Medical Notes on Hemoglobinopathies PDF

## Dua asking for knowledge and benefits «اللَّهُمَّ انْفَعْنِي بِمَا عَلَّمْتَنِي ، وَعَلِّمْنِي مَا يَنْفَعُنِي، وَزِدْنِي عِلْماً» (Sunan Attermidhiy # 3599) "O Allah, make what you teach me beneficial, teach me what is beneficial, and increase me in knowledge." ## Fatimid Center for Blood Tr...

## Dua asking for knowledge and benefits «اللَّهُمَّ انْفَعْنِي بِمَا عَلَّمْتَنِي ، وَعَلِّمْنِي مَا يَنْفَعُنِي، وَزِدْنِي عِلْماً» (Sunan Attermidhiy # 3599) "O Allah, make what you teach me beneficial, teach me what is beneficial, and increase me in knowledge." ## Fatimid Center for Blood Transfusion The image shows three people in a hospital room. A young woman is sitting on a bed with a young boy next to her. The boy has a bandage on his arm and is holding a red rose. Another young boy is out of focus in the background. ## Your patient (3 year old Shahid) The image shows the face of a young boy. He has a prominent forehead and flat nose. - thalassemia facies (maxilla hyperplasia, flat nasal bridge, frontal bossing) ## History - Shahid has severe anemia and jaundice. - His history reveals that his parents are cousins. - Parents and 2 siblings have moderate anemia. - 1 sibling has normal hemoglobin level. The image shows a diagram of a family tree. The father is a “carrier”. The mother is a “carrier”. Both have one dominant allele R and one recessive allele r. The offspring have a 1 in 4 chance of being unaffected, 1 in 4 chance of being a “carrier” without being affected, 1 in 4 chance of being a “carrier” without being affected, and 1 in 4 chance of being affected. ## Shahid’s CBC The image shows six red blood cells with varying shapes and sizes. The captions below describe the abnormalities: - Poikilocytic red cells: - elliptocytes - schistocytes - target cells - tear drop - spherocytes - hypochromic These are usually present in Thalassemia Major. ## Shahid’s Skull X-ray The image shows a x-ray of a human skull. Annotations indicate the skull has “bone deformities” and “hair on end appearance”, an indicator of extramedullary erythropoiesis. ## Thalassemia Major ## Hemoglobinopathies The image shows a diagram of a red blood cell with four components labelled “α”, “α”, “β”, and “β”. ## Learning Objectives - Definition - Classification - Qualitative Defects - Hb-S (Sickle cell anemia) - Hb-C - Hb-M (Methemoglobinemia) - Quantitative Defects - Thalassemia (a or β) - Genetic abnormality - Biochemical abnormality - Symptoms - Diagnosis - Treatment ## Normal Adult Human Hemoglobin Composition | Hemoglobin | Structure | % of Normal Adult Hb | |---|---|---| | Hb A | a2β2 | >96% | | Hb A2 | a2δ2 | ~2.5% | | Hb F | a2Y2 | <1% | ## Important point to remember - Abnormal variants are seen in hemoglobinopathies (Hb S, C, E). - Increased Hb A2 is diagnostic for beta thalassemia trait. - Hb H (tetramer of beta) and barts (tetramer of gamma) are seen in alpha thalassemia ## Hemoglobinopathies Genetic orders caused by the malproduction of hemoglobin: - I. Qualitative hemoglobinopathy (structurally abnormal hemoglobin) - a) Sickle cell anemia/ Hemoglobin S disease - b) Hemoglobin C disease - c) Hemoglobin SC disease - d) Methemoglobinemia - II. Quantitative hemoglobinopathy (Decreased production of hemoglobin) - a) Thalassemia - i) Alpha – Minor/Major - ii) Beta - Minor/Major ## Sickle Cell Anemia The image shows a young baby being held by a woman. The child has noticeably dark skin. ## 1. Sickle cell anemia - **Types** - Homozygous → Hb-S (a2β2) → sickle cell anemia - Heterozygous → normal life span (Hb-A + Hb-S) → sickle cell trait. - **Genetic Mutation** - Autosomal recessive - 2 mutant genes for βchains of globin - Single nucleotide alteration (point mutation) in β-globin gene (glutamate replaced by valine at position 6). - Infant does not show symptoms of the disease until sufficient Hb-F has been replaced by HB-S The image shows a diagram of a family tree. The father is a “carrier”. The mother is a “carrier”. Both