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Sickle Cell Disease Pathogenesis Clinical Findings and Complications

Sickle Cell Disease: Pathogenesis, Clinical Findings, and Complications
DNA point mutation in chromosome 11 causes a substitution of glutamate to valine for the sixth amino acid of the β-globin chain
Authors: Yang (Steven) Liu Priyanka Grewal Reviewers: Alexander Arnold Luiza Radu JoyAnne Krupa Yan Yu* Lynn Savoie* * MD at time of publication
  Hemoglobin S (HbS) variant formed instead of normal Hemoglobin A (HbA)
  Hb electrophoresis shows approximately 45% HbS, 52% HbA (ααββ), 2% HbA
Hb electrophoresis shows approximately 90% HbS, 8% HbF, & 2% HbA .
No HbA present
  (ααδδ), & 1% HbF (ααγγ;2 fetal hemoglobin)
Heterozygous: point mutation in one of the two chromosomes (Hb AS)
Sickle cell trait
(asymptomatic unless severely hypoxic)
Homozygous: point mutation in both chromosomes (Hb SS)
Sickle cell disease
An inherited blood disorder characterized by defective hemoglobin that leads to red blood cells sickling
2
      Dehydration Hypoxemia
Acidosis
↓ Volume of RBC cytoplasm
↓ O2 Saturation of Hb
O morereadily 2
released from Hb in low pH environment
↑ Concentration of deoxygenated HbSinred blood cells (RBCs)
Hydrophilic glutamate→ hydrophobic valine substitution makes HbS less soluble in the cytoplasm & more prone to polymerization & precipitation in its deoxygenated state
↑ Concentration of deoxygenated Hb in RBC leads to ↑ polymerization rate Polymerized & precipitated HbS forms long needle-like fibers
        RBC shape becomes sickled
Sickle cells on peripheral blood smear
     Vaso-occlusion
(sickled RBCs lodge in small vessels, blocking bloodflow to organs & tissues)
Blockage of venous outflow
Occlusion of vessels in lungs ↑ pulmonary blood pressure
Fluid extravasates into interstitial tissue leading to pulmonary edema
Acute chest syndrome (chest pain, hypoxemia (↓blood oxygen), etc.)**
to the penis:
to the spleen:
Priapism (persistent, painful erection)
Splenic Sequestration (blood pools in spleenà splenomegaly & hypotension)
Extravascular hemolysis (macrophages in the spleen phagocytose sickled RBCs)
Normocytic anemia
↑Marrow erythropoiesis (RBC production) to compensate for hemolysis
                  Infarction of bone
Pain crises
If occurring in hands
Dactylitis (inflammation of digits)
Blockage of arteries ↓ oxygenation of organs & tissues
Vaso-occlusion of the splenic artery
Splenic infarction (↓ blood supply leads to tissue death)
RBC inclusions (structures found in RBCs) not removed by spleen
Howell-Jolly bodies (RBC DNA remnants) on blood smear
Vaso-occlusion of other arteries (cranial, renal, etc)
Stroke, renal failure
↑ RBC breakdown
↑ Unconjugated bilirubin released from RBC breakdown
RBC precursors (reticulocytes) are released into the blood stream
Reticulocytosis (increased number of immature red blood cells) on peripheral blood smear
Patient’s RBC level becomes dependent on increased marrow activity
Bone marrow infarction or viral infections (i.e. Parvovirus B19) suppresses bone marrow activity
Aplastic crises (profound anemia)
       ** See corresponding Calgary Guide slide(s)
↑ Serum level of unconjugated bilirubin
Some of the circulating unconjugated bilirubin deposits in the skin
Jaundice (yellowing of skin)
↑ Conjugation of bilirubin in liver
↑Amounts of conjugated bilirubin released into bile
Gallstone formation
Cholelithiasis (presence of gallstones in the gallbladder)
         Spleen releases invasive encapsulated bacteria (eg. Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) into circulation, which causes infections
         Meningitis
Sepsis
  Legend:
 Pathophysiology
Mechanism
Sign/Symptom/Lab Finding
 Complications
 Published Sept 16, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com