Approach to anaemia


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  • Limitations-1. Given that these ranges include 95% of the normal population, the 2.5% of normal subject with values which fall below the normal range will be arbitrarily depicted as being anemic 2. The normal range for HGB and HCT is so wide that, for example a male patient with a baseline HCT of 49% may lose up to 15% of his RBC mass through hemolysis or blood loss and still have a HCT within the normal range
  • CBC-red cell indices-size-micro,macro, normo, color(chromasia) WBC-leukopenia should alert to bone marrow suppression Differential-immature forms Retic count-high-indicates increased response to continued hemolysis or blood loss stable anemia w/ low retic is strong evidence for deficient production of RBCs (reduced marrow response) Smear-as above, nuceated RBCs hematologic dz(sickle, thal,hemolytic anemia), things missed by automated counters: schistocytes, RBC parasits, evidence for hemolysis
  • Primary Bone Marrow involvement Marrow dysfunction vs. Marrow infiltration
  • Note hypersegmented polys – B12 & folate deficiency
  • AKA: hemolytic anemias
  • Approach to anaemia

    1. 1. Systematic Approach in Anemia Evaluation Dr .M.ASHOK. MD Consultant Physician & Assistant Professor of Medicine, Thanjavur medical college & hospital. Consultant : Vasan Medical Centre, Thiruverumbur
    2. 2. Objectives <ul><li>Review basic science of the RBC </li></ul><ul><li>Define Anemia </li></ul><ul><li>Review key aspects of history, physical and lab evaluation </li></ul><ul><li>Review a systematic approach to the differential diagnosis </li></ul><ul><li>Case-based application of clinical concepts </li></ul>
    3. 3. Erythropoesis-Brief Hematology Review <ul><li>Bone marrow </li></ul><ul><ul><li>Pluripotent stem cells </li></ul></ul><ul><ul><li>Chemical regulation </li></ul></ul><ul><ul><ul><li>Cytokines </li></ul></ul></ul><ul><ul><ul><li>Erythroid specific growth factor </li></ul></ul></ul><ul><ul><ul><li>Erythropoietin (EPO) </li></ul></ul></ul><ul><ul><li>Life span </li></ul></ul><ul><ul><ul><li>Reticulocyte- 4 days </li></ul></ul></ul><ul><ul><ul><li>RBC –120 days </li></ul></ul></ul>
    4. 4. RBC-The important players <ul><li>Hemoglobin </li></ul><ul><ul><li>reversibly binds and transports 02 from lungs to tissues </li></ul></ul><ul><ul><li>4 globin chains & iron </li></ul></ul>
    5. 5. RBC-The important players (2) <ul><li>Iron </li></ul><ul><ul><li>key element in the production of hemoglobin </li></ul></ul><ul><ul><li>absorption is poor </li></ul></ul><ul><li>Transferrin </li></ul><ul><ul><li>iron transporter </li></ul></ul><ul><li>Ferritin </li></ul><ul><ul><li>iron binder, measure of iron stores, *also acute phase reactant* </li></ul></ul>
    6. 6. Definitions <ul><li>Anemia-values of hemoglobin, hematocrit or RBC counts which are more than 2 standard deviations below the mean </li></ul><ul><ul><li>HGB<13.5 g/dL (men) <12 (women) </li></ul></ul><ul><ul><li>HCT<41% (men) <36 (women) </li></ul></ul>
    7. 7. CASE <ul><li>ML is a 64-year old male who has not had any primary care for several years. When he tried to give blood last week, he was told that he was anemic. He presents to your clinic for evaluation. </li></ul><ul><li>What would you do?? </li></ul>
    8. 8. Evaluation of the Patient <ul><li>HISTORY </li></ul><ul><ul><li>Is the patient bleeding? </li></ul></ul><ul><ul><ul><li>Actively? In past? </li></ul></ul></ul><ul><ul><li>Is there evidence for increased RBC destruction? </li></ul></ul><ul><ul><li>Is the bone marrow suppressed? </li></ul></ul><ul><ul><li>Is the patient nutritionally deficient? Pica? </li></ul></ul><ul><ul><li>PMH including medication review, toxin exposure </li></ul></ul>