have one dominant allele R and one recessive allele r. The offspring have a 1 in 4 chance of being unaffected, a 2 in 4 chance of being a “carrier” without being affected, and a 1 in 4 chance of being affected. The image also shows a normal red blood cell and a sickled red blood cell. ## Sickle cell anemia - **Genetic Mutation** - 6th amino acid normally Glutamate (polar) replaced by Valine (non-polar) - forms hydrophobic protrusion on β chain that fits into β chain of another Hgb molecule The image shows a diagram comparing wild-type hemoglobin DNA to mutant hemoglobin DNA. ## Formation of fibers The image shows a diagram explaining how deoxyhemoglobin S polymerizes into filaments. ## Mechanism of Sickling - ↓Oxygen concentration→ HbS polymerization - Deoxy Haemoglobin exposes a hydrophobic patch on the protein - Valine (hydrophobic side chain residue at position 6 of the beta chain in haemoglobin) associates with the hydrophobic patch - → Haemoglobin S molecules aggregate → fibrous precipitates. ## Sickle Cell Anemia - **Mechanism of Sickling** - Low pO2 → Hb-S polymerizes in RBCs → insoluble fibrous polymers → first forming gel → then stiffens distorts cell → blocks the flow of blood in capillaries. - →microvascular occlusion - This interruption leads to ischemia → pain → eventually death of tissue cells (infarction). The image shows a diagram of a normal red blood cell, a sickled red blood cell and a cross-section of blood vessels with normal and sickled red blood cells. ## Sickle Cell Anemia - **Symptoms** - Chronic hemolytic anemia →hyperbilirubinemia - Increased infections. - Lifelong episodic pain(Crises) - Organ infarction (spleen, kidney) - Chest pain - Stroke - Marrrow hyperplasia - Kidney infarct - Ischemic stroke The image shows a diagram of normal red blood cells and damaged red blood cells with the caption "ischemic stroke" and a diagram of a person with a damaged kidney. ## Symptoms of sickle cell anemia - Abdominal Pain - Bone and joints pain - Breathlessness - Delayed growth and puberty - Jaundice (yellowed skin) - Fatigue and fever - Paleness - Greater risk for infection - Adolescents and adults can develop ulcers on their legs - Chest pain - Poor eyesight, blindness. The image shows a close up of the legs of two individuals with several ulcers. ## Sickle cell anemia - **Precipitants** - Decreased oxygen - Increased carbon dioxide - Decreased pH. - Increased BPG. - Dehydration. - High altitude (eg. aeroplane). The image shows a diagram of a person hiking in a mountainous region. The image also shows a diagram of a hemoglobin-oxygen dissociation curve showing the effects of changes in pH and CO2 concentration. ## Sickle cell disease The image shows a collage of many images. These include: images of a plane, a foot with several ulcers, a foot with discoloration, an individual’s tongue, an individual grabbing their chest, a heart, a lung and an individual standing with their back facing the viewer. There is also a diagram of a person having a heart attack and a diagram of someone’s lungs with a large blood clot. ## Diagnosis - **1. Hemoglobin electrophoresis ** - 2 normal α globin chains + 2 abnormal β globin chains - (6th amino acid →Valine replaces Glutamate) - → HbS less acidic than HbA - → HbS migrates more slowly towards +anode compared to HbA - Sickle cell trait/disease - **2. DNA analysis** ## Sickle cell anemia - Hb-S has erythrocyte lifespan of 20 days (Normal 120 days) - no malaria (Plasmodium Falciparum cannot complete lifecycle in fragile, short lived RBC) - **Management** - Prenatal screening- for HgS gene - Newborn screening- Hg S - Symptomatic:-Hydration, analgesics, antibiotics - Blood transfusion - Blood and Bone marrow transplantation - Gene therapy The image shows a mosquito, a hand with an IV line and a diagram of a person getting a blood transfusion. ## Hemoglobin C Disease - Glutamic acid (-) at 6th position in β globin chain is replaced by Lysine(+) - HbC moves more slowly to Anode than HbA/HbS in