بسم الله الرحمن الرحیم

Аnemia – pathologic state,accompanied by decrease in the level of hemoglobin and the quantity of erythrocytes per unit of volume of the blood.

Erythrocytes - less informative index Erythrocytes - less informative index of anemia than the level of of anemia than the level of hemoglobin therefore, in the hemoglobin therefore, in the general practice the basic criterion general practice the basic criterion of severity is precisely Hb: of severity is precisely Hb:

Light degree of anemia - Hb 110-90 Light degree of anemia - Hb 110-90 g / l, g / l,

The average degree of severity - The average degree of severity - Hb 90-70 g / l, Hb 90-70 g / l,

Severe anemia - Hb below 70 g / Severe anemia - Hb below 70 g / literliter

Laboratory Definition of AnemiaLaboratory Definition of Anemia

Hgb:Hgb: Women: <12.0Women: <12.0 Men: < 13.5Men: < 13.5

Hct:Hct: Women: < 36Women: < 36 Men: <41Men: <41

RBC Life CycleRBC Life Cycle

In the bone marrow, erythropoietin enhances In the bone marrow, erythropoietin enhances the growth of differentiation of burst forming the growth of differentiation of burst forming units-erythroid (BFU-E) and colony forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E) into reticulocytes.units-erythroid (CFU-E) into reticulocytes.

Reticulocyte spends three days maturing in Reticulocyte spends three days maturing in the marrow, and then one day maturing in the marrow, and then one day maturing in the peripheral blood.the peripheral blood.

A mature Red Blood Cell circulates in the A mature Red Blood Cell circulates in the peripheral blood for 100 to 120 days.peripheral blood for 100 to 120 days.

Under steady state conditions, the rate of Under steady state conditions, the rate of RBC production equals the rate of RBC loss.RBC production equals the rate of RBC loss.

Erythropoetin roleErythropoetin role

Classification of AnemiaClassification of Anemia I. Anemias resulting from acute blood loss I. Anemias resulting from acute blood loss II. Anemias resulting from a deficit of erythropoesis II. Anemias resulting from a deficit of erythropoesis

1) At the expense of maturation (mainly microcyte): 1) At the expense of maturation (mainly microcyte):

violation of absorption and utilization of iron (iron) violation of absorption and utilization of iron (iron)

violation of transportation of iron (atransferrinemia) violation of transportation of iron (atransferrinemia)

violation of recycling iron (thalassemia, violation of recycling iron (thalassemia, sideroblastic anemia ) sideroblastic anemia )

violation of reutilization of iron (anemia of chronic violation of reutilization of iron (anemia of chronic disease);disease);

AnemiaAnemia ( (continuedcontinued))

2) At the expense of differentiation 2) At the expense of differentiation (essentially normal): (essentially normal):

aplastic anemia (congenital and aplastic anemia (congenital and acquired) acquired)

3) At the expense of proliferation 3) At the expense of proliferation (mainly macrocytes) (mainly macrocytes)

B12-DEFICIENCY anemia B12-DEFICIENCY anemia

Folic-DEFICIENCY anemia.Folic-DEFICIENCY anemia.

AnemiaAnemia ( (continuedcontinued)) Anemias resulting from increased Anemias resulting from increased

destruction of erythroid series cells - destruction of erythroid series cells - haemolytic: haemolytic:

1) caused by internal defects of 1) caused by internal defects of erythrocytes erythrocytes           membranopathy, enzimopathy,           membranopathy, enzimopathy, haemoglobinopathies; haemoglobinopathies;

2) the external (extracllular) effects: 2) the external (extracllular) effects: autoimmune, traumatic, etc. autoimmune, traumatic, etc.

