Tutorial Report

Blok “Hematoimunology”

Scenario 1

Created by:
Group 10

Ade Marantika 1218011002 Istighfariza Shaqina 1218011084

Alfianita Fadhilla 1218011010 M Nikhola Risol 1218011099
Christhopher P.P.P 1218011030 Melati Nurul Utami 1218011104
Ellya Rahmawati 1218011044 Putri Giani P 1218011117
Hani Zahiyah 1218011063 Rizky Indria Lestari 1218011132
Ika Agustin Putri H 1218011076 Zygawindi N 1218011167

Program Study Medical Education

Medical Faculty
Lampung University
2014

1
 PREFACE

Assalammualaikum wr.wb

Alhamdulillah, Praise God we pray to God Almighty for His blessings and grace
so that we can prepare a report this tutorial discussion.

This report was prepared to fulfill the task subjects hematoimunology. To the
faculty involved in the course of this block, we say thank you for all the guidance
and the guidance that has been given so that the report can be completed.

We realize that there are many flaws in the writing of this report, both in terms of
content, language, and so on. Therefore, we apologize for the shortage. This is due
to the still limited knowledge, insight, and skills. In addition, criticism and
suggestions from readers are we expected, to the perfection of this report and
repair for all of us.

Hopefully this report can provide benefits and can add knowledge to us.

Wassalammu’alaikum wr.wb

Bandar Lampung, March 2014

Complier

2
 CONTENTS

Preface ....................................................................................................................2

Contents...................................................................................................................3

Scenario ..................................................................................................................4

Step 1.......................................................................................................................5

Step 2.......................................................................................................................6

Step 3.......................................................................................................................7

Step 4......................................................................................................................10

Step 5......................................................................................................................27

Step 6......................................................................................................................28

Step 7......................................................................................................................29

references......................………………………………………………………….52

3
 Scenario 1

"Fatigue and pale"

Ms. Lita, 17 years old, came to the doctor because of fatigue and headache. 1
month earlier, she felt weak, fatigue and headache. Ms. Lita has
menometrorrhagia symptom every menstruation cycle. She is vegetarian to
maintain her body weight and has several activities at school. Physical
examination showed her conjunctiva is pale. Laboratory examination result
showed Hb 10 gr/dL, MCV 73 fl, MCH 24 pg, serum iron 28 mikrogram/dL
(reference value 37-145 mikrogram/dL), TIBC 450 mikrogram/dL (reference
value 228-428 mikrogram/dL), and serum ferritin 27 mikrogram/L (reference
value 30-150 mikrogram/L)

4
Step 1

Define Unfimiliar Terms

1. What is Menometrorragia ?

Menometrorrhagia is a condition in which prolonged or excessive uterine bleeding

occurs irregularly and more frequently than normal. It is thus a combination of
irregular menstruation and menorrhagia.

2. What is MCV ?

The mean corpuscular volume, or "mean cell volume" (MCV), is a measure of the
average red blood cell volume that is reported as part of a standard complete
blood count.

3. What is MCH ?

The mean corpuscular hemoglobin (MCH), or "mean cell hemoglobin" (MCH), is

the average mass of hemoglobin per red blood cell in a sample of blood. It is
reported as part of a standard complete blood count.

5
Step 2

Learning Issues

1. What is diagnosis and differential diagnosis in cases ?

2. How etiology of anemia ?
3. What is classification of anemia ?
4. Explain how the pathogenesis and of anemia ?
5. Explain how the pathofisiology of anemia ?
6. Clinical manifestations of anemia ?
7. What laboratory examination for anemia ?
8. How to do therapy diagnosis in cases ?

6
Step 3

1. What is diagnosis and differential diagnosis in cases ?

Diagnosis: iron deficiency anemia

Differential diagnosis:

 Thalasemia
 sideroblastik
 anemia of cronic disease

2. How etiology of anemia ?

Cause of Iron Deficiency :

 Increased Iron Requirements

- Blood Loss ; Gastrointestinal Tract

Genitourinary Tract

Respiratory Tract

Blood Donation

- Growth

- Pregnancy and Lactation

 Inadequate Iron Supply

- Dietary Insufficiency of Bioavailable Iron

- Impared Absorbsion of Iron ; Intestinal Malabsorpsion

Gastric Surgery

Impared Iron Transport

3. What is classification of anemia ?

7
a. Morphology

 Normokromik normositik
 Normokromik makrositik
 Hipokromik mikrositik

b. Etiology

 An increased loss of erythrocytes

 Decrease or abnormality of erythrocyte formation

4. Explain how the pathogenesis of anemia ?

Iron, which is present in trace amounts in every cell in the body, performs several
vital functions, including oxygen transport. Most of the body’s iron is used to
make heme groups within the oxygen-carrying molecules Hgb and myoglobin.
Iron also is essential for the biologic function of cytochromes and other enzymes
involved in cellular respiration. Iron is absorbed from the gastrointestinal tract and
transported in the blood bound to transferrin. Excess iron is stored primarily in the
liver, bone marrow, and spleen as ferritin.

5. Explain how the pathofisiology of anemia ?

The progression to iron deficiency can be divided into three stages:

1. Iron depletion or storage iron deficiency

2. Iron deficient erythropoietin or iron limited erythropoiesis
3. Iron deficiency anemia

6. Clinical manifestations of anemia ?

Symptoms :

- Shortness of breath particularry on exercise

- Weakness
- Lethargy
- Palpitation

8
 - Headache

Signs :

 General Signs :
- Pallor of mucous membrane
- Hyperdinamic circulation (tachycardia, a bounding pulse, etc.)
 Specific Signs :
- Koilonychia ‘spoon nails’ with iron deficiency
- Jaundice with haemolytic or megaloblastic anemias
- Leg ulcers with sickle cell and other haemolytic anemias
- Bone deformities with thalasemia major and other server congenital
haemolytic anemias

7. What laboratory examination for anemia ?

 Hemoglobin
 MCV
 MHC
 TIBC
 Serum ferritin
 Serum transferrin
 Free erythrocyte protoporphyrin (FEP)

8. How to do therapy diagnosis in cases ?

 Causal therapy
 Oral iron therapy
 Parentral iron theraphy
 dietary strategies to increase iron and vitamin C intakes
 red cell transfusion

9
Step 4

1. the diagnosis from this case is iron deficiency anemia because:

From the anamnesis she felt weak, headache and fatique. She is vegetarian and
she has menometrorrhagia symptom every menstruation cycle.

From the physical examination showed her conjunctiva is pale

From Laboratory examination result showed Hb 10 gr/dL, MCV 73 fl, MCH 24

pg, serum iron 28 mikrogram/dL (reference value 37-145 mikrogram/dL), TIBC
450 mikrogram/dL (reference value 228-428 mikrogram/dL), and serum ferritin
27 mikrogram/L (reference value 30-150 mikrogram/L)

Differential diagnosis:

Other than iron deficiency, only three conditions need to be considered in the
differential diagnosis of a hypochromic microcytic anemia. The first is an
inherited defect in globin chain synthesis: the thalassemias. These are
differentiated from iron deficiency most readily by serum iron values; normal or
increased serum iron levels and transferrin saturation are characteristic of the

10
thalassemias. In addition, red blood cell distribution width (RDW) index is
generally small in thalassemia and elevated in iron deficiency.

The second condition is the anemia of chronic inflammation with inadequate iron
supply to the erythroid marrow. The distinction between true iron-deficiency
anemia and the anemia associated with chronic inflammation is among the most
common diagnostic problem encountered by clinicians (see below). Usually the
anemia of chronic inflammation is normocytic and normochromic. The iron
values usually make the differential diagnosis clear, as the ferritin level is normal
or increased and the percent transferrin saturation and TIBC are typically below
normal.

Finally, the myelodysplastic syndromes represent the third and least common
condition. Occasionally, patients with myelodysplasia have impaired hemoglobin
synthesis with mitochondrial dysfunction, resulting in impaired iron incorporation
into heme. The iron values again reveal normal stores and more than an adequate
supply to the marrow, despite the microcytosis and hypochromia

2. Overall, the iron requirement for an individual includes not only the iron
needed to replenish physiologic losses and meet the demands of growth and
pregnancy but also any additional amounts needed to replace pathologic losses.
Physiologic iron losses generally are restricted to the small amounts of iron
contained in the urine, bile, and sweat; shedding of iron-containing cells from the
intestine, urinary tract, and skin; occult gastrointestinal blood loss; and, in women,
uterine losses during menstruation and pregnancy. In normal men, the daily basal
iron loss is slightly less than 1.0 mg/day. In normal menstruating women, the
daily basal iron loss is approximately 1.5 mg/day. The median total iron loss with
pregnancy is approximately 500 mg, or almost 2 mg/day over the 280 days of
gestation. Genetic factors may influence the risk of iron deficiency, but the
mechanisms responsible have not been identified.