    9. 9. Evaluation of the Patient (2) <ul><li>REVIW OF SYMPTOMS </li></ul><ul><li>Decreased oxygen delivery to tissues </li></ul><ul><ul><li>Exertional dyspnea </li></ul></ul><ul><ul><li>Dyspnea at rest </li></ul></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Signs and symptoms of hyperdynamic state </li></ul></ul><ul><ul><ul><li>Bounding pulses </li></ul></ul></ul><ul><ul><ul><li>Palpitations </li></ul></ul></ul><ul><ul><li>Life threatening: heart failure, angina, myocardial infarction </li></ul></ul><ul><li>Hypovolemia </li></ul><ul><ul><li>Fatiguablitiy, postural dizziness, lethargy, hypotension, shock and death </li></ul></ul>
    10. 10. Evaluation of the Patient (3) <ul><li>PHYSICAL EXAM </li></ul><ul><li>• Stable or Unstable? </li></ul><ul><li>-ABCs </li></ul><ul><li>-Vitals </li></ul><ul><li>• Pallor </li></ul><ul><li>• Jaundice </li></ul><ul><li>-hemolysis </li></ul><ul><li>• Lymphadenopathy </li></ul><ul><li>• Hepatosplenomegally </li></ul><ul><li>• Bony Pain </li></ul><ul><li>• Petechiae </li></ul><ul><li>• Rectal-? Occult blood </li></ul>
    11. 11. Laboratory Evaluation <ul><li>Initial Testing </li></ul><ul><ul><li>CBC w/ differential (includes RBC indices) </li></ul></ul><ul><ul><li>Reticulocyte count </li></ul></ul><ul><ul><li>Peripheral blood smear </li></ul></ul>
    12. 12. Reticulocyte count <ul><li>Retic count = % immature RBC </li></ul><ul><li>Normal 0.5-1.5% (for non-anemic) </li></ul><ul><li><1% Inadequate production </li></ul><ul><li>>=1% Increased production (? adequacy) </li></ul>
    13. 13. Reticulocyte Correction <ul><li>%Retic count frequently overestimates </li></ul><ul><li>Retic count should be compared to non-anemic RBC count to assess adequacy of response </li></ul><ul><li>Corrected Retic count = %Retic X HCT/45 </li></ul>
    14. 14. Reticulocyte Production Index <ul><li>Correction for left shift – Retic lifespan is increased in blood </li></ul><ul><li>RPI = % Retic X Hct/45 X 1/CF </li></ul><ul><li>Hct Correction factor (CF) </li></ul><ul><li>40-45 1.0 </li></ul><ul><li>35-39 1.5 </li></ul><ul><li>25-34 2.0 </li></ul><ul><li>15-24 2.5 </li></ul><ul><li>Normal RPI = 1 (for non-anemic pt) </li></ul><ul><li>RPI < 2 : hypoproliferative </li></ul><ul><li>RPI >=2 : hyperproliferative </li></ul>
    15. 15. Retic Production Index <ul><li>Hypoproliferative </li></ul><ul><li>- Iron def. anemia </li></ul><ul><li>- B12/folate def. </li></ul><ul><li>- Chronic disease </li></ul><ul><li>- Sideroblastic anemia </li></ul><ul><li>- Aplastic anemia </li></ul><ul><li>- Myeloproliferative </li></ul><ul><li>Hyperproliferative </li></ul><ul><li>- Hemolytic disease </li></ul><ul><li>- Hemoglobinopathy (including thalassemia) </li></ul>
    16. 16. Laboratory Evaluation (2) <ul><li>Bleeding </li></ul><ul><ul><li>Serial HCT or HGB </li></ul></ul><ul><li>Iron Deficiency </li></ul><ul><ul><li>Iron Studies </li></ul></ul><ul><li>Hemolysis </li></ul><ul><ul><li>Serum LDH, indirect bilirubin, haptoglobin, coombs, coagulation studies </li></ul></ul><ul><li>Bone Marrow Examination </li></ul><ul><li>Others-directed by clinical indication </li></ul><ul><ul><li>hemoglobin electrophoresis </li></ul></ul><ul><ul><li>B12/folate levels </li></ul></ul>
    17. 17. Differential Diagnosis <ul><li>Classification by Pathophysiology </li></ul><ul><ul><li>Blood Loss </li></ul></ul><ul><ul><li>Decreased Production </li></ul></ul><ul><ul><li>Increased Destruction </li></ul></ul><ul><li>Classification by Morphology </li></ul><ul><ul><li>Normocytic </li></ul></ul><ul><ul><li>Microcytic </li></ul></ul><ul><ul><li>Macrocytic </li></ul></ul>
    18. 18. Anemia Differential Dx by Flow Chart MCV/smear Micro Normo Macro Iron panel Retic Low Retic High High Low Iron/B12/Folate *Occult Blood Loss Yes No Coombs (+) Coombs (-) Go to *Occult Blood Loss B12/Folate B12 Low Folate/Low Normal MMA/Homocysteine MMA high – B12 Low Homocysteine high – Folate Low Normal – Go to ** **Normal Bone Marrow Bx Anemia of Chronic Dis.
