Classification of Classification of AnemiaAnemia(Adults)(Adults)Teoman SOYSAL Prof. MDTeoman SOYSAL Prof. MD

Definition of anemiaDefinition of anemia Anemia: A reduction in Anemia: A reduction in

– red cell massred cell mass– OO22-carrying capacity -carrying capacity

It is expressed in terms of It is expressed in terms of reduction in the concentration of reduction in the concentration of Hb (or RBC or Hct%)Hb (or RBC or Hct%) compared to compared to values obtained from a reference values obtained from a reference population.population.

((2 SD2 SD below normal) below normal)

Reference values (I)Reference values (I)

ParameterParameter FemaleFemale Male Male RBC (x10RBC (x101212/L)/L) 4.84.8++0.60.6

5.45.4++0.90.9 Hb (g/dL)Hb (g/dL) 1414++22 1616++22 Htc (%)Htc (%) 4242++55 4747++55

Reference values (II)Reference values (II)

Ret (% / n)Ret (% / n) 0.5-2.5 / 50-100x100.5-2.5 / 50-100x1099/L/L MCV (fl)MCV (fl) 9090++77 MCH (pg)MCH (pg) 2929++22 MCHc (g/dL)MCHc (g/dL) 3434++22 RDW (%)RDW (%) 11.5-14.511.5-14.5

50 100 200 fl

RBC

%

ReticulocyteReticulocyteNormal RangesNormal Ranges Male: % 0.8 - 2.5Male: % 0.8 - 2.5 Female: % 0.8 - 4.1Female: % 0.8 - 4.1

Corrected Rtc: Patient Hb/Normal Hb x Rtc %Corrected Rtc: Patient Hb/Normal Hb x Rtc %

Reticulocytosis: > 100.000 /mmReticulocytosis: > 100.000 /mm33

Definition of anemiaDefinition of anemia Hb level of a patient which is below the normal Hb level of a patient which is below the normal

ranges of that age and sex.ranges of that age and sex. For adults:For adults:

WHO criteria define anemia as hemoglobin level WHO criteria define anemia as hemoglobin level lower than 12 g/lower than 12 g/ddL in women and 13 g/L in women and 13 g/ddL in menL in men

But: 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

!!!!!!!!!! Plasma volume changes have to be Plasma volume changes have to be

considered before determining a considered before determining a diagnosis of anemia .diagnosis of anemia .– Volume contraction:Underestimation of Volume contraction:Underestimation of

anemiaanemia– Volume overload: Underestimation of Hb Volume overload: Underestimation of Hb

levellevel

Volume changes/acute bleeding Volume changes/acute bleeding and anemiaand anemia

normalHct (a/b%):Normal

Dehydration Hct:Increased

Acute blood loss(early) Hct:unchanged

Chronic anemia Hct: Low

1 2 3 4 5

Increased plasma volume Hct: Low

b

a

!!!!!!!!!! A A normal Hbnormal Hb in a patient in whom in a patient in whom

an elevated Hb level is expected an elevated Hb level is expected may represent anemiamay represent anemia .(eg:COPD .(eg:COPD + Hb:N)+ Hb:N)

!!!!!!!!!!!! Different red cell measures of the same Different red cell measures of the same

patient may give discordant values in patient may give discordant values in special conditions. (eg:special conditions. (eg:Thalassemia trait)Thalassemia trait)

Eg: Low Hb, high RBC, low MCVEg: Low Hb, high RBC, low MCV Hb: 10 g/dL (anemia)Hb: 10 g/dL (anemia) RBC: 6.5 million/mm3 (erythrocytosis)RBC: 6.5 million/mm3 (erythrocytosis) MVC : 70 fLMVC : 70 fL

!!!!!!!! Anemia is rarely a disease by itself,Anemia is rarely a disease by itself, It is mostly a manifestation or It is mostly a manifestation or

consequence of an underlying consequence of an underlying (genetic or acquired) disease.(genetic or acquired) disease.

The finding of anemia has to start The finding of anemia has to start attempts to disclose an underlying attempts to disclose an underlying disease . disease . – What is the cause of anemiaWhat is the cause of anemia ??

