Blood 2 Pathology PDF

HEMOLYTIC ANEMIA Hallmarks of intravascular hemolysis: (Sometimes to less than 20 days ) Hemoglobinemia...

HEMOLYTIC ANEMIA Hallmarks of intravascular hemolysis: (Sometimes to less than 20 days ) Hemoglobinemia Hemoglobinuria (dark urine) Hemosiderinuria. (Loss of iron in urine) Loss of iron Low haptoglobin (binds free hemoglobin) (manifested by the appearance of jaundice) Hemolytic anemias production of blood cells Hereditary Spherocytosis Sickle Cell Anemia Classification Thalassemia Intracorpuscular(intrinsic to RBC) and Glucose-6-Phosphate Dehydrogenase Deficiency extracorpuscular(from outside like immune mediated or due to destructed vessels) Hereditary Spherocytosis Extravascular hemolysis:(outside the vascular space) Inherited intrinsic defects in RBCs membrane Defects in RBCs >> diminished deformability >>stuck in skeleton (network of proteins that stabilizes the lipid sinusoids >> increase the destruction of red cells by bilayer), leading to formation of spherocytes phagocytes (macrophages) in the spleen. (nondeformable cells highly vulnerable to sequestration (RBC deformability is how well red blood cells bend to and destruction in the spleen). squeeze through tiny blood vessels.) Intravascular hemolysis: Injuries so severe >> RBCs literally burst within the Autosomal dominant. circulation (physical, biochemical or mechanical)- like damage by diseased heart valves- Pathogenesis Hallmarks of extravascular hemolysis: Spectrin (Major membrane skeleton protein) is Hyperbilirubinemia and jaundice (degradation of connected to the transmembrane proteins (bands 3) via hemoglobin in splenic macrophages) the linker proteins ankyrin (give RBC its shape) Splenomegaly (phagocyte and macrophage hyperplasia Mutations most frequently involve ankyrin, band 3, or in the spleen) spectrin. Bilirubin rich gallstones (pigment stones, cholelithiasis) Mutations weaken vertical interactions between the Low haptoglobin (which is a serum protein that binds membrane skeleton and intrinsic red cell membrane free hemoglobin from the lysed RBC) proteins. Remember that there is a lot of free hemoglobin in this type of anemia, so they need haptoglobin to bind.  Destabilizes the lipid bilayer of RBCs >> shed Clinical features. membrane vesicles into the circulation as they age >> Triad (moderate anemia, splenomegaly and cells become spherical with limited deformability jaundice) >> stuck in spleen >> engulfed by macrophages. RBCs increased osmotic fragility (diagnostic) Shortened life span to < 20 days. (when we place the RBC in a saline solution which is Beneficial effect of splenectomy although hypotonic, these RBC will burst). spherocytes persist the anemia is corrected. Aplastic crises, triggered by parvovirus B19 infection (To skip the process of destruction the spherocytes) (target erythroblasts) >> BM devoid of red cell progenitors. (10-14 days to recover) Splenectomy can be beneficial but with risk of infections (children) Hemoglobin is tetramer Sickle Cell Anemia Morphology Hemoglobinopathy. Spherocytes (dark red, lack central pallor) Inherited mutations leading to structural abnormalities Compensatory hyperplasia of red cell progenitors in in hemoglobin. the BM. Mutation in β-globin that creates sickle hemoglobin Reticulocytosis. (HbS) “Howell-Jolly” bodies are seen in post splenectomy Most common familial hemolytic anemia. (nuclear remnant) Protective effect against Plasmodium falciparum Marked splenomegaly (500-1000grams) maybe the malaria. largest among the hemolytic anemias Cholelithiasis,(+gallstones) in 40% to 50% of Pathogenesis patients. ❑Single amino acid substitution in β-globin. ❑Valine instead glutamate at the 6th amino acid Spherocytes and Howell-Jolly bodie 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 of deoxygenation and reocygenation >> irreversibly sickling ❑Normal adult red cell contains 