1. Classification of Anemia (Adults)
Teoman SOYSAL Prof. MD

2. Definition of anemia Anemia: A reduction in
red cell mass
O2-carrying capacity
It is expressed in terms of reduction in the concentration of Hb (or RBC or Hct%) compared to values obtained from a reference population.
(2 SD below normal)

3. Reference values (I) Parameter Female Male
RBC (x1012/L)
Hb (g/dL)
Htc (%)

4. Reference values (II) Ret (% / n) 0.5-2.5 / 50-100x109/L MCV (fl) 90+7
MCH (pg)
MCHc (g/dL) 34+2
RDW (%)

5. RBC % 50 fl
100
200

6. Reticulocyte Normal Ranges Male: % 0.8 - 2.5 Female: % 0.8 - 4.1
Corrected Rtc: Patient Hb/Normal Hb x Rtc %
Reticulocytosis: > /mm3

8. Definition of anemia
Hb level of a patient which is below the normal ranges of that age and sex.
For adults:
WHO criteria define anemia as hemoglobin level lower than 12 g/dL in women and 13 g/dL in men
But: The reference values for red cells ,Hb or Hct may difer according to
sex/age
Race
Altitude
Socioeconomical changes
Study/reference etc

9. BEUTLER andWAALEN BLOOD, 1 MARCH 2006 VOLUME 107, NUMBER 5

10. Age and blood count changes
WBC
Neutrophyls
Eos.
Baso
Lenfo
Mono Hb
12 mo
6-17.5
0-0.20
4-10.5
4 y
5.5-15
2-8
0-0.8
6 y
5-14.5
1.5-8
0-0.65
1.5-7
10 y
4.5-13
1.8-8
0-0.60
21 y
4.5-11
0-0.45
1-4.8
E: 16
K: 14
WBC: x10E3/mm3 Hb:g/dL

11. !!!!!
Plasma volume changes have to be considered before determining a diagnosis of anemia .
Volume contraction:Underestimation of anemia
Volume overload: Underestimation of Hb level

12. Volume changes/acute bleeding and anemia1 2 3 4 5 b a
Increased plasma volume Hct: Low
Dehydration Hct:Increased
normal
Hct (a/b%):Normal
Acute blood loss(early) Hct:unchanged
Chronic anemia Hct: Low

13. !!!!!
A normal Hb in a patient in whom an elevated Hb level is expected may represent anemia .(eg:COPD + Hb:N)

14. !!!!!! Eg: Low Hb, high RBC, low MCV Hb: 10 g/dL (anemia)
Different red cell measures of the same patient may give discordant values in special conditions. (eg:Thalassemia trait)
Eg: Low Hb, high RBC, low MCV
Hb: 10 g/dL (anemia)
RBC: 6.5 million/mm3 (erythrocytosis)
MVC : 70 fL

15. !!!! Anemia is rarely a disease by itself,
It is mostly a manifestation or consequence of an underlying (genetic or acquired) disease.
The finding of anemia has to start attempts to disclose an underlying disease .
What is the cause of anemia ?

16. Anemia leads to two symptom complexes;
Tissue hypoxia
Fatigue,dyspnea on exertion etc
Compensatory attempts
Tachycardia,hyperventilation etc

17. O2 carrying capacity of normal blood:1.34 ml/g-Hb (200 ml/L-blood)
The amount of O2 necessary to support life is : 250 ml/min
O2 carrying capacity of normal blood:1.34 ml/g-Hb (200 ml/L-blood)
Cardiac output: 5000 ml/min
O2 delivery to tissues : 1000 ml/min

18. Reduced levels of Hb results with reduced oxygen delivery to tissues , leading to tissue hypoxia.
The symptoms and findings of anemia concern many different systems/organs due to the widespread nature of hypoxia.

19. The most pronounced effects and symptoms derive from
skeletal muscles, heart,and central nervous system
(due to their greater oxygen demand and compensatory actions).
What is the mechanism underlying compensatory mechanisms ?

20. Hypoxia-Inducible Transcription Factor 1
A DNA binding protein
Regulated by the O2 tension
Regulates genes that promote cell survival under hypoxic conditions
Up-reg. EPO gene
Up-reg.Glycolytic enzyme genes
Up-reg. Angiogenesis
Respiratory control
Energy metabolism

21. HIF-1 Erythropoiesis Angiogenesis and vascular tone EPO
EPO producing cells
Vasc. endothelium
Muscle heart liver kidney
Energy metabolism
Decreased O2 consumption
HIF-1
All cells
Carotid body
Glomus cells
Iron metabolism
Respiration

22. Compensating mechanisms in anemia:
The release of oxygen to the tissues is increased (reduced oxygen affinity of Hb)

23. Compensating mechanisms in anemia
The rate of blood circulation and cardiac output increases.
An increase in plasma volume maintains total blood volume in normal or near normal ranges.
Redistribution of blood flow.

