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Anemia classification & pathogenesis.ppt
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- 2. Anemia • Definition • History –Age • normal values - adult, children • In < 5 yrs - Hb < 11 g/dl Anemia (WHO crit) • Girls (> 6yrs) + Boys (6 - 14 yrs) - Hb < 12 g/dl • Boys (>15yrs) - Hb < 13 g/dl Anemia • Elderly (low values - decrease in androgen secretion, age related in stem cell proliferation) • Cause of difference of values of Hb of children & adults
- 3. Anemia – Diet – Drugs –Race - Blacks - low values by 0.5 - 0.6 g/dl – Change in stool habits – Alcohol abuse – Travel to malarious zone
- 4. Anaemia • History – Menstrualflow - > 7 days, clots, > 12 pads – No. of pregnancy & abortions – Fever - infection / neoplasm / collagen dis – Skin • Hyperpigmentation - Faconi’s anemia • Bruises, ecchymosis, petechiae - PFD, liver disease • Carotenemia - IDA in infants • Jaundice - HA / Hepatitis • Cavernous haemangioma - MAHA
- 5. Anaemia • History – Facies- haemolytic - thal – Eyes • Icterus • Microcornea - Fanconi’s anemia • Microaneurysmal retinal vessels - S & C Hbpathies • Cataract - Galactosaemia • Oedema of eyelid - Inf mononucleosis • Blindness - Osteopetrosis – Mouth - glossitis, angular stomatitis
- 6. Anaemia • History – Hands •Triphalangeal thumb - Red cell aplasia • Hypoplasia of thenar eminus - Fanconi’s anaemia • Spoon nails - IDA – Spleen enlargement – Sternal tenderness – Occult blood in stool – Urine examination - • haematuria, haemoglobinuria
- 7. Clinical effects ofAnemia • CVS & Pulmonary features of Anemia – Depends on :- • rate of reduction of O2 carrying capacity • compensatory mechanism • features of underlying disorder – If anemia develops rapidly • shortness of breath, tachycardia, dizziness/ faintness, postural hypotension, extreme fatigue – In chronic anemias • moderate dysponea or palpitation present • some pts - CCF, Angina, intermittent claudication
- 8. Clinical effects ofAnemia • CVS & Pulmonary features of Anemia – Heart murmur - systolic - pulmonic area • Pallor - – D/D from • vasoconstriction of peripheral vessels • pigmentation of skin • myxedema – Pallor + icterus – Pallor + petechiae/ecchymosis = BM failure
- 9. Clinical effects ofAnemia • Skin & Mucosal changes – thinning, loss of luster, early graying of hairs – nails - loss of luster, brittle, concave – Chronic leg ulcer - SCD – Symmetric dermatitis – Fissure at angle of mouth, glossitis
- 10. Clinical effects ofAnemia • Neuromuscular features – headache, vertigo, tinnitus, faintness, scotoma – lack of mental concentration, drowsiness – restlessness & muscular weakness – paresthesias • Eye findings – 20% pts - flame shaped hge, hard exudates, cotton - wool spots
- 11. Clinical effects ofAnemia • GI changes – Manifestations of underlying disorder • hiatus hernia, DU, Gastric carcinoma – Consequence of anemic conditions • glossitis, atrophy of papillae of tongue • dysphagia (IDA)
- 13. Discordance between Hbconc & Red cell mass • Increase in plasma vol relative to RBC mass (Hb disproportionately low) – Hydremia of pregnancy – Congestive splenomegaly – Recumbency (vs. upright)
- 14. Discordance between Hbconc & Red cell mass • Decrease in plasma vol relative to RBC mass (Hb high, normal or low; but high relative to RBC mass) – Dehydration – Protracted diarrhea (especially in children) – Peritoneal dialysis with hypertonic solution – Diabetic acidosis – Diabetes insipidus with restricted fluid intake – Burn patient – Stress erythrocytosis, spurious polycythemia