    19. 19. First use size ( MCV ) to sort the Differential Dx MCV Micro Normo Macro
    20. 20. Macrocytic anemia Macro RPI >= 2 RPI < 2 Check Occult Blood Loss Check B12 and folate No Yes Coombs’ test
    21. 21. Macrocytic: RPI < 2 B12/Folate B12 Low Normal Folate Low MMA High MMA Homocysteine Normal Homocysteine High Consider Liver, Renal, Thyroid, Alcohol, Chronic dis. Consider Bone Marrow Bx
    22. 22. Macrocytic: RPI < 2 Megaloblastic Anemia <ul><li>B12 </li></ul><ul><li>Inadequate absorption </li></ul><ul><li>Synthesized by bacteria </li></ul><ul><li>Meat, fish, dairy (strict vegans) </li></ul><ul><li>Absorbed as B12-IF complex in ileum (gastrectomy) </li></ul><ul><li>Ca++ and pH dependant (PPI) </li></ul><ul><li>Folate </li></ul><ul><li>Inadequate intake </li></ul><ul><li>Synthesized by plants and micro-organism </li></ul><ul><li>Green leafy vege’s </li></ul><ul><li>Fruits </li></ul><ul><li>Absorbed in jejunum </li></ul>
    23. 23. Macrocytic: RPI >= 2 Occult Blood Loss? Yes No Investigate source Coombs’ (DAT) Check for Hemolysis Peripheral smear
    24. 24. Macrocytic: RPI >= 2 Hemolytic Anemia Coombs’ (DAT) Positive Negative Immune Hemolysis Drug related Hemolysis Transfusion, Infection, Cancer Hemoglobinopathy, G6PD, PK, Spherocytosis, Eliptocytosis, PNH, TTP, DIC
    25. 25. Coombs’ positive with Spherocytes Autoimmune hemolytic anemia <ul><li>Warm AIHA </li></ul><ul><li>Abrupt onset </li></ul><ul><li>IgG </li></ul><ul><li>Anti-Rh, e, C, c, LW, U </li></ul><ul><li>Jaundice </li></ul><ul><li>Splenomegaly </li></ul><ul><li>SLE, CLL, Lymphoma </li></ul><ul><li>Drugs: methyl-dopa, mefenamic acid, cimetidine, cefazolin </li></ul><ul><li>Cold AIHA </li></ul><ul><li>Insidious onset </li></ul><ul><li>IgM, complement </li></ul><ul><li>Anti-I, I, Pr </li></ul><ul><li>Cold agglutinin titer </li></ul><ul><li>Absent jaundice </li></ul><ul><li>Mycoplasma </li></ul><ul><li>Virus </li></ul>
    26. 26. Coombs’ positive with Spherocytes Other immune hemolytic anemia <ul><li>Alloantibody hemolytic anemia </li></ul><ul><li>Transfusion reaction </li></ul><ul><li>Feto-maternal incompatibility (Kleihauer-Betke test) </li></ul><ul><li>Drug related Hemolytic anemia </li></ul><ul><li>Toxic immune complex (drug+Ab+C3) </li></ul><ul><li>- Quinine, Quinidine, Rifampin, INH, Sulfonamides, </li></ul><ul><li>Tetracyclin </li></ul><ul><li>Hapten formation (anti-IgG) </li></ul><ul><li>- PCN, methicillin, ampicillin </li></ul>
    27. 27. Coombs’ Negative Hemolytic anemia <ul><li>Episodic - G6PD def., PNH </li></ul><ul><li>Hemoglobinopathy </li></ul><ul><li>- Sickle, crystals or target cells </li></ul><ul><li>Elliptocytosis </li></ul><ul><li>Spherocytosis </li></ul><ul><li>DIC, TTP </li></ul>
    28. 28. Normocytic Anemia Hyperproliferative (RPI >= 2) <ul><li>Use same flow chart as macrocytic hyperproliferative </li></ul>Occult Blood Loss? Yes No Investigate source Coombs’ (DAT) Check for Hemolysis Peripheral smear
