Done by :Aseel Twaijer & Laith Sorour Hemolytic Anemias

Transcription

1 Hemolytic Anemias

2 Hemolytic anemias share the following features: - A shortened red cell life < 120 days - Elevated erythropoietin levels (compensatory increase in erythropoiesis) - Accumulation of hemoglobin degradation products (red cell hemolysis)

3 Extravascular hemolysis (within phagocytes): m.c Cause: RBCs deformability sequestration/phagocytosis Splenomegaly (hyperplasia of phagocytes) Anemia Jaundice (unconjugated bilirubin) Tx: splenectomy

4 Intravascular hemolysis: Less common Cause: mechanical injury (cardiac valves, thrombotic narrowing of the Microcirculation, repetitive physical trauma ) complement fixation intracellular parasites exogenous toxic factors (clostridial sepsis/release ofenzymes that digest the red cell membrane) Anemia hemoglobinemia hemoglobinuria hemosiderinuria jaundice (unconjugated bilirubin) Lysed RBCs---- free hemoglobin------haptoglobin------phagocytes If haptoglobin free hemoglobin/ methemoglobin Red-brown urine No splenomegaly

5 MORPHOLOGY: erythroid precursors (normoblasts) in BM prominent reticulocytosis in the p. blood Erythropoietin Hemosiderosis (accumulation of the iron containing pigment hemosiderin, particularly in the spleen, liver, and bone marrow) Extramedullary hematopoiesis (liver, spleen, and lymph nodes)----- Anemia pigment gallstones (cholelithiasis)----- biliary excretion of bilirubin

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9 Hereditary Spherocytosis autosomal dominant defects in RBC membrane skeleton---spheroid RBCs---- less deformable ----splenic sequestration/destruction HS is caused by diverse mutations that lead to an insufficiency of membrane skeletal components.

10 Young HS red cells are normal in shape, but the destabilized lipid bilayer sheds membrane fragments as red cells age in the circulation. the life span of the affected red cells is decreased on average to 10 to 20 days from the normal 120 days.

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13 MORPHOLOGY: Spherocytosis destinctive but not pathognomonic Other features of hemolytic anemias Moderate splenic enlargement ( gm)

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15 Clinical Features: family history RBCs---hypotonic salt solutions---osmotic lysis (influx of water) mean cell hemoglobin concentration (dehydration loss of K+ H2O) If compensated by erythropoiesis asymptomatic If decompensated-----hemolytic anemia--- Splenomegaly Anemia Jaundice

16 aplastic crises ---- acute parvovirus infection. Hemolytic crises----intercurrent events leading to increased splenic destruction of red cells (e.g., infectious mononucleosis) Gallstones

17 Splenectomy treats the anemia and its complications

18 Glucose-6-Phosphate Dehydrogenase X-linked trait Deficiency Hemolytic disease due to red cell enzyme defect (G6PD)----- antioxidant enzyme hemolysis result in misfolding of the protein, making it more susceptible to proteolytic degradation

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20 Several hundred G6PD genetic variants are known, but most are harmless. clinically significant variants: G6PD : 10% of American blacks G6PD Mediterranean: in the Middle East Reduced half-life of G6PD G6PD activities fall quickly to levels inadequate to protect against oxidant stress as red cells age.

21 Episodic hemolysis is characteristic Intravascular and extravascular hemolysis exposures that generate oxidant stress. The most common triggers ar: infections ---- oxygen-derived free radicals/activated leukocytes Drugs ---- antimalarials, sulfonamides, nitrofurantoins certain foods ---- fava bean Favism

22 Morphology: Heinz bodies (denatured globin forming membrane bound Precipitates/inclusions) Bite cells ( when macrophages pluck out the Heinz bodies in spleen) spherocytes

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24 Clinical features: Acute intravascular hemolysis Anemia --- hemoglobinemia ---- hemoglobinuria begins 2 to 3 days following exposure of G6PD-deficient individuals to oxidants. greater G6PD Mediterranean variant. Because only older red cells are at risk for lysis, the episode is selflimited Intermittent hemolysis (not chronic) --- No splenomegaly No cholelithiasis

25 Sickle Cell Disease common hereditary hemoglobinopathy Mainly in individual of African descent point mutation in the sixth codon of β-globin--- replacement of a glutamate residue with a valine residue.