24. The severity of the symptoms of anemia are related to;
Different patients may have different severity of symptoms even for the same level of Hb.
The severity of the symptoms of anemia are related to;
The severity of anemia
The age,CVS,pulmonary status etc of the patient
The rate of the development of anemia
Gradual or
Rapid onset

25. Clinical symptoms and findings of anemia (1)
The symptoms and findings are related to anemia itself or to the underlying disease that causes anemia .
The symptoms and findings related to anemia itself will be mentioned during this course.

26. Clinical symptoms and findings of anemia (2)
Fatigue, weakness
Tiredness, lassitude, reduced exercise tolerence
Generalized muscular weakness
Pallor /skin or mucous membranes
Skin color may change due to other reasons;
eg :Blood flow of skin, subcutaneous fluid , pigment changes

27. Pallor (paleness): Look at
Mucous membranes of mouth and pharynx
Conjunctivae,lips, nail beds,palms
Creases of the palms lose their pink colour when the Hb < 7g/dL
In pernicious anemia there is a lemon yellow pallor.
Pallor + mild scleral icterus suggests hemolytic anemia.
Pallor+ petechiae suggests severe bone marrow failure

28. Some other skin/mucosal changes
Premature graying of hair:pern.anemia
Hair loss and fragility + spooning of the nails:iron deficiency
Chronic leg ulcers:Sickle cell or other hemolytic anemia
Glossitis/burning sense :Pern. anemia, iron deficiency(rare)
Chelitis(angular stomatitis):iron def.
Siideropenic dysphagia: iron def.
Painful ulcerative mouth lesions: aplastic anemia/leukemia

29. Clinical symptoms and findings of anemia (3) Cardiovascular System(1)
Palpitation and dyspnea (during activity)
Angina pectoris
Claudicatio intermittans
Murmurs: Mid systolic (rarely diastolic) , mainly pulmonary valvular or apical
or over major peripheral arteries
or jugulary veins

30. High output state: Collapsing pulse, high pulse pressure Cardiomegaly
Clinical symptoms and findings of anemia (3) Cardiovascular System(2)
High output state: Collapsing pulse, high pulse pressure
Cardiomegaly
Congestive failure
Ischemic ECG changes

31. Clinical symptoms and findings of anemia (4) Central nervous system
Headache
Faintness
Giddiness
Tinnitus
Decreased concentration ability
Drowsiness,decreased muscle strength
Clouding of consciousness
Symptoms are more prominent in older patients
Paresthesias:Vitamin B12 deficiency (or other).

32. Clinical symptoms and findings of anemia (5)
Reproductive system
Menstrual changes:
Amenorrhea ,
Menorrhagia(mostly a cause of anemia)
Loss of libido

33. Clinical symptoms and findings of anemia (6)
Gastrointestinal system
(these symptoms may indicate underlying disorder that might indeed be a cause of anemia)
Anorexia
Flatulence
Nausea
Constipation
Weight loss
These should remind GIS disease as a cause of anemia
(eg:a bleeding lesion-ulcer/malignancy etc)

34. Clinical symptoms and findings of anemia (7)
Ocular Fundi:
Pale and
sometimes
Hemorrhages
Papillaedema

35. Clinical symptoms and findings of anemia (8)
Renal Changes
Slight proteinuria
Concentrating defects
Further reduction of renal function in patients with previous renal impairment
(Renal failure itself is a cause of anemia!!!!)
Pyrexia: Due to a hypermetabolic state or other underlying disease (which may be a cause of anemia)

36. Some Other examples for history and physical examination
The duration of symptoms (acute/insidious)
Bleeding ? Nose/skin/urine/mens/stool etc
Family history
Anemia, gall stones and splenectomy
Bleeding disorder
Occupation, hobbies,dietary history,alcohol or drug use,travel history etc (toxic/infectious contacts)
Ask for skin and hair/nail changes

37. Some Other examples for history and physical examination
Pain / mass / fever/systemic overview for an underlying disease
Renal/endocrine/liver disease or
Chronic infection/malignancy/imflamatory condition
Parasitis
Pregnancies
Paresthesias ,walking difficulty
Sternal or other bone tenderness
Splenomegaly, hepatomegaly
Lymphadenomegaly

38. Diagnosis and investigation:
Is the patient anemic?
What is the type of anemia?
What is the cause of anemia?

39. Classification of anemia
Morphologic
Normocytic: MCV= fL
Macrocytic: MCV > 100 fL
Microcytic : MCV < 80 fL
Pathogenic (underlying mechanism)
Blood loss (bleeding)
Decreased RBC production
Increased RBC destruction/pooling

40. Normocytic Anemias Acute post-hemorrhagic anemia
Hemolytic anemia (except thalassemia and some other Hb disorders)
Aplastic anemia
Pure red cell aplasia
Bone marrow infiltration
Endocrin diseases
Renal failure
Liver disease
Chronic disease anemia
Protein malnutrition
Hypovitaminosis C