    29. 29. Normocytic Anemia Hypoproliferative (RPI < 2) <ul><li>1. Get iron panel (ferritin)/B12/folate </li></ul><ul><li>- some clue from RBC indices to check early disease, high RDW, peripheral smear. </li></ul><ul><li>2. Consider liver, renal, drugs, toxin, endocrine (thyroid), and anemia of chronic disease. </li></ul><ul><li>3. Get BM bx </li></ul><ul><li>- Leukopenia, thrombocytopenia, CRI < 0.1 </li></ul><ul><li>- Aplastic anemia/pancytopenia </li></ul><ul><li>- Abnormal (immature) cells on smear </li></ul>
    30. 30. Blood Loss <ul><li>Acute </li></ul><ul><ul><li>Traumatic </li></ul></ul><ul><ul><li>Variety of sources </li></ul></ul><ul><ul><ul><li>Melena, hematemesis, menometrorrhagia </li></ul></ul></ul><ul><li>Chronic </li></ul><ul><ul><li>Occult bleeding </li></ul></ul><ul><ul><ul><li>Colonic polyp/carcinonma </li></ul></ul></ul>
    31. 31. Decreased Production <ul><li>Infectious </li></ul><ul><li>Neoplastic </li></ul><ul><li>Endocrine </li></ul><ul><li>Nutritional Deficiency </li></ul><ul><li>Anemia of Chronic Disease </li></ul>
    32. 32. Decreased Production INFECTIOUS <ul><li>Bacterial </li></ul><ul><ul><li>Tuberculosis </li></ul></ul><ul><ul><li>MAI </li></ul></ul><ul><li>Viral </li></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>Parvovirus </li></ul></ul>
    33. 33. Decreased Production NEOPLASTIC <ul><li>Leukemia </li></ul><ul><li>Lymphoma/Myeloma </li></ul><ul><li>Myeloproliferative Syndromes </li></ul><ul><li>Myelodysplasia </li></ul>
    34. 34. Decreased Production ENDOCRINE <ul><li>Thyroid Dysfunction </li></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><li>Erythropoietin Deficiency </li></ul><ul><ul><li>Renal Failure </li></ul></ul>
    35. 35. Decreased Production NUTRITIONAL DEFICIENCY <ul><li>Iron </li></ul><ul><li>B12 </li></ul><ul><li>Folate </li></ul>
    36. 36. Macrocytic Anemia <ul><li>MCV > 100 </li></ul><ul><li>Megaloblastic:Abnormalities in nucleic acid metabolism </li></ul><ul><ul><li>B12, Folate </li></ul></ul><ul><li>Non-megaloblastic:Abnormal RBC maturation </li></ul><ul><ul><li>Myelodysplasia </li></ul></ul><ul><li>ETOH, liver dz, hypothryroidism, chemotherapy/drugs </li></ul>
    37. 37. Microcytic Anemia <ul><li>MCV <80 </li></ul><ul><li>Reduced iron availability </li></ul><ul><li>Reduced heme synthesis </li></ul><ul><li>Reduced globin production </li></ul>
    38. 38. Microcytic Anemia REDUCED IRON AVAILABILTY <ul><li>Iron Deficiency </li></ul><ul><ul><li>Deficient Diet/Absorption </li></ul></ul><ul><ul><li>Increased Requirements </li></ul></ul><ul><ul><li>Blood Loss </li></ul></ul><ul><ul><li>Iron Sequestration </li></ul></ul><ul><li>Anemia of Chronic Disease </li></ul><ul><ul><li>Low serum iron, low TIBC, normal serum ferritin </li></ul></ul><ul><ul><li>MANY!! </li></ul></ul><ul><ul><ul><li>Chronic infection, inflammation, cancer, liver disease </li></ul></ul></ul>