The most common pathologic cause of increased iron requirements leading to iron
deficiency is blood loss. In men and post-menopausal women, iron deficiency
almost inevitably signifies gastrointestinal blood loss. Within the gastrointestinal

11
tract, any hemorrhagic lesion may result in blood loss, and the responsible lesion
may be asymptomatic. Iron deficiency often is the first sign of an occult
gastrointestinal malignancy or other unrecognized conditions such as coeliac
disease, or autoimmune, atrophic, or Helicobacter pylori gastritis. Chronic
ingestion of drugs such as alcohol, salicylates, steroids, and nonsteroidal
antiinflammatory drugs may cause or contribute to blood loss. Worldwide, the
most frequent cause of gastrointestinal blood loss is hookworm infection, but
other helminthic infections, such as Schistosoma mansoni and Schistosoma
japonicum, and severe Trichuris trichiura infection also may be responsible.

In women of childbearing age, genitourinary blood loss with menstruation adds to

iron requirements. Menstrual losses tend to decrease with use of oral
contraceptives but increase with use of intrauterine devices. Other, less frequent
causes of genitourinary bleeding should be considered, including chronic
hemoglobinuria and hemosiderinuria resulting from paroxysmal nocturnal
hemoglobinuria or from chronic intravascular hemolysis.

Uncommonly, respiratory tract blood loss resulting from chronic recurrent

hemoptysis of any cause produces iron deficiency. In two rare conditions,
Goodpasture syndrome and idiopathic pulmonary siderosis, hemoptysis and
intrapulmonary bleeding may be inapparent but lead to sequestration of iron in
pulmonary macrophages. Although still within the body, the sequestered iron is
“lost” from systemic use, and severe iron-deficiency anemia may develop.
Recurrent blood donation may lead to iron deficiency, particularly in menstruating
women.

In infants, children, and adolescents, the need for iron for growth may exceed the
supply available from diet and stores. Premature infants, who have a lower birth
weight and a more rapid postnatal rate of growth, are at high risk for iron
deficiency unless given iron supplements. With rapid growth during the first year
of life, the body weights of term infants normally triple, and iron requirements are
at high levels. Iron requirements decline as growth slows during the second year
of life and into childhood but rise again with the adolescent growth spurt.

12
3. Classification of anemia

Anemia can be classified from three points of view: pathogenesis, red cell
morphology, and clinical presentation. All are important to guide the diagnosis.
Pathogenic mechanisms involved in the production of anemia are very simple:
inadequate production and loss of erythrocytes a a result of bleeding or hemolysis.
Based on these pathogenic mechanisms, anemia can be divided into two types

1. Hypo-regenerative: when bone marrow production is decrease as a result of

impaired function, decreased number of precursor cells, reduced bone marrow
infiltration, or lack of nutrients;

2. Regenerative: when bone marrow responds appropriately to a low erythrocyte

mass by increasing production of erythrocytes.

Anemia also can be classified according to the form of clinical presentation as

acute (usually bleeding or hemolysis) or chronic.

Anemia can be classified as microcytic, normocytic or macrocytic, depending on

MCV. As stated above, it can be hypo-regenerative or regenerative, which
depends on the number of reticulocytes. Using both, the list of possible diagnoses
in the individual patient is reduced considerably. Both parameters can be supplied
routinely by most of the automatic hematological cell counters

MORPHOLOGICAL CLASSIFICATION

Pathogenic classification is very important to understand the mechanisms

involved in the genesis of anemia However, in daily clinical practice, it is more
useful to start with the analytical parameters of the hemogram. MCV allows us to
classify anemia as microcytic (MCV < 82 fL), normocytic (MCV = 82-98 fL) and
macrocytic (MCV > 98 fL) MCV has a relationship with mean corpuscular
hemoglobin (MCH), which reports on the mean hemoglobin per erythrocyte
expressed in picograms (normal range: 27-32 pg). Therefore, MCV and MCH
decrease (microcytic, hypochromic anemia) or increase (macrocytic,
hyperchromic anemia) jointly. The MCH concentration (MCHC) reports on the
average concentration of hemoglobin in each erythrocyte expressed as a

13
percentage (normal range: 32%-36%), and its variations are very small, even in
the presence of hypochromia. MCHC increases only in a few rare diseases such as
hereditary spherocytosis, and therefore, its practical utility is scarce.

It should always be borne in mind that MCV is an average value and therefore
does not provide information about the homogeneity of the erythrocyte
population. To resolve this problem, hematological analyzers provide the
erythrocyte distribution curve, with an index of dispersion: red blood cell
distribution width (RDW) (normal range: 10%-14%). RDW is a rough indicator of
anisocytosis and is an essential complement to MCV

Microcytic, Normocytic, Macrocytic

Hypocromic Normochromic

MCV < 80 fl MCV = 80 - 95 fl MCV > 95fl

MCH < 27 pg MCH ≥ 27 pg

Iron Deficiency Many haemolytic Megaloblastic : vitamin

anemias B12 or folate deficiency

Thalasemia Anemia of chronic Non Megaloblastic :

disease (some cases) alcohol, liver disease,
myelodysplasia,
aplastic anemia, etc.

Anemia of chronic After acute blood loss

disease (some cases)

Lead poisoning Renal disease

Sideroblastic anemia Mixed deficiencies

(some cases)

Bone marrow failure (e.g.

post-chemothrerapy,
infiltration by carcinoma,

14
 etc.

4. Pathogenesis of Iron Deficiency Anemia

Iron, which is present in trace amounts in every cell in the body, performs several
vital functions, including oxygen transport. Most of the body’s iron is used to
make heme groups within the oxygen-carrying molecules Hgb and myoglobin.
Iron also is essential for the biologic function of cytochromes and other enzymes
involved in cellular respiration.

Iron is absorbed from the gastrointestinal tract and transported in the blood bound
to transferrin. Excess iron is stored primarily in the liver, bone marrow, and spleen
as ferritin.

The developing fetus builds iron stores from maternal supplies. Unless maternal
iron deficiency is severe, a normal term infant is born having sufficient iron stores
for at least 4 to 6 months of postnatal growth. During the first months of life, the
newborn uses iron at a high rate for accelerated growth and expansion of blood
volume. By 4 months of age, an infant’s iron stores have decreased by 50% (and
birthweight usually has doubled). The preterm infant has less time to accumulate
iron in utero and, therefore, is born with lower iron stores. In addition, the preterm
infant has a demonstrably faster rate of postnatal growth than the term infant and
may deplete iron stores within 2 to 3 months.

Adequate iron must be available to meet these demands. Although the majority of
iron in the body is conserved and reused, some is lost through the gastrointestinal
tract, skin, and urine. During the first year of life, normal infants need to absorb
approximately 0.8 mg/d of dietary iron (0.6 mg for growth, 0.2 mg to replace
ongoing losses).

Toward the end of the second year of life, this swift rate of growth begins to slow,
so routine diets tend to include sufficient iron-rich foods to meet demands. Iron

15
requirements increase again during adolescence due to rapid growth; adolescent
females need additional iron to replace losses from menstruation.

Iron is a critical element in the function of all cells, although the amount of iron
required by individual tissues varies during development. At the same time, the
body must protect itself from free iron, which is highly toxic in that it participates
in chemical reactions that generate free radicals such as singlet O2 or OH–.
Consequently, elaborate mechanisms have evolved that allow iron to be made
available for physiologic functions while at the same time conserving this element
and handling it in such a way that toxicity is avoided.

The major role of iron in mammals is to carry O2 as part of hemoglobin. O2 is

also bound by myoglobin in muscle. Iron is a critical element in iron-containing
enzymes, including the cytochrome system in mitochondria

There are two types of dietary iron: heme and nonheme. Heme iron already has
been incorporated into the heme molecules of Hgb and myoglobin and is well
absorbed by the body. Approximately 10% of the iron in a typical Western diet is
heme iron, derived from meat, poultry, and fish. The majority of dietary iron is
nonheme, in the form of iron salts. The bioavailability (amount absorbed by the
body) of nonheme iron is highly variable and influenced by several factors,
including current diet and the amount of iron already present in the body. Bran,
dietary fiber, calcium, tannins (in tea and coffee), and oxalates, phytates, and
polyphenols (in certain plant-based foods) inhibit iron absorption. Absorption is
enhanced by reducing substances such as hydrochloric acid and ascorbic acid. The
consumption of heme iron, even in small amounts, enhances the absorption of
nonheme iron. Absorption of iron also is increased when total body stores are
decreased or when the demand for iron increases, such as during adolescent
growth spurts.

