Hemolytic Anemias Lecture Notes

—Anemiaswhichresultfromanincreaseintherateoftheredcelldestruction.—Thelifespanofnormalredcellis~120days.—Inseverehemolysisthecellsurviveonlyafewdays.Hemolysis is defined as Premature destruction of the red cellsDefinition The hemolysis occurs either extravascularlyby the macrophages of the spleen l...

—Anemiaswhichresultfromanincreaseintherateoftheredcelldestruction.—Thelifespanofnormalredcellis~120days.—Inseverehemolysisthecellsurviveonlyafewdays.Hemolysis is defined as Premature destruction of the red cellsDefinition The hemolysis occurs either extravascularlyby the macrophages of the spleen leading to: anemia, jaundice, and splenomegaly. Or directly in the circulation intravascularly General evidence of hemolysis:1. Evidence of Hb breakdown :-Increased unconjugated(Indirect) Bilirubin.-Increased urinary Urobilinogen.2. Evidence of increased red cell production:-Reticulocytosis–in blood. -Erythroid hyperplasia –in marrow. 3. Evidence of RBC Damage :-Spherocytes, fragmented red cells..4. If intravascular hemolysis:-Hemoglobinuria-Hemoglobinaemia.General evidence of hemolysis: Classification:A-Hereditary 1-RBC Membrane defect: e.g. hereditary spherocytosis, hereditary elliptocytosis.2-Defect in metabolism: e.g. G6PD deficiency3-Genetic defect of hemoglobin: e.g. Thalassemias and sickle cell anemia. B-Acquired1-ImmuneAutoimmune•Idiopathic, lymphoma, SLE, etcAlloimmune•Hemolytic transfusion reactions•Hemolytic disease of the newborn 2-Drugassociated3-Red cell fragmentationsyndromes e.g. Arterial grafts, cardiac valves and MAHA.4-Infections: e.g. Malaria5-Chemical(e.g. industrial agents) and physical agents (Burns).6-Acquired membrane defectsas in liver disease and PNH .B-Acquired(continued): Hereditary Spherocytosis(HS):Inheritance: Autosomal DominantPathogenesis: HS is due to a defect in the main structural protein (spectrin) of the red cell membrane. The marrow produces cells of normal biconcave shape but they lose membrane as they circulate in the spleen.RBCs become spherical and the ratio of surface area to volume decreases.Spherocytes are unable to pass through splenic microcirculation where they die prematurely. Clinical Features: AnemiaJaundiceSplenomegaly.HS Laboratory finding: The blood film shows microspherocytes(densely stained cells, smaller than normal RBCs)Reticulocytosis.Increased osmotic fragility.HS Reticulocytosis G6PD deficiency: Inheritance: sex linked disorder affecting males and carried by femalesPathogenesis:G6PD normally functions to reduce NADP (nicotinamide-adenine-dinucleotide-phosphate) to form NADPH.NADPH is necessary for production of reduced glutathione (GSH) by which RBC are protected from damage by oxidant stress. In G6PD deficiency there is impaired reduction of glutathione leading to acute hemolytic anemia in response to oxidant stress e.g. (drugs, fava beans, infections, and oxidant chemicals). EXAMPLES OF DRUGS INDUCING HAEMOLYSIS IN G6PD PrimaquineChloroqineSulphanilamideSulphamethoxazoleNitofurantoinNalidixic acidPhenylhydrazineeNiridazoleParacetamolAspirin Clinical features:Intravascular hemolysis: hemoglobinemiawith hemoglobinuria. Blister cellsMicrospherocyte Are inherited disorders of globinsynthesisHemoglobin abnormalities result from the followingsReduced rate of synthesis of normal α-or β-globin chains e.g α-thalassemia and β-Thalassemia.Synthesis of an abnormal hemoglobin e.g Hb S (Sickle cell anemia) Function:The main function of Hemoglobin is to carry O2 to the tissues and to return carbon dioxide (CO2) from the tissues to the lungs. Structure: Each molecule of hemoglobin is composed of a tetramer of four globin (polypeptide) chains each with its own haemgroup. HbA: α2β296 –98 %Hb A2: α2δ21.5 –3.2 %Hb F: α2γ20.5 –0.8 Ty p e s o f H e m o g l o b i n ThalassemiasAre heterogeneous group of genetic disorders which result from reduced rate of synthesis of α or β globinchains.Inheritance: Mendelianrecessive fashion 1-Thalassemia major: which is transfusion dependent. 2-Thalassemia intermedia: moderate anemia with splenomegaly and iron overload3-Thalassemia minor: symptomless carrier with mild or no anemia.Clinically, Thalassemias are divided into: Are the most important types of thalassemiabecause they are very common and usually produce severe anemia in their homozygous state.Result from reduce or no synthesis of beta-globin chain of the hemoglobin.The majority of genetic lesions are point mutation. Distribution: occur widely in Mediterranean region, and parts of north and west Africa, Middle East, India and South East Asia —There is one Beta globin gene on each chr-11 i n human genome.—The inheritance of this disorder is autosomal recessive, so that heterozygotes are usually symptomless, while homozygotes are severely or moderately affected.β/normal:Heterozygous (trait) (minor)β/β:Homozygous (major)Genetics of bthalassemia β-thalassemia major β Thalassaemia major also known as Mediterranean anemia and occurs in 25% of offspring (1/4) if both parents are carriers of β thalassemia trait. Thalassemia major is often due to inheritance of two mutations; this result in either no β chain synthesized, or small amount of β-chainsynthesis. Excess α chains precipitate in erythroblasts and mature red cells causing hemolysis. Clinical FeaturesSevere anemia (becomes apparent at 3 –6 months after birth), pallor, poor feeding, failure to thrive.Enlargement of the liver and spleen due to excessive red cell destruction; extramedullaryhemopoiesisand iron overload. Expansion of bones due to intense marrow hyperplasia leads to thalassemicface (bossing of skull bones) Iron overload will result due to repeated blood transfusion; this will lead to multiple organ failure . Hypochromic microcytic anemiaIncreased reticulocytecountDistortion of red cells (anormalshapes and sizes “anisocytosis& poikilocytosis”)Hbelectrophoresis reveals absent or ↓ HbAlevels with increased HbF.Lab. Findings Mild anemia: hypochromic microcytic type.Sometimes normal Hb.Lab. findings:Low MCH and MCV with raised HbA2 level. Blood Film in thal minorThalassemia minorNormal blood film α -Thalassaemia syndromesDistribution: occur wildly in Africa, Mediterranean region, Middle east, India and south east Asia. α -Thalassaemia syndromesThere are 2 alpha-globin genes on each Chr-16So: 4 alpha genes are normally present αα/αα--/--HydropsThe majority of genetic lesions results from gene deletionInheritance: Autosomalrecessive.1-Deletion of 4 genes lead to completely suppressed α-chain synthesis; since the α-chain is essential in foetal as well as adult haemoglobin this will lead to death in utero (hydrops foetalis).no Hb F but g4 (Hb Barts) which is ineffective as an Oxygen carrier 2-Deletion of 3 α genes leads to Hb H disease which is a moderate hypochromic microcytic anema (both MCV and MCH are reduced) and splenomegaly (Thalassemia intermedia phenotype).Hb H (made by union of 4 B globin chain B4) can be detected by electrophoresis.--/-αHbH The red cells are hypochromic microcyticThe MCV and MCH are reduced.3-Deletion of 1 or 2 or genes (-α/αα, -α/-α, --/αα) (α-thalassemia trait) is not associated with anaemia.Silentα-thalminor-α/αα-α/-α--/αα