96% HbA Morphology (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). Blood smears: spindled, or boat-shaped sickled RBCs -Patients: HbA completely replaced by HbS. and target cells. -Carriers: only half of HbA is replaced. Compensatory hyperplasia of erythroid progenitors in (one allele is mutated while the other is normal) the BM. Asymptomatic or mild symptomatic Bone deformities (due to expansion of BM)(Prominent Factors that affect sickling cheekbones, changes in the skull “crewcut” in ❑The intracellular levels of hemoglobin other radiographs). HbS Extramedullary hematopoiesis (liver and spleen). HbS heterozygotes (one allele is mutated)(sickle cell Splenomegaly (large spleen in children) trait) >> little tendency to sickle Autosplenectomy due to infarcts(Spleen will be small Newborns do not manifest disease until HbF falls to and fibrotic in adults ) (complete by adulthood) adult levels (5 to 6 months). Vascular thrombosis and infarction: (due to the The intracellular levels of hemoglobin other than HbS Whether a normal aggregation of sickled RBC leading to occlusion of hemoglobin A or a fetal hemoglobin F will decrease the sickling blood vessels which we call Vaso-occlusive chrisis)at ❑The intracellular concentration of HbS. any organ even BM. RBCs dehydration >> increases Hb concentration Hemosiderosis and pigment gallstones >> facilitates sickling Sickled cells Target cells :cytoplasm collects ❑The time required for red cells to pass through the microvasculature in a central, dark- red “puddle.” sluggish (slow) circulation in spleen, BM and in inflammation, When rapidly passing there will be reduced or no sickling. Pathologic consequences of sickling Chronic moderately severe hemolytic anemia due to RBC membrane damage (life span > ischemic ❑Moderate to severe anemia. tissue damage and pain crises.increased by: (infection, ❑Hyperbilirubinemia and compensatory reticulocytosis. inflammation, dehydration, and acidosis) ❑Aplastic crisis (parvovirus B19) ❑Vaso-occlusive crises (pain and tissue damage) β-Thalassemia ( There is four main types based on the location of - Single β-globin gene located on chromosome 11. the blockage). (1) β0, in which no β-globin chains are produced Hand-foot syndrome (children) (2) β+, in which there is reduced β-globin synthesis Acute chest syndrome (with pneumonia and embolism) Stroke sometimes it accompanies acute chest syndrome - >100 different causative mutations (single-base Proliferative retinopathy (blindness) changes). occlusion in blood vessels supplying the retina - Β thalassemia minor (β thalassemia trait): inheriting one abnormal allele (asymptomatic or mildly symptomatic) ❑Functionally asplenic (susceptible to infections by - Β thalassemia major: any two β0 and β+ alleles. encapsulated bacteria, pneumococci) (in children, in which - B thalassemia intermedia: there is splenomegaly, with increase in the number of macrophages , or in the adults with autosplenectomy. ❑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. Defective synthesis of β-globin leads to anemia Thalassemia ❑ Inherited diseases: mutations in globin genes 1- Inadequate HbA formation resulting in small ❑ Decrease the synthesis of α- or β-globin. microcytic hypochromic RBCs ❑ HbA (adult Hb): tetramer of 2α and 2β chains (reflected by Low mcv in complete blood count , decrease size and increase ❑ Decreased synthesis of one globin >> deficiency of central pallor ) Hb and RBC damage by precipitates of unpaired normal 2- Accumulation of unpaired α-globin >> toxic globin chains. precipitates >> damage RBC membranes and if we have a deficiency of beta-globin chains the unpaired alpha-globin chains will precipitate in the cell, leading to toxic damage to its membranes. erythroid precursors ❑ Common in Mediterranean, African, and Asian regions. -Ineffective erythropoiesis. ❑ Protect against falciparum malaria. due to decreased life span of RBC Most erythroblasts die in the bone marrow because of toxic precipitates in this RBC cytoplasm. ❑ Wide variation depending on the combination of -Shortened RBC life span. mutated alleles due to deposition of unpaired alpha globin chain leading to toxic damage). -Increased iron absorption(increased erythropoiesis) >> iron overload.