    39. 39. Microcytic Anemia REDUCED HEME SYNTHESIS <ul><li>Lead poisoning </li></ul><ul><li>Acquired or congenital sideroblastic anemia </li></ul><ul><li>Characteristic smear finding: Basophylic stippling </li></ul>
    40. 40. Microcytic Anemia REDUCED GLOBIN PRODUCTION <ul><li>Thalassemias </li></ul><ul><li>Smear Characteristics </li></ul><ul><ul><li>Hypochromia </li></ul></ul><ul><ul><li>Microcytosis </li></ul></ul><ul><ul><li>Target Cells </li></ul></ul><ul><ul><li>Tear Drops </li></ul></ul>
    41. 41. Lab tests of iron deficiency of increased severity NORMAL Fe deficiency Without anemia Fe deficiency With mild anemia Fe deficiency With severe anemia Serum Iron 60-150 60-150 <60 <40 Iron Binding Capacity 300-360 300-390 350-400 >410 Saturation 20-50 30 <15 <10 Hemoglobin Normal Normal 9-12 6-7 Serum Ferritin 40-200 <20 <10 0-10
    42. 42. Differential Diagnosis-Revisited <ul><li>Classification by Pathophysiology </li></ul><ul><ul><li>Blood Loss </li></ul></ul><ul><ul><li>Decreased Production </li></ul></ul><ul><ul><li>Increased Destruction </li></ul></ul>
    43. 43. INCREASED DESTRUCTION <ul><li>Immune Mediated </li></ul><ul><li>Non-immune Mediated </li></ul>
    44. 44. Increased Destruction IMMUNE MEDIATED <ul><li>Cold Agglutinin </li></ul><ul><ul><li>Paroxysmal nocturnal hemoglobinuria </li></ul></ul><ul><ul><li>Post mycoplasmal hemolytic anemia </li></ul></ul><ul><li>Warm Agglutinin </li></ul><ul><ul><li>Drug induced </li></ul></ul><ul><ul><li>Autoimmune hemolytic anemia </li></ul></ul><ul><ul><li>Transfusion reaction </li></ul></ul>
    45. 45. Increased Destruction NON-IMMUNE MEDIATED <ul><li>Extra-corpuscular </li></ul><ul><ul><li>Macro-circulatory </li></ul></ul><ul><ul><ul><li>Hypersplenism </li></ul></ul></ul><ul><ul><ul><li>Extracorporeal circulation </li></ul></ul></ul><ul><ul><li>Micro-circulatory </li></ul></ul><ul><ul><ul><li>DIC </li></ul></ul></ul><ul><ul><ul><li>TTP </li></ul></ul></ul><ul><ul><ul><li>HUS </li></ul></ul></ul><ul><li>Intra-corpuscular </li></ul><ul><ul><li>RBC Wall (membrane or enzyme defects) </li></ul></ul><ul><ul><li>Heme or globin abnormalities (HbS, C) </li></ul></ul>
    46. 46. Back to M.L.- You appropriately decide to obtain more history! <ul><li>HPI: “I’ve been a little more tired than usual, but I’ve been busy at work. I’m getting close to retirement. Nothing else is unusual. I avoid doctors if I can” </li></ul><ul><li>PMH: Inguinal hernia repair 20 yrs ago </li></ul><ul><li>FH: F & MGF-heart attack(age 80), brother-alcoholism </li></ul><ul><li>SH: Married x44yr, smokes 1ppd, “a couple beers/night” </li></ul><ul><li>MEDS: daily multivitamin </li></ul><ul><li>ALLERGIES: none </li></ul><ul><li>ROS:+fatigue, +urine seems a little darker lately </li></ul>
