1. ANAEMIA- BASIC ASPECTS
H.A. MWAKYOMA, MD

2. Objectives Review basic science of the RBC Define Anemia
Review key aspects of history, physical and lab evaluation
Review a systematic approach to the differential diagnosis
Case-based application of clinical concepts

3. RBC-The important players
Hemoglobin
reversibly binds and transports 02 from lungs to tissues
4 globin chains & iron

4. RBC-The important players (2)
Iron
key element in the production of hemoglobin
absorption is poor
Transferrin
iron transporter
Ferritin
iron binder, measure of iron stores, *also acute phase reactant*

5. Definitions
Anemia-values of hemoglobin, hematocrit or RBC counts which are more than 2 standard deviations below the mean
HGB<13.5 g/dL (men) <12 (women)
HCT<41% (men) <36 (women)
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

7. Definition of anemia 1. Reduction in the hemoglobin concentration in
blood
2. Decreased total circulating red cell mass

8. Normal values for peripheral blood
Female Male
Erythrocytes (per µl) 4.8±0.6x ±0.8x106
Hemoglobin (g/dl) ±2 16 ±2
Hematocrit (%) ±5 47 ±5
Reticulocytes (%)
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Mean corpuscular volume (MCV; µm3)
Mean corpuscular hemoglobin (MCH; pg)
Mean corpuscular hemoglobin concentration (MCHC; %)

9. Etiologic classification of anemias
Impaired red cell production
A. Disturbance of proliferation and differentiation of
stem cells
B. Disurbance of proliferation and maturation of erythrocytes
II Increased rate of destruction (hemolytic anemias)
A. Intrinsic abnormalities
B. Extrinsic abnormalities

10. Etiologic classification of anemias (1)
I. Impaired red cell production
A. Disturbance of proliferation and differentiation of
stem cells ( aplastic anemia, pure red cell aplasia)
B. Disurbance of proliferation and maturation of erythrocytes:
1.Defective DNA synthesis (megaloblastic anemias)
2.Defective Hb synthesis:
a/. Deficient heme synthesis (iron deficiency)
b/. .Deficient globin synthesis (thalassemia)
3. Unknown or multiple mechanisms (anemia of chronic disease, anemia of marrow replacement)

11. Etiologic classification of anemias (2)
II. Increased rate of destruction (hemolytic anemias)
A. Intrinsic abnormalities
Hereditary
1. Red cell membrane defects (hereditary spherocytosis, hereditary eliptocytosis)
2. Red cell enzyme deficiencies
a/. Glycolytic enzymes: pyruvate kinase, hexokinase
b/. Enzymes of hexose monophosphate shunt:
G-6PD, glutathione synthetase
3. Disorders of globin synthesis
a/. Deficient globin synthesis (thalassemia)
b/. Structurally abnormal globin synthesis
(sickle cell anemia, unstable hemoglobins)
Acquired
1. Membrane defect: paroxysmal nocturnal hemoglobinuria

12. Etiologic classification of anemias (3)
B. Extrinsic abnormalities
1. Antibody mediated
a/. Autoantibodies (idiopathic, drug-associated, SLE, malignancies)
b/. Isohemagglutinins (transfusion reactions, erythroblastosis fetalis)
2. Mechanical trauma of RBC
a/. Microangiopathic hemolytic anemias (thrombotic
thrombocytopenic purpura, DIC)
b/. Cardiac traumatic hemolytic anemia
3. Chemicals and microorganisms
4. Sequestration in mononuclear phagocytic system
- hypersplenism

13. Classification of anemias (simplified)
1. Deficiency anemias
2. Aplastic anemia
3. Hemolytic anemias
4. Secondary anemias

14. Morphologic classification of anemias
Type MCV MCHC Common cause
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Macrocytic anemia increased normal Vitamin B12 deficiency
Folic acid deficiency
Microcytic anemia
- hypochromic decreased decreased Iron deficiency
Thalassemia
- normochromic decreased normal Spherocytosis
or normal
Normocytic anemia normal normal Aplastic anemia
- normochromic Chronic renal failure
Some hemolytic anemia

15. Stem cell disorder 2. Pure red cell aplasia B. Acquired
1. Aplastic anemia
2. Pure red cell aplasia
A. Congenital
B. Acquired

17. CASE
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.
What would you do??

18. Evaluation of the Patient
HISTORY
Is the patient bleeding?
Actively? In past?
Is there evidence for increased RBC destruction?
Is the bone marrow suppressed?
Is the patient nutritionally deficient? Pica?
PMH including medication review, toxin exposure