Mature human milk and cow milk contain the same amount of iron,
approximately 0.5 mg/L; fortified formulas contain 10 to 13 mg/L. However,
about 50% of iron from human milk is absorbed compared with only 10% from
cow milk and less than 5% from iron-fortified formula. The reasons for the

16
enhanced bioavailability of iron from human milk are not well understood, but
they include a lower concentration of calcium and a higher concentration of
ascorbic acid in human milk.

5. The progression to iron deficiency can be divided into three stages The first
stage is negative iron balance, in which the demands for (or losses of) iron exceed
the body's ability to absorb iron from the diet. This stage results from a number of
physiologic mechanisms, including blood loss, pregnancy (in which the demands
for red cell production by the fetus outstrip the mother's ability to provide iron),
rapid growth spurts in the adolescent, or inadequate dietary iron intake. Blood loss
in excess of 10–20 mL of red cells per day is greater than the amount of iron that
the gut can absorb from a normal diet. Under these circumstances the iron deficit
must be made up by mobilization of iron from RE storage sites. During this
period, iron stores—reflected by the serum ferritin level or the appearance of
stainable iron on bone marrow aspirations—decrease. As long as iron stores are
present and can be mobilized, the serum iron, total iron-binding capacity (TIBC),
and red cell protoporphyrin levels remain within normal limits. At this stage, red
cell morphology and indices are normal

When iron stores become depleted, the serum iron begins to fall. Gradually, the
TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron
stores are absent when the serum ferritin level is <15 g/L. As long as the serum
iron remains within the normal range, hemoglobin synthesis is unaffected despite
the dwindling iron stores. Once the transferrin saturation falls to 15–20%,
hemoglobin synthesis becomes impaired. This is a period of iron-deficient
erythropoiesis. Careful evaluation of the peripheral blood smear reveals the first
appearance of microcytic cells, and if the laboratory technology is available, one
finds hypochromic reticulocytes in circulation. Gradually, the hemoglobin and
hematocrit begin to fall, reflecting iron-deficiency anemia. The transferrin
saturation at this point is 10–15%.

When moderate anemia is present (hemoglobin 10–13 g/dL), the bone marrow
remains hypoproliferative. With more severe anemia (hemoglobin 7–8 g/dL),
hypochromia and microcytosis become more prominent, target cells and

17
misshapen red cells (poikilocytes) appear on the blood smear as cigar- or pencil-
shaped forms, and the erythroid marrow becomes increasingly ineffective.
Consequently, with severe prolonged iron-deficiency anemia, erythroid
hyperplasia of the marrow develops, rather than hypoproliferation.

6. Symptoms

If the patient does have symptoms these are usually shorhless of breath
particularly on' exercise, weakness, lethargy, palpitation and headaches. In older
subjects, symptoms of cardiac failure, angina pectoris or intermittent claudication
or confusion may be present. Visual disturbances because of retinal haemorrhages
may complicate very severe anaemia, particularly of rapid onset.

Signs

These may be divided into general and specific. General signs include pallor of
mucous membranes which occurs if the haemoglobin level is less than 9-10 g/dL .
Conversely, skin colour is not a reliable sign. A hyperdynamic circulation may be
present with tachycardia, a bounding pulse, cardiomegaly and a systolic flow
murmur especially at the apex. Particularly in the elderly, features of congestive
heart failure may be present. Retinal haemorrhages are unusual.

Specific signs are associated with particular types of anaemia (e.g. koilonychia
'spoon nails' with iron deficiency, jaundice with haemolytic or megaloblastic
anaemias, leg ulcers with sickle cell and other haemolytic anaemias, bone
deformities with thalassaemia major and other severe congenital haemolytic
anaemias). The association of feahlres of anaemia with excess infections or
spontaneous bruising suggest that neutropenia or thrombocytopenia may be
present, possibly as a result of bone marrow failure.

18
(a) Pallor of the conjunctival mucosa

(b) the nail bed

7. laboratory examination

Hemoglobin and Hematocrit Values Diagnostic of Anemia

Gender/Age (yrs) Hemoglobin<g/dL Hematocrit<%
Females
12-14.9 11.8 35.7
15-17.9 12.0 35.9
18+ 12.0 35.9

Males
12-14.9 12.5 37.3
15-17.9 13.3 39.7
18+ 13.5 39.9

Laboratory Test Value

Ferritin <15 ug/L
Serum transferrin receptor concentration (TfR) >8.5 mg/L
Transferrin saturation <16%
Mean cell volume (MCV) <82/85 fL

19
Red cell distribution width (RDW) >14%
Erythrocyte protoporphyrin (FEP) >70 ug/dL

Complete Blood Count

Often, the first test used to diagnose anemia is a complete blood count (CBC). The
CBC measures many parts of your blood.

The test checks hemoglobin and hematocrit) levels. Hemoglobin is the iron-rich
protein in red blood cells that carries oxygen to the body. Hematocrit is a measure
of how much space red blood cells take up in your blood. A low level of
hemoglobin or hematocrit is a sign of anemia.

The normal range of these levels might be lower in certain racial and ethnic
populations. Your doctor can explain your test results to you.

The CBC also checks the number of red blood cells, white blood cells, and
platelets in your blood. Abnormal results might be a sign of anemia, another blood
disorder, an infection, or another condition.

Finally, the CBC looks at mean corpuscular (kor-PUS-kyu-lar) volume (MCV).

MCV is a measure of the average size of your red blood cells and a clue as to the
cause of your anemia. In iron-deficiency anemia, for example, red blood cells
usually are smaller than normal.

Serum Iron and Total Iron-Binding Capacity

The serum iron level represents the amount of circulating iron bound to
transferrin. The TIBC is an indirect measure of the circulating transferrin. The
normal range for the serum iron is 50–150 g/dL; the normal range for TIBC is
300–360 g/dL. Transferrin saturation, which is normally 25–50%, is obtained by
the following formula: serum iron x 100 ÷ TIBC. Iron-deficiency states are

20
associated with saturation levels below 20%. There is a diurnal variation in the
serum iron. A transferrin saturation >50% indicates that a disproportionate
amount of the iron bound to transferrin is being delivered to nonerythroid tissues.
If this persists for an extended time, tissue iron overload may occur.

Serum Ferritin

Free iron is toxic to cells, and the body has established an elaborate set of
protective mechanisms to bind iron in various tissue compartments. Within cells,
iron is stored complexed to protein as ferritin or hemosiderin. Apoferritin binds to
free ferrous iron and stores it in the ferric state. As ferritin accumulates within
cells of the RE system, protein aggregates are formed as hemosiderin. Iron in
ferritin or hemosiderin can be extracted for release by the RE cells, although
hemosiderin is less readily available. Under steady-state conditions, the serum
ferritin level correlates with total body iron stores; thus, the serum ferritin level is
the most convenient

Evaluation of Bone Marrow Iron Stores

Although RE cell iron stores can be estimated from the iron stain of a bone
marrow aspirate or biopsy, the measurement of serum ferritin has largely
supplanted bone marrow aspirates for determination of storage iron The serum
ferritin level is a better indicator of iron overload than the marrow iron stain.
However, in addition to storage iron, the marrow iron stain provides information
about the effective delivery of iron to developing erythroblasts. Normally, when
the marrow smear is stained for iron, 20–40% of developing erythroblasts—called
sideroblasts—will have visible ferritin granules in their cytoplasm. This represents
iron in excess of that needed for hemoglobin synthesis. In states in which release
of iron from storage sites is blocked, RE iron will be detectable, and there will be
few or no sideroblasts. In the myelodysplastic syndromes, mitochondrial
dysfunction can occur, and accumulation of iron in mitochondria appears in a

21
necklace fashion around the nucleus of the erythroblast. Such cells are referred to
as ringed sideroblasts

Red Cell Protoporphyrin Levels

Protoporphyrin is an intermediate in the pathway to heme synthesis. Under

conditions in which heme synthesis is impaired, protoporphyrin accumulates
within the red cell. This reflects an inadequate iron supply to erythroid precursors
to support hemoglobin synthesis. Normal values are <30 g/dL of red cells. In iron
deficiency, values in excess of 100 g/dL are seen. The most common causes of
increased red cell protoporphyrin levels are absolute or relative iron deficiency
and lead poisoning.