41. Microcytic anemias Iron deficiency anemia Thalassemia
Sideroblastic anemia
Lead poisoning
Anemia of chronic diseases
(some cases)

42. Macrocytic anemias
Megaloblastic
Non-megaloblastic

43. Megaloblastic Macrocytic Anemias
Vit B12 deficiency
Folic acid deficiency
Other.

44. Non-megaloblastic Macrocytic Anemias
Anemia of acute bleeding
Hemolytic anemias
Leukemias
(esp: acute)
Myelodysplastic syndromes
Liver disease
Aplastic anemia
Diseases infiltrative to the bone marrow
Alcoholism
Hypothyroidism
Scurvy

45. Pathogenic classification (Causes of anemia)
Relative (increased plasma volume)
Decreased RBC production
Blood loss
Anemia due to acute bleeding
Increased RBC destruction

46. Pathogenic classification (Causes of anemia)
Decreased RBC production
Decreased Hb production
Defective DNA synthesis
Stem cell defects
Pluripotent stem cell
Erythroid stem cell(progenitors)
Other less defined reasons
Blood loss
Anemia due to acute bleeding
Increased RBC destruction
Relative(increased plasma volume)

47. Decreased Hb production
Iron deficiency anemia
Thalassemia
Sideroblastic anemia
Lead poisoning

48. Defective DNA synthesis
Vit B12 deficiency
Folic acid deficiency
Other.

49. Pluripotent stem cell defects
Aplastic anemia
Leukemia or myelodysplastic syndromes
Defective erythroid stem cell
Pure red cell aplasia
Anemia of chronic renal failure
Endocrin disease anemia
Congenital dyserythropoetic anemias

50. Decreased RBC production due to multipl or undefined mechanisms
Anemia of chronic diseases
Bone marrow infiltration
Anemia due to nutritional defects

51. Anemias caused by increased RBC destruction (hemolytic anemias)
Can be classified as;
Hemolysis due to intracorpuscular defects
Hemolysis due to extracorpuscular defects Or
Hereditary hemolytic diseases
Acquired hem. diseases
Intravascular hemolysis
Extravascular hemolysis etc.

52. A Very Simple Classification of Hemolytic Anemias
Intracorpuscular
1- Abnormalities of RBC interior
a. Enzyme defects
b. Hemoglobinopathies & Thalassemia M
2-RBC membrane abnormalities
a. Hereditary spherocytosis, elliptocytosis etc
b. Paroxysmal nocturnal hemoglobinuria
c. Spur cell anemia
3- Extrinsic factors
a. Hypersplenism
b. Antibody : immune hemolysis
c. Traumatic & Microangiopathic hemolysis
d. Infections , toxins , etc
Hereditary
Extracorpuscular
Acquired

53. Is the patient anemic ?
RBC count
HB level
Hct level
Volume status

54. What is the type of anemia?
History and physical exam.
RBC,HB,Hct ,
MCV, MCH,RDW
Red cell morphology ( peripheral smear)
Reticulocyte count
Incresed ?
Other Lab. investigations

55. Lab. investigation of anemia(1)
WBC count and differential
Platelet count and morphology
ESR
Biochemistry, special tests and others
Bone marrow exam.(only when indicated)

56. Lab. investigation of anemia(2)
Serum values of
Iron
TIBC
Ferritin
Bilirubins
Proteins / electrophoresis
LDH
Vit B12 and /or Folic acid
(None of these tests are routine screening tests)

57. Lab. Investigation of Anemia(3)
Red cell enzymes
Hb F,A2,Hb electrophoresis
Coombs tests
Liver, renal, endocrin functional tests
Urinalysis
Hemosiderin
Occult GIS bleeding / parasites etc
(tests should be chosen individually-do not order routinly )

58. Investigation of a microcytic hypochromic anemia
Blood Film
Serum Iron
Serum iron high Serum iron normal/high Serum iron low
Marrow for iron Hemoglobin studies Ferritin level
Low Normal / High
Sideroblastic anemia Thalassemia İron deficiency Anemia of Abnormal Hb chronic disease

59. Bone marrow morphology hemolysis acute blood loss
Investigation of a normocytic, normochromic anemia
Reticulocyte count
Retic. normal / low Retic. high
Bone marrow morphology hemolysis acute blood loss
 Normal Abnormal
Hypoplastic infiltration dysplastic
Secondary anemia eg. Inflammation aplastic anemia leukemia myelodysplasia
liver disease myelofibrosis
Renal failure metastases
endocrine failure
response to anemia treatment

60. Macrocytic anemia (MCV: high)
Blood film
Reticulocyte count
Retic. High Retic. Normal/low
Bone marrow
Non-megaloblastic Megaloblastic
Acute blood loss or
Hemolytic anemia normoblastic dysplastic(MDS) folate or B12 levels
(Other macrocytic anemias)
folate Vit B12
deficiency deficiency
Treatment response