1

MINISTRY OF HEALTH OF UKRAINE

The Odessa State Medical University

METHODIC FORMULATION OF LECTURES

In internal medicine
For students of the 4th course of the medical faculty

MODULE 1 “Internal medicine”

Informative module #2 “Basis of diagnostics, treatment and prophylaxis of
principle diseases of circulatory system”

Lecture #___ “Anemia”

The lecture was discussed on methodic session

of the department on____________,
Report of proceedings № ____
Head of the department – Doctor of Medicine, Karpenko Yu. I.

Odessa
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Topic of the lecture: “Iron deficiency anemia” (IDA) – 2 hours

I. Actuality of this topic. Under the data of CART 700-800 million of people
suffer from iron deficiency anemia (IDA). The IDA is recorded for 30% of all
women and for half of children in early age. The concentration of hemoglobin (Hb)
for men is less 130 g\l and for women is less 120 g\l being ill with anemia.

II. The aims of the lecture.

A. Educational aims:
1. spread among population in Ukraine and other countries
2. etiology and pathogenesis of IDA
3. to know clinical manifestations of IDA
4. laboratory methods of diagnostics in patients with IDA
5. to know medical treatment of patients with IDA

B. Pedagogic aims:
1. to form deontological conceptualization when working at patients with
AMI
2. to develop sense of one’s responsibility for timeliness and accuracy of
professional activity on the basis of examined topic
3. to form ideas about the basis of psychotherapeutic treatment of patients
4. to form ideas about medical ethics

III. Plan and organization structure of the lecture.

№ Main stages of the lecture, Aims. Type of the Time.

their content. lecture.
Equipment.
Preparation stage.
1. Definition of educational Multimedia 3%
aims. presentation
2. Ensure success in 2%
motivation.
3. The main stage. 90%
Presentation of the
lecture.
Plan.
1. Spread and
epidemiology of IDA II
2. Exchange
Ferri lactase in the II
organism II
3. Etiology of II
IDA
4. Pathogenesis II
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IDA
5. Clinical II
developments
of IDA II
6. A complex of II
examination at
4. IDA
5. 7. Differential
6. diagnostics List with main
8. Treatment of and additional
IDA literature.

The final stage.

Sum up.
Lecturer’s answers on
possible questions.
Task for independent
preparation.

1. Perederiy V.G., Tkatch S.M. Fundamentals of internal medicine. Part 2. –

Vinnitsa, Novaya Kniga, 2009.

Questions:
1. Give definition of IDA
2. Clinical manifestations of IDA
3. Laboratory diagnostics of IDA
4. Principles and methods of IDA treatment and prophylaxis.

IV. Topic

Anemia is a decrease in normal number of red blood cells (RBCs) or less

than the normal quantity of hemoglobin in the blood. However, it can include
decreased oxygen-binding ability of each hemoglobin molecule due to deformity
or lack in numerical development as in some other types of hemoglobin deficiency.
Because hemoglobin (found inside RBCs) normally carries oxygen from the lungs
to the tissues, anemia leads to hypoxia (lack of oxygen) in organs. Because all
human cells depend on oxygen for survival, varying degrees of anemia can have a
wide range of clinical consequences.
Anemia is the most common disorder of the blood. There are several kinds
of anemia, produced by a variety of underlying causes. Anemia can be classified in
a variety of ways, based on the morphology of RBCs, underlying etiologic
mechanisms, and discernible clinical spectra, to mention a few. The three main
classes of anemia include excessive blood loss (acutely such as a hemorrhage or
chronically through low-volume loss), excessive blood cell destruction (hemolysis)
or deficient red blood cell production (ineffective hematopoiesis).
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There are two major approaches: the "kinetic" approach which involves
evaluating production, destruction and loss, and the "morphologic" approach which
groups anemia by red blood cell size. The morphologic approach uses a quickly
available and cheap lab test as its starting point (the MCV). On the other hand,
focusing early on the question of production may allow the clinician more rapidly
to expose cases where multiple causes of anemia coexist.
Microcytic anemia
Microcytic anemia is primarily a result of hemoglobin synthesis
failure/insufficiency, which could be caused by several etiologies:
- Heme synthesis defect
-- Iron deficiency anemia
-- Anemia of chronic disease (more commonly presenting as
normocytic anemia)
Globin synthesis defect
-- alpha-, and beta-thalassemia
-- HbE syndrome
-- HbC syndrome
-- and various other unstable hemoglobin diseases
Sideroblastic defect
-- Hereditary sideroblastic anemia
-- Acquired sideroblastic anemia, including lead toxicity
-- Reversible sideroblastic anemia

