Iron-Deficiency Anaemia (IDA)

Please note that there are separate articles entitled 'Anaemia in Childhood' and 'Anaemia
in Pregnancy' that cover iron deficiency anaemia in these patient groups.

Iron deficiency anaemia (IDA) occurs when the body is iron deficient to the extent that
red blood cell production is reduced.1,2 A state of non-anaemic iron deficiency usually
precedes actual anaemia. Iron deficiency is the most common cause of anaemia
worldwide.

The World Health Organisation defines anaemia as:1

• Hb <13 g/dL in men over 15 years old

• Hb <12 g/dL in non-pregnant women over 15 years old

• Hb <12 g/dL in children aged 12-14 years

Failure to investigate IDA properly by practitioners in primary care can cause significant
delay in final diagnosis with associated morbidity.3 This article is based on the Clinical
Knowledge Summary Guidance on iron deficiency anaemia.4
Epidemiology

• In the developed world, 2-5% of adult men and post-menopausal women have
iron deficiency anaemia.5

• 4-13% of referrals to gastroenterologists are because of iron deficiency anaemia.5

• Pre-menopausal women have a higher incidence of iron deficiency anaemia

because of heavy menstrual blood losses and pregnancy.2
Aetiology
Causes of iron deficiency may be classified as those due to:

Excessive blood loss

• Blood loss from the gastrointestinal tract is the commonest cause of iron
deficiency anaemia in adult men and postmenopausal women.4

• Blood loss due to menorrhagia is the commonest cause of iron deficiency in

premenopausal women.

• In other countries, infestation of the gut may cause IDA, especially with
hookworm and schistosomiasis.

• Common causes of blood loss include:

 • Non steroidal anti-inflammatory drug (NSAID) use

• Χολονιχ χαρχινοµα

• Γαστριχ χαρχινοµα

• Gastric or duodenal ulceration

• Ανγιοδψσπλασια

• Heavy menstruation

• Other causes include:

• Other gastrointestinal tract malignancies

• Βλεεδινγ οεσοπηαγεαλ ϖαριχεσ

• Ινφλαµµατορψ βοωελ δισεασε

• Ηαεµορρηοιδσ

• Οεσοπηαγιτισ and gastro-oesophageal reflux disease

• Ποστ−παρτυµ ηαεµορρηαγε

• Recurrent epistaxis

• Malignancy of the renal tract

• After major surgery of major trauma if replacement has been inadequate

• After blood donation

Dietary inadequacy
• Dietary iron deficiency is fairly uncommon.

• Meat tends to be more rich in iron than vegetables and so vegetarians are at
greater risk. However, green vegetables are a good source of iron and a proper
vegetarian diet should not lead to deficiency.

• Growing children and elderly people with iron-poor diets may become deficient.

Failure of iron absorption

• Not only does the diet have to contain adequate amounts of iron but the iron has
to be in a form that can be absorbed.

• Iron can be absorbed in the ferrous state much more readily than in the ferric
 state.

• Factors affecting iron absorption:

• Some drugs can bind to iron and prevent absorption. Tetracyclines and
quinolones chelate with iron so that neither the antibiotic nor the iron is
absorbed.

• Antacids and proton pump inhibitors may also impair absorption by

raising gastric pH.4

• Phytate (found in wholegrain cereals, nuts, seeds and legumes),

polyphenols (found in tea and coffee) and calcium (in dairy products)
impair iron absorption. Iron absorption can be increased in a diet rich in
fish, red and white meat.6,7

• Vitamin C may enhance iron absorption. Patients can be encouraged to

drink a glass of orange juice with their iron tablets.

• Μαλαβσορπτιον conditions such as coeliac disease (usually

accompanied by folate deficiency).

• May occur after partial or total gastrectomy, more commonly with

increased number of post-operative years.8

• Ηελιχοβαχτερ πψλορι colonisation appears to impair iron uptake and

increase iron loss.

Excessive requirements for iron

• Times of high demand for iron should be met by greater absorption from the diet.

