Diagnostic Approach to Anemia

Prof. Dr. Teoman SOYSAL

Definition of anemia Anemia: A reduction in

– red cell mass

– O2-carrying capacity of blood 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)

Reference values (adults) (I)

Parameter Female Male RBC (x1012/L) 4.8+0.6

5.4+0.9 Hb (g/dL) 14+2 16+2 Htc (%) 42+5 47+5

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

<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

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

age WBC Neutrophyls Eos. Baso Lenfo Mono Hb

12 mo 6-17.5 1.5-8.5 0.05-0.7 0-0.20 4-10.5 0.05-1.1 11.1-14.1

4 y 5.5-15 1.5-8.5 0.02-0.65

0-0.20 2-8 0-0.8 11.2-14.3

6 y 5-14.5 1.5-8 0-0.65 0-0.20 1.5-7 0-0.8 11.4-14.5

10 y 4.5-13 1.8-8 0-0.60 0-0.20 1.5-6.5 0-0.8 11.8-15

21 y 4.5-11 1.8-7.7 0-0.45 0-0.20 1-4.8 0-0.8 E: 16K: 14

WBC: x10E3/mm3 Hb:g/dL

Age and blood count changes

Reference values (II)

Ret (% / n) 0.5-2.5 / 50-100x109/L MCV (fl) 90+7

MCH (pg) 29+2

MCHc (g/dL) 34+2

RDW (%) 11.5-14.5

50 100 200 fl

RBC

%

50 100 200 fl

RBC

%

50 100 200 fl

RBC

%RDW: Red cell distribution width

50 100 200 fl

RBC

%

Reticulocyte

Normal Ranges Male: % 0.8 - 2.5 Female: % 0.8 - 4.1

Corrected Rtc: Patient Hb/Normal Hb x Rtc

%

Reticulocytosis: > 100.000 /mm3

Increased counts• Hemolysis• Acute bleeding• Response to

treatment

Diagnosis and investigation:

Is the patient anemic? What is the type of anemia? What is the cause of anemia?

Classification of anemia Morphologic

– Normocytic: MCV= 80-100fL– Macrocytic: MCV > 100 fL– Microcytic : MCV < 80 fL

Pathogenic (underlying mechanism)– Blood loss (bleeding)– Decreased RBC production– Increased RBC destruction/pooling

!!!!!

Plasma volume changes have to be considered before determining a diagnosis of anemia .– Volume contraction:Underestimation of

anemia– Volume overload: Underestimation of Hb

level

Volume changes/acute bleeding

and anemia

normal

Hct:Normal

Dehydration Hct:Increased

Acute blood loss(early) Hct:unchanged

Chronic anemia Hct: Low

1 2 3 4 5

Increased plasma volume Hct: Low

!!!!!

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

!!!!!!

Different red cell measures of a patient may give discordant values in special conditions.

eg:Thalassemia trait Low Hb, high RBC, low MCV,normal RDW

Hb: 10 g/dL (anemia) RBC: 6.5 million/mm3

(erythrocytosis) MVC : 65 fL RDW: Normal

!!!!

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 ?

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

Microcytic anemias

Iron deficiency anemia Thalassemia Sideroblastic anemia Lead poisoning Anemia of chronic diseases (some cases)

Macrocytic anemias

Megaloblastic– Oval macrocytes

Non-megaloblastic

Megaloblastic Macrocytic Anemias

Vit B12 deficiency Folic acid deficiency Other.

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

Pathogenic classification(Causes of anemia)

Relative (increased plasma volume) Decreased RBC production Blood loss

– Anemia due to acute bleeding Increased RBC destruction

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)

Decreased Hb production Iron deficiency anemia Thalassemia Sideroblastic anemia Lead poisoning

Defective DNA synthesis

Vit B12 deficiency Folic acid deficiency Other.

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

Decreased RBC production due to multipl or undefined mechanisms

Anemia of chronic diseases Bone marrow infiltration Anemia due to nutritional defects

Anemias caused by increased RBC destruction (hemolytic anemias) Can be classified as; Hemolysis due to intracorpuscular

defects Hemolysis due to extracorpuscular

defectsOr Hereditary hemolytic diseases Acquired hem. diseasesOr Intravascular hemolysis Extravascular hemolysis etc.

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

Intr

acor

pu

scu

lar

Ext

raco

rpu

scu

lar

Hereditary

Acquired

A Very Simple Classification of Hemolytic Anemias

Is the patient anemic ?