Macrocytic anemia
- Megaloblastic anemia, the most common cause of macrocytic anemia, is
due to a deficiency of either vitamin B12, folic acid (or both). Deficiency in folate
and/or vitamin B12 can be due either to inadequate intake or insufficient
absorption. Folate deficiency normally does not produce neurological symptoms,
while B12 deficiency does.
-- Pernicious anemia is caused by a lack of intrinsic factor. Intrinsic
factor is required to absorb vitamin B12 from food. A lack of intrinsic factor
may arise from an autoimmune condition targeting the parietal cells
(atrophic gastritis) that produce intrinsic factor or against intrinsic factor
itself. These lead to poor absorption of vitamin B12.
-- Macrocytic anemia can also be caused by removal of the functional
portion of the stomach, such as during gastric bypass surgery, leading to
reduced vitamin B12/folate absorption. Therefore one must always be aware
of anemia following this procedure.
- Hypothyroidism
- Alcoholism commonly causes a macrocytosis, although not specifically
anemia. Other types of Liver Disease can also cause macrocytosis.
- Methotrexate, zidovudine, and other drugs that inhibit DNA replication.

Normocytic anemia
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Normocytic anemia occurs when the overall hemoglobin levels are always
decreased, but the red blood cell size (Mean corpuscular volume) remains normal.
Causes include:
- Acute blood loss
- Anemia of chronic disease
- Aplastic anemia (bone marrow failure)
- Hemolytic anemia
Iron deficiency anemia
Iron deficiency anemia is a common type of anemia, and is known as
sideropenic anemia. It is the most common cause of microcytic anemia.
Iron deficiency anemia occurs when the dietary intake or absorption of iron
is insufficient, and hemoglobin, which contains iron, cannot be formed. In the
United States, 20% of all women of childbearing age have iron deficiency anemia,
compared with only 2% of adult men.[citation needed] The principal cause of iron
deficiency anemia in premenopausal women is blood lost during menses. Iron
deficiency anemia can be caused by parasitic infections, such as hookworms.
Intestinal bleeding caused by hookworms can lead to fecal blood loss and
heme/iron deficiency. Chronic inflammation caused by parasitic infections
contributes to anemia during pregnancy in most developing countries.
Iron deficiency anemia is an advanced stage of iron deficiency. When the
body has sufficient iron to meet its needs (functional iron), the remainder is stored
for later use in the bone marrow, liver, and spleen as part of a finely tuned system
of human iron metabolism. Iron deficiency ranges from iron depletion, which
yields little physiological damage, to iron deficiency anemia, which can affect the
function of numerous organ systems. Iron depletion causes the amount of stored
iron to be reduced, but has no effect on the functional iron. However, a person with
no stored iron has no reserves to use if the body requires more iron. In essence, the
amount of iron absorbed and stored by the body is not adequate for growth and
development or to replace the amount lost.
Symptoms and Signs
Iron deficiency anemia is characterized by pallor (reduced amount of
oxyhemoglobin in skin or mucous membrane), fatigue and weakness. Because it
tends to develop slowly, adaptation occurs and the disease often goes unrecognized
for some time. In severe cases, dyspnea (trouble breathing) can occur. Unusual
obsessive food cravings, known as pica, may develop. Pagophagia or pica for ice is
a very specific symptom and may disappear with correction of iron deficiency
anemia. Hair loss and lightheadedness can also be associated with iron deficiency
anemia..
Other symptoms and signs of iron deficiency anemia include: constipation,
sleepiness, tinnitus, palpitations, hair loss, fainting or feeling faint, depression
breathlessness on exertion, twitching muscles, tingling, numbness, or burning
sensations, missed menstrual cycle, heavy menstrual period, slow social
development, glossitis (inflammation or infection of the tongue), angular cheilitis
(inflammatory lesions at the mouth's corners), koilonychia (spoon-shaped nails) or
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nails that are weak or brittle, poor appetite, pruritus (itchiness), dysphagia due to
formation of esophageal webs (Plummer-vinson syndrome), angular stomatitis
Infant development
Iron deficiency anemia for infants in their earlier stages of development may
have significantly greater consequences than it does for adults. An animal made
severely iron deficient during its earlier life cannot recover to normal iron levels
even with iron therapy. In contrast, iron deficiency during later stages of
development can be compensated with sufficient iron supplements. Iron deficiency
anemia affects neurological development by decreasing learning ability, altering
motor functions, and permanently reducing the number of dopamine receptors and
serotonin levels. Iron deficiency during development can lead to reduced
myelination of the spinal cord, as well as a change in myelin composition.
Additionally, iron deficiency anemia has a negative effect on physical growth.
Growth hormone secretion is related to serum transferrin levels, suggesting a
positive correlation between iron-transferrin levels and an increase in height and
weight.
Cause
The diagnosis of iron deficiency anemia requires further investigation as to
its cause. It can be a sign of other disease, such as colon cancer, which will cause
the loss of blood in the stool. In adults, 60% of patients with iron deficiency
anemia may have underlying gastrointestinal disorders leading to chronic blood
loss. In addition to dietary insufficiency, malabsorption, chronic blood loss,
diversion of iron to fetal erythropoiesis during pregnancy, intravascular hemolysis
and hemoglobinuria or other forms of chronic blood loss should all be considered.
Diagnosis
Anemia may be diagnosed from symptoms and signs, but when anemia is
mild it may not be diagnosed from mild non-specific symptoms. Anemia is often
first shown by routine blood tests, which generally include a complete blood count
(CBC). A sufficiently low hemoglobin (HGB) or hematocrit (HCT) value is
characteristic of anemia, and further studies will be undertaken to determine its
