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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