1-10 Hemoglobinopathies + Associated Anemias.pdf

Hemoglobinopathies and Associated Anemias 202410 Michael M. Yakubovskyy, MD, PhD 1 The Place of Hemoglobinopathy-Associated Anemias in the Working Classification Learning Objectives LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory...

Hemoglobinopathies and Associated Anemias 202410 Michael M. Yakubovskyy, MD, PhD 1 The Place of Hemoglobinopathy-Associated Anemias in the Working Classification Learning Objectives LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) LO2. Discuss the underlying mutation and pathogenesis of HbC disease, identify the RBCs with HbC inclusion, explain the clinical behavior of HbSC disease LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺-thalassemia 3 Sickle Cell Disease 4 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Sickle Cell Disease (SCD): General • A normocytic hemolytic anemia with extravascular hemolysis - NB: A small proportion of sickled RBCs undergo intravascular hemolysis • Demographics: African Americans • Genetics - Autosomal recessive disorder - Point mutation (Glu —> Val at amino acid 6) in β-globin (HBB) gene on chr. 11 • Major steps in pathogenesis 1. Polymerization of deoxygenated HbS 2. Distortion of RBC shape (sickling) 3. Extravascular hemolysis (spleen), microvascular obstruction, and ischemic tissue damage (various organs) S (=Hb⍺2ß 2) 5 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Sickle Cell Disease: Variants • Sickle cell anemia (SCA): both HBB genes are mutated (homozygosity) - Hb electrophoresis: 90% of HbS, 8% of HbF, and 2% of HbA2 (no HbA) • NB: the terms “sickle cell disease” and “sickle cell anemia” can be used interchangeably • Sickle cell trait: single HBB gene is mutated (heterozygosity) - Hb electrophoresis: <50% of HbS, >50% of HbA, and ≈2% of HbA2 - ≈10% of African Americans are affected - As a rule, there is no sickling, and patients are asymptomatic 6 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Formation of Sickle Polymers • Left: deoxygenation of HbS leads to the formation of a double strand of aggregated HbS molecules • Middle: seven double strands aggregate to form a 14-strand helical polymer • Right: Deoxygenation and polymerization of HbS induce deformation into sickle and other abnormal shapes 7 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Few Relevant Details of Sickling With reoxygenation, sickle cells may acquire a normal shape, but with repetitive deoxygenation and polymerization of 8 HbS, sickling becomes irreversible LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Factors Influencing Sickling Enhancing Factors 1 Hypoxia (hypoxemia) Dehydration —> ↑HbS 2 concentration Acidosis —> ↑O2 release —> 3 RBC deoxygenation ↓O2 tension 4 - At high altitude - In the renal medulla Preventing Factors HbF with higher than HbA affinity to O2 1 - No sickling in infants < 6 months 2 Hydroxyurea —> ↑HbF synthesis HbS/HbC heterozygosity (HbSC disease) —> milder sickling if 3 compared with SCA - HbC/HbSC diseases are delivered later 9 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Clinical Correlates • Mild-to-moderate-to-severe normocytic normochromic anemia - HCT: 20% - 30% Hb: 50 - 110 g/L Reticulocytosis (CRC: 3 - 15%) —> normal MCV Irreversible sickled RBCs • Chronic clinical course - Anemia (pallor, fatigue, dyspnea, etc.) - Hyperbilirubinemia (UCB > CB) • Jaundice • Pigmented gallstones - Erythroid hyperplasia in BM —> bone changes • Cortical thinning • “Crew-cut” or “hair-on-end” appearance on skull x-ray • Crisis (four types, see the next slide) 10 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Crises • • • • Vaso-occlusive (pain) crises Sequestration crisis Aplastic crisis Hyperhemolytic crisis 11 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Vaso-occlusive Crisis • Vaso-occlusion (blockage of microcirculation by sickled cells) —> vaso-occlusive (pain) crises: hypoxic ischemia and infarctions with severe pain • Common sites/manifestations of vaso-occlusion - Dactylitis (hand-foot syndrome): bone infarcts with swelling of hands and feet in infants - Acute chest syndrome: lung infarctions, chest pain, fever, and cough; a common cause - - of death in adulthood Repetitive splenic infarcts —> fibrosis and shrinkage (autosplenectomy)—> risk of infection with encapsulate bacteria (Streptococcus pneumoniae and Haemophilus influenzae): common cause death in children Priapism: continuous painful erection Other manifestations • • • • Aseptic necrosis of femoral head Infarctions in the renal medulla Ischemic stroke Retinopathy —> loss of visual acuity —> blindness 12 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Capillary Occlusion by Sickle Cells, Liver 13 https://commons.wikimedia.org/wiki/File:Sickle_cell_di sease_and_cirrhosis_-_very_high_mag.jpg Nephron, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) Other Types of Crisis • Sequestration crisis - Children with intact spleen - Massive