cause and the exact diagnosis. One of the first abnormal values to be noted on a
CBC will be a high red blood cell distribution width (RDW), reflecting a varied
size distribution of red blood cells (RBCs). A low MCV, MCH or MCHC, and the
appearance of the RBCs on visual examination of a peripheral blood smear will
narrow the diagnosis to a microcytic anemia. The blood smear of a patient with
iron deficiency shows many hypochromatic and rather small RBCs, and may also
show poikilocytosis (variation in shape) and anisocytosis (variation in size). With
more severe iron deficiency anemia the peripheral blood smear may show target
cells, hypochromic pencil-shaped cells, and occasionally small numbers of
nucleated red blood cells. Microcytic anemia can also be the result of
malabsorption phenomena associated with coeliac disease.
The diagnosis of iron deficiency anemia will be suggested by appropriate
history (e.g., anemia in a menstruating woman), and by such diagnostic tests as a
low serum ferritin, a low serum iron level, an elevated serum transferrin and a high
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total iron binding capacity (TIBC). Serum ferritin is the most sensitive lab test for
iron deficiency anemia.
Iron deficient anemia and thalassemia minor present with many of the same
lab results. It is very important not to treat a patient with thalassemia with an iron
supplement as this can lead to hemochromatosis (accumulation of iron in various
organs especially liver). A hemoglobin electrophoresis would provide useful
evidence in distinguishing these two conditions, along with iron studies.
Gold standard
Traditionally, a definitive diagnosis requires a demonstration of depleted
body iron stores by performing a bone marrow aspiration, with the marrow stained
for iron. Because this is invasive and painful, while a clinical trial of iron
supplementation is inexpensive and non-traumatic, patients are often treated based
on clinical history and serum ferritin levels without a bone marrow biopsy.
Furthermore, a study published April 2009 questions the value of stainable bone
marrow iron following parenteral iron therapy.
Treatment
If the cause is dietary iron deficiency, iron supplements, usually with iron
(II) sulfate, ferrous gluconate, or iron amino acid chelate ferrous bisglycinate,
synthetic chelate NaFerredetate, EDTA will usually correct the anemia.
Recent research suggests the replacement dose of iron, at least in the elderly
with iron deficiency, may be as little as 15 mg per day of elemental iron. An
experiment done in a group of 130 anemia patients showed a 98% increase in iron
count when using an iron supplement with an average of 100 mg of iron. Women
who develop iron deficiency anemia in mid-pregnancy can be effectively treated
with low doses of iron (20–40 mg per day). The lower dose is effective and
produces fewer gastrointestinal complaints.
Many tests have shown that iron supplementation can lead to an increase in
infectious disease morbidity in areas where bacterial infections are common. For
example, children receiving iron-enriched foods have demonstrated an increased
rate in diarrhea overall and enteropathogen shedding. Iron deficiency protects
against infection by creating an unfavorable environment for bacterial growth.
Nevertheless, while iron deficiency might lessen infections by certain pathogenic
diseases, it also leads to a reduction in resistance to other strains of viral or
bacterial infections, such as Salmonella typhimurium or Entamoeba histolytica.
Overall, it may be concluded that iron supplementation can be both beneficial and
harmful to an individual in an environment that is prone to many infectious
diseases.
There can be a great difference between iron intake and iron absorption, also
known as bioavailability. Scientific studies indicate iron absorption problems when
iron is taken in conjunction with milk, tea, coffee and other substances. There are
already a number of proven solutions for this problem, including:
Fortification with ascorbic acid, which increases bioavailability in both
presence and absence of inhibiting substances, but which is subject to deterioration
from moisture or heat. Ascorbic acid fortification is usually limited to sealed dried
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foods, but individuals can easily take ascorbic acid with basic iron supplement for
the same benefits.
Microencapsulation with lecithin, which binds and protects the iron particles
from the action of inhibiting substances. The primary benefit over ascorbic acid is
durability and shelf life, particularly for products like milk which undergo heat
treatment.
Using an iron amino acid chelate, such as NaFeEDTA, which similarly binds
and protects the iron particles. A study performed by the Hematology Unit of the
University of Chile indicates that chelated iron (ferrous bis-glycine chelate) can
work with ascorbic acid to achieve even higher absorption levels
Separating intake of iron and inhibiting substances by a couple of hours.
Using goats' milk instead of cows' milk.
Gluten-free diet resolves some instances of iron-deficiency anemia, especially if
the anemia is a result of celiac disease.
It is believed that "heme iron”, found only in animal foods such as meat, fish
and poultry, is more easily absorbed than "non-heme" iron, found in plant foods
and supplements.
Iron bioavailability comparisons require stringent controls, because the
largest factor affecting bioavailability is the subject's existing iron levels. Informal
studies on bioavailability usually do not take this factor into account, so
exaggerated claims from health supplement companies based on this sort of
evidence should be ignored. Scientific studies are still in progress to determine
which approaches yield the best results and the lowest costs.
If anemia does not respond to oral treatments, it may be necessary to
administer iron parenterally (e.g., as iron dextran) using a drip or hemodialysis.
Parenteral iron involves risks of fever, chills, backache, myalgia, dizziness,
syncope, rash and anaphylactic shock. A follow up blood test is essential to
demonstrate whether the treatment has been effective.
Iron supplements should be kept out of the reach of children, as iron-
containing supplements are a frequent cause of poisoning in children.