Anemia leads to two Anemia leads to two symptom complexes;symptom complexes; Tissue hypoxiaTissue hypoxia

– Fatigue,dyspnea on exertion etcFatigue,dyspnea on exertion etc Compensatory attemptsCompensatory attempts

– Tachycardia,hyperventilation etcTachycardia,hyperventilation etc

The amount of The amount of OO22 necessary to necessary to support life support life is : 250 ml/min is : 250 ml/min

OO22 carrying capacity of normal carrying capacity of normal blood:1.34 ml/g-Hb (200 ml/L-blood)blood:1.34 ml/g-Hb (200 ml/L-blood)

Cardiac output: 5000 ml/minCardiac output: 5000 ml/minOO2 2 delivery to tissues : 1000 ml/mindelivery to tissues : 1000 ml/min

Reduced levels of Hb results with Reduced levels of Hb results with reduced oxygen delivery to tissues , reduced oxygen delivery to tissues , leading to tissue hypoxia.leading to tissue hypoxia.

The symptoms and findings of The symptoms and findings of anemia concern many different anemia concern many different systems/organs due to the systems/organs due to the widespread nature of hypoxia.widespread nature of hypoxia.

The most pronounced effects and The most pronounced effects and symptoms derive from symptoms derive from – skeletal muscles, heart,and central skeletal muscles, heart,and central

nervous system nervous system (due to their greater oxygen demand and compensatory (due to their greater oxygen demand and compensatory

actions).actions). What is the mechanism underlying What is the mechanism underlying

compensatory mechanisms ?compensatory mechanisms ?

Hypoxia-Inducible Hypoxia-Inducible Transcription Factor 1Transcription Factor 1

A DNA binding proteinA DNA binding protein Regulated by the ORegulated by the O2 2 tensiontension Regulates genes that promote cell Regulates genes that promote cell

survival under hypoxic conditionssurvival under hypoxic conditions Up-reg. EPO gene Up-reg. EPO gene Up-reg.Glycolytic enzyme genesUp-reg.Glycolytic enzyme genes Up-reg. AngiogenesisUp-reg. Angiogenesis Respiratory controlRespiratory control Energy metabolismEnergy metabolism

EPO producing cells

HIF-1Muscle heart liver kidney

Carotid bodyGlomus cells

All cells

Vasc. endothelium

Erythropoiesis

Angiogenesis and vascular tone

Energy metabolismDecreased O2 consumption

Iron metabolism

Respiration

EPO

Compensating mechanisms Compensating mechanisms in anemia:in anemia:

The release of oxygen to the tissues The release of oxygen to the tissues is increased (reduced oxygen affinity is increased (reduced oxygen affinity of Hb)of Hb)

Compensating mechanisms Compensating mechanisms in anemiain anemia

The rate of blood circulation and The rate of blood circulation and cardiac output increases.cardiac output increases.

An increase in plasma volume An increase in plasma volume maintains total blood volume in maintains total blood volume in normal or near normal ranges.normal or near normal ranges.

Redistribution of blood flow.Redistribution of blood flow.

Different patients may have different severity Different patients may have different severity of symptoms even for the same level of Hb.of symptoms even for the same level of Hb.

The severity of the symptoms of anemia are The severity of the symptoms of anemia are related to;related to;– The severity of anemiaThe severity of anemia– The age,CVS,pulmonary status etc of the patientThe age,CVS,pulmonary status etc of the patient– The rate of the development of anemiaThe rate of the development of anemia

Gradual orGradual or Rapid onsetRapid onset

Clinical symptoms and Clinical symptoms and findings of anemia (1)findings of anemia (1)

The symptoms and findings are The symptoms and findings are related to anemia itself or to the related to anemia itself or to the underlying disease that causes underlying disease that causes anemia .anemia .

The symptoms and findings related The symptoms and findings related to anemia itself will be mentioned to anemia itself will be mentioned during this course.during this course.