Serum Levels of Transferrin Receptor Protein

Because erythroid cells have the highest numbers of transferrin receptors of any
cell in the body, and because transferrin receptor protein (TRP) is released by
cells into the circulation, serum levels of TRP reflect the total erythroid marrow
mass. Another condition in which TRP levels are elevated is absolute iron
deficiency. Normal values are 4–9 g/L determined by immunoassay. This
laboratory test is becoming increasingly available and, along with the serum
ferritin, has been proposed to distinguish between iron deficiency and the anemia
of chronic inflammation (see below).

8. therapy diagnosis
 Causal therapy
This therapy is given by underlying causes of anemia iron deficiency. The causal
therapy should be done immediately if not, it will easily anemia relapse or even
giving iron preparations will not give the desired results
 oral iron supplement
Typically, for iron replacement therapy, up to 300 mg of elemental iron per day is
given, usually as three or four iron tablets (each containing 50–65 mg elemental

22
iron) given over the course of the day. Ideally, oral iron preparations should be
taken on an empty stomach, since food may inhibit iron absorption. Some patients
with gastric disease or prior gastric surgery require special treatment with iron
solutions, as the retention capacity of the stomach may be reduced. The retention
capacity is necessary for dissolving the shell of the iron tablet before the release of
iron. A dose of 200–300 mg of elemental iron per day should result in the
absorption of iron up to 50 mg/d. This supports a red cell production level of two
to three times normal in an individual with a normally functioning marrow and
appropriate erythropoietin stimulus. However, as the hemoglobin level rises,
erythropoietin stimulation decreases, and the amount of iron absorbed is reduced.
The goal of therapy in individuals with iron-deficiency anemia is not only to
repair the anemia, but also to provide stores of at least 0.5–1 g of iron. Sustained
treatment for a period of 6–12 months after correction of the anemia will be
necessary to achieve this.
Preparations are available in the form of :
- Ferro Sulfate: is the best preparation , with a dose of 3 x 200 mg,
given current empty stomach [before the meal]. If this side effects
occur eg nausea, abdominal pain, constipation or diarrhea, should be
given after meals / concurrent with eating or replace it with other
iron preparations.
- Ferrous gluconate: a preparation with a lower iron content than
ferrous sulfate. Prices are more expensive but almost the same
effectiveness.
- Ferro fumarate, lactate Ferro.

Timing of oral iron should be that is enough long to restore a backup iron body if
not, then the anemia is often relapse again. The success of this oral iron therapy
causing rapid reticulocytosis in one week and it’s mean hemoglobin levels repairs
within 2-4 weeks, which will be improvement perfect repairs within 1-3 months.
This does not mean the therapy is stopped but therapy should be continued for up
to 6 months fill the body's iron reserves. If the giving response to oral iron therapy
is poor, to think about the possibilities before it is replaced with parenteral iron
preparations.

23
Some things that cause failure response to giving of oral iron preparations among
others, which are still on going bleeding (kausanya not resolved), non-compliance
patients in taking medication (not regular) doses less, malabsorption, incorrect
diagnosis or anemia is multifactorial.

Of the complications of oral iron therapy, gastrointestinal distress is the most

prominent and is seen in 15–20% of patients. Abdominal pain, nausea, vomiting,
or constipation may lead to noncompliance. Although small doses of iron or iron
preparations with delayed release may help somewhat, the gastrointestinal side
effects are a major impediment to the effective treatment of a number of patients

 Parentral iron theraphy

Parenteral iron is used in two ways: one is to administer the total dose of iron
required to correct the hemoglobin deficit and provide the patient with at least 500
mg of iron stores; the second is to give repeated small doses of parenteral iron
over a protracted period. The latter approach is common in dialysis centers, where
it is not unusual for 100 mg of elemental iron to be given weekly for 10 weeks to
augment the response to recombinant EPO therapy. The amount of iron needed by
an individual patient is calculated by the following formula:

Body weight (kg) x 2.3 x (15–patient's hemoglobin, g/dL) + 500 or 1000 mg (for
stores).

There are several examples of parenteral iron preparations:

 Iron Sorbitol Citrate (Jectofer) Giving at intramuscularly and repeated.
 Ferric hydroxide-sucrose (Venofer) slow intravenous or infusion.

Price of parenteral iron preparations are obviously more expensive than oral iron
preparations. In addition to the adverse effects of parental iron preparations more
dangerous. Some of the side effects that may result from the parenteral giving iron
include local pain and brown color at the site of injection, phlebitis, headache,
fever, arthralgia, nausea, vomiting, back pain, flushing, urticaria, bronchospasm,

24
and anaphylaxis and death rarely occurs. Given the many side effects of the
parenteral administration should be considered correct. Intravenous should be
carefull at giving. First tests hypersensitivity, and patients should be observed for
intravenous administration so that the possibility of anaphylaxis can be
anticipated.

 dietary strategies to increase iron and vitamin C intakes

Dietary iron sources include meat, fish and poultry, lentils, dried beans, grain
products, vegetables, dried fruit, and molasses. Sources of heme iron from
hemoglobin and myoglobin found in meat, fish,and poultry are effectively
absorbed by receptors in the gut, while the bioavailability of non-heme iron from
plants is determined by the presence of dietary factors that enhance or inhibit its
absorption

Dietary Factors That Enhance and Inhibit Iron Absorption

Enhance Inhibit

Fish Phosphate
Poultry Calcium
Seafood Tea (tannic acid)
Gastric acid Coffee
Ascorbic acid Colas
Malic acid Soy protein
Citric acid High doses of minerals
Bran/fiber

Vitamin C is necessary because this will helps the absorption of iron. is given by 3
x 100mg doses.

 red cell transfution

Transfusion therapy is reserved for individuals who have symptoms of anemia,
cardiovascular instability, continued and excessive blood loss from whatever

25
source, and require immediate intervention. The management of these patients is
less related to the iron deficiency than it is to the consequences of the severe
anemia. Not only do transfusions correct the anemia acutely, but the transfused
red cells provide a source of iron for reutilization, assuming they are not lost
through continued bleeding. Transfusion therapy will stabilize the patient while
other options are reviewed

26
Step 5

1. what is the relationship between menstruation and anemia?

2. what is the classification anemia based on the degree of anemia?

3. what is the meaning microcytic anemia and normocytic anemia?

4. what is the thalassemia?

5. what is the pathophysiology of anemia

27
Step 6

28
Step 7

1. menstrual relationship with anemia

• Women are more at risk for anemia

Biological cycle makes women more susceptible to anemia than men.

Unfortunately many women tend to ignore it.

Anemia or anemia disease is often regarded as a disease that is not harmful.

Usually in the mild stage, anemia often cause significant disruption. That makes
this disease tends to be ignored. In fact, if allowed berlarutlarut, anemia not only
lowers the quality of life, can also bring death.

The women now have to be more vigilant. Therefore, a disease characterized by

symptoms of dizziness is more common in women.

Monthly menstruation, childbirth, and excessive dieting, be the culprit of anemia

in women. However it is unfortunate, many women underestimate this disease.
Especially in the light phase.

• Anemia (in Greek: Without Blood) is a state when the number of red
blood cells or amount of hemoglobin (the oxygen-carrying protein) in red blood
cells are below normal.

Red blood cells contain hemoglobin which enables them to carry oxygen from the
lungs and deliver it to all parts of the body.

Anemia causes a reduced number of red blood cells or amount of hemoglobin in

red blood cells, so that the blood can not carry oxygen as required in a number of
body

• menstruation

Menstruation or menstrual or menstruation is physiological changes in a woman's

body that occur periodically and are influenced by reproductive hormones. This
period is important in halreproduksi. In humans, this usually happens every month
between adolescence sampaimenopause. In addition to humans, this period only

29
occurs in large primates, other mammals sementarabinatang-experienced estrous
cycle.

• In the female menstrual cycle occurs on average about 28 days, although it

is generally accepted, but not all women have the same menstrual cycle,
sometimes the cycle occurs every 21 days to 30 days. Typically, menstruation
occurred on average 5 days, sometimes menstruation also may occur about 2 days
to 7 days. Generally due to menstrual blood loss was 10ml to 80ml per day but
usually with an average of 35ml per day.

Usually when a woman's menstrual wear pads to accommodate the blood that
comes out during the move, especially during sleep so that the buttocks and pants
do not get wet and stay comfortable. Bandages should be changed at least twice a
day to prevent this from happening padavagina infection or other disorders. Use
anti-bacterial pads and have a smooth air cycle.