- 15. Discordance between Hbconc & Red cell mass • Decrease in both plasma volume & RBC mass (Hb normal, RBC mass low) – Acute blood loss – Chronic disease
- 16. Questions to beasked in evaluation of anemia Is anaemia associated with other hematologic abnormalities Yes No • BM examination Is there an appropriate Retic - Leukemia response to anemia - Aplastic anemia - MDS Yes No - Myelofibrosis - Megaloblastic anemia - Metastatic carcinoma
- 17. Questions to beasked------- Yes No • Is there Hemolysis? - Decrease in red cell prec ( Bilirubin, LDH, Haptoglobin - Ineffective erythropoiesis Haemosidnuria) What are red cell indices Yes No • Evaluate for cause Evaluate for of hemolysis hemorrhagic cause MCV (>100) MCV (80-100) MCV (<80) - Megaloblastic A - ACD, PRCA - IDA, Thal, HbE
- 18. Reticuloctye count • Correctedretic count = – % retic x pts Hct / 45 • Reticulocyte index = Corrected retic x 0.5 (corrected for extended period of presence in the circulation) • Absolute retic count = – % retic x RBC count / L3 – Normal = 25 to 75 x 109 / L
- 19. Reticulocyte count • Correctedretic count < 2% or • Absolute reticulocyte count < 100,000/l Hypoproliferative anaemias • Values above these – – associated with either an appropriate response to blood loss or with hemolytic anemias
- 21. MCV & RDW •MCV – fl, average cell size • RDW – – the SD of red blood cell volume divided by the mean volume – Reflects the variation in cell size (anisocytosis) in the population of red blood cells – upper limit 14.6% (12.4 - 14.6%) - CV – Increased in • IDA (even before MCV falls) • Megaloblastic anaemia
- 22. Red cell Indices •MCV = Hct (%) / RBC count (x1012/L) x 100 normal = 80 - 100 fl • MCHC = Hb (g/dl) / Hct (%) x 100 normal = 31 - 36% • MCH = Hb (g/dl) / RBC count (x1012/L) x 10 normal = 28 - 32 pg • Hematological rule of THREE
- 25. Is anemia associatedwith abnormalities in PBS • Most informative & rewarding diagnostic procedure • Confirm the findings of automated CBC – which can be inaccurate in presence of nucleated NRBC or rouleaux formation • Hypersegmented neutrophil – first to appear • Other findings in PBS
- 26. Peripheral smear • Crenatedred cells - – evenly distributed spiny projections - blunt end • Acanthocytes (irregularly spaced large coarse spicules having sharp ends) – Abetalipoproteinaemia – Acqd causes • HA of cirrhosis • Deficiency of Vit E • Uraemia • Hypothyroidism • Lack of Kell blood group (McLeod Phenotype)
- 27. Peripheral smear • Burrcells (D/D from acanthocytes) – Pointed projections, more numerous, uniform in size & regularly spaced • Stomatocytes – Hereditary stomatocytosis – Liver cirrhosis – Rh null phenotype Cause – Osmotic swelling through cation imbalance ( RBC Na+ & K+) – Redistribution of membrane phospholipid ( Lecithin levels)
- 28. Peripheral smear • Sicklecells – Related to formation of intracellular “Tactoids” of HbS intertwine to form rigid projections along cell periphery – Other HbS with sickling: • Hb CHARLEM, Hb CGEORGETOWN, Hb PORTO ALEGRE, Hb I • Target cells (reflect cholesterol abnormalities) – Hemolytic Anemia, HbC disease – Thal – IDA, Liver disease – After splenectomy
- 29. Peripheral smear • Inclusionbodies – Basophilic stippling – Pappenheimer bodies – H – J bodies – Heinz bodies – Cabot’s ring – Parasitized red cells – Hb H inclusions
- 30. Peripheral smear • Basophilicstippling – Sideroblastic anaemia – Acute Haemolytic anemia – Lead poisoning – Severe alcoholism – PV • H – J bodies (rounded aggregation of chromatin material) – Post splenectomy patients – Acute H.A