electrophoresis - Mild chronic hemolytic anemia - Substitution of glutamic acid by lysine in the 6th β- chain - RBCs do not sickle - Mild hemolytic anemia ## 2. Met-hemoglobinemia - Fe++ normally present in heme →replaced by Fe+++ - Fe +++cannot bind O₂ → Hb cannot act as an O2 carrier - Spontaneous oxidation of Hb(reactive oxygen species, drugs eg Nitrates, Sulfonamides)→ Normal erythrocytes contain small amount of met Hb - →Met Hb is normally reconverted to Hb by reducing systems in the RBC (eg NADH-methemoglobin reductase) The image shows a diagram of the methemoglobinemia mechanism, showing the transition of iron from Fe2+ to Fe3+ in the heme group. ## Met-hemoglobinemia - **HbM** - 1. Mutation in globin chain →HbM - 2. ↓NADH Cytochrome b5 reductase (NADH methemoglobin reductase) - **Symptoms** - Chocolate cynosis (brownish-blue skin & membranes) - Chocolate colored blood. - Tissue hypoxia anxiety,headache, dyspnea - Polycythemia. - Coma → death. The image shows two tubes of blood, one appears to be chocolate brown and the other is red. ## Treatment for methemoglobinemia - Exchange Transfusion - Hyperbaric Oxygen. - Methylene blue is the primary emergency treatment. 1-2 mg/kg as a 1% solution in IV saline over 3-5 minutes. - Methylene blue is oxidised reduces Fe+3 →Fe+2 The image depicts a diagram of the process by which Methylene Blue is oxidised to reduce Fe+3 to Fe +2. ## 3. Thalassemia - Hereditary hemolytic disease. - Synthesis of either a or β globin chain is defective - Most common single gene disorder in humans. Alpha and beta thalassemias - Erythroblast - α thalassemia (Excess β chains) - β thalassemia (Excess α chains) The image shows a diagram showing the erythroblasts for alpha-thalassemia and beta-thalassemia. The image also shows a table identifying the chromosomes associated with deletions and mutations for both alpha and beta thalassemia. - Two types; - α thalassemia (major, minor) - β thalassemia (major, minor) - αº- or βº-thalassemia =no globin chains - α⁺- or β⁺-thalassemia= reduced rate ## Thalassemia - Classification | | | | | |---------------------------------------|---------------------------------------|---------------------------------------|---------------------------------------| | On the basis of Globin chains | On the basis of Inheritance | Homozygous | Heterozygous | | | | | | | α-Thalassemia | β-Thalassemia | α-Thalassemia major | α-Thalassemia minor | | Impaired α- chain production | Impaired β- chain production | β-Thalassemia major | β-Thalassemia minor | ## Genes for Globin Chains | **Alpha Globin Genes** | **Beta Globin Genes** | |---|---| | a1 | b1 | | a2 | b2 | | a3 | | | a4 | | The image shows a diagram of the chromosomes 11 and 16 with their corresponding alpha and beta-globin genes. ## Thalassemia - Thalassemia can be caused by variety of mutations including: - Entire gene deletion, or - Substitution, or - Deletion of one to many nucleotides in the DNA The image shows a diagram explaining these mutation types. ## α - Thalassemia - synthesis of α globin chain is decreased or absent → deletional mutation - α° = No α globin chains synthesised - α⁺ = Few α globin chains synthesised - Each individual contains 4 copies of α globin chain The image shows a diagram of the α-globin gene, showing the four copies of the gene on chromosome 16. ## Genetics of α thalassemia - Each Chromosome 16 →Two genes: HBA1 and HBA2→ two copies of HBA1 and two copies of HBA2 gene in each cell. - Each copy is called an allele→ 4 alleles that produce alpha-globin - Each of the 2 genes⇒ one allele is inherited from father and one from mother →2 alleles from each parent. - Loss of some / all alleles→ Different types of alpha-thalassemia - 1 mutated allele– carrier→ no signs or symptoms - 2 mutated alleles– alpha-thalassemia minor / trait→ mild signs or symptoms - 3 mutated alleles→ HbH disease (tetramer of β)→ moderate to severe symptoms - 4 mutated alleles alpha-thalassemia major /hydrops fetalis → affected fetus stillborn/newborn does