RBC count HB level Hct level Volume status

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

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)

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)

Lab. Investigation of Anemia(3)

Liver, renal, endocrin functional tests Urinalysis

– Hemosiderin Occult GIS bleeding / parasites etc(tests should be chosen individually-do not order routinly ) Tests to diagnose the type of hemolytic

anemia– If hemolytic anemia is considered

Normocytic anemia

Retic. count normal/low

Secondary anemia

Renal, Hepatic, Endocrin , Chronic

disease(Normal marrow)

Hypoplastic Marrow

AA, pure red cell aplasia

Bone marrow infiltrative diseases

Leukemia , Myelofibrosis

Metastatic disease

Dysplastic marrow:

MDS

Retic. count increased

Response to treatment

Hemolytic anemia

Acute bleeding

• No sign of secondary anemia

• Other signs of bone marrow disease may be +

Microcytic anemia

Serum iron high

Bone marrow iron content

and sideroblasts

Sideroblastic anemia

Serum iron normal /high

Hemoglobin studies

Thalassemia , HbC , others

Serum iron decreased

Ferritin low

Iron deficiency

Ferritin: Normal or increased

Anemia of chronic

diseases

Macrocytic anemia

Peripheral smearRetic. count

Retic. count Increased

HemolysisAcute

bleeding

Retic. count Normal/

decreased

Megaloblastic

Deficiencies of VitB12 ,Folic acid or other

causes

Non-MegaloblasticLiver diseases

Myelodysplastic syndrome

Bone marrow infiltrationAcute leukemia

Aplastic Anemia,Alcoholism

Hypothyoidism etc

Case I 38 years old, ♀ Tiredness, hair loss, nail changes

Microcytic anemia

Serum iron high

Bone marrow iron content

and sideroblasts

Sideroblastic anemia

Serum iron normal /high

Hemoglobin studies

Thalassemia , HbC , others

Serum iron decreased

Ferritin low

Iron deficiency

Ferritin: Normal or increased

Anemia of chronic

diseases

Microcytic anemiasDiagnosis(type of anemia)

MCV RDW Serum Iron

Iron binding capacity

Ferritin

ESR/acute phase signs

Hemogl. changes

Iron deficiency

May change None

Thalassemia N N Normal

May be diagnostic

Chronic disease anemia

N Elevated None

RBC count:Thalassemia minor >Iron deficiency

Case I 38 years old, ♀ Tiredness, hair loss, nail changes

What is your diagnosis?

What is the next step?– Prove iron deficiency

Serum iron, TIBC, Ferritin– Find out the cause of iron deficiency

Chronic blood loss / excessive need-inadequate intake

– Menstruel bleeding, Pregnancy – GI bleeding– Inadequate intake or malabsorbtion etc

– Treat both iron deficiency and the cause

Case II26 y oSlight symptoms• Decreased

excercise tolerence

• Paleness• Long history of

being anemic on routine CBC’s ,non responsive to iron

RBC:5.500.000/mm3

Hb: 10 g/dLMCV: 60 fLRDW: 14.3Retic: %2WBC: 5000/mm3

Plt: 200.000/mm3

Name the blood picture.Further questions to ask to the patient?Further tests to do ?Ferritin : slightly elevatedHbA2: slightly elevated, Hb F: normalFinal Diagnosis ?

Case III• 70 y o, male• Fatigue, weakness• Sore tongue, poor taste

sensation• Papill. atrophy-beefy tongue• Paresthesias• Loss of position sense, ataxia• Decreased deep tendon

reflexes

3 units of red cell transfusion made before admission

Macrocytosis Anisocytosis, neutrophyl hypersegmentation, oval macrocytes

WBC: 2.300/µl Hgb: 11 g/dLHct: %33MCV: 122 fLMCH: 39pgMCHC: %34RDW: 30.5Plt: 100.000/µlRetic: 1%

Macrocytic anemia

Peripheral smearRetic. count

Retic. count Increased

HemolysisAcute bleeding

Retic. count Normal/

decreased

Megaloblastic

Deficiencies of

VitB12 ,Folic acid

or other causes

Non-Megaloblastic

Liver diseasesMyelodysplastic

syndromeBone marrow infiltration

Acute leukemiaAplastic Anemia,

Alcoholism Hypothyoidism etc

What is the blood picture ?(The type of the disorder) What is your diagnosis?

– Why?

Normocytic anemia

Retic. count normal/low

Secondary anemia

Renal, Hepatic, Endocrin , Chronic

disease(Normal marrow)

Hypoplastic Marrow

AA, pure red cell aplasia

Bone marrow infiltrative diseases

Leukemia , Myelofibrosis

Metastatic disease

Dysplastic marrow:

MDS

Retic. count increased

Response to treatment

Hemolytic anemia

Acute bleeding

• No sign of secondary anemia

• Other signs of bone marrow disease may be +

60 y o Normocytic anemiaReticulocytes: 1%

Pale, pruritus, hypertensionUrea + creatinin elevated

Hoarse voiceLethargyHair lossDry skinWeight gainPoor memoryBradycardia

?

