1 / 64

HEMOLYTIC

Advanced Hematology (Medi 6304). HEMOLYTIC. ANMEIA. Ahmad Silmi. Second semester MAR 6 th 2017. Hemolytic anemia: Definition

bloch
Download Presentation

HEMOLYTIC

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Advanced Hematology (Medi 6304) HEMOLYTIC ANMEIA Ahmad Silmi Second semester MAR 6th 2017

  2. Hemolytic anemia: Definition • Anemia results from an excessive hemolysis of RBC’s • BM compensatory capacity: 6-8 folds of normal •  Several folds destruction rate •  Life span with erythrocytes less than 30 days •  Anemia developed (Signs & symptoms) • Two type of hemolysis: • 1. Intra-vascular hemolysis • 2. Extra-vascular hemolysis

  3. Hemolytic anemia: Hemolysis routes • Intravascular Hemolysis • Senescence: Reduced biological activities •  Glycolytic pathway deterioration • - Loss of NADPH and NADH pool • - loss of ATP generation: • loss of Membrane permeability & deformability •  Structural membrane abnormalities • Intracelluar Na+ () Intracelluar K+ () •  Surface-volume ratio ()  Spheroidals h

  4. Hemolytic anemia: Hemolysis routes • Intravascular Hemolysis (cont.) • Hemoglobin release into the circulation (Free) • Loaded on Haptoglobin (To BM or Liver) • Upon haptoglobin saturation • - Free Hemoglobin filtration (Kidney) & Reabsorption • - Excessive hemolysis •  Reabsorption capacity exceeded •  Hemoglobinuria and Hemoglobinemia

  5. Hemolytic anemia: Hemolysis routes • Extravascular Hemolysis (cont.) • IgG accumulation on effete erythrocytes • RES Macrophages recognition & phagocytosis • Degradative enzymatic digestion by macrophages • Hemoglobin disassembling: • - Iron released  Transferrin  BM or Hepatocytes • - Globin  components amino acids  a.a. pool • - Protoporphyrin  Bilirubin  Conjugated (Liver) •  Intestine (via Bile) •  Stercobilinogen & Stercobilin (with feces) •  Reabsorption  to Kidney  Urobilinogen (Urine

  6. Hemolytic anemia: Hemolysis routes

  7. Bilirubin

  8. Bilirubin

  9. Bilirubin

  10. Bilirubin

  11. Hemolytic anemia: Clinical and diagnostic features • Associated with excessive destruction of erythrocytes •  Liver capacity fail to conjugate •  Bilirubin concentration elevated •  Jaundice •  Urobilinogen (in urine) elevated • Darkening of urine on standing •  Stercobilinogen (in feces) elevated •  Serum haptoglobin: absent

  12. Hemolytic anemia: Complications Hyperbilirubinemia

  13. Hemolytic anemia: Complications Hyperbilirubinemia

  14. Hemolytic anemia: Complications Hyperbilirubinemia

  15. Hemolytic anemia: Complications Hypercoagulability

  16. Hemolytic anemia: Complications Hypercoagulability

  17. Hemolytic anemia: Complications Hypercoagulability

  18. Hemolytic anemia: Complications Hypercoagulability

  19. Hemolytic anemia: Clinical and diagnostic features • CBC and Blood film examination

  20. Hemolytic anemia: Clinical features

  21. Hemolytic anemia: Diagnostic features

  22. Hemolytic anemia: Clinical and diagnostic features • CBC and Blood film examination

  23. Hemolytic anemia: Clinical and diagnostic features • CBC and Blood film examination

  24. Hemolytic anemia: Clinical and diagnostic features • Associated with increased erythropoiesis rate: •  Reticulocytosis and other evidences of BM hyperactivation

  25. Hemolytic anemia: Clinical and diagnostic features • Associated with increased erythropoiesis rate: •  Reticulocytosis and other evidences of BM hyperactivation

  26. Hemolytic anemia: Clinical and diagnostic features • Associated with increased erythropoiesis rate: •  Reticulocytosis and other evidences of BM hyperactivation

  27. Hemolytic anemia: Clinical and diagnostic features • Associated with increased erythropoiesis rate: •  BM index (Hyperplasia): Myeloid:Erthroid Hyperplasia (1:1)

  28. Hemolytic anemia: Clinical and diagnostic features • Associated with morphological abnormalities: •  Osmotic fragility and Autohemolysis • - Incubation of test RBC’s in hypotonic solution under sterile • conditions for 24 hours.

  29. Hemolytic anemia: classification • Classification: Based on the etiology and pathophysiology • 1. Hereditary: 2. Acquired: • a. Membrane defects a. Immune-mediated: • (ex. Spherocytosis) Auto~ , Allo~ , Drug-induced ~ • b. Metabolic defects b. Microangipathic (MAHA) • (ex. G6PD deficiency) TTP, HUS, DIC • c. Haemoglobin Abnormalities c. Paroxysmal Noctunal Haemoglobinuria • (ex. Hb-S and Hb-C) d. Secondary: • Infections, Liver and renal disease

  30. Hemolytic Anemia: Membrane defect > Vertical interactions stabilize the lipid bilayer. >> Deficiencies of spectrin, ankyrin, or band 3 protein causes decoupling of the lipid bilayer from the underlying skeletal lattice >>>subsequent membrane loss in the form of microvesicles. >>>>This leads to the formation of spherocytes (hereditary spherocytosis).