• If the diet is not adequate, an intake that would otherwise be sufficient becomes
inadequate. For example in:

• Times of rapid growth in children

• Pregnancy, especially with twins

• Exfoliative skin disease

Presentation
Iron deficiency anaemia is often an incidental finding rather than a presenting feature.
Chronic, slow blood loss can lead to compensation by the body and little in the way of
symptoms. If symptoms occur, they can include:

• Fatigue
 • Shortness of breath on exertion

• Παλπιτατιονσ

• Sore tongue and taste disturbance

• Changes in the hair/hair loss

• Πρυριτισ

• Ηεαδαχηε

• Τιννιτυσ

• Angina can occur if there is pre-existing coronary heart disease

• Very rarely, there may be dysphagia due to an oesophageal web with chronic iron
deficiency. This is the Paterson-Brown-Kelly or Plummer-Vinson Syndrome and
there is an association with oesophageal carcinoma.
Symptoms of severe anaemia (usually not occurring until Hb is <7 g/dL) include:
shortness of breath at rest, angina and ankle swelling. These symptoms may occur at
higher Hb levels if there is co-existing cardiorespiratory disease).4
History
To look for potential causes, cover the following points:

• Current/recent diet - could account for poor iron intake

• Drug history - NSAIDs, SSRIs, clopidogrel, corticosteroids could be a potential

cause

• Any overt bleeding seen by patient - e.g. nosebleeds, rectal bleeding etc.

• History of recent blood donation

• Menstrual history in women

• History of recent illness - could suggest gastrointestinal bleeding, e.g. weight loss,
change in bowel habit, dyspepsia

• History of previous gastrointestinal disease or surgery

• Travel history - e.g. hookworm infestation is possible if recent travel to the tropics

• Family history - including inherited haematological disorders such as

thalassaemia; bleeding disorders and telangiectasia; iron deficiency anaemia (may
indicate potential inherited disorder of iron absorption)
Examination

• Examine the abdomen for abdominal masses, organomegaly, lymphadenopathy

and any other features of intra-abdominal disease.

• Perform a rectal examination to look for signs of bleeding, malaena and masses.

• If menorrhagia is thought to be the cause: perform a vaginal/bimanual

examination, examine the cervix and perform a cervical smear and swabs as
appropriate (please refer to article on menorrhagia for further details).

Signs
• Pallor (best seen in the mucosa of tongue and mouth, especially in people with
dark skin)

• Κοιλονψχηια (spoon shaped nails with longitudinal ridging)

• Ανγυλαρ χηειλιτισ (ulceration at the corners of the mouth)

• Ατροπηιχ γλοσσιτισ

• In marked anaemia there may be tachycardia, a flow murmur, cardiac

enlargement, ankle oedema and heart failure.
FPRIVATE "TYPE=PICT;ALT=KOILONYCHIA (OM985a.jpg)"

Note the spoon-shaped nail of koilonychia with the longitudinal ridges

Other signs that may be seen include:

• Stigmata of chronic liver disease, perhaps cirrhosis

• Multiple telangiectasia may be a feature of hereditary haemorrhagic

telangiectasia, also known as Osler-Weber-Rendu Syndrome

• Pigmentation of the lips and oral mucosa may suggest Peutz-Jeghers syndrome

Confirming the diagnosis

• Full blood count: shows a hypochromic microcytic anaemia (although there may
be a mixed picture with coexistent B12 or folate deficiency).

• Hypochromia means that there is as a low mean corpuscular haemoglobin

 (MCH).

• Microcytosis means that there is as a low mean corpuscular volume

(MCV).

• Remember that a haemoglobinopathy will also cause a hypochromic

microcytic anaemia.

• Serum ferritin: should be measured to confirm iron deficiency (except during

pregnancy).

• This correlates with total body iron stores.

• However, ferritin levels can be raised if infection or inflammation is

present, even if iron stores are low.1

• A ferritin level < 15 mcg/L confirms iron deficiency.5

• If there is coexisting chronic inflammatory disease, the clinician should

consider seeking specialist advice about other measures of iron status.