?

Symmetric polyarthritisMorning stiffnessSc nodules

?

Normocytic anemia, MCV normal, RDW ↑,

Case IV• 65 y o , male• One month history of fever, cough and hemoptysis• ESR: 80mm/h; high CRP• Sputum + for TBC bacteria; chest x-ray shows right apical infiltrate

What is the type of anemia?

What is the diagnosis?

• This case could also present as a

microcytic anemia .What would

you expect from the iron studies

in that situation?

Low iron, Low TIBC, High

Ferritin

Retic.: 2%

Normocytic anemia

Retic. count normal/low

Secondary anemia

Renal, Hepatic, Endocrin , Chronic

disease(Normal marrow)

Hypoplastic Marrow

AA, pure red cell aplasia

Bone marrow infiltrative diseases

Leukemia , Myelofibrosis

Metastatic disease

Dysplastic marrow:

MDS

Retic. count increased

Response to treatment

Hemolytic anemia

How to decide the next step?

HistoryPE

SmearOther tests

Acute bleeding

• No sign of secondary anemia

• Other signs of bone marrow disease

Case IX

67 y o, male• Anemia

symptoms• Severe bone

painCBC• Normocytic

anemia

What is your possible diagnosis?What is the next step?

• ESR:>100mm/h• Hypercalcemia• Hyperglobulinem

ia• Renal failure

Morphologic abnormalities in hemolytic anemias

• Sickle cell:

• Target cels:

• Schistocytes:

• Agglutination:

• Heinz bodies:

Sickle cell anemia

Thalassemia, HbC disease, liver disease,

splenectomy

Microangiopathic hem anemia, uremia, DIC,

malignant hypertesion, eclampsia,

disseminated vasculitis or malignancy,

Cold agglutinin disease

Unstable Hb, G6PD deficiency and oxidant stress

Special Lab. Examinations

Coombs antiglobulin test - immune hemolysis Osmotic fragility test - spherocytosis Autohemolysis- G6PD,PK, spherocytosis Red cell enzyme assays- RBC enzyme defects Membrane protein analysis- membrane defects Red cell sickling, HbS- sickle cell anemia Hemoglobin electrophoresis and HbA2, Hb F ,

HHb,etc - Hemoglobinopathies and thalassemias HAM and sucrose lysis tests and GPI-linked protein

analysis by flow cytometry- PNH Oxygen dissociation curve- High oxygen affinity

Hb

Case V

18 y o , maleWeakness, paleness, slight icterus, splenomegaly, bile stonesFamily history +WBC: 5600/µl Hgb: 9,6 g/dLMCHC: %37Plt: 300.000/µl Retic: %9

spherocyte

Normal RBC

Ind Bil: slightly elevatedLDH: elevatedHaptoglobin : lowRed cell osmotic fragility increased

?

?

Case VI38 y o Cough , fever

WBC: 12.000/µl Hgb: 11 g/dL Hct: 22 %MCV: 130 MCH: 40 MCHC: 36RDW:28Plt: 160.000/µl

Case VII

34 y o, male2-3 weeks history of• Decreased exercise

capacity• Paleness• Headache, sore throat2 days history of • Cough and fever• Red spots on the skin

CBCWBC: 33.000/mm3

Hb: 7 g/dLRetic: 1%Plt: 12.000/mm3

Case IX60 y o, femaleSudden onset

Pallor, palpitationSlight scleral icterussplenomegaly

CBC Hb: 8 g/dL WBC: 10.000/mm3 Plt: 450.000/mm3 Retic: 10%

What is your diagnosis?What is your next step?

Indirect bilirubin: highLDH: highHaptoglobin: lowD/I: Coombs +

Case X

70 y o , male• Under examination

for prostat enlargement

+One month history of• Bone pain• Symptoms of anemiaWBC: 8000/mm3Hb: 8 g/dLMCV: 88 fLRDW: 14Retic: 2%Plt: 220.000/mm3

Morphologic abnormalities in hemolytic anemias

Polychromasia:

Spherocyte :

Elliptocytes: Stomatocytes

: Acanthocytes

:

Echinocytes:

Reticulocytes

Hereditary spherocytosis, immune hem. anemia,

burns, chemical injury to RBC

Hereditary ovalocytosis,

Hereditary stomatocytosis, alcoholism

Spur cell anemia with liver disease,

abetalipoproteinemia

Pyruvate kinase deficiency, uremia