Classification D. Nathan, F. Oski, 2003, (book «Anemias Classification D. Nathan, F. Oski, 2003, (book «Anemias in children», NA Finogenova et al, 2004.): in children», NA Finogenova et al, 2004.):

The clinical value of bloodThe clinical value of blood

AutomaticAutomaticalal

CountingCounting

Units Units

Measure-Measure-mentment

Normal Normal LevelLevel

Short Short FormForm

HGB- Hemoglobin

G/Liter 120-160 HbHb

RBC - erythrocyte

1210 /L

3,9-5,9 ErEr

HCT -Hematocryte

%% 36,0-48,0 HtHt

MCV- average volume of erythrocyte

31 micron = 1 - femtoliter (fl)

80 - 9580 - 95

MCH – the average content of Hb in erythrocyte

Pikogram1 г =1012pikograms

27,0-31,02

Colour Index (0,85-1,0)

MCHC – average concentration of Hb in erythrocyte

G/dl или g %, less g/l

32,0-36,0

RDW – width of the distribution curve of erythrocyte by volume

%% 11,5-14,5 anisocytosis

Measurements of AnemiaMeasurements of Anemia HemoglobinHemoglobin = grams of hemoglobin per 100 = grams of hemoglobin per 100

mL of whole blood (g/dL)mL of whole blood (g/dL) HematocritHematocrit = percent of a sample of whole = percent of a sample of whole

blood occupied by intact red blood cellsblood occupied by intact red blood cells RBCRBC = millions of red blood cells per microL of = millions of red blood cells per microL of

whole bloodwhole blood MCVMCV = Mean corpuscular volume = Mean corpuscular volume

If > 100If > 100 → → Macrocytic anemiaMacrocytic anemia If 80 – 100 → If 80 – 100 → Normocytic anemiaNormocytic anemia If < 80If < 80 → → Microcytic anemiaMicrocytic anemia

RDW RDW = Red blood cell distribution width= Red blood cell distribution width = (Standard deviation of red cell = (Standard deviation of red cell

volume ÷ mean cell volume) × 100 volume ÷ mean cell volume) × 100 Normal value is 11-15%Normal value is 11-15% If elevated, suggests large variability in If elevated, suggests large variability in

sizes of RBCssizes of RBCs

Anemia due to Anemia due to Decreased Decreased Response to ErythropoietinResponse to Erythropoietin

Iron-DeficiencyIron-Deficiency Vitamin B12 DeficiencyVitamin B12 Deficiency Folate DeficiencyFolate Deficiency Anemia of Chronic DiseaseAnemia of Chronic Disease

Iron DeficiencyIron Deficiency Can result from:Can result from:

Pregnancy/lactationPregnancy/lactation Normal growthNormal growth Blood lossBlood loss Intravascular hemolysisIntravascular hemolysis Gastric bypassGastric bypass MalabsorptionMalabsorption

Iron is absorbed in proximal small bowel; Iron is absorbed in proximal small bowel; decreased abosrption in celiac disease, decreased abosrption in celiac disease, inflammatory bowel diseaseinflammatory bowel disease

May manifest as PICAMay manifest as PICA Tendency to eat ice, clay, starch, crunchy Tendency to eat ice, clay, starch, crunchy

materialsmaterials May have pallor, koilonychia of the nails, May have pallor, koilonychia of the nails,

beeturiabeeturia Peripheral smear shows Peripheral smear shows microcytic, microcytic,

hypochromic red cells with marked hypochromic red cells with marked anisopoikilocytosisanisopoikilocytosis..

Iron Deficiency Anemia - koilonychiaIron Deficiency Anemia - koilonychia

IroIron in n in

the the BoBodydy

Serum TransferrinSerum Transferrin((Beta-globulinBeta-globulin).).

Main function - transport of absorbed iron in the depot Main function - transport of absorbed iron in the depot (liver, spleen), into the medullary erythroid (liver, spleen), into the medullary erythroid predecessors and into the reticulocytes. predecessors and into the reticulocytes.

Basic place of synthesis - liver. Basic place of synthesis - liver. An increase in the content of transferrin with lowering An increase in the content of transferrin with lowering

in the level of iron of serum is characteristic for the in the level of iron of serum is characteristic for the iron-deficiency state. iron-deficiency state.

A decrease in the level of transferrin can be with the A decrease in the level of transferrin can be with the damage of the liver (different genesis) and with the damage of the liver (different genesis) and with the loss of protein (for example, in nephrotic syndrome). loss of protein (for example, in nephrotic syndrome).

The level of transferrin is increased in the last term of The level of transferrin is increased in the last term of pregnancy. pregnancy.