• menstrual phase

That is, the entire uterine wall and the release of the body. This is due to reduced
levels of sex hormones. Hali is gradually happening in harike-1 to 7.

preovulatory phase

Namely, the formation and maturation of ova in the ovaries that are triggered by
elevated levels of estrogen in the body. This occurs gradually on days 7 to 13.

ovulatory phase

Ovulation is the fertile period or a period in a woman's menstrual cycle where a

mature egg ready to be fertilized. If the woman had sexual intercourse in the
fertile period or ovulation then the possibility of pregnancy.

Determine the fertile period

• Several methods for determining the fertile period can be seen in several
ways:

1. Changes in Menstrual Period

30
2. The cervix mucus changes

3. Basal Body Temperature Changes

post-ovulatory phase

That is, a period of decline in the absence of fertilization of the ovum. At this
stage, an increase in the production of progesterone to the endometrium becomes
thicker and ready to receive the embryo to develop. If fertilization does not occur,
then the sex hormones in the body and occurs fasemenstruasi be repeated again.

2. The degree of anemia according to WHO classification cited in the book Handy
W, and Haribowo U.S., (2008):

1. Lightweight once Hb 10.00 g% g% -13.00

2. Lightweight Hb g% 8.00% -9.90 g

3. 'mHb 6.00 g% g% -7.90

4. Weight Hb<6.00 g%

Other Anemia

Distribution of anemia based on hemoglobin by Manuaba (2007), are:

1. Not anemia: Hb 11.00 g%

2. Mild anemia: Hb from 9.00 to 10.00 g%

3. Moderate anemia: Hb from 7.00 to 8.00 g%

4. Severe anemia: Hb<7.00 g%

CLASSIFICATION

Anemia can be classified from three points of view: pathogenesis, red cell
morphology, and clinical presentation. All are important to guide the diagnosis.
Pathogenic mechanisms involved in the production of anemia are very simple:

31
inadequate production and loss of erythrocytes aa result of bleeding or hemolysis.
Based on these pathogenic mechanisms, anemia can be divided into two types. (1)
Hypo-regenerative: when bone marrow production is decrease as a result of
impaired function, decreased number of precursor cells, reduced bone marrow
infiltration, or lack of nutrients; (2) Regenerative: when bone marrow responds
appropriately to a low erythrocyte mass by increasing production of erythrocytes.

In practice, classification based on basic parameters of red cell morphology such

as mean corpuscular volume (MCV), allows for a quicker diagnostic approach.

Anemia also can be classified according to the form of clinical presentation as

acute (usually bleeding or hemolysis) or chronic.

Anemia can be classified as microcytic, normocytic or macrocytic, depending on

MCV. As stated above, it can be hypo-regenerative or regenerative, which
depends on the number of reticulocytes. Using both, the list of possible diagnoses
in the individual patient is reduced considerably. Both parameters can be supplied
routinely by most of the automatic hematological cell counters.

PATHOGENIC CLASSIFICATION

The reticulocyte count is useful to distinguish anemia in which there is an

appropriate bone marrow response from that in which there is a decrease in the
production of erythrocytes. The concentration of reticulocytes reports on the bone
marrow response to anemia. This approach is especially useful when MCV is
normal.

A decrease in hemoglobin stimulates erythropoiesis through an increase in

circulating erythropoietin. Therefore, when the bone marrow shows a normal
regenerative capacity, there should be an inverse relationship between the
decrease in hemoglobin and the increased number of reticulocytes (regenerative
anemia). The expected reticulocyte count is much higher than normal to
compensate for the anemia. However, when the hemoglobin decreases and the
bone marrow does not have regenerative capacity, the expected increase in

32
reticulocytes fails, despite the increase in erythropoietin plasma level (hypo-
regenerative anemia).

The reticulocyte count is expressed as a proportion of the number of erythrocytes,

which must be corrected for anemia, and for increased lifespan of reticulocytes in
peripheral blood. Most hematological analyzers provide directly the number of
reticulocytes per mm3, which is a better estimation of erythropoietic activity than
a percentage. However, the absolute reticulocyte enumeration per mm3
overestimates the actual activity of erythropoiesis, since reticulocytes are released
earlier and remain longer in the circulating blood. To avoid these confounding
events, it is recommended to calculate the reticulocyte index.

The next step is the calculation of reticulocyte production index (RPI):

RPI = correcteds reticulocyte count (%) × (haematocrit observed/normal

hematocrit) : F (reticulocyte maturation times in vivo)

RPI in a healthy person is 1. An RPI > 3 in a patient with anemia suggests an

appropriate bone marrow response, and therefore, regenerative anemia.
Nevertheless, the best estimate of the actual erythropoieticactivity and easiest to
calculate, is to divide by two the number of reticulocytes per mm3.

Regenerative anemia

This is characterized by increased generation of erythropoietin in response to

decreased hemoglobin concentration, and generally reflects a loss of erythrocytes,
due to bleeding or hemolysis In both cases, there is a typical increase in
reticulocytes. The bleeding can be intense, with a sharp drop of hematocrit and
obvious clinical signs; or of small intensity and chronic, with progressive decrease
in hematocrit and MCV, which may go unnoticed. Over time, chronic
hemorrhagic anemia becomes hypo-regenerative and microcytic because of
depletion of iron stores.

Etiopathogenic classification of anemia

33
Hemolysis, can be acute (usually intravascular) or chronic (usually extravascular).
Acute hemolysis is characterized by sudden episodes with very obvious clinical
signs (fever, chills, back pain, dark urine) and typical laboratory data
(hemoglobinuria and reduced plasma haptoglobin

Hypo-regenerative anemia

This is caused by alteration of bone marrow progenitor cells, which can be located
at different stages of differentiation and maturation. The impairment of pluripotent
stem cells usually produces pancytopenia (anemia, leukopenia and
thrombocytopenia). Pancytopenia may be caused by intrinsic [bone marrow
aplasia, leukemia, myelodysplastic syndrome (MDS) or myelofibrosis] or
extrinsic (metastasis, Gaucher disease and other thesaurismosis, tuberculosis,
histoplasmosis, viral and parasitic infections). All of them are capable of
displacing normal hematopoiesis or changing the microenvironment necessary for
regeneration, differentiation and proliferation of stem cells.

Less frequently, progenitor cells committed to the erythroid line (burst-forming

unit-erythroid and colony-forming unit-erythroid) are affected selectively, and the
result is pure red cell aplasia. When progenitor red cells are impaired selectively,
bone marrow erythroblasts are much reduced or absent, while other hematological
cellular lines remain normal. Pure red cell aplasia, hereditary or acquired, is very
rare. However, a qualitative alteration of the red cell line (dyserythropoiesis) is
often seen in clinical practice. In contrast to pure red cell aplasia, the bone marrow
is rich in erythroblasts in patients with dyserythropoiesis. In these cases, the
erythropoiesis is abnormal morphologically and functionally. Erythroblastopenia
as dyserythropoiesis may have a hereditary or acquired origin. The former is
extremely rare. Thymoma is the most common cause of acquired pure red cell
aplasia. MDS is the most common cause of acquired dyserythropoiesis. In MDS
patients, the lesion is located at the level of very primitive multipotent
progenitors, and thus, the morphological and functional alterations can affect all
blood cell lines (erythrocyte, granulocyte-monocyte and megakaryocyte)

34
Anemia caused by nutritional deficiencies or decreased production of
erythropoietin is much more frequent than that caused by a primitive defect in
bone marrow.

morphological classification

Pathogenic classification is very important to understand the mechanisms

involved in the genesis of anemia However, in daily clinical practice, it is more
useful to start with the analytical parameters of the hemogram. MCV allows us to
classify anemia as microcytic (MCV < 82 fL), normocytic (MCV = 82-98 fL) and
macrocytic (MCV > 98 fL).

Morphological classification

MCV has a relationship with mean corpuscular hemoglobin (MCH), which

reports on the mean hemoglobin per erythrocyte expressed in picograms (normal
range: 27-32 pg). Therefore, MCV and MCH decrease (microcytic, hypochromic
anemia) or increase (macrocytic, hyperchromic anemia) jointly. The MCH
concentration (MCHC) reports on the average concentration of hemoglobin in
each erythrocyte expressed as a percentage (normal range: 32%-36%), and its
variations are very small, even in the presence of hypochromia. MCHC increases
only in a few rare diseases such as hereditary spherocytosis, and therefore, its
practical utility is scarce.