Pernicious anemia
Pernicious anemia (or pernicious anemia - also known as Biermer's anemia,
Addison's anemia, or Addison–Biermer anemia) is a form of megaloblastic anemia.
Usually seated in an atrophic gastritis, the autoimmune destruction of gastric
parietal cells leads to a lack of intrinsic factor, and since the absorption from the
gut of vitamin B12,[2] is dependent on intrinsic factor this leads to vitamin B12
deficiency, one of the many causes of megaloblastic anemia.
While the term 'pernicious anemia' is sometimes also incorrectly used to
indicate megaloblastic anemia due to any cause of vitamin B12 deficiency, its
proper usage refers to that caused by atrophic gastritis and parietal cell loss only.
The loss of ability to absorb vitamin B12 is the most common cause of adult
vitamin B12 deficiency.
Pernicious anemia (PA) was generally detected only after it became clinical
and the anemia was well-established, i.e. liver stores of B12 had been depleted; the
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"pernicious" aspects of this once uniformly fatal type of anemia are peripheral
nerve damage and - prior to treatment options - death. However, modern tests
which specifically target B12 absorption can be used to diagnose the disease before
it becomes clinically apparent. Replacement of vitamin stores does not correct the
defect in absorption which technically defines the disease. A person who has
pernicious anemia (inability to absorb vitamin B12 normally) will have it for the
remainder of his or her life.
Unless the patient has sustained permanent peripheral nerve damage, regular B12
replacement will keep the disease in check, with no further damage.
Signs and symptoms
Pernicious anemia presents insidiously. While it may consist of the triad of
paraesthesias, sore tongue and weakness, this is not the chief symptom complex.
The patient may complain of weight loss due to anorexia, low-grade fevers, nausea
and gastrointestinal symptoms, as well as unsteady gait, weakness and clumsiness.
Because PA affects the spinal cord, the patient may also complain of impaired
micturition. Tachycardia and murmurs may be present, along with a waxy pallor.
In severe cases, the patient may complain of heartburn and evidence of congestive
heart failure.
Long term complications may include gastric cancer and carcinoids.
Many signs and symptoms are attributed to anemia:
- Fatigue, low blood pressure, rapid heart rate, pallor, and shortness of breath
(known as 'the sighs')
- Difficulty in proprioception
- Mild cognitive impairment, colloquially referred to as brain fog
- Neuropathic pain
- Frequent diarrhea
- Paresthesias, such as pins and needles sensations or numbness in fingers or
toes, due to B12 deficiency affecting nerve function
- Jaundice due to impaired formation of blood cells
- Glossitis (swollen red tongue) due to B12 deficiency
- May present with hyperthyroidism or hypothyroidism
- Personality or memory changes.
A complication of severe chronic PA is subacute combined degeneration of spinal
cord, which leads to distal sensory loss (posterior column), absent ankle reflex,
increased knee reflex response, and extensor plantar response.
Causes
Most commonly (in temperate climates), the cause for impaired binding of
vitamin B12 by intrinsic factor is autoimmune atrophic gastritis,[6] in which
autoantibodies are directed against parietal cells (resulting in their loss), as well as
against the intrinsic factor itself (rendering it unable to bind vitamin B12).
Less frequently, loss of parietal cells may simply be part of a widespread
atrophic gastritis of nonautoimmune origin, such as that frequently occurring in
elderly people affected with long-standing chronic gastritis of any cause (including
Helicobacter pylori infection).
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Forms of vitamin B12 deficiency other than pernicious anemia must be
considered in the differential diagnosis of megaloblastic anemia. For example, a
B12 deficient state which causes megaloblastic anemia and which may be
mistaken for classical pernicious anemia, may be caused by infection with the
tapeworm Diphyllobothrium latum, possibly due to the parasite's competition for
vitamin B12.
A similar disorder involving impaired B12 absorption can also occur
following gastric removal (gastrectomy) or gastric bypass surgery, especially the
Roux-en-Y bypass. In this procedure, the stomach is separated into two sections,
one a very small pouch for holding small amounts of food, and the other, the
remainder of the stomach, which is resultingly nonfunctional. Therefore, the
mucosal cells are no longer available, nor is the required intrinsic factor. This
results in inadequate GI absorption of B12, and may result in a syndrome
indistinguishable from pernicious anemia. Gastric bypass or gastrectomy patients
must take B12 as in treatment of pernicious anemia: either oral megadoses, or B12
by injection.
Pathophysiology
Vitamin B12 cannot be produced by the human body, and must be obtained
from the diet. Normally, dietary vitamin B12 is absorbed by the body in the small
bowel only when it is bound by the intrinsic factor (IF) produced by parietal cells
of the gastric mucosa. Pernicious anemia is thought to occur when the body's
immune system mistakenly targets the intrinsic factor, with a loss of parietal cells.
Insufficient IF results in insufficient absorption of the vitamin. Although the