TransferrinTransferrinLIMITATION The concentration of TF is subjected to the The concentration of TF is subjected to the

daily variations daily variations Acute inflammation contributes to lowering Acute inflammation contributes to lowering

the TF levelthe TF levelCLINICAL SIGNIFICANCE Basic clinical index for the differentiation Basic clinical index for the differentiation

between the iron-deficiency ([TF]↑) and between the iron-deficiency ([TF]↑) and hemolytic anemia ([TF]↓) hemolytic anemia ([TF]↓)

More precise index than total iron binding More precise index than total iron binding capacity capacity

After the liberation of iron from the After the liberation of iron from the complex, TF ion of Fe3+ must be restored complex, TF ion of Fe3+ must be restored into Fe2+ into Fe2+

FerritinFerritin water-soluble complex of iron water-soluble complex of iron

hydroxide with the protein hydroxide with the protein apoferritin.apoferritin.

It is located in cells of the liver, It is located in cells of the liver, spleen, bone marrow, in the spleen, bone marrow, in the reticulocytes. reticulocytes.

Ferritin is the basic protein in Ferritin is the basic protein in human which deposits iron and human which deposits iron and concentration of ferritin in the concentration of ferritin in the serum reflects the reserve of iron serum reflects the reserve of iron in the organism. in the organism.

Iron Deficiency Anemia – Lab Iron Deficiency Anemia – Lab FindingsFindings

Serum IronSerum Iron LOWLOW (< 50 micrograms/dL) (< 50 micrograms/dL)

Total Iron Binding Capacity (TIBC)Total Iron Binding Capacity (TIBC) HIGHHIGH ( > 360 micrograms/dL) ( > 360 micrograms/dL)

Serum FerritinSerum Ferritin LOWLOW (< 20 nanograms/mL) (< 20 nanograms/mL) Can be “falsely”normal in inflammatory Can be “falsely”normal in inflammatory

statesstates

Treatment of Iron Deficiency AnemiaTreatment of Iron Deficiency Anemia

Oral iron saltsOral iron salts Ferrous sulfate – 325 mg(50 mg Ferrous sulfate – 325 mg(50 mg

absorption)absorption) Side effects: constipation, black stools, Side effects: constipation, black stools,

positive hemmoccult testpositive hemmoccult test Vitamin C can facilitate iron absorption.Vitamin C can facilitate iron absorption.

Treatment of Iron Deficiency Treatment of Iron Deficiency AnemiaAnemia

Diet: meat, liver, yeast, fishDiet: meat, liver, yeast, fish Oral preparations: recovery rate Hb Oral preparations: recovery rate Hb

does not differ from parenteral does not differ from parenteral introduction, side effects are less, introduction, side effects are less, excessive introduction does not lead excessive introduction does not lead to hemosiderosis. to hemosiderosis.

- Dosage : 1 hour prior to the meal- Dosage : 1 hour prior to the meal

in the evening time (absorption in the evening time (absorption increase in the second-half of a day) increase in the second-half of a day)

Possibilities : dark colour of stool and Possibilities : dark colour of stool and transitory dyspeptic disorders (nausea, transitory dyspeptic disorders (nausea, diarrhea or watery stool) diarrhea or watery stool)

Check analysis of the blood: in 7-10 days – Check analysis of the blood: in 7-10 days – reticulocyte reaction; 4 weeks - increase Hb reticulocyte reaction; 4 weeks - increase Hb and Htand Ht

- Iron tolerance test(2 tablet-2 h-100 micro/dl- Iron tolerance test(2 tablet-2 h-100 micro/dl

During the normalization of the indices of the During the normalization of the indices of the blood – reduce the dose of preparationblood – reduce the dose of preparation

Parenteral Introduction of IronParenteral Introduction of Iron

in exceptional casesin exceptional cases in severe iron deficiency anemiain severe iron deficiency anemia intolerance of oral preparations (after repeated intolerance of oral preparations (after repeated

replacement and reduction in the dose)replacement and reduction in the dose) diseases of gastro-intestinal tractdiseases of gastro-intestinal tract syndrome of the disrupted intestinal absorbtionsyndrome of the disrupted intestinal absorbtion after the extensive resection of the small after the extensive resection of the small

intestineintestine continuous blood losscontinuous blood loss

Complications of Parenteral Complications of Parenteral IntroductionIntroduction

Local reactions (pains, phlebitis)Local reactions (pains, phlebitis) General reactions (anaphylaxis, fever, General reactions (anaphylaxis, fever,

head and articulate pains, vomiting, head and articulate pains, vomiting, rash, bronchospasm). rash, bronchospasm).