It should always be borne in mind that MCV is an average value and therefore
does not provide information about the homogeneity of the erythrocyte
population. To resolve this problem, hematological analyzers provide the
erythrocyte distribution curve, with an index of dispersion: red blood cell
distribution width (RDW) (normal range: 10%-14%). RDW is a rough indicator of
anisocytosis and is an essential complement to MCV

Classification of anemia as RDW and MCV

Microcytic anemia

35
Faced with microcytic anemia, the three main diagnostic possibilities include iron
deficiency anemia (IDA), thalassemia, and anemia of chronic disorders (ACD). A
fourth possibility, sideroblastic anemia, is so rare that is not considered in the
initial diagnosis, unless there is a history of contact with lead

Evaluation of microcytic anemia. TSI: Transferrin saturation index; MCV: Mean

corpuscular volume; Hb: Hemoglobin.

Iron deficiency is the most common cause of anemia, so the first step in diagnosis
should be directed toward confirmation or exclusion of IDA. Serum ferritin allows
us to confirm the diagnosis. Despite ferritin being an acute phase reactant, the
diagnosis of IDA is unlikely with normal or elevated ferritin levels. Other
parameters of iron metabolism (serum iron, total transport capacity of iron, and
transferrin) are unable to distinguish with certainty IDA from ACD.

It is important to note that microcytosis without anemia is characteristic of

thalassemia trait, but also of polycythemia associated with iron deficiency

The simple analysis of different parameters provided by the hematological

analyzer gives a diagnosis of microcytic anemia. RDW helps to distinguish
thalassemia from IDA. RDW is normal in thalassemia; on the contrary, microcytic
anemia with RDW > 15 is probably IDA.

In recent years, the importance of serum soluble transferrin receptor has been
recognized in differential diagnosis of IDA and ACD. Serum soluble transferrin
receptor is increased in IDA, without interference in case ACD is present.Intra-
erythrocytic ferritin and erythrocyte zinc-protoporphyrin also help to differentiate
IDA from ACD. These parameters allow the diagnosis of borderline patients who,
at another time, would have undergone unnecessary investigation of iron in the
bone marrow.

In men and postmenopausal women, the bigger concern should be to rule out the
presence of occult bleeding. If positive, the first exploration should be a
colonoscopy, mainly in men, because of the frequent association of occult blood
with adenocarcinomaIf the colonoscopy does not reveal the cause of the anemia,

36
gastroscopy should be performed. The study of the small bowel is more
controversial, but it is convenient to keep in mind that celiac disease is a cause of
IDA

In premenopausal women, genital bleeding is the most frequent cause of anemia.

Therefore, gastrointestinal exploration is controversial. An anamnesis directed
towards the characteristics of menstrual bleeding, although a subjective criterion,
may be useful for distinguishing a subgroup of women without excessive genital
bleeding, who require direct assessment of occult bleeding, followed by
gastrointestinal exploration if positive. In cases in which occult bleeding is
negative, the exploration should be directed to the genital system.

Microcytosis associated with normal ferritin guides the diagnosis toward

hereditary diseases, mainly thalassemia. If there are no family antecedents of
microcytosis, it is necessary to investigate acquired causes of non-iron deficiency
microcytosis, mainly ACD and sideroblastic anemia. Normal RDW guides the
diagnosis toward the former and a high RDW toward the latter.

Normocytic anemia

The fundamental question in normocytic anemia is to recognize the causes and

susceptibility to treatment as soon as possible. Among the causes are nutritional
deficiency, renal failure and hemolytic anemia. Nutritional mixed anemia that
combines deficiency of vitamin B12, folic acid and iron is frequent. In
consequence, these three parameters should be requested in the initial phase of the
diagnosis of normochromic anemia.

In order to differentiate among regenerative (hemolysis and bleeding) or hypo-

regenerative anemia (bone marrow aplasia, chronic disease, nutrition deficiency
and hemopathy), it is necessary to determine the corrected RPI In anemia of renal
failure, morphological alterations in the blood are scarce and serum erythropoietin
may be normal, but inappropriately low for the degree of anemia. The severity of
anemia is not evident until the disease is very advanced.

Evaluation of normocytic anemia. RPI: Reticulocytes production index.

37
It will always be necessary to rule out hemolysis, by performing easily accessible
laboratory tests [lactate dehydrogenase (LDH), indirect bilirubin, haptoglobin and
reticulocytes]. These parameters do not inform us about the origin of hemolysis,
and it is necessary to evaluate others, such as schistocytes in peripheral blood
(intravascular hemolysis), the Coombs test (autoimmune hemolysis), tests of
osmotic fragility (extravascular hemolysis), and tests to rule out hemolysis
induced by drugs\ A detailed anamnesis and Coombs test, with and without the
suspected drugs, are very useful in the investigation of drug-induced hemolytic
anemia.

When the cause of normocytic anemia is not any of the previously mentioned
causes, it is necessary to guide the diagnosis toward a chronic disease or to
primitive hematological disease\It is difficult to arrive at the definitive diagnosis.
In this situation, it is fundamental that a careful clinical evaluation is carried out to
rule out other causes of normocytic anemia: alcoholism (more frequently
macrocytic), effects of drugs (chemotherapy, immunosuppression), radiotherapy,
neoplasia (bone marrow infiltration), infections (mainly in hospitalized patients),
surgery, or recent trauma (first phase of bleeding). The association with
pathological concomitant processes, elevation of erythrocyte sedimentation rate
(ESR) and the absence of morphological alterations in peripheral blood smears
supports the suspicion of ACD .ACD is the most frequent cause of anemia after
ferropenia. It is observed in patients that have immune hyperactivity. Activation
of cytokines and the reticuloendothelial system induces changes in iron
homeostasis, erythroid precursor proliferation, erythropoietin secretion, and
erythrocyte life span. All of these contribute to the pathogenesis of anemia.

ACD can be complicated with chronic bleeding, and in this case, the diagnosis is
more difficult because of the presence of microcytosis and ferropenia. The
biochemical parameter that better differentiates ACD from IDA is serum ferritin

Serum levels that differentiate ACD, IDA and mixed anemia

38
The hematologist must revise the blood smear if primitive disease of bone marrow
is suspected. Depending on the result, a bone marrow study may be necessary to
detect hematological diseases or metastasis. The biopsy, bone marrow smear, or
both inform us of: the morphology of the hematopoietic cells, on their quantitative
distribution, especially the myelo-erythroid ratio (normal 3:1); fibrosis; the
presence of non-hematopoietic cell; or possible bone marrow aplasia. Perls’
specific iron stain informs us of the state of iron stores, and it allows
quantification of siderocytes and sideroblasts. In a patient with anemia and fever
of unknown origin, we must carry out careful microscopic examination of bone
marrow, some selective staining, and bone marrow cultures to diagnose any
underlying infectious diseases. Some infectious or parasitic diseases that are
diagnosed with relative frequency are: tuberculosis, histoplasmosis, kala-azar and
malaria.

Macrocytic anemia

Macrocytosis is observed frequently using blood cell analyzers (Figure

(Figure3).3). Its prevalence is 1.7%-3.9%, but 60% of the patients with
macrocytosis do not have anemia[48]. On the other hand, macrocytosis can be
physiological in some circumstances (infants, pregnancy, some families). Even
keeping in mind the precedent data is convenient to make a careful evaluation of
macrocytosis in every patient, to rule out any underlying pathology. In vitamin
B12 and folic acid deficiency, as well as in other diseases, macrocytosis (blood) is
accompanied by megaloblastosis (bone marrow). In such cases, both terms can be
used interchangeably

Evaluation of macrocytic anemia.

The starting point in the diagnostic process for macrocytic anemia will be to rule
out therapy with drugs that interfere with nucleic acid metabolism, such
as.hydroxyurea, methotrexate, trimethoprim, zidovudine or 5-fluorouracil, as well
as habitual intake of alcoholHydroxyurea is the drug that increases most the MCV

39
(> 110 fL); the other drugs and alcohol induce a moderate macrocytosis (100-110
fL).

In the absence of intake of any of the drugs mentioned above or alcohol, the most
frequent cause of microcytic anemia is nutritional deficiencyTherefore, serum
vitamin B12 and folic acid levels should be evaluated. The last can be modified by
the previous day’s folic acid intake. A better alternative is intra-erythrocyte folate,
which remains stable during the lifetime of red blood cells and gives a better
indication of possible chronic folic acid deficiency. The measurement of
erythrocyte folate is a difficult technique that is not available in every laboratory.
The determination of homocysteine is an accessible alternative to intra-
erythrocyte folate. In the absence of folic acid, homocysteine levels increase
rapidly because it cannot be converted into methionine. Normal serum levels of
homocysteine are highly unlikely in folatedeficiency

In the same way, vitamin B12 deficiency is correlated with low serum levels,
although there are clinical situations in which low serum levels are not correlated
with vitamin B12 deficiency (pregnancy, elderly patients, and those with low
white blood cell counts). In these circumstances, normal serum methyl-malonic
acid levels, in the absence of congenital errors of metabolism or renal failure,
preclude a deficiency of vitamin B12.

