pediatr, vol 20 (no 1) 69-74, March 2010 [cited 2015, April 28] available from www.bioline.org.br/pdf?pe10009

[13] Thame M, Grandison Y, Mason K, Thompson M, Higgs D, Morris J, Serjeant B, Serjeant G. The Red Cell Distribution Width in Sickle Cell Disease – is it of Clinical Value? [internet] Clinical and Laboratory Hematology volume 13 [p 229-237] September 1991 [cited 2015, April 26] available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.1991.tb00277.x/abstract

[14] Lichtin AE, Sickle Cell Disease [internet] Merck Manual, October 2013 [cited 2015, April 26] available from: www.merckmanuals.com/professional/hematology-and-oncology/anemias-caused-by-hemolysis/sickle-cell-disease

[15] Kuo K. Case Study: A 12-Year-Old Boy With Normocytic Anemia and Bone Pain [internet] American Society of Hematology (ASH) ©2015 [cited 2015, April 27] available from: http://www.hematology.org/Fellows/Case-Studies/725.aspx

[16] Helena Laboratories: Haemoglobin Electrophoresis Procedure [internet] Beaumont, Texas: Helena Laboratories [date unknown] [cited 2015, April 20] available from: http://www.helena.com/Procedures/Pro015%20Rev6.pdf

[17] Diagnosis, last updated 2001, August 16. [cited 2015, April 25] available from: http://erasmeinfo.ulb.ac.be/globule/English/sickle_diag.htm

[18] Streck, Sickledex [internet] Omaha, USA [date unknown] [cited 2015, April 27] available from: http://www.indianablood.org/lab-services/DonorTestingLab/Documents/Package%20Inserts-Donor%20Testing/Donor%20Tesing_Uploaded_8-22-2013/SICKLEDEX%20for%20Hgb-S.pdf

[19] National Institutes of Health, D.o.H.a.H.S., How Is Sickle Cell Anemia Treated. September 28, 2012.

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