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Sickle cell disease



Last author update: 25 January 2023
Last staff update: 25 January 2023

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PubMed Search: Sickle cell disease

Yvette C. Tanhehco, Ph.D., M.D., M.S.
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Cite this page: Tanhehco Y. Sickle cell disease. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedsicklecell.html. Accessed February 8th, 2023.
Definition / general
  • Sickle cell disease is a hemoglobinopathy caused by a point mutation in the β globin gene that leads to the production of hemoglobin S, which polymerizes under deoxygenated conditions and causes red blood cells (RBCs) to form a sickle shape
  • Sickle RBCs result in hemolysis, vaso-occlusive pain crises and endothelial damage
Essential features
  • Sickle cell disease is caused by a single point mutation in the β globin gene that results in the production of hemoglobin S, which polymerizes under deoxygenated conditions and causes RBCs to sickle (Lancet 2010;376:2018)
  • Sickle RBCs are rigid and less deformable, which causes vaso-occlusive pain crises, hemolytic anemia, endothelial injury and inflammation (Lancet 2010;376:2018)
  • Complications of sickle cell disease include stroke, acute chest syndrome, priapism, multiorgan failure, splenic / hepatic sequestration, intrahepatic cholestasis, aplastic crisis, pulmonary hypertension and avascular necrosis
  • Current treatment options include simple and exchange RBC transfusions, disease modifying drug therapies and hematopoietic stem cell transplantation (Lancet 2017;390:311)
  • Sickle cell trait is protective against the parasite Plasmodium falciparum
Terminology
  • Sickle cell anemia
Pathophysiology
  • Single point mutation (A to T substitution) in the first exon of the β globin gene, converting glutamic acid into valine
  • Defective hemoglobin tetramers are formed (Hemoglobin S, Hgb S) that polymerize under deoxygenated conditions
  • Polymerized Hgb S causes RBCs to form a sickle shape
  • Sickle RBCs are rigid, less deformable and have a shortened lifespan of 10 - 20 days
  • Rigid sickle RBCs lead to hemolysis, vascular occlusion, endothelial injury and inflammation
  • Patients have hemolytic anemia and experience vaso-occlusive pain crises
  • Sickle RBCs and leukocytes adhere to the vascular endothelium, causing vascular obstruction and tissue ischemia
  • Chronic inflammation with an increased risk of thrombosis especially during vasooclussive event (J Thromb Thrombolysis 2013;35:352)
  • Immunocompromised due to autoinfarction of spleen or surgical splenectomy (Birth Defects Orig Artic Ser 1975;11:322)
  • Have hypercoagulable state based on thermoelastographic profiles (Arch Pathol Lab Med 2005;129:760, J Clin Pathol 1980;33:622)
Diagrams / tables

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Pathophysiology

Clinical features
  • Stroke
  • Acute chest syndrome
  • Priapism
  • Multiorgan failure
  • Splenic / hepatic sequestration
  • Intrahepatic cholestasis
  • Aplastic crisis
  • Pulmonary hypertension
  • Avascular necrosis
  • Reference: J Clin Med 2021;10:4232
Transmission
  • Autosomal recessive gene inheritance pattern
  • Variable genotypes: SS, SC, S/β0 thalassemia, S/β+ thalassemia, SD, SE are common ones
  • Reference: Lancet 2010;376:2018
Symptoms
Screening
  • Newborn screening is performed as early as 24 - 48 hours after birth
  • Methods used to detect the presence of Hgb S include gel electrophoresis and high performance liquid chromatography (HPLC) (Syst Rev 2020;9:250)
  • Confirmatory testing is performed for positive screen results
Blood donor screening
  • Donors with sickle cell disease are not eligible to donate blood; donors with sickle cell trait may be eligible
  • Blood with sickle cell trait often causes failure of leukocyte reduction filters and may be deferred due to this
Laboratory
  • Positive for anemia: low hemoglobin, low hematocrit, low RBC, high reticulocyte
  • Positive for hemolysis: low haptoglobin, high lactate dehydrogenase, high total bilirubin, high indirect bilirubin
  • Positive for Hgb S: high hemoglobin S
  • Positive for inflammation: high C reactive protein, high erythrocyte sedimentation rate
  • Positive for iron studies if chronically transfused and iron overloaded: high serum ferritin, high serum iron, high serum transferrin saturation, low total iron binding capacity
  • Associated with increases in thrombin generation, fibrinolytic activation, platelet activation, increased antiphospholipid antibodies, decreased levels of circulating anticoagulants and contact factors
  • Also increased circulating levels of tissue factor and endothelial cells expressing a tissue factor phenotype
  • Reference: Ann Intern Med 2021;174:ITC1
Laboratory images

Contributed by Patricia Tsang, M.D., M.B.A.
Sickle cell trait

Sickle cell trait

SS hemoglobin

SS hemoglobin

Alkaline gel hemoglobin electrophoresis

Alkaline gel hemoglobin electrophoresis

Case reports
Treatment
Microscopic (histologic) description
  • May have increased normoblasts and megaloblastic changes due to folate deficiency
  • Increased perivascular fibrosis in small and medium sized vessels (Arch Pathol Lab Med 2004;128:634)
  • Occasional aplastic crisis
Peripheral smear images

Contributed by Patricia Tsang, M.D., M.B.A.
Sickle cell blood smear

Sickle cell blood smear

Positive stains
Sample assessment & plan
  • Patient with sickle cell disease (Hgb SS) and a history of stroke, priapism and vaso-occlusive pain crisis presented with shortness of breath and was subsequently diagnosed with acute chest syndrome. Hemoglobin S level found to be 80%. Patient to undergo red blood cell exchange with 8 units of ABO compatible and crossmatch compatible packed RBCs that are Rh and K antigen matched, leukocyte reduced, irradiated and Hgb S negative. Post procedure target Hgb S is less than 30% and target hematocrit is 27%.
Board review style question #1
A 12 year old girl with sickle cell disease presents to the emergency department with fever (102 °F), difficulty breathing, cough and chest pain. Her mother reported that the patient had a cold 2 weeks ago. On physical exam, her vitals were T 102 °F, BP 100/60, P 80, RR 25 and SaO2 80%. She was coughing and appeared to be in pain. No other abnormal findings were noted. A chest Xray was performed and showed a new pulmonary opacity. Her hematocrit was 15% and Hgb S level was 75%.

What is the most likely diagnosis for the patient?

  1. Acute chest syndrome
  2. Asthma
  3. Influenza
  4. Pneumonia
Board review style answer #1
A. Acute chest syndrome

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Reference: Sickle cell disease
Board review style question #2
A 12 year old girl with sickle cell disease presents to the emergency department with fever (102 °F), difficulty breathing, cough and chest pain. Her mother reported that the patient had a cold 2 weeks ago. On physical exam, her vitals were T 102 °F, BP 100/60, P 80, RR 25 and SaO2 80%. She was coughing and appeared to be in pain. No other abnormal findings were noted. A chest Xray was performed and showed a new pulmonary opacity. Her hematocrit was 15% and Hgb S level was 75%.

The patient is being managed with red blood cell exchange. What should the target hematocrit (Hct) and Hgb S levels be?

  1. Hct > 30%, Hgb S < 30%
  2. Hct > 30%, Hgb S > 30%
  3. Hct < 30%, Hgb S < 30%
  4. Hct < 30%, Hgb S > 30%
Board review style answer #2
C. Hct < 30%, Hgb S < 30%

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Reference: Sickle cell disease
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