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27 Normal adult red cells: contain mainly HbA (α2β2) small amounts of HbA2 (α2δ2) fetal hemoglobin (HbF; α2γ2)

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29 sickle cell trait: heterozygous for HbS (HbS:40%, HbA:60%) Asymptomatic do not sickle except under profound hypoxia sickle cell disease: homozygous for HbS Symptomatic

30 Pathogenesis: HbS molecules undergo polymerization when deoxygenated. Chronic hemolysis Microvascular occlusions Tissue damage

31 Several variables affect the rate and degree of sickling: - Interaction of HbS with the other types of hemoglobin in the cell: HbA ---- HbS polymerization ---- heterozygous HbF ---- HbS polymerization---- infants >5 or 6 months of age HbC ---- Lysine/ Glutamate milder, HbSC (50%, 50%) - Mean cell hemoglobin concentration (MCHC): MCHC ---- intracellular dehydration ---- sickling/polymerization MCHC ---- α-thalassemia sickling/polymerization - Intracellular Ph: Ph O2 affinity ---- sickling - Transit time of red cells through microvascular beds If slow --- sickling ---- spleen, BM, inflamed tissue

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33 extravascular hemolysis (mainly) intravascular hemolysis Microvascular occlusion sickle cells express adhesion molecule so sticky

34 MORPHOLOGY: sickled cells reticulocytosis target cells (red cell dehydration) Howell-Jolly bodies (small nuclear DNA remnants)/asplenia BM is hyperplastic as a result of a compensatory erythroid hyperplasia. bone resorption and secondary new bone formation, resulting in prominent cheekbones

35 Childhood----spleen is enlarged up to 500 gm Adolescence/early adulthood ---- splenic infarction, fibrosis (autosplenectomy). Infarctions caused by vascular occlusions can occur in many other tissues as well, including the bones, brain, kidney In adult patients, vascular stagnation in subcutaneous tissues often leads to leg ulcers

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39 Clinical Features: Vaso-occlusive crises/ pain crises: Infection/dehydration/acidosis---in most instances no predisposing cause is identified. bones, lungs, liver, brain, spleen, and penis. hand-foot syndrome or dactylitis of the bones of the hands or feet, Acute chest syndrome (fever, cough, chest pain, and pulmonary infiltrates) fatal Priapism loss of visual In children, painful bone crises are extremely common and often difficult to distinguish from acute osteomyelitis The most common cause of patient morbidity and mortality

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41 Sequestration crises: Massive entrapment of sickle red cells---rapid splenic enlargement----hypovolemia---shock---- fatal-----treatment with exchange transfusions. Aplastic crises: parvovirus B erythropoiesis----anemia.

42 Chronic hypoxia is responsible for a generalized impairment of growth and development, as well as organ damage affecting the spleen, heart, kidneys, and lungs. Increased susceptibility to infection with encapsulated organisms Pneumococcus pneumoniae and Haemophilus influenzae septicemia and meningitis are common, particularly in children, but can be reduced by vaccination and prophylactic antibiotics

43 Diagnosis: mixing a blood sample with an oxygen-consuming reagent, which induces sickling of red cells. Hemoglobin electrophoresis. Prenatal diagnosis is possible by analysis of fetal DNA obtained by amniocentesis or chorionic biopsy.