normal body stores three to five years' worth of vitamin B12 in the liver, the
usually undetected autoimmune activity in one's gut over a prolonged period of
time leads to vitamin B12 depletion and the resulting anemia. Inhibition of DNA
synthesis in red blood cells results in the formation of large, fragile megaloblastic
erythrocytes.
Diagnosis
The insidious nature of the disease, and the fact that there is no single
definitive test for pernicious anemia, may mean that a diagnosis is delayed.
Pernicious anemia is suspected when the patient's blood smear shows large, fragile,
immature erythrocytes (megaloblasts). The Schilling test is no longer widely
available, and the other main diagnostic signpost of low levels of serum B12
cannot be relied upon, as sufferers can have high levels of serum B12 and still have
pernicious anemia. Blood and urine tests for methylmalonic acid may indicate a
B12 deficiency, even though serum B12 is within the normally-acceptable range.
Serum B12 is not necessarily an indicator of efficient use by the body, in the
muscles, for example.
A diagnosis of pernicious anemia first requires demonstration of
megaloblastic anemia (through a full blood count) which evaluates the mean
corpuscular volume (MCV), as well the mean corpuscular hemoglobin
concentration (MCHC). Pernicious anemia is identified with a high MCV and a
normal MCHC (that is, it is a macrocytic, normochromic anemia).[10] Ovalocytes
are also typically seen on the blood smear, and a pathognomonic feature of
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megaloblastic anemias (which include pernicious anemia and others) is
hypersegmented neutrophils.
Pernicious anemia can also be diagnosed by evaluating its direct cause,
vitamin B12 deficiency, by measuring B12 levels in serum. A Schilling test can
then be used to distinguish pernicious anemia from other causes of vitamin B12
deficiency (notably malabsorption).
The diagnosis of atrophic gastritis Type A should be confirmed by
gastroscopy and stepwise biopsy. Approximately 90% of individuals with PA have
antibodies for parietal cells; however, only 50% of all individuals in the general
population with these antibodies have pernicious anemia.
Treatment
The treatment of pernicious anemia varies from country to country and from
area to area. There is no permanent cure for pernicious anemia, although repletion
of vitamin B12 may result in a cessation of anemia-related symptoms. Repletion of
B12 can be accomplished in a variety of ways.
The most accessible and inexpensive method of repletion is through dietary
supplementation, in the form of oral or sublingual B12 tablets. B12 supplements
are widely available at supermarkets, health food stores, and drug stores, though
quality and cost may vary. In some countries, the cobalamin preparation may be
available only via prescription. Doctors can prescribe cobalamin tablets that
contain doses higher than what is commercially available.
It is reported[who?] that many patients die within 7 days of no treatment
while in a severe symptomatic state[citation needed].
A 2003 study found that oral and sublingual B12 were absorbed equally
well, but the study's subjects were not noted to be suffering from pernicious
anemia. Some patients may need treatment with sublingual (under the tongue)
cyanocobalamin or methylcobalamin tablets, which allows B12 to be absorbed via
the mucous membranes in the mouth. This may be the preferred method of B12
repletion due to the fact that it bypasses the gastrointestinal tract. When oral tablets
are used to treat PA, higher-than-normal doses may be needed. The efficacy of
using high dose B12 tablets to treat ordinary PA (i.e. anemia due to atrophic
gastritis) is well established. Oral supplementation allows B12 to be absorbed in
places other than the terminal ileum (where B12 absorption usually takes place). A
2006 study found that oral B12 repletion has the potential to be as effective as
injections.
However, if oral and sublingual repletion of B12 is inadequate, the patient
may require B12 injections,which are usually given once a month, bypassing the
need for gastrointestinal absorption altogether. Eventually, the patient may be able
to do this at home. Cobalamin (one of the forms of B12) is usually injected into the
patient's muscle (intramuscular or IM) using cyanocobalamin (the United States,
Canada and most European countries) or hydroxocobalamin (Australia and the
U.K.). The injections will typically need to be given for the remainder of the
patient's life. The frequency of injections varies by country and health care
practitioner, and may be as infrequent as once every three months in some
countries. The most common complaint by members of the Pernicious Anaemia
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Society is that patients have different needs, with some patients needing more
frequent injections than others. Some medical professionals[who?] believe that
subcutaneous injections are more effective than intramuscular injections,[citation
needed] but the evidence for this is currently unclear.
There are other methods of administering B12, including nasal sprays and
behind-the-ear patches. One small study from 1997, with six participants,[19]
found that intranasal delivery of B12 led to increases in plasma cobalamin as high
as eight times a given patient's baseline measurement. Further investigation of
these delivery methods is needed.