19. Evaluation of the Patient (2)
REVIW OF SYMPTOMS
Decreased oxygen delivery to tissues
Exertional dyspnea
Dyspnea at rest
Fatigue
Signs and symptoms of hyperdynamic state
Bounding pulses
Palpitations
Life threatening: heart failure, angina, myocardial infarction
Hypovolemia
Fatiguablitiy, postural dizziness, lethargy, hypotension, shock and death

20. Evaluation of the Patient (3)
PHYSICAL EXAM
•Stable or Unstable?
-ABCs
-Vitals
•Pallor
•Jaundice
-hemolysis
•Lymphadenopathy
•Hepatosplenomegally
•Bony Pain
•Petechiae
•Rectal-? Occult blood

21. Laboratory Evaluation
Initial Testing
CBC w/ differential (includes RBC indices)
Reticulocyte count
Peripheral blood smear
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

22. Laboratory Evaluation (2)
Bleeding
Serial HCT or HGB
Iron Deficiency
Iron Studies
Hemolysis
Serum LDH, indirect bilirubin, haptoglobin, coombs, coagulation studies
Bone Marrow Examination
Others-directed by clinical indication
hemoglobin electrophoresis
B12/folate levels

23. Differential Diagnosis
Classification by Pathophysiology
Blood Loss
Decreased Production
Increased Destruction
Classification by Morphology
Normocytic
Microcytic
Macrocytic

24. Blood Loss Acute Chronic Traumatic Variety of sources Occult bleeding
Melena, hematemesis, menometrorrhagia
Chronic
Occult bleeding
Colonic polyp/carcinonma

25. Decreased Production Infectious Neoplastic Endocrine
Nutritional Deficiency
Anemia of Chronic Disease

26. Decreased Production INFECTIOUS
Bacterial
Tuberculosis
MAI
Viral
HIV
Parvovirus

27. Decreased Production NEOPLASTIC
Leukemia
Lymphoma/Myeloma
Myeloproliferative Syndromes
Myelodysplasia
Primary Bone Marrow involvement
Marrow dysfunction vs. Marrow infiltration

28. Decreased Production ENDOCRINE
Thyroid Dysfunction
Hypothyroidism
Erythropoietin Deficiency
Renal Failure

29. Decreased Production NUTRITIONAL DEFICIENCY
Iron
B12
Folate

30. Macrocytic Anemia MCV > 100
Megaloblastic:Abnormalities in nucleic acid metabolism
B12, Folate
Non-megaloblastic:Abnormal RBC maturation
Myelodysplasia
ETOH, liver dz, hypothryroidism, chemotherapy/drugs
Note hypersegmented polys – B12 & folate deficiency

31. Microcytic Anemia MCV <80 Reduced iron availability
Reduced heme synthesis
Reduced globin production

32. Microcytic Anemia REDUCED IRON AVAILABILTY
Iron Deficiency
Deficient Diet/Absorption
Increased Requirements
Blood Loss
Iron Sequestration
Anemia of Chronic Disease
Low serum iron, low TIBC, normal serum ferritin
MANY!!
Chronic infection, inflammation, cancer, liver disease

33. Microcytic Anemia REDUCED HEME SYNTHESIS
Lead poisoning
Acquired or congenital sideroblastic anemia
Characteristic smear finding: Basophylic stippling

34. Microcytic Anemia REDUCED GLOBIN PRODUCTION
Thalassemias
Smear Characteristics
Hypochromia
Microcytosis
Target Cells
Tear Drops

35. Differential Diagnosis-Revisited
Classification by Pathophysiology
Blood Loss
Decreased Production
Increased Destruction

36. INCREASED DESTRUCTION
Immune Mediated
Non-immune Mediated
AKA: hemolytic anemias

37. Increased Destruction IMMUNE MEDIATED
Cold Agglutinin
Paroxysmal nocturnal hemoglobinuria
Post mycoplasmal hemolytic anemia
Warm Agglutinin
Drug induced
Autoimmune hemolytic anemia
Transfusion reaction

38. Increased Destruction NON-IMMUNE MEDIATED
Extra-corpuscular
Macro-circulatory
Hypersplenism
Extracorporeal circulation
Micro-circulatory
DIC
Intra-corpuscular
RBC Wall (membrane or enzyme defects)
Heme or globin abnormalities (HbS, C)

39. A haemolytic state exists when the in vivo survival of the RBC is shortened.
Anaemia occurs if the onset of haemolysis is sudden with no time for marrow compensation or in severe chronic haemolysis when the mean red cell life is very short.