44 About 90% of patients survive to age 20, and close to 50% survive beyond the fifth decade Treatment: Blood transfusion Antibiotics Bone marrow transplant Hydroxyurea (DNA inhibitor) : + HbF

45 Thalassemia Syndromes inherited mutations that decrease the synthesis of either the α-globin or β-globin chains that compose adult hemoglobin, HbA (α2β2) endemic in the Mediterranean basin, the Middle East, tropical Africa, the Indian subcontinent,

46 β-thalassemias mutations that diminish the synthesis of β-globin chains. more than 100 different causative mutations, mostly consisting of point mutations two β chains are encoded by a single β-globin gene on chromosome 11 β0 mutations: absent β-globin synthesis β+ mutations: reduced β-globin synthesis

47 Impaired β-globin synthesis results in anemia by two mechanisms: 1- The deficit in HbA synthesis produces underhemoglobinized hypochromic, microcytic red cells with subnormal oxygen transport capacity. 2- diminished survival of red cells and their precursors. α chains precipitate within red cell precursors, forming insoluble inclusions----membrane damage----- apoptosis ---- ineffective erythropoiesis insoluble inclusions----membrane damage----- sequestration---- extravascular hemolysis

48 erythroid hyperplasia in the marrow Extensive extramedullary hematopoiesis skeletal abnormalities extraosseous masses in the thorax, abdomen, and pelvis. excessive absorption of dietary iron/due to - hepcidin secondary hemochromatosis

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50 β-thalassemia Major: Anemia---6 /9 m after birth---switches HbF-HbA Hb: 3 to 6 gm/dl RBCs: lack HbA (β0/β0) or small amounts (β+/β+ or β0/β+) HbF: The major RBCs Hb HbA2: normal, low, high

51 MORPHOLOGY: Anisocytosis poikilocytosis Microcytosis Hypochromia Target cells Basophilic stippling fragmented red cells enlargement of the spleen The liver and the lymph nodes can also be enlarged by extramedullary hematopoiesis. new bone formation

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54 clinical course: Untreated children suffer from growth retardation and die at an early age from the effects of anemia. cheekbones and other bony prominences are enlarged and distorted.

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56 With transfusions and iron chelation, survival into the third decade is possible BM transplantation is the only therapy offering a cure Cardiac disease resulting from progressive iron overload and secondary hemochromatosis

57 β-thalassemia Minor: More common Asymptomatic or mild anemia HbA2 (4-8%) HbF : normal or slightly increased

58 α-thalassemias inherited deletions that result in reduced or absent synthesis of α-globin chains The two α chains in HbA are encoded by an identical pair of α-globin genes on chromosome 16,

59 Newborns----γ4 tetramers--hemoglobin Barts older children/adults---β4 tetramers---hbh--- more in Asian high affinity for O2 so not useful for O2 delivery hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias because free β and γ chains are more soluble than free α chains and form fairly stable homotetramers HbA2: normal or low

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61 Paroxysmal Nocturnal Hemoglobinuria acquired mutations in the phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for the synthesis of certain membraneassociated complement regulatory proteins (GBI=glycosylphosphatidylinositol) PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity: (1) CD55 (2) CD59 (3) C8 binding protein. Of these

62 Red cells deficient in these GPI-linked factors are abnormally susceptible to lysis or injury by complement. intravascular hemolysis: paroxysmal and nocturnal ( PH/+complement) in only 25% of cases; chronic hemolysis without dramatic hemoglobinuria is more typical. Anemia Venous thrombosis (platelet dysfunction) Acute leukemia/mds (Hematopoietic stem cells)

63 diagnosed by flow cytometry (CD59, CD55) Tx: C5 inhibitor therapy Immunosuppressive drugs BM transplantation

64 Immunohemolytic/autoimmune hemolytic Anemias caused by antibodies that bind to red cells, leading to their premature destruction. direct Coombs antiglobulin test Patient s RBCs with sera AB indirect Coombs antiglobulin test Patient s serum with RBCs/Ag

65 Warm Antibody Type: M.C Extravascular hemolysis, Tx: removal of initiating cause, immunosuppressive therapy, splenectomy

66 Cold Agglutinin Type: Finger, nose, ears---- vascular occlusion---pallor, cyanosis, Raynaud phenomenon Hemolysis