Hemolytic anemia
Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of
red blood cells (RBCs) either in the blood vessels (intravascular hemolysis) or
elsewhere in the body (extravascular). It has numerous possible causes, ranging
from relatively harmless to life-threatening. The general classification of hemolytic
anemia is either inherited or acquired. Treatment depends on the cause and nature
of the breakdown.
Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue
and shortness of breath), but in addition the breakdown of red cells leads to
jaundice and increases the risk of particular long-term complications such as
gallstones and pulmonary hypertension.
Basic features
- Abnormal and accelerated destruction of red cells and in some anemias,
their precursors.
- Increased breakdown of hemoglobin which may result in:
-- increased bilirubin level (mainly indirect-reacting) with jaundice.
-- increased fecal and urinary urobilinogen.
-- Hemoglobinanemia, methaemalbuminaemia, hemoglobinuria and
hemosiderinuria (where there is significant intravascular hemolysis).
- Bone marrow compensatory reaction:
-- Erythroid hyperplasia with accelerated production of red cells,
reflected by reticulocytosis and slight macrocytosis in periphral blood.
-- Expansion of bone marrow in infants and children with severe
chronic hemolysis-changes in bone configuration visible on X-ray.
- The balance between red cell destruction and marrow compensation
determines the severity of anemias.
Signs and symptoms
Signs of anemia (pallor, fatigue, shortness of breath, and potentially heart
failure) are generally present. In small children, failure to thrive may occur in any
form of anemia. Certain aspects of the medical history can suggest a cause for
hemolysis, such as drugs, consumption of fava beans, the presence of prosthetic
heart valve, or other medical illness.
Chronic hemolysis leads to an increased excretion of bilirubin into the
biliary tract, which in turn may lead to gallstones. The continuous release of free
hemoglobin has been linked with the development of pulmonary hypertension
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(increased pressure over the pulmonary artery); this in turn leads to episodes of
syncope (fainting) and chest pain, and progressive breathlessness. Pulmonary
hypertension eventually causes right ventricular heart failure, the symptoms of
which are peripheral edema (fluid accumulation in the skin of the legs) and ascites
(fluid accumulation in the abdominal cavity).
Causes
They may be classified according to the means of hemolysis, being either
intrinsic in cases where the cause is related to the RBC itself or extrinsic in cases
where factors external to the RBC dominate. Intrinsic effects may include
problems with RBC proteins or oxidative stress handling while external factors
include immune attack and microvascular angiopathies ( RBC's are mechnically
damaged in circulation).
Hereditary (inherited) hemolytic anemia can be due to:
- Defects in hemoglobin production (as in thalassemia and sickle-cell
disease)
- Defects of red blood cell membrane production (as in hereditary
spherocytosis and hereditary elliptocytosis)
- Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase
deficiency and pyruvate kinase deficiency).
- Acquired hemolytic anemia may be caused by immune-mediated causes,
drugs and other miscellaneous causes.
- Immune-mediated causes could include transient factors as in Mycoplasma
pneumoniae infection (cold agglutinin disease) or permanent factors as in
autoimmune diseases like autoimmune hemolytic anemia (itself more common in
diseases such as systemic lupus erythematosus and chronic lymphocytic leukemia)
- Any of the causes of hypersplenism (increased activity of the spleen) such
as portal hypertension
- Acquired hemolytic anemia is also encountered in burns and certain
infections
Finally, runners can suffer hemolytic anemia due to "footstrike hemolysis", the
venous destruction of red blood cells at foot impact.
Pathophysiology
In a healthy person, a red blood cell survives 90 to 120 days in the
circulation, so about 1% of human red blood cells break down each day. The
spleen (part of the reticulo-endothelial system) is the main organ which removes
old and damaged RBCs from the circulation. In healthy individuals, the breakdown
and removal of RBCs from the circulation is matched by the production of new
RBCs in the bone marrow.
In conditions where the rate of RBC breakdown is increased, the body
initially compensates by producing more RBCs; however, breakdown of RBCs can
exceed the rate that the body can make RBCs, and so anemia can develop.
Bilirubin, a breakdown product of hemoglobin, can accumulate in the blood
causing jaundice, and be excreted in the urine causing the urine to become a dark
brown colour.
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Hemolytic anemia generally occurs as a modification of the RBC lifecycle.
That is, instead of being collected at the end of its useful life and disposed of
normally, the RBC disintegrates in a manner allowing free iron containing
molecules to reach the blood. It is perhaps then helpful to understand the
physiology of the RBC and things that can go wrong to cause it to "die"
prematurely. With their complete lack of mitochondria, RBC's rely on glycolysis
for the materials needed to reduce oxidative damage. Any limitations of glycolysis
can result in more susceptibility to oxidative damage and a short or abnormal
lifecycle. If the cell is unable to signal to the reticuloendothelial phagocytes by
externalizing phosphatidylserine, it is likely to lyse through uncontrolled means.
Dogs and cats differ slightly from humans in some details of their RBC
composition and have altered susceptibility to damage, notably increased
susceptbility to oxidative damage from onion or garlic.
The distinguishing feature of intravascular hemolysis is the release of RBC
contents into the blood stream. The metabolism and elimination of these products,
largely iron containing compounds capable of doing damage through Fenton
reactions, is an important part of the condition. Several reference texts exist on the
elimination pathways, for example. Free hemoglobin can bind to haptoglobin or it
may oxidize and release the heme group which is able to bind to either albumin or
hemopexin. The heme is ultimately converted to bilirubin and removed in stool
and urine. Hemoglobin may be cleared directly by the kidneys resulting in fast
clearance of free hemoglobin but causing the continued loss of hemosiderin loaded
renal tubular cells for many days.
Additional effects of free hemoglobin seem to be due to specific reactions
with NO.
Diagnosis
- Peripheral blood smear microscopy:
-- fragments of the red blood cells ("schistocytes") can be present
-- some red blood cells may appear smaller and rounder than usual
(spherocytes)
-- Reticulocytes are present in elevated numbers. This may be overlooked if
a special stain is not used.
- The level of unconjugated bilirubin in the blood is elevated. This may lead to
jaundice.
- The level of lactate dehydrogenase (LDH) in the blood is elevated
- Haptoglobin levels are decreased
- If the direct Coombs test is positive, hemolysis is caused by an immune process.
- Hemosiderin in the urine indicates chronic intravascular hemolysis. There is also
urobilinogen in the urine.
Treatment
Definitive therapy depends on the cause:
- Symptomatic treatment can be given by blood transfusion, if there is marked
anemia.
- In severe immune-related hemolytic anemia, steroid therapy is sometimes
necessary.
 15
- Sometimes splenectomy can be helpful where extravascular hemolysis is
predominant (ie most of the red blood cells are being removed by the spleen).

Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce
sufficient new cells to replenish blood cells. The condition, per its name, involves
both aplasia and anemia. Typically, anemia refers to low red blood cell counts, but
aplastic anemia patients have lower counts of all three blood cell types: red blood
cells, white blood cells, and platelets, termed pancytopenia.
Signs and symptoms
- Anemia with malaise, pallor and associated symptoms such as palpitations
- Thrombocytopenia (low platelet counts), leading to increased risk of hemorrhage,
bruising and petechiae
- Leukopenia (low white blood cell count), leading to increased risk of infection
- Reticulocytopenia (low reticulocyte counts)
Causes
In many cases, the etiology is considered to be idiopathic (cannot be
determined), but one known cause is an autoimmune disorder in which white blood
cells attack the bone marrow.
Aplastic anemia is also sometimes associated with exposure to toxins such
as benzene, or with the use of certain drugs, including chloramphenicol,
carbamazepine, felbamate, phenytoin, quinine, and phenylbutazone. Many drugs
are associated with aplasia mainly according to case reports but at a very low
probability. As an example, chloramphenicol treatment is followed by aplasia in
less than 1 in 40,000 treatment courses, and carbamazepine aplasia is even more
rare.
Exposure to ionizing radiation from radioactive materials or radiation-
producing devices is also associated with the development of aplastic anemia.
Aplastic anemia is present in up to 2% of patients with acute viral hepatitis.
In some animals aplastic anemia may have other causes. For example, in the
ferret (Mustela putorius furo) aplastic anemia is caused by estrogen toxicity. This
is because female ferrets are induced ovulators, so mating is required to bring the
female out of heat. Intact females, if not mated, will remain in heat, and after some
time the high levels of estrogen will cause the bone marrow to stop producing red
blood cells.
Diagnosis
The condition needs to be differentiated from pure red cell aplasia. In
aplastic anemia the patient has pancytopenia (i.e., anemia, neutropenia and
thrombocytopenia) resulting in decrease of all formed elements. In contrast, pure
red cell aplasia is characterized by reduction in red cells only. The diagnosis can
only be confirmed on bone marrow examination. Before this procedure is
 16
undertaken, a patient will generally have had other blood tests to find diagnostic
clues, including a complete blood count (CBC), renal function and electrolytes,
liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.
Following tests aid in determining differential diagnosis for aplastic anemia:
- Bone marrow aspirate and biopsy: to rule out other causes of pancytopenia (i.e.
neoplastic infiltration or significant myelofibrosis).
- History of iatrogenic exposure to cytotoxic chemotherapy: can cause transient
bone marrow suppression
- X-rays, computed tomography (CT) scans, or ultrasound imaging tests: enlarged
lymph nodes (sign of lymphoma), kidneys and bones in arms and hands (abnormal
in Fanconi anemia)
- Chest X-ray: infections
- Liver tests: liver diseases
- Viral studies: viral infections
- Vitamin B12 and folate levels: vitamin deficiency
- Blood tests for paroxysmal nocturnal hemoglobinuria
- Test for antibodies: immune competency
Treatment
Treating immune-mediated aplastic anemia involves suppression of the
immune system, an effect achieved by daily medicine intake, or, in more severe
cases, a bone marrow transplant, a potential cure. The transplanted bone marrow
replaces the failing bone marrow cells with new ones from a matching donor. The
multipotent stem cells in the bone marrow reconstitute all three blood cell lines,
giving the patient a new immune system, red blood cells, and platelets. However,
besides the risk of graft failure, there is also a risk that the newly created white
blood cells may attack the rest of the body ("graft-versus-host disease").
Medical therapy of aplastic anemia often includes a short course of anti-
thymocyte globulin (ATG) or anti-lymphocyte globulin (ALG) and several months
of treatment with ciclosporin to modulate the immune system. Mild chemotherapy
with agents such as cyclophosphamide and vincristine may also be effective.
Antibody therapy, such as ATG, targets T-cells, which are believed to attack the
bone marrow. Steroids are generally ineffective, though are often used to combat
serum sickness caused by ATG use.
One prospective study involving cyclophosphamide was terminated early
due to a high incidence of mortality, due to severe infections as a result of
prolonged neutropenia.
In the past, before the above treatments became available, patients with low
leukocyte counts were often confined to a sterile room or bubble (to reduce risk of
infections), as in the famed case of Ted DeVita.