• Blood film: anisocytosis (variation in size between red blood cells) and
poikilocytosis (abnormally shaped red blood cells) can be seen.
Differential diagnosis
Other causes of microcytic anaemia including:

• Thalassaemia

• Sideroblastic anaemia

• Αναεµια οφ χηρονιχ δισεασε

• Λεαδ ποισονινγ

Investigations
The following groups of people do not usually require investigation before treatment is started:4

• Otherwise healthy young people in whom the history clearly suggests a cause (e.g.
regular blood donors).

• Menstruating young women without history of gastrointestinal symptoms nor family

history of colorectal cancer (although some suggest coeliac disease screening in this
group).9

• Pregnant women - unless the anaemia is severe or the history/examination suggest

another cause for the iron deficiency (e.g. inflammatory bowel disease), or there is no
 response to iron supplementation.

• People who are terminally ill or unable to undergo invasive investigations.

• People who refuse further investigations.

However, consider investigations if there is a poor response to treatment or the anaemia recurs
with no obvious cause.

Otherwise, investigations that should be considered include:

• Urinalysis for blood (approximately 1% of patients with iron deficiency anaemia

have a renal tract malignancy)

• Screening for coeliac disease (serology looking for anti-endomysial antibody or

tissue transglutaminase antibody)

• Referral for upper and lower gastrointestinal investigations

• Stool examination looking for parasites if recent travel to endemic area

If menorrhagia is thought to be the cause of iron deficiency anaemia, please refer to the separate
article on menorrhagia for details about appropriate investigations.
Who should be referred to secondary care?4

• If someone has profound anaemia and signs of acute heart failure, they should be
admitted urgently to hospital.

• People of any age with dyspepsia and iron deficiency anaemia should be referred
for endoscopy, or to a specialist in upper gastrointestinal cancer, within 2 weeks.

• Men of any age with unexplained iron deficiency anaemia and a haemoglobin of
11 g/dL or below, should be referred within 2 weeks to a gastroenterologist.

• Women who are not menstruating with unexplained iron deficiency anaemia and
a haemoglobin of 10 g/dL or below should be referred within 2 weeks to a
gastroenterologist.
Clinical judgement should be used in people with unexplained iron deficiency anaemia who do
not fall into the above categories. They will still need referral for further investigation but the
clinician will have to determine the urgency.

Sideroblastic Anaemia
Synonyms: Refractory anemia with ringed sideroblasts (RARS)
Sideroblastic anaemias are a heterogeneous group of refractory anaemias. They are
characterized by the presence of abnormal ringed sideroblasts in bone marrow aspirate.
The sideroblasts form due to reduced haemoglobin synthesis, resulting in the
accumulation of iron within red blood cell precursors. Cases can, rarely, be congenital but
are more usually acquired and sometimes represent a stage in the development of
myelodysplastic syndromes.
Epidemiology
This accounts for 5-15% of all myelodysplastic syndromes.1 70% of all patients are aged
>50years old.
Hereditary forms of sideroblastic anaemia are X-linked and more common in males.
Cases can be related to ataxia and the condition may not present until the fourth decade or
later if mild.2
Aetiology
In addition to the myelodysplastic syndromes, sideroblastic anaemia can also occur in
other bone marrow diseases including:

• Myeloma

• Πολψχψτηαεµια ρυβρα ϖερα

• Μψελοσχλεροσισ

• Λευκαεµιασ

Secondary causes include:

• Inflammatory conditions e.g. rheumatoid arthritis

• Σψστεµιχ λυπυσ ερψτηεµατοσυσ

• Chronic infections

• ∆ρυγ τοξιχιτψ - e.g. chloramphenicol, cycloserine, isoniazid, linezolid,

pyrazinamide

• Χηρονιχ αλχοηολισµ

• Ηαεµολψτιχ αναεµια

• Μαλαβσορπτιον syndromes

• Μψξοεδεµα

• Λεαδ ποισονινγ

• Πρεγνανχψ
Presentation
Clinical features are those related to anaemia in general. Symptoms reflect the
cytopenias, i.e. anaemia, infection, bruising and haemorrhage.
There are no specific signs or symptoms related to sideroblastic anaemia alone.
Investigations

• A FBC usually shows a moderate anaemia.