    47. 47. More on M.L. <ul><li>P.E. findings </li></ul><ul><ul><li>T 98.4 HR 98 Resp 20 BP 112/70 </li></ul></ul><ul><ul><li>Gen: NAD, appears younger than stated age </li></ul></ul><ul><ul><li>HEENT: skin and conjunctiva slightly pale </li></ul></ul><ul><ul><li>NECK: no adenopathy or thyromegally </li></ul></ul><ul><ul><li>Chest: CTAB </li></ul></ul><ul><ul><li>CV: RRR, no murmur </li></ul></ul><ul><ul><li>ABD: no HSM, soft, normoactive bowel sounds </li></ul></ul><ul><ul><li>GU: normal male </li></ul></ul><ul><ul><li>Rectal: no masses, prostate smooth/not enlarged, guaiac negative stool </li></ul></ul>
    48. 48. M.L.’s Initial Labs <ul><li>Only a CBC w/ diff was obtained: </li></ul><ul><ul><li>WBC: 8.2, HCT 32.2, MCV 79, Platelets 221, differential - normal </li></ul></ul>
    49. 49. Initial Thoughts? <ul><li>Blood loss? </li></ul><ul><ul><li>Age places him at risk for colon CA </li></ul></ul><ul><li>Decreased Production? </li></ul><ul><ul><li>Alcohol use, Iron deficiency </li></ul></ul><ul><li>Increased Destruction? </li></ul><ul><ul><li>“ Darker urine” lately </li></ul></ul>
    50. 50. Further Work-up <ul><li>CAGE questions </li></ul><ul><li>Peripheral Blood Smear </li></ul><ul><li>Reticulocyte count </li></ul><ul><li>Iron Studies </li></ul><ul><ul><li>Ferritin </li></ul></ul><ul><ul><li>TIBC </li></ul></ul><ul><ul><li>% Saturation </li></ul></ul><ul><li>Urinalysis </li></ul><ul><li>FOBT or colonoscopy referal </li></ul>
    51. 51. More Results <ul><li>CAGE screen reveals no positive responses </li></ul><ul><li>Smear reveals microcytic, microchromic RBCs </li></ul><ul><li>Retic count is interpreted as “low” </li></ul><ul><li>Urinalysis negative for hemoglobin </li></ul><ul><li>FOBT: not completed by patient </li></ul><ul><li>Iron Studies </li></ul><ul><ul><li>Ferritin: 10 </li></ul></ul><ul><ul><li>TIBC: 350 </li></ul></ul><ul><ul><li>% Sat: 15 </li></ul></ul>
    52. 52. What’s next? <ul><li>Rule out Sources of Bleeding </li></ul><ul><ul><li>Counseling regarding colon CA and referral for colonoscopy </li></ul></ul><ul><li>Consider oral iron therapy </li></ul><ul><li>Dietary counseling (iron sources, limiting etoh, etc) </li></ul><ul><li>Encourage follow-up for health care maintenance </li></ul><ul><ul><li>Vaccinations (Tetnus/pneumovax) </li></ul></ul><ul><ul><li>Other cancer screening </li></ul></ul><ul><ul><li>Cholesterol Screen </li></ul></ul>
    53. 53. Diagnosis <ul><li>Colonoscopy revealed small suspicious lesion in sigmoid colon, pathology revealing adenocarcinoma. – Excised surgically, no mets. </li></ul><ul><li>Routine labs, one year later, reveal an HCT of 40%. He feels “better than ever”! </li></ul>
    54. 54. References <ul><li>Schrier, Stanley.Approach to the patient with anemia. Up to Date. 2004 </li></ul><ul><li>Schrier, Stanley. Anemia of Chronic Disease. Up to Date. 2004 </li></ul><ul><li>Schrier, Stanley. Anemias due to decreased red Cell Production. Up to Date 2004 </li></ul><ul><li>Schrier, Stanley. Causes and diagnosis of anemia due to iron deficiency. Up to Date. 2004 </li></ul><ul><li>Tierney, et al. Anemias. Current Medical Diagnosis and treatment. 2003. Pp469-489 </li></ul>
    55. 55. <ul><li>THANK YOU </li></ul>