SEARCH RESULTS FOR: Thalassemia

Pathogenesis of Beta Thalassemia

Beta Thalassemia Signs Symptoms Treatment

Alpha Thalassemia Pathogenesis

Hemolytic Anemia - Pathophysiology

Hemolytic Anemia: Pathophysiology behind the Normocytic Anemia Note • Extreme bone marrow compensation for hemolysis (↑ RBC synthesis/reticulocytosis) may result in slightly macrocytic anemia (because reticulocytes have larger volumes than RBCs) Defects in the RBC’s environment Defects in RBC membranes Ex. Hereditary Spherocytosis: mutation causing deficiency of RBC structural proteins like ankyrin or spectrin RBC membranes become weakened and form blebs that break off ↓ RBC surface area while volume remains constantà RBC becomes spherical Spherocytes in spleen trapped and phagocytosed by splenic macrophages (extravascular hemolysis) Defects in RBC internal contents (thalassemia, hemoglobinopathies, and metabolic defects) Ex. Sickle Cell Disease: point mutation in hemoglobin (Hgb) structure (GluàVal) Inappropriate Hgb polymerization in low oxygen environments due to mutationàRBC becomes rigid, forms a sickle shape Inflexible RBCs become trapped in the spleen’s sinusoid membranes àphagocytosed by splenic macrophages (extravascular hemolysis) Infection triggers immune system activation Autoimmune processes TTP/HUS (abnormal platelet aggregation blocking blood vessels) Production of abnormal antibodies and immune complexes targeted against RBC surface antigens Immunoglobulin-bound RBCs are marked for destruction by the immune system (by either the cell- mediated or complement- mediated pathways) DIC (fibrin deposition blocking blood vessels) Artificial heart valve RBCs are sheared when they flow past an abnormal surface Rate of hemolytic RBC destruction > rate of bone marrow RBC synthesis (reticulocytosis) ↓ total number of RBCs in the body (despite normal RBC production/volume) Normocytic anemia Authors: Yan Yu Katie Lin Man-Chiu Poon* Reviewers: Andrew Brack Julia Heighton JoyAnne Krupa Lynn Savoie* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 15, 2019 on www.thecalgaryguide.com

beta-thalassemia-minor

Beta Thalassemia Minor: Pathogenesis and clinical findings Authors: Andrew Brack Yan Yu Huneza Nadeem Reviewers: Wendy Yao Katie Lin Liana Martel Ran (Marissa) Zhang Man-Chiu Poon* Lynn Savoie* * MD at time of publication Composition of normal adult hemoglobin (Hb): Ineffective erythropoiesis Excessive free α-chains accumulate, and α-chains precipitate in RBC precursors and RBCs These precipitants (inclusion bodies) give RBCs an abnormal shape Spleen destroys abnormally shaped RBCs Spleen accumulates destroyed red blood cells and enlarges to an abnormal size Splenomegaly (*See Splenomegaly slide for clinical findings) Mild microcytic anemia Hb: ↓ MCV: ↓ • • • 96% HbA (ααββ=2 α chains + 2 β chains) 2% HbA2 (ααẟẟ) 2% HbF (αα!!; fetal hemoglobin) Genetic point mutation on a single allele of the β globin gene on chromosome 11 (heterozygous with one normal alleleà HbA ααββ0 or ααββ+) Mild ↓ of β-chain production relative to ⍺- chain ↓ β-chain available for HbA synthesis Body compensates by ↑ production of non-affected globins (HbA , HbF) 2 ↑ HbF (nonspecific), ↑ HbA2 (hallmark sign specific to Beta Thalassemia Minor) on electrophoresis • • α-chain precipitates form structures visible under the microscope Inclusion bodies Heme from the destroyed RBCs is degraded into bilirubin and iron Excess unconjugated bilirubin is released into the blood Excess bilirubin is deposited in the skin Jaundice Excess iron is stored as ferritin ↑ or normal ferritin Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 8, 2022 on www.thecalgaryguide.com

Unconjugated Hyperbilirubinemia

Pre-hepatic causes of ↑ bilirubin production Pathologic Unconjugated Neonatal Hyperbilirubinemia: Pathogenesis and clinical findings Hemolytic disease of the newborn** Isoimmune- mediated hemolysis Rhesus (Rh) factor incompatibility Maternal sensitization against Rh-positive fetal cells Maternal antibodies against Rh factor attack fetal RBCs ABO incompatibility Native maternal antibodies against non- native blood types attack fetal RBCs Sepsis** Widespread systemic inflammation Cytokines & complement factors damage RBC membranes Disseminated intravascular coagulation** (clotting proteins become overactive) Clots form in systemic circulation Small clots shear & damage RBCs in circulation Red blood cell (RBC) enzyme defects Glucose-6 phosphatase dehydrogenase (G6PD) deficiency** G6PD protects RBCs against oxidative damage ↑ RBC sensitivity to oxidative stress (during acute stressors) Pyruvate kinase deficiency (PKD) Abnormal glycolysis & cellular energy production ↓ RBCs life spans RBC membrane defects Hereditary spherocytosis RBCs are abnormally round (spherocytes) RBC membranes easily damaged in circulation Bilverdin reductase Hereditary elliptocytosis RBCs are abnormally elongated or oval converts bilverdin to Sickle cell Abnormal hemoglobin (HbS) RBCs become abnormally unconjugated bilirubin disease** polymerizes under ↓ O2 sickle shaped Hemoglobinopathies Thalassemia's** Defective hemoglobin chains in RBCs Irregularly shaped RBCs trapped in spleen RBC sequestration ↑ Production of RBCs (Polycythemia**) Accumulation of blood (i.e. Cephalohematoma, hemorrhage) ↑ RBC load & turnover Causes of ↓ hepatocellular bilirubin clearance Genetic defects in uridine diphosphate glucuronosyltransfe rase (UGT) enzyme (conjugates bilirubin in liver) Gilbert syndrome Unconjugated bilirubin ↓ UGT production remains insoluble & cannot Crigler–Najjar be excreted in bile syndrome Type II Crigler–Najjar syndrome Type I No UGT production Breast milk jaundice Breast milk contains β-glucuronidase Causes of ↑ entero-hepatic bilirubin circulation Intestinal obstruction Obstruction blocks bile flow from liver to intestines Breastfeeding jaundice Inadequate milk intake (volume depletion/dehydration) ↑ Reabsorption of bilirubin in the intestines **See corresponding Calgary Guide slide Legend: Macrophages engulf old or damaged RBCs in spleen & liver ↑ Hemolysis (RBC breakdown) RBCs release cellular contents including heme (from hemoglobin) Heme oxygenase converts heme to bilverdin ↑ Unconjugated (indirect) bilirubin accumulation in blood ↑ Total serum bilirubin levels Excess bilirubin deposition into elastin- rich tissues (eg. skin, sclera) due to ↑ affinity for elastin Pathologic neonatal jaundice (yellow discoloration of skin within first 24 hours of life) Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 13, 2025 on www.thecalgaryguide.com Authors: Merry Faye Graff Khushi Arora Reviewers: Annie Pham Emily J. Doucette Danielle Nelson* * MD at time of publication Hemolytic anemia** ↓ Bilirubin conjugation β-glucuronidase deconjugates bilirubin Bilirubin builds up in hepatic system Unconjugated bilirubin crosses blood-brain barrier Bilirubin-induced neurologic dysfunction (BIND) Kernicterus (bilirubin- induced neurological damage) Scleral icterus (yellowing of sclera in eyes)