entrapment of sickle red cells —> rapid splenic - enlargement, hypovolemia, and shock May be fatal • Aplastic crisis - Infection of red cell progenitors by parvovirus B19 —> transient cessation of erythropoiesis —> sudden worsening of anemia with reduction in reticulocyte count (CRC) • Hyperhemolytic crisis - An acute drop in hemoglobin with high reticulocyte count (CRC) 14 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Speen Pathology • Mechanism: repetitive splenic infarcts —> fibrosis and shrinkage (autosplenectomy) • Sequelae - Risk of infection with encapsulate bacteria (Streptococcus pneumoniae and Haemophilus influenzae); common cause death in children - Risk of Salmonella parathyphi osteomyelitis - Howell-Jolly bodies (nuclear remnants the RBCs) on PBS 15 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Splenic Infarct and Howell-Jolly Bodies (Arrows) https://openi.nlm.nih.gov/detailedresult?img=PMC3829791_tm_6p02f2&query=&req=4 16 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: PBS and BM • PBS - Nucleated RBCs - Polychromasia with reticulocytes - Sickle cells • Occasional shistocytes due to intravascular hemolysis - Howell-Jolly bodies (with hyposplenism and autosplenectomy) • BM: erythroid hyperplasia • Biochemistry - ↑ serum bilirubin (UCB > CB) - ↑ urine urobilinogen - ↓ serum haptoglobin due to intravascular hemolysis 17 SCA: Nucleated RBCs, Polychromasia, Sickle Cells https://commons.wikimedia.org/wiki/File:Polychromasia.jpg Prof. Osaro Erhabor, CC0, via Wikimedia Commons 18 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Special Tests • High performance liquid chromatography (HPLC): the best test (Access Medicine: Harrison, Willams, etc.) • Sickling/metabisulphite test: the test used in review books - Uptodate: “There is no clinical situation in which a sodium metabisulfite test (Sickledex) is clinically indicated in the screening or management of sickle cell disorders (trait or disease)” • https://www.uptodate.com/contents/diagnosis-of-sickle-celldisorders?search=sickle cell anemia&topicRef=7145&source=see_link#H11 • Hb electrophoresis: a standard test • Newborn screening (“heel stick”): identification of HbS - Family genetic study 19 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SCA: Hb Electrophoresis 20 LO1. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease (anemia and trait) SC Trait, SCA, and HbCS Disease: High Performance Liquid Chromatography 21 HbC Disease 22 LO2. Discuss the underlying mutation and pathogenesis of HbC disease, identify the RBCs with HbC inclusion, explain the clinical behavior of HbSC disease HbC-Associated Conditions • Demographics: African Americans • Genetics - Autosomal recessive disorder - Point mutation (Glu —> Lys at amino acid 6) in β-globin gene • Variants - HbC disease (in homozygotes): a mild hemolytic anemia with extravascular hemolysis and splenomegaly • MCV: 70 - 75 fL —> microcytic anemia • CRC: 3 - 4% - HbC trait (in heterozygotes): asymptomatic - HbSC disease: similar to SCA, but with a milder clinical course + 0 - HbC-ß /ß -thalassemia 23 LO2. Discuss the underlying mutation and pathogenesis of HbC disease, identify the RBCs with HbC inclusion, explain the clinical behavior of HbSC disease HbC: PBS • HbC disease - HbC crystals, particularly after splenectomy - Damage of RBC membrane by HbC crystals + K - —> loss of and water —> spherocytes (with decreased osmotic fragility) Target cells with ↑MCHC Reticulocytes • HbSC disease - Sickle cells - HbC crystals - Target cells 24 https://commons.wikimedia.org/wiki/File:Blood_film_of_Hemoglobin_SC_disease.jpg Spicy, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons Thalassemias 25 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia Thalassemias (Thal) • Inherited disorders characterized by - Decreased production of α- or β-globin chains with following - Anemia, hypoxia, and extravascular hemolysis related to imbalance in synthesis of globin chains • Demographics: Mediterranean, African, and Asian regions endemic for malaria - As with HbS, globin mutations may be protective against falciparum malaria • RBC biology in thalassemias - Heme synthesis is not affected - Deficiency of α- or β-globin chain—> excess of the unaffected globin chain • α-thalassemia: decreased/absent α-globin chains with excess of β-globin chains • β-thalassemia: decreased/absent β-globin chains with excess of α-globin chains 26 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal: ß-Globin Gene Mutations (Deletion: 0 ß, Point Mutation: + ß) Legend (common mutation sites): PR (promoter site27 mutations); SPL (splicing mutations); chain termin LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia β-Thal: Mechanisms of Anemia • Reduction/absence of β-globin —> inadequate HbA formation — > production of hypo-hemoglobinized red cells that are - Small in size (microcytic) and - Pale (hypochromic) • An excess in unpaired α-chains —> formation of insoluble hemoglobin