Clinical symptoms and findings Clinical symptoms and findings of anemia (2)of anemia (2)

Fatigue, weaknessFatigue, weakness– Tiredness, lassitude, reduced exercise Tiredness, lassitude, reduced exercise

tolerencetolerence– Generalized muscular weaknessGeneralized muscular weakness

Pallor /Pallor /skin or mucous membranesskin or mucous membranes– Skin color may change due to other Skin color may change due to other

reasons;reasons;eg :Blood flow of skin, subcutaneous fluid , eg :Blood flow of skin, subcutaneous fluid ,

pigment changespigment changes

Pallor (paleness):Pallor (paleness): Look atLook at

– Mucous membranes of mouth and pharynxMucous membranes of mouth and pharynx– Conjunctivae,lips, nail beds,palmsConjunctivae,lips, nail beds,palms

Creases of the palms lose their pink colour when the Creases of the palms lose their pink colour when the Hb < 7g/dLHb < 7g/dL

In pernicious anemia there is a lemon yellow In pernicious anemia there is a lemon yellow pallor.pallor.

Pallor + mild scleral icterus suggests hemolytic Pallor + mild scleral icterus suggests hemolytic anemia.anemia.

Pallor+ petechiae suggests severe bone Pallor+ petechiae suggests severe bone marrow failuremarrow failure

Some other skin/mucosal changesSome other skin/mucosal changes– Premature graying of hair:pern.anemiaPremature graying of hair:pern.anemia– Hair loss and fragility + spooning of the nails:iron Hair loss and fragility + spooning of the nails:iron

deficiencydeficiency– Chronic leg ulcers:Sickle cell or other hemolytic Chronic leg ulcers:Sickle cell or other hemolytic

anemiaanemia– Glossitis/burning sense :Pern. anemia, Glossitis/burning sense :Pern. anemia, iron iron

deficiency(rare)deficiency(rare)– Chelitis(angular stomatitis):iron def.Chelitis(angular stomatitis):iron def.– Siideropenic dysphagia: iron def.Siideropenic dysphagia: iron def.– Painful ulcerative mouth lesions: Painful ulcerative mouth lesions: aplasticaplastic

anemia/leukemiaanemia/leukemia

Clinical symptoms and findings Clinical symptoms and findings of anemia (3)of anemia (3)Cardiovascular System(1)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

Clinical symptoms and findings Clinical symptoms and findings of anemia (3)of anemia (3)Cardiovascular System(2)Cardiovascular System(2)

High output state: Collapsing pulse, high pulse pressure

CardiomegalyCongestive failure Ischemic ECG changes

Clinical symptoms and findings Clinical symptoms and findings of anemia (4)of anemia (4)Central nervous systemCentral 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).

Clinical symptoms and findings Clinical symptoms and findings of anemia (5)of anemia (5)

Reproductive systemReproductive system Menstrual changes:Menstrual changes:

– Amenorrhea ,Amenorrhea ,– Menorrhagia(mostly a cause of Menorrhagia(mostly a cause of

anemia)anemia) Loss of libidoLoss of libido

Clinical symptoms and findings Clinical symptoms and findings of anemia (6)of anemia (6)

Gastrointestinal systemGastrointestinal system(these symptoms may indicate underlying (these symptoms may indicate underlying

disorder that might indeed be a cause of disorder that might indeed be a cause of anemia)anemia)

AnorexiaAnorexia FlatulenceFlatulence NauseaNausea Constipation Constipation Weight loss Weight loss

These should remind GIS disease as a cause of anemia (eg:a bleeding lesion-ulcer/malignancy etc)

Clinical symptoms and findings Clinical symptoms and findings of anemia (7)of anemia (7)

Ocular Fundi:Ocular Fundi:– Pale andPale and sometimessometimes– HemorrhagesHemorrhages– PapillaedemaPapillaedema

Clinical symptoms and findings Clinical symptoms and findings of anemia (8)of anemia (8)

Renal ChangesRenal Changes – Slight proteinuriaSlight proteinuria– Concentrating defectsConcentrating defects– Further reduction of renal function in Further reduction of renal function in

patients with previous renal impairmentpatients with previous renal impairment(Renal failure itself is a cause of (Renal failure itself is a cause of

anemia!!!!)anemia!!!!) Pyrexia:Pyrexia: Due to a hypermetabolic state Due to a hypermetabolic state

or other underlying disease or other underlying disease (which may (which may be a cause of anemia)be a cause of anemia)