Preparations: Preparations: Venofer - for the intravenous Venofer - for the intravenous

introduction,introduction,Maltofer, Ferrum-Lek - intramuscularMaltofer, Ferrum-Lek - intramuscular

Overdose of IronOverdose of Iron

In the first 6-8 hours - epigastral pains, In the first 6-8 hours - epigastral pains, nausea, vomiting (including with the blood), nausea, vomiting (including with the blood), diarrhea, pallor, sleepiness, acrocyanosis)diarrhea, pallor, sleepiness, acrocyanosis)

For 12-24 hours - metabolic acidosis, For 12-24 hours - metabolic acidosis, leukocytosis, there can be spasms, coma, leukocytosis, there can be spasms, coma, after 2-4 days - necroses of the liver and after 2-4 days - necroses of the liver and kidneys.kidneys.

Treatment: emetic means, stomach Treatment: emetic means, stomach lavage, the method of milk with the egg lavage, the method of milk with the egg white, Deferoksamin, Desferal, symptomatic white, Deferoksamin, Desferal, symptomatic therapy. therapy.

Iron Overload SyndromeIron Overload Syndrome Human does not have special mechanism of the Human does not have special mechanism of the

excretion of iron! Its excessive introduction leads to excretion of iron! Its excessive introduction leads to hemosiderosis. Clinical manifestations: Gradual hemosiderosis. Clinical manifestations: Gradual increase of the dimensions of the liver, spleen, increase of the dimensions of the liver, spleen, cardiopathy, suprarenal insufficiency, diabetes cardiopathy, suprarenal insufficiency, diabetes mellitusmellitus

Laboratory signs: Laboratory signs:

Increase in serum iron (more than 30 mmol/liter), Increase in serum iron (more than 30 mmol/liter), percentage of saturation transferrin by iron it is percentage of saturation transferrin by iron it is more than 50%, ferritin of serum it is more than more than 50%, ferritin of serum it is more than 1000 ng/ml1000 ng/ml

Megaloblastic AnemiaMegaloblastic Anemia

A subclass of macrocytic anemia A subclass of macrocytic anemia

(under morphologic classification)(under morphologic classification)

OrOr A subclass of anemias due to A subclass of anemias due to

defective DNA synthesis defective DNA synthesis

(pathogenetic classification)(pathogenetic classification)

Vit.B12Vit.B12

Average diet contains Average diet contains 5 – 305 – 30 g Vit. Bg Vit. B1212 dailydaily

The amount of Vit. BThe amount of Vit. B12 12 in the body is about in the body is about 2 – 52 – 5 mg. mg.

Most of it is in the liver. Most of it is in the liver. The store is sufficient for The store is sufficient for 3-63-6 years in case years in case

of impaired absorbtion.of impaired absorbtion. The storage form is mainly The storage form is mainly

adenosylcobalamin. adenosylcobalamin.

stomach

Enterohepatic circulation

Ileum cells

Pancreas enzymes

Parietal cell

Duodenum and jejunum

B12 in diet R-Binder

R - B12

R- B12

B12 B12

IF B12

TC II

B12

İleum

IF

IF - B12

Functions of Vit.BFunctions of Vit.B1212

2- 2-

Methyl FHMethyl FH44 FHFH44

HomocysteinHomocystein MethioninMethionin SAMSAM

BB1122

Methionin synthase

Vit.B12Vit.B12

Food sources rich in Vit.B12Food sources rich in Vit.B12 LiverLiver KidneyKidney MuscleMuscle EggEgg Milk ,Cheese and other diary productsMilk ,Cheese and other diary products SeafoodSeafood

Folic acidFolic acidDaily requirementsDaily requirements

AgeAge

0 - 10 0 - 10 3.63.6g /kg g /kg > 10 > 10 33g /kgg /kg Pregnants Pregnants 500 500 g g Lactation +100 Lactation +100 g g

Diet contains 100 - 500 Diet contains 100 - 500 g folate/dayg folate/day..

Folate absorbtionFolate absorbtion

Mainly jejunum. Mainly jejunum.

In the form of monoglutamate . In the form of monoglutamate .

Methyltetrahydrofolate monoglutamate Methyltetrahydrofolate monoglutamate is is

the form it is found in serumthe form it is found in serum . .