- 31. Peripheral smear • Heinzbodies – Irregular retractile granules 1 - 2 in diameter & found at periphery of RBC – Supravital stain – Never fix with methyl alcohol or stained with methyl alcohol based dye – Seen in • Thal, Unstable Hbs • Cabot rings – Results from damage to lipoprotein of the cell stroma
- 32. Is BM neededto clarify the cause of anemia • Useful in reticulocytopenic patients – Hypoplasia – Marrow infiltration (myelophthisic anemia) – Myelofibrosis • Normocellular marrow with erythropoiesis – Red cell aplasia – Renal disease – Endocrinopathy • Iron stores - Sideroblastic anaem, IDA (rarely)
- 33. Is BM neededto clarify the cause of anemia • Low retic count with normal marrow erythropoiesis - ineffective erythropoiesis – Megaloblastic anemia – Thal – Sideroblastic anemia
- 34. Macrocytic anemia • Commonfinding • 1.7% - 3.6% pts.- MCV is in absence of anaemia • Mild macrocytosis - common & may remain unexplained • This finding should not be ignored • This could be imp. clue to underlying disorder
- 35. Macrocytic Anaemia • Megaloblasticmacrocytic anaemia • Normoblastic macrocytic anaemia
- 36. Normoblastic macrocytic anemia (MCV- 100 - 110 fl) • Pathology in RBC membrane lipids Causes • Macrocytosis Common - Haemolytic anaemia Post - haemorrhagic anaemia • Macrocytosis occasional Liver disease, CDA I & III, Hypothyroidism, Alcohol, Cytotoxic drugs, Leukemia's, MDS Myelophthisic anaemia, Aplastic anaemia
- 37. Macrocytic anaemia &liver disease • Cause : Multi factorial - – Intravascular dilution due to hypervoluemia – Impaired ability of marrow to respond – Severe HA (spur cell anaemia) • Characterized by – thin macrocytes (target cells) – surface area without increase in vol – memb lipids - esp cholesterol & phospholipids
- 38. Megaloblast • Ehrlich -1880 - first described • Minot & Murphy - 1926 - disease could be reversed by eating liver - Nobel prize • Castle - 1929 -Gastric juice - IF which binds with extrinsic factor in meat
- 39. Megaloblastic Anaemia • ImpairedDNA synthesis & • Distinctive morphologic changes in blood and bone marrow
- 45. Etiology of MegaloblasticAnaemia • Vitamin B12 deficiency • Folic acid deficiency • MDS • Combined deficiency • Inherited disorders of DNA synthesis • Drugs - inhibit DNA synthesis
- 46. Etiology of VitB12 deficiency • Dietary animal products Vit B12 (microorganism) • Plants & vegetable contains little Vit B12 • Daily requirement - 2 - 3 mg • Body stores - sufficient for many years (Body stores to daily requirement ratio 1000:1) • 1g - lost daily - biliary or renal excretion
- 47. Vitamin B12 deficiency •Nutritional - vegans • Malabsorption of B12 – Gastric causes - Pernicious anaemia Partial or total gastrectomy – Intestinal causes - Bacterial overgrowth, terminal ileum (resection, bypass, Crohn’s disease, TB, lymphoma) • D. latum • Cong absence of B12 binders (Immerslund-Grasbeck syndr) • Chronic pancreatic disease • Zollinger – Ellison syndrome
- 48. Etiology of Folatedeficiency • Present in leafy vegetables, fruits, mushrooms & animal protein • Destroyed by prolonged cooking • After ingestion interacts with small int. brush border associated binding proteins uptake • Serum levels maintained by – diet & – enterohepatic circulation
- 49. Folic acid deficiency •Poor intake - extremes of age, alcoholics • Increased demand - pregnancy & lactation, Hemolysis, Exfoliative dermatitis, Rapidly growing malignancy • Malabsorption - Sprue, Crohn’s disease, Short bowel syndrome, Amyloidosis