precipitates —> - Damage of RBC membrane —> splenic sequestration —> - extravascular hemolysis Damage of erythroid precursor membrane and their apoptosis —> ineffective erythropoiesis • 70% - 80% of erythroid precursors die in the BM 28 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺-thalassemia ß-Thal: Key Events in Pathogenesis • Excess in and precipitation of α-chains —> destruction of erythroid precursors —> anemia • Erythropoietin release —> marrow expansion - Massive erythroid hyperplasia in BM —> - erythroferrone synthesis Impaired bone growth and skeletal deformities Extensive extramedullary hematopoiesis —> hepato- and splenomegaly • Repetitive blood transfusions and erythroferrone release (see the next slide) —> iron overload—> secondary hemochromatosis 29 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺-thalassemia β-Thal: BM Erythropoiesis Hemochromatosis 1. 2. 3. 4. 5. 6. 7. Destruction of erythroid precursors Erythropoietin release Hyperplasia of erythroid precursors Erythroferrone release Inhibition of hepcidin synthesis Increased iron absorption Secondary hemochromatosis 30 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia β-Thal: Genetic Foundation of Clinical Classification • Clinical classification is based on the severity of anemia (minor/trait, intermedia, and severe), which in turn depends on the 0 + gene defect (β or β ) and gene dosage (homo- or and heterozygous) - β-thalassemia minor/trait: a patient inherits only one - 0 β + β or allele; the condition is is asymptomatic or mildly symptomatic 0 + β-thalassemia intermedia: variable inheritance of β or β alleles; anemia is severe, but not so bad as with ß-thal major 0 + β-thalassemia major: patients have two β or two β alleles —> severe anemia 31 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal: Clinico-Genetic Correlates Classification Type ß-thal minor (trait) ß-thal intermedia Genotype • Heterozygous ß-thal • β0/β + • β /β • Variable genotype 0 β /β + β /β • From and + + 0 + 0 0 • To β /β and β /β (but not β /β ) Manifestations Asymptomatic with mild or no anemia Severe, but does not require regular blood transfusions • Homozygous β-thal ß-thal major Severe, requires regular blood transfusion 0 0 β /β • + + • β /β 0 + • β /β 32 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal Minor: PBS • RBCs: small (microcytic) and pale (hypochromic), but regular in shape • Target cells: cells with an increased surface area-tovolume ratio and central accumulation of the cytoplasm • Basophilic stippling • Fragmented RBCs 33 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal Major: PBS • • • • • • RBCs: microcytic, hypochromic Target cells Basophilic stippling Fragmented RBCs + Poikilocytosis: variation in cell shape • Anisocytosis: variation in cell size • Nucleated RBCs (normoblasts) 34 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal Intermedia: PBS • RBCs abnormalities are similar to ß-thal major, but less severe - Severity is difficult to estimate looking at a single image 35 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal: Hb Spectrum (%) HbA(α2β2) HbA2(α2δ2) HbF(α2γ2) Normal Adult 96 3 1 ß-Thal Minor 80-85 5 10-15 5-10 8-10 85-90 ß-Thal Interm. ß-Thal Major 36 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia ß-Thal (Major > Intermedia > Minor): Visceral Pathology • Extramedullary hematopoiesis —> - Bones: crew-cut skull, chipmunk face - Hepato- and splenomegaly • Extravascular hemolysis —> jaundice • Secondary hemochromatosis: “bronze diabetes” • Pigmented gallstones 37 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia HB Electrophoresis (ß-Thal, Sickle Cell Trait, and HbSC Disease + ß heterozygous 1. (trait): HbA/HbA2 2. Normal adult: HbA + 3. ß homozygous (ß-thal intermedia/ major): HbA/HbF 10.Sickle cell trait: HbA/HbS 11.HbSC disease: HbS/HbC 38 https://pubmed.ncbi.nlm.nih.gov/22089618/#&gid=article-figures&pid=fig-1-uid-0 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia α-Thal: Genetics • α-thalassemia: deletion of one or more α-globin genes 39 LO3. Describe the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of β- and ⍺thalassemia α-Thal: Genetic Foundation of Clinical Classification • The severity of the disease is proportional to the number of missing α-globin genes • The loss of a single α-globin gene (-/α α/α)—> silent carrier state • The loss of two α-globin genes (αα/-- or α/- α/-)—> α-thal trait with manifestations similar to ß-thal minor - (α/α -/-) genotype is common in Asia and is more severe then α/- α/- • The loss of three α-globin genes —> relative excess on β-globin chains—> formation of stable β4 tetramers (HbH) —> HbH disease: extravascular hemolysis and anemia similar to ß-thal intermedia - Common in Asians • Deletion of all four α-globin genes may be lethal in utero because RBCs have virtually no oxygen-delivering capacity. An excess in γ-globin chains —> formation of γ4 tetramers (Hb Barts) —> hydrops fetalis 40