• The MCV is normal or increased but can be low.

• High serum iron and transferring saturation also occur.

• The blood film shows a dimorphic population of both normal and hypochromic
red blood cells.

• Diagnosis is made from bone marrow examination demonstrating the presence of

ring sideroblasts with a generalized increase in iron stores.
Management

Non-Drug
• Treatment is mainly supportive.

• Red cell transfusion is given for symptomatic anaemia.

Iron chelation with desferrioxamine should be considered after 20-25 units of red
cells have been received.3
Anemia (AmE) or anæmia/anaemia (BrE), from the Greek (Ἀναιμία) (an-haîmia)
meaning "without blood," is defined as a qualitative or quantitative deficiency of
hemoglobin, a molecule found inside red blood cells (RBCs). Since hemoglobin normally
carries oxygen from the lungs to the tissues, anemia leads to hypoxia (lack of oxygen) in
organs. Since all human cells depend on oxygen for survival, varying degrees of anemia
can have a wide range of clinical consequences.
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).
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.
There are two major approaches of classifying anemias, the "kinetic" approach which
involves evaluating production, destruction and loss[1], 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.

Contents
[hide]

• 1 Signs and symptoms

• 2 ∆ιαγνοσισ

• 3 Χλασσιφιχατιον

• 3.1 Production vs. destruction or loss

• 3.2 Ρεδ βλοοδ χελλ σιζε

• 3.2.1 Microcytic anemia

• 3.2.2 Νορµοχψτιχ ανεµια

• 3.2.3 Μαχροχψτιχ ανεµια

• 3.2.4 ∆ιµορπηιχ ανεµια

• 3.2.5 Ηεινζ βοδψ ανεµια

• 4 Specific anemias

• 5 Ποσσιβλε χοµπλιχατιονσ

• 6 Ανεµια δυρινγ πρεγνανχψ

• 7 Τρεατµεντσ φορ ανεµια

• 7.1 Blood transfusions for anemia

• 7.2 Ηψπερβαριχ Οξψγενατιον

• 8 References

• 9 Βοοκσ

• 10 Σεε αλσο

• 11 Εξτερναλ λινκσ
[edit] Signs and symptoms
Anemia goes undetected in many people, and symptoms can be small and vague. Most
commonly, people with anemia report a feeling of weakness or fatigue in general or
during exercise, general malaise and sometimes poor concentration. People with more
severe anemia often report dyspnea (shortness of breath) on exertion. Very severe anemia
prompts the body to compensate by increasing cardiac output, leading to palpitations and
sweatiness, and to heart failure.
Pallor (pale skin, mucosal linings and nail beds) is often a useful diagnostic sign in
moderate or severe anemia, but it is not always apparent. Other useful signs are cheilosis
and koilonychia.
Pica, the consumption of non-food such as dirt, paper, wax, grass, ice and hair, may be a
symptom of iron deficiency, although it occurs often in those who have normal levels of
hemoglobin.
Chronic anemia may result in behavioral disturbances in children as a direct result of
impaired neurological development in infants, and reduced scholastic performance in
children of school age.