Some Other examples for Some Other examples for history and physical history and physical examinationexamination

The duration of symptoms (acute/insidious)The duration of symptoms (acute/insidious) Bleeding ? Nose/skin/urine/mens/stool etcBleeding ? Nose/skin/urine/mens/stool etc Family historyFamily history

– Anemia, gall stones and splenectomyAnemia, gall stones and splenectomy– Bleeding disorderBleeding disorder

Occupation, hobbies,dietary history,alcohol or Occupation, hobbies,dietary history,alcohol or drug use,travel history etc (toxic/infectious drug use,travel history etc (toxic/infectious contacts)contacts)

Ask for skin and hair/nail changesAsk for skin and hair/nail changes

Some Other examples for Some Other examples for history and physical history and physical examinationexamination Pain / mass / fever/systemic overview for an Pain / mass / fever/systemic overview for an

underlying diseaseunderlying disease– Renal/endocrine/liver disease orRenal/endocrine/liver disease or– Chronic infection/malignancy/imflamatory conditionChronic infection/malignancy/imflamatory condition

ParasitisParasitis PregnanciesPregnancies Paresthesias ,walking difficultyParesthesias ,walking difficulty Sternal or other bone tendernessSternal or other bone tenderness Splenomegaly, hepatomegalySplenomegaly, hepatomegaly LymphadenomegalyLymphadenomegaly

Diagnosis and Diagnosis and investigation:investigation:

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

Classification of Classification of anemiaanemia MorphologicMorphologic

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

PathogenicPathogenic (underlying mechanism) (underlying mechanism)– Blood loss (bleeding)Blood loss (bleeding)– Decreased RBC productionDecreased RBC production– Increased RBC destruction/poolingIncreased RBC destruction/pooling

Normocytic AnemiasNormocytic Anemias Acute post-Acute post-

hemorrhagic anemiahemorrhagic anemia Hemolytic anemia Hemolytic anemia

(except thalassemia (except thalassemia and some other Hb and some other Hb disorders)disorders)

Aplastic anemiaAplastic anemia Pure red cell aplasiaPure red cell aplasia Bone marrow Bone marrow

infiltrationinfiltration

Endocrin diseasesEndocrin diseases Renal failureRenal failure Liver diseaseLiver disease Chronic disease Chronic disease

anemiaanemia Protein malnutritionProtein malnutrition Hypovitaminosis CHypovitaminosis C

Microcytic anemiasMicrocytic anemias Iron deficiency anemiaIron deficiency anemia ThalassemiaThalassemia Sideroblastic anemiaSideroblastic anemia Lead poisoningLead poisoning Anemia of chronic diseases Anemia of chronic diseases (some cases)(some cases)

Macrocytic anemiasMacrocytic anemias MegaloblasticMegaloblastic

Non-megaloblasticNon-megaloblastic

Megaloblastic Macrocytic Megaloblastic Macrocytic AnemiasAnemias Vit BVit B1212 deficiency deficiency Folic acid deficiencyFolic acid deficiency Other.Other.

Non-megaloblastic Non-megaloblastic Macrocytic AnemiasMacrocytic Anemias Anemia of acute Anemia of acute

bleedingbleeding Hemolytic Hemolytic

anemiasanemias Leukemias Leukemias (esp: acute)(esp: acute) Myelodysplastic Myelodysplastic

syndromessyndromes Liver diseaseLiver disease

Aplastic anemiaAplastic anemia Diseases Diseases

infiltrative to the infiltrative to the bone marrowbone marrow

AlcoholismAlcoholism HypothyroidismHypothyroidism ScurvyScurvy

Pathogenic Pathogenic classificationclassification(Causes of anemia)(Causes of anemia)

Relative (increased plasma volume)Relative (increased plasma volume) Decreased RBC productionDecreased RBC production Blood lossBlood loss

– Anemia due to acute bleedingAnemia due to acute bleeding Increased RBC destructionIncreased RBC destruction