- 50. Inherited disorders ofDNA synthesis • Orotic aciduria • Lesch – Nyhan syndrome • Thiamine responsive megaloblastic anaemia • MTHFR • Formiminotransferase • Dihydrofolate reductase • Transcobalamin II deficiency
- 51. Other causes • Myelodysplasia& Erythroleukemia • Medications – Folate antagonists (e.g. methotrexate) – Purine antagonists (e.g. 6 – mercaptopurine) – Pyrimidine antagonists (e.g. cytosine arabinoside) – Alkylating agents (e.g. cyclophosphamide) – Zidovudine , OC, Nitrous oxide, Arsenic – Dihydrofolate reductase inhibitors (sulfa drugs, methotrexate) • Toxins – Nitrous oxide, Arsenic, Chlordane • CDA
- 52. Do PBS revealhypersegmented neutrophil or macroovaloctytes Yes No Megaloblastic anemia Nonmegaloblastic anemia • BM exam to confirm • Test for Vit B12 & folate Reticulocytosis Vit B12 defi No defi Folate defi Schilling test - Inherited disorders Poor diet corrects with IF - Drugs Malabsorption Increased needs Yes No
- 53. Reticulocytosis Increased Normal ordecreased Hemolytic anemia Alcohol toxicity Hemorrhagic anemia Hypothroidism Liver disease If above negative, get BM exam MDS, Red cell aplasia Acqd sideroblastic anemia
- 54. Microcytic anemia • Disordersof Iron metabolism – IDA, ACD • Disorders of globin synthesis – Alpha and beta thal – Hb E syndromes – Hb C syndromes – Unstable Hbs • Sideroblastic anemia • Lead intoxication (usually normocytic)
- 55. Approach to Microcyticanemia Reticulocytosis Low / Normal Increased s. iron s. iron N serum iron s. iron TIBC N / TIBC Normal TIBC Normal TIBC Ferritin N or Ferritin Normal ferritin Ferritin IDA Increased Hb electrophoresis BM + iron stain - ESR, CRP ACD Thal Sideroblastic an
- 56. Reticulocytosis - Review PBSfor abnormal morphology - Lab test for increased red cell destruction - obtain Hb studies Homozygous beta thal Hemolytic elliptocytosis Hereditary pyropokilocytosis
- 57. Classification of Normocyticanemia • Anemia associated with appropriately increased erythrocyte production – Post hemorrhagic anemia – Hemolytic anemia • Decreased erythropoietin secretion – Impaired source - Renal or hepatic – Reduced stimulus (decreased tissue needs) • Anemia of endocrine deficiency – PCM, ACD
- 58. Classification of Normocyticanemia • Anemia with impaired marrow response – BM hypoplasia • Red blood cell aplasia • Aplastic anemia – BM infiltrative disorders – MDS – CDA II – IDA - early
- 59. Approach to Normocyticanemia Reticulocytosis Increased RBC production N / decreased RBC production H/O jaundice, splenomegaly Presence of PBS abnormality Elevated bilirubin or LDH Yes No Hemolysis Hemorrhogic abnormalities
- 60. Normal / decreasedRBC production - Serum chemistries to screen for S. iron renal, hepatic and endocrine disease - Consider EPO levels, thyroid studies Positive Negative N / high Low Anemia of BM aspirate / biopsy - renal dis - liver dis - Infiltrative disorders ACD - endocrine - Red cell aplasia Early IDA failure - MDS, CDA - II
- 61. Diagnostic approach toHA • Anaemia - RBC destruction RBC production OR BOTH • BM – normally – increased production 6 – 8 times normal whenever destruction • H.A. - destruction inspite of production
- 62. Clinical History • Pallor,jaundice • Passage of yellow / dark urine • H/O gallstones, leg ulcers, skeletal abnormalities • Splenomegaly, Hepatomegaly, aplastic crises Family History (since birth/early childhood) Yes No Heriditary HA H/O – infection - fever, drugs, (ACQUIRED H.A.)
- 63.