[edit] Diagnosis
Generally, clinicians request complete blood counts in the first batch of blood tests in the
diagnosis of an anemia. Apart from reporting the number of red blood cells and the
hemoglobin level, the automatic counters also measure the size of the red blood cells by
flow cytometry, which is an important tool in distinguishing between the causes of
anemia. Examination of a stained blood smear using a microscope can also be helpful,
and is sometimes a necessity in regions of the world where automated analysis is less
accessible.
In modern counters, four parameters (RBC count, hemoglobin concentration, MCV and
RDW) are measured, allowing others (hematocrit, MCH and MCHC) to be calculated,
and compared to values adjusted for age and sex. Some counters estimate hematocrit
from direct measurements. For adult men, a hemoglobin level less than 13.0 g/dl (grams
per deciliter) is diagnostic of anemia, and for adult women, the diagnostic threshold is
below 12.0 g/dl.
Reticulocyte counts, and the "kinetic" approach to anemia, have become more common
than in the past in the large medical centers of the United States and some other wealthy
nations, in part because some automatic counters now have the capacity to include
reticulocyte counts. A reticulocyte count is a quantitative measure of the bone marrow's
production of new red blood cells. The reticulocyte production index is a calculation of
the ratio between the level of anemia and the extent to which the reticulocyte count has
risen in response. If the degree of anemia is significant, even a "normal" reticulocyte
count actually may reflect an inadequate response.
If an automated count is not available, a reticulocyte count can be done manually
following special staining of the blood film. In manual examination, activity of the bone
marrow can also be gauged qualitatively by subtle changes in the numbers and the
morphology of young RBCs by examination under a microscope. Newly formed RBCs
are usually slightly larger than older RBCs and show polychromasia. Even where the
source of blood loss is obvious, evaluation of erythropoiesis can help assess whether the
bone marrow will be able to compensate for the loss, and at what rate.
When the cause is not obvious, clinicians use other tests: ESR, ferritin, serum iron,
transferrin, RBC folate level, serum vitamin B12, hemoglobin electrophoresis, renal
function tests (e.g. serum creatinine).
When the diagnosis remains difficult, a bone marrow examination allows direct
examination of the precursors to red cells.

[edit] Classification

[edit] Production vs. destruction or loss

The "kinetic" approach to anemia yields what many argue is the most clinically relevant
classification of anemia. This classification depends on evaluation of several
hematological parameters, particularly the blood reticulocyte (precursor of mature RBCs)
count. This then yields the classification of defects by decreased RBC production versus
increased RBC destruction and/or loss. Clinical signs of loss or destruction include
abnormal peripheral blood smear with signs of hemolysis; elevated LDH suggesting cell
destruction; or clinical signs of bleeding, such as guiaic-positive stool, radiographic
findings, or frank bleeding.
Here is a simplified schematic of this approach:
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* For instance, sickle cell anemia with superimposed iron deficiency; chronic gastric
bleeding with B12 and folate deficiency; and other instances of anemia with more than
one cause. ** Confirm by repeating reticulocyte count: ongoing combination of low
reticulocyte production index, normal MCV and hemolysis or loss may be seen in bone
marrow failure or anemia of chronic disease, with superimposed or related hemolysis or
blood loss.

[edit] Red blood cell size

In the morphological approach, anemia is classified by the size of red blood cells; this is
either done automatically or on microscopic examination of a peripheral blood smear.
The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller than
normal (under 80 fl), the anemia is said to be microcytic; if they are normal size (80-100
fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified
as macrocytic. This scheme quickly exposes some of the most common causes of anemia;
for instance, a microcytic anemia is often the result of iron deficiency. In clinical workup,
the MCV will be one of the first pieces of information available; so even among
clinicians who consider the "kinetic" approach more useful philosophically, morphology
will remain an important element of classification and diagnosis.
Here is a schematic representation of how to consider anemia with MCV as the starting
point:
 An
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Other characteristics visible on the peripheral smear may provide valuable clues about a
more specific diagnosis; for example, abnormal white blood cells may point to a cause in
the bone marrow.

[edit] 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

• Ανεµια οφ χηρονιχ δισεασε (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

Iron deficiency anemia is the most common type of anemia overall and it has many
causes. RBCs often appear hypochromic (paler than usual) and microcytic (smaller than
usual) when viewed with a microscope.