not survive long after birth ## α-thalassemia(genetic) | NO. OF GENES PRESENT | GENOTYPE | CLINICAL CLASSIFICATION | |---|---|---| | 4 genes | aa/aa | Normal | | 3 genes | aa/- a | Silent carrier | | 2 genes | - a/- a | α thalassemia trait | | | or | | | | aa/- | | | | - | | | 1 gene | -α/- - | Hb H Ds (β4) | | 0 genes | -/- - | Hb Barts / Hydrops fetalis (γ4) | ## α- THALASSEMIA Level of deficiencies: - a) If one gene defective silent carrier → no physical menifestations - b) If two genes defective → α thalassemia trait. - c) If three genes defective → Hb-H disease (β4) - no heme-heme interactions → hyperbolic curve - very high oxygen affinity → fails to deliver oxygen - d) If all four genes defective → or Hb-Barts (γ4) - hydrops fetalis → fetal death - (∵ α chains are required for synthesis of Hb-F). ## β-THALASSEMIA - synthesis of β-globin chain is decreased or absent → point mutation →decrease mRNA for β- globin chain → α chains normal. - Only 2 copies of β globin gene in each cell (each chromosome 11) The image shows a diagram explaining the point mutation that occurs in wild-type hemoglobin DNA that leads to mutant hemoglobin DNA. ## Pathology - α chains cannot form stable tetramer →precipitate → premature RBCs death - →accumulation of Hb- A2(α2δ2) and Hb-F (α2γ2) ## β-THALASSEMIA Each individual contains 2 copies of β globin chain - Level of deficiencies: - a) If one gene defective → β thalassemia minor → β thalassemia trait → no physical menifestations - b) If both genes defective → β thalassemia major → Cooley's anemia → The image shows a diagram of the β-globin gene, showing the two copies of the gene on chromosome 11. - As β-globin gene is not expressed until late fetal gestation, the physical manifestations of β-thalassemia appear only after birth. - Symptoms appear several months after birth (1-2 year old)→ - ineffective erythropoiesis - severe anemia + - skeletal changes (extramedullary hematopoiesis ## Classification of β Thalassemia(genetic) | CLASSIFICATION | GENOTYPE | CLINICAL SEVERITY | |---|---|---| | β thal minor/trait | β/β+, β/βο | Silent | | β thal intermedia | β+ /β+, β+/βο | Moderate | | β thal major | βο/βο | Severe | ## β-THALASSEMIA - Infants born with β thalassemia major → healthy at birth. (because of HbF, or α2Υ2 ) - But during first or second year of life → severly anemic (hemolytic anemia) → icterus → splenomegaly → stunted growth. The image shows a diagram of two individuals. The first is a baby that has a yellowed skin color, indicating jaundice and an enlarged spleen. The second individual has a notably short height, indicating stunted growth. ## Normal vs β-thalassemia - **Normal** - HbA (α2β2) - Normal erythroblast - Normal red blood cells - Heart - Systemic iron overload (secondary hemochromatosis) - **β-Thalassemia** - Reduced β-globin synthesis, with relative excess of α-globin - Abnormal erythroblast - Few abnormal red cells leave - Most erythroblasts die in bone marrow (ineffective erythropoiesis) - Hypochromic red cell - α-globin aggregate - Normal HbA - Destruction of aggregate-containing red cells in spleen - Anemia - Blood transfusions Reduce - Tissue anoxia Erythropoietin increase - Marrow expansion - Skeletal deformities The image shows a diagram comparing the progression of normal erythroblasts into normal red blood cells to the progression of abnormal erythroblasts into abnormal red blood cells in β-thalassemia. The image also shows diagrams showing the individual organs affected by β-thalassemia and the consequences of the disease, such as anemia, systemic iron overload, skeletal defects, and an increase in erythropoietin. ## β-THALASSEMIA - **Treatment** - Transfusion (cumulative transfusion → iron overload → hemosiderosis). - Bone marrow replacement therapy /Hematopoietic stem cell transplantation The image shows a diagram of an allogenic transplant, where healthy stem cells are transferred from a donor to a recipient. The image also shows a diagram of a person getting a blood transfusion.