(secondary hemochromatosis)  Pathogenesis of β-thalassemia major MORPHOLOGY β-thalassemia minor and α-thalassemia trait ❑ only of blood smears (microcytic hypochromic cells) + Target cells β-thalassemia major ❑ marked microcytosis and hypochromia, ❑ poikilocytosis (variation in cell shape), ❑ anisocytosis (variation in cell size ) ❑ Nucleated red cells (normoblasts) red blood cells don’t fully mature because the bone marrow is trying to compensate ***‫الرسمة مهمة‬ for anemia by producing RBCs faster. This rush leads to the release of nucleated red repeated blood transfusions will build up iron in the body leading to secondary hemochromatosis -Changes less severe with HbH diseases and B Small in size , increase,hypo chromic, pallor in the center, when passing in the spleen they will be engulfed by splenic macrophages leading to extravascular hemolysis and thalassemia intermedia anemia Clinical features α-Thalassemia -Iron deficiency anemia must be excluded in the setting - 2 α-globin genes on chromosome 16 of B thalassemia minor and α-thalassemia trait. In total 4 alleles for alpha globin - Β thalassemia major manifests postnatally as HbF - Deletions involving one or more of the α-globin genes. synthesis diminishes. - Skeletal deformities - Variable severity: - Splenomegaly, hepatomegaly, and lymphadenopathy. 1- Loss of a single α-globin gene: Silent-carrier state -Growth retardation and cachexia (Asymptomatic). -Patients sustained by blood transfusions (improve 2- Deletion of all four α-globin genes: Lethal in utero the anemia and reduce the skeletal deformities) (hydrops fetalis) -Unless patients are treated aggressively with iron 3- Loss of three α-globin genes: relatively stable β4 chelators, cardiac dysfunction from secondary tetramers (HbH ) and γ4tetramers (Hb Bart) hemochromatosis. - Ineffective erythropoiesis is less pronounced in α- Diagnosis thalassemia β-thalassemia major: - HbH (4B chains)and Hb Bart(4γ chains) >> Hb electrophoresis shows profound reduction or absence inefficient oxygen delivery bc they have High affinity of HbA (α2β2) and increased levels of HbF (α2γ2). The for oxygen. 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 more at risk of symptomatic disease While in females we need 2 mutated alleles to have the disease. - Carrier females (2 RBCs populations) one with deficient G6PD enzyme and one with normal enzyme. - More than 400 G6PD variants, only few cause disease. - Deficient (African type) or non-functioning (Mediterranean) (worse) - Regeneration of reduced GSH (antioxidant) is impaired in G6PD-deficient cells - Red cells do not synthesize enzymes(Bc they don't Clinical features have a nucleus), older red cells more sensitive to (usually normal until exposure to stressful conditions such as infections, oxidant damage. Hemolysis typically develops suddenly 2 or 3 days Pathogenesis after drug exposure+- pain.(pain crisis) -Episodes of intravascular hemolysis caused by exposure to an environmental factor (infectious or drugs): oxidant The most common triggers are: stress. (1) infections, free radicals are produced by activated -Oxidants attack globin >> Oxidized hemoglobin leukocytes precipitates > Heinz bodies >> damage RBCs (2) Drugs (anti malaria, sulfonamides, aspirin) membrane >> intravascular hemolysis. (3) Fava beans (favism) -Hemolysis here is within the vasculature. (Not in the spleen like spherocytosis, thalassemia, and sickle cell anemia) - Splenic macrophages identify Heinz bodies and pluck them out resulting in indentation “bite cells”