• Iron deficiency anemia is caused by insufficient dietary intake or absorption of

iron to replace losses from menstruation or losses due to diseases.[2] Iron is an
essential part of hemoglobin, and low iron levels result in decreased incorporation
of hemoglobin into red blood cells. In the United States, 20% of all women of
childbearing age have iron deficiency anemia, compared with only 2% of adult
men. The principal cause of iron deficiency anemia in premenopausal women is
blood lost during menses. Studies[who?] have shown that iron deficiency without
anemia causes poor school performance and lower IQ in teenage girls. Iron
deficiency is the most prevalent deficiency state on a worldwide basis. Iron
deficiency is sometimes the cause of abnormal fissuring of the angular (corner)
sections of the lips (angular stomatitis).
 • Iron deficiency anemia can also be due to bleeding lesions of the gastrointestinal
tract. Fecal occult blood testing, upper endoscopy and lower endoscopy should be
performed to identify bleeding lesions. In men and post-menopausal women the
chances are higher that bleeding from the gastrointestinal tract could be due to
colon polyp or colorectal cancer.

• Worldwide, the most common cause of iron deficiency anemia is parasitic

infestation (hookworm, amebiasis, schistosomiasis and whipworm).[3]

[edit] Normocytic anemia

Normocytic anaemia 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

• Ανεµια οφ χηρονιχ δισεασε

• Απλαστιχ ανεµια (bone marrow failure)

• Ηεµολψτιχ ανεµια

[edit] 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 an autoimmune condition thought to be due to a

directed attack against intrinsic factor produced by the parietal cells of the
stomach. Intrinsic factor is required to absorb vitamin B12 from food.
Therefore, the destruction of intrinsic factor, leads 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 vit B12/folate absorption. Therefore one must always be aware of
anemia following this procedure.

• Alcoholism causes a macrocytosis, although not specifically anemia

• Μετηοτρεξατε, zidovudine, and other drugs that inhibit DNA replication.

Macrocytic anemia can be further divided into "megaloblastic anemia" or "non-
megaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a
failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell
division of the progenitor cells. The megaloblastic anemias often present with neutrophil
hypersegmentation (6-10 lobes). The non-megaloblastic macrocytic anemias have
different etiologies (i.e. there is unimpaired DNA globin synthesis,) which occur, for
example in alcoholism.
In addition to the non-specific symptoms of anemia, specific features of vitamin B12
deficiency include peripheral neuropathy and subacute combined degeneration of the
cord with resulting balance difficulties from posterior column spinal cord pathology.[4]
Other features may include a smooth, red tongue and glossitis.
The treatment for vitamin B12-deficient anemia was first devised by William Murphy
who bled dogs to make them anemic and then fed them various substances to see what (if
anything) would make them healthy again. He discovered that ingesting large amounts of
liver seemed to cure the disease. George Minot and George Whipple then set about to
chemically isolate the curative substance and ultimately were able to isolate the vitamin
B12 from the liver. All three shared the 1934 Nobel Prize in Medicine.[5]

[edit] Dimorphic anemia

When two causes of anemia act simultaneously, e.g., macrocytic hypochromic, due to
hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid [6]
or following a blood transfusion more than one abnormality of red cell indices may be
seen. Evidence for multiple causes appears with an elevated RBC distribution width
(RDW), which suggests a wider-than-normal range of red cell sizes.

[edit] Heinz body anemia

Heinz bodies are an abnormality that form on the cells in this condition. This form of
anemia may be brought on by taking certain medications; it is also triggered in cats by
eating onionsHYPERLINK \l "cite_note-6"[7] or acetaminophen (Tylenol). It can be
triggered in dogs by ingesting onions or zinc, and in horses by ingesting dry red maple
leaves.

[edit] Specific anemias

• Anemia of prematurity occurs in premature infants at 2 to 6 weeks of age and
results from diminished erythropoietin response to declining hematocrit levels

• Φανχονι ανεµια is an hereditary disorder or defect featuring aplastic anemia and

various other abnormalities
 • Ηεµολψτιχ ανεµια causes a separate constellation of symptoms (also featuring
jaundice and elevated LDH levels) with numerous potential causes. It can be
autoimmune, immune, hereditary or mechanical (e.g. heart surgery). It can result
(because of cell fragmentation) in a microcytic anemia, a normochromic anemia,
or (because of premature release of immature red blood cells from the bone
marrow), a macrocytic anemia.

