Hemolytic Anemias PDF

Blood disorders Hemolytic anemias University of Jordan, faculty of medicine Manar Hajeer, MD, FRCPath HEMOLYTIC ANEMIA Definition: the red cell life span is shortened to less than its normal 120 days. Accelerated RBC destruction. Diverse group of disorders Erythroid hyperplasia and reticulocytosis...

Blood disorders Hemolytic anemias University of Jordan, faculty of medicine Manar Hajeer, MD, FRCPath HEMOLYTIC ANEMIA Definition: the red cell life span is shortened to less than its normal 120 days. Accelerated RBC destruction. Diverse group of disorders Erythroid hyperplasia and reticulocytosis are hallmarks of all hemolytic anemias. Accumulation of Hg degradation products (bilirubin) Extramedullary hematopoiesis appears in the liver, spleen, and lymph nodes.  Classification Intracorpuscular and extracorpuscular. Extravascular hemolysis: Defects in RBCs >> diminished deformability >>stuck in sinusoids >> increase the destruction of red cells by phagocytes (macrophages) in the spleen. Intravascular hemolysis: Injuries so severe >> RBCs literally burst within the circulation (physical, biochemical or mechanical) Hallmarks of extravascular hemolysis: Hyperbilirubinemia and jaundice (degradation of hemoglobin in splenic macrophages) Splenomegaly (phagocyte hyperplasia) Bilirubin rich gallstones (pigment stones, cholelithiasis) Low haptoglobin (binds free hemoglobin) Hallmarks of intravascular hemolysis: Hemoglobinemia Hemoglobinuria (dark urine) Hemosiderinuria. Loss of iron Low haptoglobin (binds free hemoglobin) Hemolytic anemias Hereditary Spherocytosis Sickle Cell Anemia Thalassemia Glucose-6-Phosphate Dehydrogenase Deficiency Hereditary Spherocytosis Inherited intrinsic defects in RBCs membrane skeleton (network of proteins that stabilizes the lipid bilayer), leading to formation of spherocytes (nondeformable cells highly vulnerable to sequestration and destruction in the spleen). Autosomal dominant.  Pathogenesis Spectrin (Major membrane skeleton protein) is connected to the transmembrane proteins (bands 3) via the linker proteins ankyrin. Mutations most frequently involve ankyrin, band 3, or spectrin. Mutations weaken vertical interactions between the membrane skeleton and intrinsic red cell membrane proteins.  Destabilizes the lipid bilayer of RBCs >> shed membrane vesicles into the circulation as they age >> cells become spherical with limited deformability >> stuck in spleen >> engulfed by macrophages. Shortened life span to < 20 days. Beneficial effect of splenectomy although spherocytes persist the anemia is corrected. MORPHOLOGY Spherocytes (dark red, lack central pallor) Compensatory hyperplasia of red cell progenitors in the BM. Reticulocytosis. “Howell-Jolly” bodies are seen in post splenectomy (nuclear remnant) Marked splenomegaly (500-1000grams) Cholelithiasis, in 40% to 50% of patients. Spherocytes and Howell-Jolly bodies Clinical features. Triad (moderate anemia, splenomegaly and jaundice) RBCs increased osmotic fragility (diagnostic) Aplastic crises, triggered by parvovirus B19 infection (target erythroblasts) >> BM devoid of red cell progenitors. (10-14 days to recover) Splenectomy can be beneficial but with risk of infections (children) Sickle Cell Anemia Hemoglobinopathy. Inherited mutations leading to structural abnormalities in hemoglobin. Mutation in β-globin that creates sickle hemoglobin (HbS) Most common familial hemolytic anemia. Protective effect against Plasmodium falciparum malaria.  Pathogenesis ❑Single amino acid substitution in β-globin. ❑Valine instead glutamate at the 6th amino acid position. ❑Deoxygenated HbS self-associate into polymers >> distort the RBC >> assumes an elongated crescentic shape. ❑Sickling is reversible on reoxygenation >> membrane distortion on repeated episodes >> irreversibly sickling ❑Normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). ❑Patients: HbA completely replaced by HbS. ❑Carriers: only half of HbA is replaced. Factors that affect sickling ❑The intracellular levels of hemoglobin other than HbS HbS heterozygotes (sickle cell trait) >> little tendency to sickle Newborns do not manifest disease until HbF falls to adult levels (5 to 6 months). ❑The intracellular concentration of HbS. RBCs dehydration >> increases Hb concentration >> facilitates sickling ❑The time required for red cells to pass through the microvasculature sluggish circulation in spleen, BM and in inflammation Pathologic consequences of sickling Chronic moderately severe hemolytic anemia due to RBC membrane damage (life span 20 days) Increased breakdown of heme to bilirubin (jaundice) Vascular obstructions (vaso-occlusion) >> ischemic tissue damage and pain crises (infection, inflammation, dehydration, and acidosis) Morphology Blood smears: spindled, or boat-shaped sickled RBCs and target cells. Compensatory hyperplasia of erythroid progenitors in the BM. Bone deformities (Prominent cheekbones, changes in the skull “crewcut” in