- 64. What type ofH.A. Intrisic Defect Extrinsic Defect 1. Hereditary I. Acquired a) Membrane defect 1. Immune mediated – HS, HE, HPP a) AIHA (warm Abs, cold Abs) b) Enzyme defects b)Isoimmune H.A. – G6PD defi, PK defi Transfusion related, HDN – Others- Glutathione reductase defi (rare) c) Haemoglobinopathies / 2. Infections globin chain defects 3. Hypersplenism – Hb SS, Hb S - 4. Sec to Renal / Liver pathology – Thal, Abnormal Hb / HTN II. Acqd. 5. Mechanical, chemical, - PNH thermal damage - TTP, HUS
- 65. What type ofH.A. Extrinsic Defects II. Hereditary – Abetalipoprotenemia – LCAT def (lecithin cholesterol acyl transferase def)
- 66. Conditions with Intravascular haemolysis •PNH • RBC fragmentation disorder • HTR from ABO isoantibodies • PCH • Acqd AIHA • Associated with infections – Blackwater fever - Clostridial sepsis • Chemical agents – Arsenic, snake & spider venom, Ac drug reaction with G6PD defi, I.V. D.W. • Thermal injury
- 67. Screening tests • CBC- Hb - / N - MCV, RDW - Retic count BM – erythroid hyperplasia • PS – macrocytes, polychramasia, NRBC, spherocytes, elliptocytes, schistocyes, acanthocyes, stippling • Biochemical tests - unconj bilirubin (>5 mg/dl is unusual) s. LDH – isoenzyme II Absent / s. haptoglobin (N=30 –190 mg/dl Plasma Hb > 10 mg/dl Fecal urobilinogen, Urine haemosiderin +ve • Others – Red cell survival studies
- 68. Screening tests • Rateof Carbon Monoxide production – provides assessments of rate of heme catabolism – 2 - 10 times of normal values in HA • Glycosylated Hb – reduced – this reflects the young RBC age in these pts
- 69. Features of I.V.haemolysis • / absent Haptoglobin* • Haemoglobinaemia (N < 1 mg/dl) • Haemoglobinuria • Haemosidinuria • Methemalbuminemia – Schumm test • Hemopexin *Haptoglobin – acute phase reactant - in inflam disorder - R.A., SLE - neoplastic cond, & infections
- 70. Signs of Acceleratederythropoiesis • Reticulocytosis • Red cell creatine – levels in young RBC - 6 to 8 times higher – elevation persists for 20 days of RBC life span compared to retic maturation time of 1 to 3 days • Morphologic findings in PBS & BM • Ferrokinetic studies – increased plasma iron turn over - 2 to 8 times
- 71. Lab test usefulin the D/D of Hemolysis • Specific morphologic abnormalities • DAT • Osmotic fragility test • Hemolytic disorders with Heinz bodies – G6PD defi (acute hemolytic episode) – Unstable Hb disease – Thal – Chemical injury
- 72. Specific tests PS Spherocytes(+) +ve - ve – AIHA (Warm Ab, Cold Ag, PCH) OF – ABO & Rh incompatibility – Drug induced HA -VE +VE Incubated Enzymopathies OFT G6PD def PK def s/o HS Heinz bodies confirm by Enzyme screening test - Family studies Enzyme assay - Memb protein anal Autohaemolysis test Coombs test
- 73. Specific tests PS –Microcytic anaemia Reticulocytosis - mild / N Refractory anaemia Leucopenia Ham’s test +ve -ve Sucrose lysis test Other Ref anemia CDA PNH (confirm by CD55/59)
- 74. Autohemolysis test • Measuresspontaneous haemolysis of RBC when incubated at 370C for 48 h in sterile conditions • N= 0.2 – 2% • With addition of Glucose = 0 – 0.9% • With addition of ATP = 0 – 0.8% • Type 1: slightly to moderately increased partially corrected with glucose seen in – G6PD def, HE (Disorders of Pentose Phosphate Pathway)
- 75. Autohemolysis test • TypeII – autohaemolysis greatly increased corrected with ATP & not with Glucose seen in PK def (disorders of glycolytic pathway) • Type III – autohaemolyis greatly increased correction with ATP or Glucose seen in HS (membrane defect) • Comments- neither specific nor sensitive - But when positive – differentiate membrane abnormality from enzyme defects
- 76. Conditions sometimes mistaken forH.A. • Associated with anemia & reticulocytosis – Hge, Recovery from iron, folate or vit B12 def – Recovery from marrow failure • Associated with jaundice & anemia – Ineffective erythropoiesis (intramedullary haemolysis) – Bleeding into body cavity or tissue • Associated with jaundice without anemia – Defective bilirubin conjugation – Crigler – Najar syndrome – Gilbert syndrome • Marrow invasion (MF, metastatic disease) • Myoglobinuria
- 77. Approach to Haemoglobinopathies &Thalassemia CBC + PS ( Hb, micro – hypo) MCV (normal) MCV (<77fl) MCH (>27pg) MCH (<27pg) Hb electrophoresis Abn band Hb F Hb A2 Sickling test Quantitation Symptoms + Thal maj Assymptomatic thal / HPFH +ve Hb S (HPLC for subclassfication) - ve Hb D Punjab / Rare Hb variant (HPLC)
- 78. Approach to Haemoglobinopathies &Thalassemia Hb A2 Normal Border line Raised IDA Thal > 3.5% >10% thal IDA but <10% Normal – A2 Thal Repeat after IDA Thal HbE / correction triat variant-HPLC