• Ηερεδιταρψ σπηεροχψτοσισ is a hereditary defect that results in defects in the

RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by
the spleen. This leads to a decrease in the number of circulating RBCs and, hence,
anemia.

• Σιχκλε−χελλ ανεµια, a hereditary disorder, is due to homozygous hemoglobin S

genes.

• Ωαρµ αυτοιµµυνε ηεµολψτιχ ανεµια is an anemia caused by autoimmune

attack against red blood cells, primarily by IgG

• Χολδ αγγλυτινιν ηεµολψτιχ ανεµια is primarily mediated by IgM

• Περνιχιουσ ανεµια is a form of megaloblastic anaemia due to vitamin B12

deficiency dependent on impaired absorption of vitamin B12.

• Μψελοπητηισιχ ανεµια or Myelophthisis is a severe type of anemia resulting

from the replacement of bone marrow by other materials, such as malignant
tumors or granulomas.

[edit] Possible complications

Anemia diminishes the capability of individuals who are affected to perform physical
activities. This is a result of one's muscles being forced to depend on anaerobic
metabolism. The lack of iron associated with anemia can cause many complications,
including hypoxemia, brittle or rigid fingernails, cold intolerance, and possible behavioral
disturbances in children. Hypoxemia resulting from anemia can worsen the cardio-
pulmonary status of patients with pre-existing chronic pulmonary disease. Cold
intolerance occurs in one in five patients with iron deficiency anemia, and becomes
visible through numbness and tingling.[citation needed]

[edit] Anemia during pregnancy

Anemia affects 20% of all females of childbearing age in the United States. Because of
the subtlety of the symptoms, women are often unaware that they have this disorder, as
they attribute the symptoms to the stresses of their daily lives. Possible problems for the
fetus include increased risk of growth retardation, prematurity, intrauterine death, rupture
of the amnion and infection.
During pregnancy, women should be especially aware of the symptoms of anemia, as an
adult female loses an average of two milligrams of iron daily. Therefore, she must intake
a similar quantity of iron in order to make up for this loss. Additionally, a woman loses
approximately 500 milligrams of iron with each pregnancy, compared to a loss of 4-100
milligrams of iron with each period. Possible consequences for the mother include
cardiovascular symptoms, reduced physical and mental performance, reduced immune
function, tiredness, reduced peripartal blood reserves and increased need for blood
transfusion in the postpartum period.

[edit] Treatments for anemia

There are many different treatments for anemia and the treatment depends on severity
and the cause.
Iron deficiency from nutritional causes is rare in non-menstruating adults (men and post-
menopausal women). The diagnosis of iron deficiency mandates a search for potential
sources of loss such as gastrointestinal bleeding from ulcers or colon cancer. Mild to
moderate iron deficiency anemia is treated by iron supplementation with ferrous sulfate
or ferrous gluconate. Vitamin C may aid in the body's ability to absorb iron.
Vitamin supplements given orally (folic acid) or subcutaneously (vitamin B-12) will
replace specific deficiencies.
In anemia of chronic disease, anemia associated with chemotherapy, or anemia associated
with renal disease, some clinicians prescribe recombinant erythropoietin, epoetin alfa, to
stimulate red cell production.
In severe cases of anemia, or with ongoing blood loss, a blood transfusion may be
necessary.