radiographs). Extramedullary hematopoiesis (liver and spleen). Splenomegaly (children) Autosplenectomy due to infarcts (complete by adulthood) Vascular thrombosis and infarction: any organ even BM. Hemosiderosis and pigment gallstones Sickled cells Target cells :cytoplasm collects in a central, dark- red “puddle.” Clinical features ❑Unremitting course punctuated by sudden crises ❑Manifests at 6 months. ❑Moderate to severe anemia. ❑Hyperbilirubinemia and compensatory reticulocytosis. ❑Vaso-occlusive crises (pain and tissue damage) Hand-foot syndrome (children) Acute chest syndrome (with pneumonia and embolism) Stroke Proliferative retinopathy (blindness) ❑Aplastic crisis (parvovirus B19) ❑Functionally asplenic (susceptible to infections by encapsulated bacteria, pneumococci) (In children and adults). ❑Prophylactic penicillin to prevent pneumococcal infections (children younger than 5) ❑Predisposed to Salmonella osteomyelitis. ❑The diagnosis is confirmed by electrophoretic demonstration of HbS. ❑Bone marrow transplantation is curative. Thalassemia ❑ Inherited diseases: mutations in globin genes ❑ Decrease the synthesis of α- or β-globin. ❑ HbA (adult Hb): tetramer of 2α and 2β chains ❑ Decreased synthesis of one globin >> deficiency of Hb and RBC damage by precipitates of unpaired normal globin chains. ❑ Common in Mediterranean, African, and Asian regions. ❑ Protect against falciparum malaria. ❑ Wide variation depending on the combination of mutated alleles. β-Thalassemia  Single β-globin gene located on chromosome 11.  (1) β0, in which no β-globin chains are produced  (2) β+, in which there is reduced β-globin synthesis  >100 different causative mutations (single-base changes).  Β thalassemia minor (β thalassemia trait): inheriting one abnormal allele (asymptomatic or mildly symptomatic)  Β thalassemia major: any two β0 and β+ alleles.  B thalassemia intermedia: Defective synthesis of β-globin leads to anemia by:  1- Inadequate HbA formation resulting in small microcytic hypochromic RBCs  2- Accumulation of unpaired α-globin >> toxic precipitates >> damage RBC membranes and erythroid precursors.  >>Ineffective erythropoiesis.  >>Shortened RBC life span.  >>Increased iron absorption >> iron overload. Pathogenesis of β-thalassemia major α-Thalassemia  2 α-globin genes on chromosome 16  Deletions involving one or more of the α-globin genes.  Variable severity:  Loss of a single α-globin gene: Silent-carrier state.  Deletion of all four α-globin genes: Lethal in utero (hydrops fetalis)  Loss of three α-globin genes: relatively stable β4 tetramers (HbH ) and γ4 tetramers (Hb Bart)  Ineffective erythropoiesis is less pronounced in α-thalassemia  HbH and Hb Bart >> inefficient oxygen delivery MORPHOLOGY  β-thalassemia minor and α- thalassemia trait ❑ only of blood smears (microcytic hypochromic cells) + Target cells  Changes less severe with HbH diseases and B thalassemia intermedia.  β-thalassemia major ❑ marked microcytosis and hypochromia, ❑ poikilocytosis (variation in cell shape), ❑ anisocytosis (variation in cell size ) ❑ Nucleated red cells (normoblasts) Clinical features  Iron deficiency anemia must be excluded in the setting of B thalassemia minor and α-thalassemia trait.  Β thalassemia major manifests postnatally as HbF synthesis diminishes.  Skeletal deformities  Splenomegaly, hepatomegaly, and lymphadenopathy.  Growth retardation and cachexia  Patients sustained by blood transfusions (improve the anemia and reduce the skeletal deformities)  Unless patients are treated aggressively with iron chelators, cardiac dysfunction from secondary hemochromatosis. Diagnosis  β-thalassemia major:  Hb electrophoresis shows profound reduction or absence of HbA (α2β2) and increased levels of HbF (α2γ2). The HbA2 level may be normal or increased.  β-thalassemia minor:  Hb electrophoresis, shows a reduced level of HbA (α2β2) and an increased level of HbA2 (α2δ2). Glucose-6-Phosphate Dehydrogenase Deficiency  Recessive X-linked trait.  Males risk of symptomatic disease.  Carrier females (2 RBCs populations)  More than 400 G6PD variants, only few cause disease.  Deficient (African type) or non-functioning (Mediterranean)  Regeneration of reduced GSH (antioxidant) is impaired in G6PD- deficient cells  Red cells do not synthesize enzymes, older red cells more sensitive to oxidant damage. Pathogenesis  Episodes of intravascular hemolysis caused by exposure to an environmental factor (infectious or drugs): oxidant stress.  Oxidants attack globin >> Oxidized hemoglobin precipitates > Heinz bodies >> damage RBCs membrane >> intravascular hemolysis.  Splenic macrophages identify Heinz bodies and pluck them out resulting in indentation “bite cells”. Clinical features  Hemolysis typically develops suddenly 2 or 3 days after drug exposure +- pain.  The most common triggers are: ❑ (1) infections, free radicals are produced by activated leukocytes ❑ (2) Drugs (anti malaria, sulfonamides, aspirin) ❑ (3) Fava beans (favism)