  31. Hemolytic Anemia: Membrane defect > Horizontal interactions provide mechanical stability to the membrane. >> defects include abnormal spectrin heterodimer association to form tetramers and defective skeletal protein interactions of junctional complexes at the end of the spectrin tetramers (spectrin, actin, protein 4.1) >>> result in fragmentation of the red blood cell (schistocytosis).

  32. Hereditary spherocytosis • HS Molecular Defects: Spectrin • - Spectrin deficiency is the most common protein alteration in HS. • - Not all spectrin defects lead to the formation of spherocytes. • - Mutations that affect the self-association of Spectrin heterodimers lead to hereditary elliptocytosis. • HS Molecular Defects: Ankyrin • - Patients with ankyrin defects have prominent spherocytosis without other morphologic defects. • - About 2/3 of patients have a combined defect of both ankyrin and spectrin.

  33. Hereditary spherocytosis • HS Molecular Defects: Band 3 • - Generally milder. • - Many of the mutations affect the protein’s ability to be inserted into membranes • - All patients with band 3 deficiency have a proportional • decrease in protein 4.2 because band 3 is apparently needed for 4.2 stability. • HS Molecular Defects: Band 4.2 • - Protein 4.2 deficiency is associated with loss of band 3; and, in some cases, a loss of ankyrin. • - The morphology in these patients is variable and sometimes stomatocytes and ovalocytes are more common than spherocytes.

  34. Hereditary spherocytosis: Diagnosis • Required criteria: • At least one sign of increased red cell destruction: • (ex. reticulocytosis, increased bilirubin, decreased haptoglobin, increased lactate dehydrogenase). • Increased spherocytes and anisocytosis on the blood film. • Increased red cell osmotic fragility. • Optional criteria • 1. Positive family history • 2. Splenomegaly • 3. Anemia (1/3 of HS patients are NOT anemic)

  35. Hereditary ellipocytosis: - HE is inherited as an autosomal dominant gene. Heterozygous individuals are asymptomatic; homozygous individuals have mild to severe hemolysis. - Spectrin and band 4.1 mutations are invloved in the etiology of HE; abnormalities in protein 4.1 are much less common than spectrin mutations

  36. Hereditary ellipocytosis: - The hallmark is the presence of large numbers of elliptocytes in the peripheral blood. - Red cell fragmentation may be seen in the more severe forms. - Osmotic fragility is generally normal. - If hemolysis is present, reticulocytosis, and other evidence of red cell destruction will be apparent as listed earlier for HS.

  37. Hemolytic anemia: classification • Classification: Based on the etiology and pathophysiology • 1. Hereditary: 2. Acquired: • a. Membrane defects a. Immune-mediated: • (ex. Ellipocytosis, Spherocytosis) Auto~ , Allo~ , Drug-induced ~ • b. Metabolic defects b. Microangipathic (MAHA) • (ex. G6PD deficiency) TTP, HUS, DIC • c. Haemoglobin Abnormalities c. Paroxysmal Noctunal Haemoglobinuria • (ex. Hb-S and Hb-C) d. Secondary: • Infections, Liver and renal disease

  38. Glucose 6-phosphate dehydrogenase (G6PD): G6PD Glucose G6P6-PG NADP NADPH Reductase Hexose Monophosphate Shunt GSH GSSH Peroxidase H202 H2O

  39. G6PD deficiency:

  40. G6PD deficiency:

  41. G6PD deficiency: • G6PD gene is located on the X chromosome (q28). • Lyon’s hypothesis: • Heterozygous female: 2 cell populations • 50% of cell are G6PD normal & 50% are deficient • Clinically: features ranging from normal to severely deficient • G6PD variants: • - Point mutations (single amino acid substitution) • - >400 G6PD variants were identified. • - variants shows variable enzyme stability and/or kinetics

  42. G6PD variants:

  43. Chronic nonspherocytic hemolytic anemia (CNHA) • Evidenced by chronic hyperbilirubinemia, decreased serum haptoglobin level, and increased lactate dehydrogenase level. • The RBC morphology is unremarkable and is referred to as nonspherocytic. • The hemolysis is mostly extravascular (no hemoglobinurea). • Characterized by chronic anemia diagnosed at birth as having neonatal hyperbilirubinemia and the hemolysis continues into adulthood. • Usually with compensatory reticulocytosis but can be transfusion dependent.

  44. G6PD deficiency: Clinical features • Normally, patients are asymptomatic till …. • Hemolytic crises: Intravascular hemolytic anemia following to the exposure of oxidizing agents • jaundice: 2-3 days after exposure • Anemia worsens till the 7th-8th day • Self limiting anemia • G6PD deficiency & Favism • G6PD deficiency and Resistance to P. falciparum

  45. G6PD deficiency Pathogenesis

  46. G6PD deficiency: Consequences Blister cells: red cells with a clearing at the periphery, like a blister Arises when bite cells undergo repair of the cell membrane, resulting in a clearing within the red cell where the Heinz body previous was. Bite cells: red cells with ‘bites’ taken out Bites’ are from splenic macrophages removing the part of the red blood cell with a Heinz body.

  47. G6PD deficiency: diagnosis

  48. G6PD deficiency: Following to oxidative stress • Blood film morphology: • Normocytic, normochromic anemia • Red cells fragmentation ( Bite cells and Blister cells) • Occasional spherocytes • Dimorphisms (Females)

  49. G6PD deficiency: Following to oxidative stress • Hemolytic features: • Increased reticulocytes after hemolytic crises • Hemoglobinemia & Hemoglobinuria

More Related