Folate levels:Folate levels:

Normal rangesNormal ranges Serum:Serum: 6 – 21 6 – 21 g/L g/L (RBC volume) (RBC volume)

Red cell: Red cell: 160 – 640 160 – 640 g/L g/L (RBC volume)(RBC volume)

Folate deficiencyFolate deficiency Serum folate : Serum folate : <4<4g /L g /L Red cell folate: Red cell folate: <140<140g /Lg /L

Folate storesFolate stores

Total body folate:Total body folate: 5 – 20 mg 5 – 20 mg

Storage place :Storage place : LiverLiver

Storage form: Storage form: Methyl-Methyl-FHFH44

polyglutamatepolyglutamate

Dihydrofolate

THFA

Methylene

THFA

Deoxyuridilate Thymidilate DNA-thymine

Methyl THFA

Homocystein

Methyonine

B12

Dihydrofolate reductaseserine

glycine

Thymidylate synthase

Tissues or organs other than bone Tissues or organs other than bone marrow are also affectedmarrow are also affected

Skin,GIS, female genital system mucosal Skin,GIS, female genital system mucosal epitheliumepithelium

Congenital abn.(neural tube defects)Congenital abn.(neural tube defects) Neurologic changesNeurologic changes(Vit.B(Vit.B1212 deficiency) deficiency)

Peripheral neuropathyPeripheral neuropathy Subacute combined degeneration of spinal cordSubacute combined degeneration of spinal cord Cerebral -Mental changesCerebral -Mental changes

HyperhomocysteinemiaHyperhomocysteinemia

Clinical findings(1)Clinical findings(1) Anemia:Anemia:

Symptoms of anemia + palor+slight icterusSymptoms of anemia + palor+slight icterus

Glossitis :Glossitis :

Sore tongue, poor taste sensation, painSore tongue, poor taste sensation, pain

Papill. atrophy-beefy tonguePapill. atrophy-beefy tongue

RBC Indexes:RBC Indexes:

MCVMCV MCHMCH RDWRDW

Biochemical findingsBiochemical findings

LDHLDH ( LDH -1> LDH - 2)( LDH -1> LDH - 2) Bilirubin(indirect) Bilirubin(indirect) Ferritin and serum iron Ferritin and serum iron Haptoglobin Haptoglobin

Criteria of Effective TreatmentCriteria of Effective Treatment

Subjective improvement during the first Subjective improvement during the first days of treatment;days of treatment;

Reticulocytosis, maximally expressed (to Reticulocytosis, maximally expressed (to 20%) on 5-720%) on 5-7thth day of treatment; day of treatment;

Increase in hemoglobin and number of Increase in hemoglobin and number of erythrocytes, beginning from the 2nd erythrocytes, beginning from the 2nd week of treatment; week of treatment;

The normalization of the blood index, The normalization of the blood index, number of leukocytes and thrombocytes number of leukocytes and thrombocytes in 3-4 weeks of treatment. in 3-4 weeks of treatment.

AnemiaAnemiaCase Study #1Case Study #1

A 72 year A 72 year old male old male has the CBC has the CBC findings findings shown. shown. Peripheral Peripheral RBCs are RBCs are hypochromihypochromic & c & microcytic.microcytic.

AnemiaAnemiaCase Study #2Case Study #2

A 48 year old male A 48 year old male has become has become progressively progressively more fatigued at more fatigued at the end of the day. the end of the day. This has been This has been going on for going on for months. In the months. In the past month he has past month he has noted paresthesias noted paresthesias with numbness in with numbness in his feet. A CBC his feet. A CBC demonstrates the demonstrates the findings shown.findings shown.

Case #3Case #3

Labs:Labs: Hgb: 5.1 g/dLHgb: 5.1 g/dL MCV: 112MCV: 112 RDW: 21%RDW: 21% Platelets: 109Platelets: 109 WBC: 4.6WBC: 4.6

Case #3Case #3 Which of the following blood levels Which of the following blood levels

are most likely in this patient?are most likely in this patient?

Vitamin B12

Folate Methylmalonic Acid

Homocysteine

(A) Low Normal High High

(B) Low Normal Normal High

(C) Normal Low High Normal

(D) Normal Low Normal High

(D) Normal Normal Normal Normal