To complete the study of vitamin B12 deficiency, it is necessary to look for

antibodies to intrinsic factor, which if positive, confirms the diagnosis of
pernicious anemia. If not present, it is necessary to investigate malabsorption by
performing the Schilling test.

Anemia is classified as mild, moderate, or severe based on the concentrations of

hemoglobin in the blood. Mild anemia corresponds to a level of hemoglobin
concentration of 10.0-10.9 g/dl for pregnant women and children under age 5 and
10.0-11.9 g/dl for nonpregnant women. For all of the tested groups, moderate
anemia corresponds to a level of 7.0-9.9 g/dl, while severe anemia
corresponds to a level less than 7.0 g/dl.

40
Almost every second woman had some degree of anemia. The level of anemia
was severe in about 1 percent of the women, while 8 percent had a moderate level
and 38 percent had mild anemia.
Age was associated with anemia levels, with older women being somewhat more
likely to
be moderately or severely anemic than younger women. The rate of moderate-to-
severe anemia
(moderate and severe anemia combined) among women age 35-49 is almost three
times as high as among women age 15-19. High rates of moderate and severe
anemia were found among women living in the Balkan
andDashoguz regions (15 percent and 12 percent, respectively), while only 6
percent of women inAshgabad City were diagnosed as having moderate or severe
anemia.
Women with a higher education are less frequently anemic than women with a
primary or secondary-special education. The rates of moderate and severe anemia
are higher among ethnic Turkmen and Uzbek women (10 percent each) than
among women of other ethnic groups (7 percent).
There are differentials in the anemia rates by nutritional and reproductive health
characteristics. the prevalence of moderate-to-severe anemia is higher among
women with a body mass index (BMI) less than 18.5 (11 percent) than among
women with a higher BMI (9 percent). The prevalence of moderate-to-severe
anemia among women with two or more births (12 percent) is twice as high as
that among women with fewer than two births or no pregnancies (6 and 5 percent,
respectively). There is a relatively small association between the birth intervals
and the rate of anemia.
Thirty-six percent of the children under the age of five suffer from some degree of
anemia;
16 percent have moderate anemia, and 1 percent are severely anemic.
As was the case with women, there are substantial differences in the anemia rates
among
children by residence, region, level of mother’s education, and ethnicity. The
prevalence of

41
moderate-to-severe anemia among children living in urban areas is higher than
among children
living in rural areas (18 and 15 percent, respectively). As with the women, the rate
of moderate-tosevereanemia is highest among children living in Balkan and
Dashoguz regions (24 and 25 percent, respectively). Prevalence of moderate-to-
severe anemia is relatively low among children living in Mary and Akhal regions:
7 and 10 percent, respectively. As in Ashgabad City, in Mary and Akhalregions,
no cases of severe anemia were diagnosed among children. Intermediate levels of
moderate-to-severe anemia were found among children in Ashgabad City and
LebapRegion: 19 and 20 percent, respectively.
The rate of moderate-to-severe anemia among Turkmen children (16 percent) is
relatively lower than among children of Uzbek and other ethnicities (20 and 19
percent, respectively).
Considering differentials by child’s nutritional status, the greatest variation in
moderate-tosevere
anemia is observed for height-for-age (stunting) and weight-for-age. The rate of
moderate-tosevereanemia among children with height-for-age below -2 SD was
23 percent, compared with15 percent among children with height-for-age -2 SD or
above. The moderate-to-severe anemia rateamong children with weight-for-age
below -2 SD was 26 percent, compared with 15 percent among the children with
weight-for-age -2 SD or above.

3. normochromic normocytic anemia and normochromic macrocytic anemia

In the morphologic classification of anemia, micro-or macro erythrocytes size and

chromic to show color. Already known for three major categories.

a. First, normochromic normocytic anemia, erythrocytes has a normal size

and shape and contain jtxmlah normal hemoglobin (mean corpuscular
volume [MCV] and mean corpuscular hemoglobin concentration [MCHC]
normal or low normal). The causes of this type of anemia is acute blood
loss, hemolysis, chronic diseases include infections, endocrine disorders,

42
 kidney disorders, bone marrow failure, and metastatic infiltrative diseases
of the bone marrow.
Normokrom normocytic anemia may occur due to :
a. hemolytic
b. Post-acute hemorrhage
c. aplastic anemia
d. myelodysplasia syndrome
e. alcoholism
f. anemia in chronic liver disease
The pathophysiology of anemia occurs because of blood loss / destruction
of excess blood, causing the bone marrow have to work harder in
erythropoiesis. So many young erythrocytes (reticulocytes) are seen in the
peripheral blood picture. If the reticulocyte is not found, then the suspected
aplastic anemia, iron def anemia and b12 are not treated, radiation therapy,
endocrine problems, bone marrow failure, myelodysplasia syndrome, and
alcoholism

b. The second major category is normochromic macrocytic anemia, which

has a larger than normal erythrocytes but normokromik for normal
hemoglobin concentration (MCV increased; MCHC normal). This
situation is caused by the disruption or interruption of the synthesis of
deoxyribonucleic acid (DNA) as found in B deficiency, or folic acid, or
both. Normochromic anemia may also occur due to cancer chemotherapy
agents interfere with DNA synthesis.

DEFINITION

Anemia Due to Vitamin B12 deficiency (pernicious anemia) is a

megaloblastic anemia caused by vitamin B12 deficiency.
In addition to iron, bone marrow requires vitamin B12 and folic acid to
produce red blood cells. If the shortage of one of them, megaloblastic anemia
can occur.

43
 In this type of anemia, the bone marrow produces red blood cells and
abnormal large (megaloblas). White blood cells and platelets are also usually
abnormal.
Megaloblastic anemia is most often caused by a deficiency of vitamin B12 and
folic acid in the diet, or an inability to absorb the vitamin.
Sometimes anemia is caused by certain drugs used to treat cancer (eg,
methotrexate, hydroxyurea, fluorouracil and cytarabine).

CAUSE

Inadequate absorption of vitamin B12 ( cobalamin ) causes pernicious anemia

.Vitamin B12 is widely available in the flesh and in normal circumstances has
been absorbed in the last part of the small intestine leading to the large intestine
(ilium ) .In order to be absorbed , vitamin B12 should be joined with intrinsic
factor ( a protein made in the stomach ) , which then transports it to the ilium
vitamins , penetrate walls and into the bloodstream . Without intrinsic factor ,
vitamin B12 remains in the intestine and excreted through feces .

In pernicious anemia , gastric intrinsic factor can not be formed , so that vitamin
B12 can not be absorbed and there was anemia , although a large number of
vitamins consumed in the daily diet .

But because the liver stores large amounts of vitamin B12 , the anemia usually
does not appear until about 2-4 years after stopping the body absorb vitamin B12 .

In addition due to lack of intrinsic factor , other causes of vitamin B12 deficiency
are :

- abnormal growth of bacteria in the small intestine that prevents the absorption
of vitamin B12

certain diseases ( eg Crohn's disease )

44
 - removal of a portion of the stomach or small intestine where vitamin B12 is
absorbed

vegetarian .

SYMPTOMS

In addition to lessen the formation of red blood cells, vitamin B12 deficiency also
affects the nervous system and causes:

 tingling in hands and feet

 loss of feeling in the legs, feet and hands
 rigid movements.

Other symptoms are:

 certain color blindness, including yellow and blue

 open sores on the tongue or tongue burning
 weight loss
 skin color becomes darker
 dazed
 depression
 decline in intellectual function

4. thalassemia

Thalassaemias are hereditary haemolytic anaemias due to a quantitative disorder

of the globin chain synthesis. Haemoglobin anomalies are genetically
predetermined haemoglobin variants resulting from a disorder of the globin
synthesis. In accordance with the four globin chains, there are four basic types of
thalassaemia: alpha, beta, gamma and delta thalassaemia. In particular the alpha
and beta thalassaemias are

clinically significant because the affected alpha and beta globin chains are the
main components of normal haemoglobin in adults.

45
The clinical picture is characterised by a chronic haemolytic anaemia whose
severity depends on the genetic situation. As a rule, one normal gene and one
thalassaemia gene (= heterozygous) will mostly result in a mild form of the
disease (thalassaemia minor, thalassaemia minima). Two identical or similar
thalassaemia genes (= homo-zygous) lead to a profound disorder of haemoglobin
synthesis and, correspondingly,

a severe clinical picture.