V. Materials for the student’s activation during the lecture.

1. What datum of level of HB for men\ women?
2. What is the standard color index of blood in the norm?
3. How much reticulocyts in blood is there in the norm?
4. What functions fulfill the iron in an organism?
 17
5. Where the iron in an organism is deposited?
6. What products contain the most of Ferri lactas?
VI. Common material and methodical equipment.
- auditorium
- tables, schemes, pictures, multimedia
- ECG
VII. Materials for independent preparation of the students.
*) Under this topic: Anemia
a). Literature:
1. Perederiy V.G., Tkatch S.M. Fundamentals of internal medicine. Part 2. –
Vinnitsa, Novaya Kniga, 2009.
b). Questions
1. Give definition of IDA
2. Clinical manifestations of IDA
3. Laboratory diagnostics of IDA
4. Principles and methods of IDA treatment and prophylaxis.

c). Task:
- tests, clinical tasks, ECG, drugs
*) Under the topic of the following lecture: “Leucosis”
a). Literature
1. Perederiy V.G., Tkatch S.M. Fundamentals of internal medicine. Part 2. –
Vinnitsa, Novaya Kniga, 2009.
b). List of basic questions:
1. Tell the schema of hemopoiesis.
2. What is the role in immunity of T-1, B-1 leucocytes?
3. What series of cells do myelocytes, megacariocytes, plasma cells concern
to?

VIII. Literature used by a lecturer while preparating for the lecture:

1. Perederiy V.G., Tkatch S.M. Fundamentals of internal medicine. Part 2. –
Vinnitsa, Novaya Kniga, 2009.
2. Okorokov A.N. Diagnostics of inner organs diseases. – Vitebsk:
Belmedkniga, 1998.
3. Okorokov A.N. Treatment of inner organs diseases. – Vitebsk:
Belmedkniga, 1998.

The lecture was drawn up by Doctor of Medicine, Karpenko Yu. I.