Pathogenic Pathogenic classificationclassification(Causes of anemia)(Causes of anemia)

Decreased RBC productionDecreased RBC production– Decreased Hb productionDecreased Hb production– Defective DNA synthesisDefective DNA synthesis– Stem cell defectsStem cell defects

Pluripotent stem cell Erythroid stem cell(progenitors)

– Other less defined reasonsOther less defined reasons Blood lossBlood loss

– Anemia due to acute bleedingAnemia due to acute bleeding Increased RBC destructionIncreased RBC destruction Relative(increased plasma volume)Relative(increased plasma volume)

Decreased Hb Decreased Hb productionproduction Iron deficiency anemiaIron deficiency anemia ThalassemiaThalassemia Sideroblastic anemiaSideroblastic anemia Lead poisoningLead poisoning

Defective DNA Defective DNA synthesissynthesis Vit BVit B1212 deficiency deficiency Folic acid deficiencyFolic acid deficiency Other.Other.

Pluripotent stem cell Pluripotent stem cell defectsdefects

Aplastic anemiaAplastic anemia Leukemia or myelodysplastic syndromesLeukemia or myelodysplastic syndromes

Defective erythroid stem cellDefective erythroid stem cell Pure red cell aplasiaPure red cell aplasia Anemia of chronic renal failureAnemia of chronic renal failure Endocrin disease anemiaEndocrin disease anemia Congenital dyserythropoetic anemiasCongenital dyserythropoetic anemias

Decreased RBC production due Decreased RBC production due to multipl or undefined to multipl or undefined mechanismsmechanisms

Anemia of chronic diseasesAnemia of chronic diseases Bone marrow infiltrationBone marrow infiltration Anemia due to nutritional defectsAnemia due to nutritional defects

Anemias caused by Anemias caused by increased RBC increased RBC destruction destruction (hemolytic (hemolytic anemias)anemias) Can be classified as;Can be classified as; Hemolysis due to intracorpuscular defectsHemolysis due to intracorpuscular defects Hemolysis due to extracorpuscular defectsHemolysis due to extracorpuscular defectsOrOr Hereditary hemolytic diseasesHereditary hemolytic diseases Acquired hem. diseasesAcquired hem. diseasesOrOr Intravascular hemolysisIntravascular hemolysis Extravascular hemolysis etc.Extravascular hemolysis etc.

1- Abnormalities of RBC interior a. Enzyme defects b. Hemoglobinopathies & Thalassemia M2-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

Int r

acor

pus c

ular

Ext

raco

rpus

cula

r

Hereditary

Acquired

A Very Simple Classification of Hemolytic Anemias

Is the patient anemic ?Is the patient anemic ? RBC countRBC count HB levelHB level Hct levelHct level Volume statusVolume status

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

– Incresed ? Incresed ? Other Lab. investigationsOther Lab. investigations

Lab. investigation of Lab. investigation of anemia(1)anemia(1)

WBC count and differentialWBC count and differential Platelet count and morphologyPlatelet count and morphology ESRESR Biochemistry, special tests and Biochemistry, special tests and

othersothers Bone marrow exam.(only when Bone marrow exam.(only when

indicated)indicated)

Lab. investigation of Lab. investigation of anemia(2)anemia(2)

Serum values ofSerum values of– IronIron– TIBCTIBC– FerritinFerritin– BilirubinsBilirubins– Proteins / electrophoresisProteins / electrophoresis– LDHLDH– Vit B12 and /or Folic acidVit B12 and /or Folic acid((None of these tests are routine screening testsNone of these tests are routine screening tests))

Lab. Investigation of Lab. Investigation of Anemia(3)Anemia(3)

Red cell enzymesRed cell enzymes Hb F,AHb F,A22,Hb electrophoresis,Hb electrophoresis Coombs testsCoombs tests Liver, renal, endocrin functional testsLiver, renal, endocrin functional tests UrinalysisUrinalysis

– HemosiderinHemosiderin Occult GIS bleeding / parasites etcOccult GIS bleeding / parasites etc((tests should be chosen individually-do not order routinlytests should be chosen individually-do not order routinly ) )

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

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

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