The substitute, immature and defective haemoglobins are not sufficient to

compensate for the lack of haemoglobin and, moreover, will cause a premature
death of the blood corpuscles. Instead of their normal life span of about 120 days,
the blood corpuscles only have a life span of 30 to 40 days. Iron will be released
in this process and is partly deposited in internal organs and the skin, which
severely damages them. In addition, the bone marrow will extend into all
available marrow spaces, which has considerable effects on the form and structure
of the bones. Facial bones, legs, as well as arms are particularly affected by the
deformations which are extremely distressing for the patients. Liver and spleen
will enlarge until they fill up the entire abdominal

Alpha thalassemia

In the homozygous form of alpha thalassaemia, the α-chain cannot be formed.

Either a tetramer of γ-chains is formed (Hb Barts, not viable), or a tetramer of β-
chains (Hb H, viable). With the last named, no ineffective erythropoiesis is
observed but increased haemolysis due to damage of the red blood cell membrane.

Diagnosis is confirmed by the presence of Hb H-containing red blood cells.

These are identified via the detection of β-tetramers inside the cells in the form of
inclusion corpuscles after supravital staining with brilliant cresyl blue. Today, this
diagnosis is validated molecular-genetically. Heterozygous forms present a mild
clinical course of the disease.

Alpha thalassemia is a condition caused by having fewer alpha globin genes than
normal.

46
Normally, people have 4 genes for alpha globin. People with alpha thalassemia
can be missing one (1), 2, 3, or 4 alpha globin genes.

1. People missing one (1) alpha globin gene (αα/α-) are called silent carriers of
alpha thalassemia. This means they can pass on the condition of having one (1)
gene missing. However, being without a gene does not affect their health or the
way they feel.

• A silent carrier does not have any symptoms.

• If you are a silent carrier, you do not have hemoglobin H disease and cannot
develop it later in life.

2. People with 2 missing alpha globin genes (α/-- or α α -/ α -) have alpha

thalassemia trait.

• This normally does not cause health problems but can cause low red blood cell
levels (anemia) and

small red blood cells.

• If you have alpha thalassemia trait, you do not have hemoglobin H disease and
cannot develop it later

in life.

3. People with 3 missing genes have hemoglobin H disease (-/α --).

• This disease causes health problems. People with this disease need a doctor’s
treatment.

There are 2 types of alpha thalassemia trait.

1. People with the fi rst type of alpha thalassemia trait have one (1) alpha globin
gene missing on each chromosome

(α- α /-). This is called the trans form of alpha thalassemia trait.

• The trans form of alpha thalassemia trait (α -/ α -) is common in African-

Americans (20–30 percent)

47
and people of African descent.

2. People with the second type of alpha thalassemia trait have 2 missing alpha
globin genes on the same

chromosome (α α /--). This is called the cis form of alpha thalassemia trait.

The trans and cis types of alpha thalassemia trait are found most often in people
whose ancestors come from

Southeast Asia, Southern China, the Mediterranean, and the Middle East.

People with alpha thalassemia trait do not develop hemoglobin H disease or

hydrops fetalis later in life.

Beta thalassemia

Beta-thalassemia syndromes are a group of hereditary blood disorders

characterized by reduced or absent beta globin chain synthesis, resulting in
reduced Hb in red blood cells (RBC), decreased RBC production and anemia.

Most thalassemias are inherited as recessive traits. Beta-thalassemias can be

classified into:

- Beta-thalassemia

• Thalassemia major

•Thalassemia intermedia

•Thalassemia minor

- Beta-thalassemia with associated Hb anomalies

• HbC/Beta-thalassemia

• HbE/Beta-thalassemia

• HbS/Beta-thalassemia (clinical condition more similar

to sickle cell disease than to thalassemia major or

48
intermedia)

- Hereditary persistence of fetal Hb and beta-thalassemia

- Autosomal dominant forms

- Beta-thalassemia associated with other manifestations

• Beta-thalassemia-tricothiodystrophy

• X-linked thrombocytopenia with thalassemia

Beta-thalassemia major

Clinical presentation of thalassemia major occurs between 6 and 24 months.

Affected infants fail to thrive and become progressively pale. Feeding problems,
diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the
abdomen caused by spleen and liver enlargement may occur. In some developing
countries, where due to the lack of resources patients are untreated or poorly
transfused, the clinical picture of thalassemia major is characterized by growth
retardation, pallor, jaundice, poor musculature, genu valgum,
hepatosplenomegaly, leg ulcers, development of masses from extramedullary
hematopoiesis, and skeletal changes resulting from expansion of the bone marrow.
Skeletal changes include deformities in the long bones of the legs and typical
craniofacial changes (bossing of the skull, prominent malar eminence, depression
of the bridge of

the nose, tendency to a mongoloid slant of the eye, and hypertrophy of the
maxillae, which tends to expose the upper teeth).

If a regular transfusion program that maintains a minimumHb concentration of 9.5

to 10.5 g/dL is initiated, growth and development tends to be normal up to 10 to12
years.

Beta-thalassemia intermedia

49
Individuals with thalassemia intermedia present later than thalassemia major, have
milder anemia and by definition do not require or only occasionally require
transfusion.

At the severe end of the clinical spectrum, patients present between the ages of 2
and 6 years and although they are capable of surviving without regular blood
transfusion, growth and development are retarded. At the other end of the
spectrum are patients who are completely

asymptomatic until adult life with only mild anemia. Hypertrophy of erythroid
marrow with the possibility of extramedullary erythropoiesis, a compensatory
mechanism of bone marrow to overcome chronic anemia, is common. Its
consequences are characteristic deformities of the bone and face, osteoporosis
with pathologic fractures of long bones and formation of erythropoietic masses
that primarily affect the spleen, liver, lymph nodes, chest and spine. Enlargement
of the spleen is also a consequence of its major role in clearing damaged red cells
from the bloodstream. Extramedullary erythropoiesis may cause neurological
problems such as spinal cord compression with paraplegia and intrathoracic
masses. As a result of ineffective erythropoiesis and peripheral hemolysis,
thalassemia intermedia patients may develop gallstones, which occur more
commonly than in thalassemia major.

Beta-thalassemia minor

Carriers of thalassemia minor are usually clinically asymptomatic but sometimes

have a mild anemia. When both parents are carriers there is a 25% risk at each
pregnancy of having children with homozygous thalassemia

5. Pathofisiology

Iron-deficiency anemia is the condition in which there is anemia and clear

evidence of iron lack. The progression to iron deficiency can be divided into three
stages . The first stage is negative iron balance, in which the demands for (or
losses of) iron exceed the body's ability to absorb iron from the diet. This stage
results from a number of physiologic mechanisms, including blood loss,

50
pregnancy (in which the demands for red cell production by the fetus outstrip the
mother's ability to provide iron), rapid growth spurts in the adolescent, or
inadequate dietary iron intake. Blood loss in excess of 10–20 mL of red cells per
day is greater than the amount of iron that the gut can absorb from a normal diet.
Under these circumstances the iron deficit must be made up by mobilization of
iron from RE storage sites. During this period, iron stores—reflected by the serum
ferritin level or the appearance of stainable iron on bone marrow aspirations—
decrease. As long as iron stores are present and can be mobilized, the serum iron,
total iron-binding capacity (TIBC), and red cell protoporphyrin levels remain
within normal limits. At this stage, red cell morphology and indices are normal.

When iron stores become depleted, the serum iron begins to fall. Gradually, the
TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron
stores are absent when the serum ferritin level is <15 𝜇g/L. As long as the serum
iron remains within the normal range, hemoglobin synthesis is unaffected despite
the dwindling iron stores. Once the transferrin saturation falls to 15–20%,
hemoglobin synthesis becomes impaired. This is a period of iron-deficient
erythropoiesis . Careful evaluation of the peripheral blood smear reveals the first
appearance of microcytic cells, and if the laboratory technology is available, one
finds hypochromic reticulocytes in circulation. Gradually, the hemoglobin and
hematocrit begin to fall, reflecting iron-deficiency anemia. The transferrin
saturation at this point is 10–15%.

51
 REFERENCE

1. Anthony S. Fauci, 2008. Harrison’s Internal Medicine, 17th Edition, USA,

McGraw – Hill
2. Hoffbrand, A.V. 2006. Essensial Haematology, 5th Ed. United Kingdom :
Blackwell Publishing Ltd.
3. Hoffman, R. 2009. Hematology : Basic Principles and Practices, 5th Ed.
Philadelphia : Elsevier Inc.
4. Williams. Hematology, 7th Ed. McCraw-Hill Medical

52