[edit] Blood transfusions for anemia

Doctors attempt to avoid blood transfusion in general, since multiple lines of evidence
point to increased adverse patient clinical outcomes with more intensive transfusion
strategies. The physiological principle that reduction of oxygen delivery associated with
anemia leads to adverse clinical outcomes is balanced by the finding that transfusion does
not necessarily mitigate these adverse clinical outcomes.
In severe, acute bleeding, transfusions of donated blood are often lifesaving.
Improvements in battlefield casualty survival is attributable, at least in part, to the recent
improvements in blood banking and transfusion techniques.[citation needed]
Transfusion of the stable but anemic hospitalized patient has been the subject of
numerous clinical trials, and transfusion is emerging as a deleterious intervention.
Four randomized controlled clinical trials have been conducted to evaluate aggressive
versus conservative transfusion strategies in critically ill patients. All four of these studies
failed to find a benefit with more aggressive transfusion strategies. [8] [9] [10] [11]
In addition, at least two retrospective studies have shown increases in adverse clinical
outcomes with more aggressive transfusion strategies. [12] [13]

[edit] Hyperbaric Oxygenation

Treatment of exceptional blood loss (anemia) is recognized as an indication for
hyperbaric oxygen (HBO) by the Undersea and Hyperbaric Medical
Society.[14]HYPERLINK \l "cite_note-14"[15] The use of HBO is indicated when
oxygen delivery to tissue is not sufficient in patients who cannot be transfused for
medical or religious reasons. HBO may be used for medical reasons when threat of blood
product incompatibility or concern for transmissible disease.[14] The beliefs of some
religions (ex: Jehovah's Witnesses) may prohibit the receipt transfused blood
products.[14]
In 2002, Van Meter reviewed the publications surrounding the use of HBO in severe
anemia and found that all publications report a positive result.[16]
Macrocytic is from Greek words meaning "large cell." A macrocytic class of anemia is
an anemia (defined as blood with an insufficient concentration of hemoglobin) in which
the erythrocytes ("red blood cells" or RBCs) are larger than their normal volume. This
normal RBC volume in humans is about 80 to 100 femtoliters (fL= 10-15 L). In slightly
less correct metric terminology which does not use standard volume units, the size may
be given in equivalent cubic micrometres (1 μm3 = 1 fL). The condition of having red
cells which are on average too large, is called macrocytosis.
In a macrocytic anemia the larger red cells are always associated with insufficient
numbers of cells and often also insufficient hemoglobin content per cell, both factors
which more than make up for the larger cell size, to produce a total blood hemoglobin
concentration deficiency.
Macrocytic anemia is not a disease, but a condition: a general classification of a set of
pathologies. Many specific pathologies are known which result in macrocytic-type
anemias, but which produce slightly different sets of appearances, some of which are
detectable from red and white cell mophology, and others only from chemical tests on the
blood.
Contents
[hide]

• 1 Types of macrocytic anemias

• 1.1 Megaloblastic anemias (DNA replication disorders)

• 1.2 Ρεδ χελλ µεµβρανε δισορδερσ προδυχινγ χοδοχψτεσ

• 1.3 Αλχοηολ

• 1.4 Ασσοχιατιον ωιτη ραπιδ ρεδ χελλ τυρνοϖερ ανδ ρετιχυλοχψτοσισ

• 2 References

[edit] Types of macrocytic anemias

[edit] Megaloblastic anemias (DNA replication disorders)

Especially common causes of macrocytic anemias are the so-called megaloblastic
anemias, in which cells are larger because they cannot produce DNA quickly enough to
divide at the right time as they grow, and thus grow too large before division. Causes for
the DNA synthetic problem range from lack of certain vitamins needed to produce DNA
(notably folate and B12), to poisons or inhibitors of DNA replication, such as some kinds
of antiviral drugs and chemotherapeutic agents. Classically these megaloblastic types of
anemias are associated also with more specific features, such as megaloblasts in the bone
marrow, the presense of ovalocytes in the (peripheral) blood smear, and the
pathognomonic presense of hypersegmented neutrophils.

[edit] Red cell membrane disorders producing codocytes

Other disorders which cause macrocytosis without DNA replication problems (i.e., non-
megaloblastic macrocytic anemias), are disorders associated with increased red cell
membrane surface area, such as pathologies of the liver and spleen which produce
codocytes or "target cells" which have a central collection of hemoglobin surrounded by a
pallor (a thin area) then followed by a thicker collection of hemoglobin at the rim of the
cell.
[edit] Alcohol
Round macrocytes which are not codocytes are produced in chronic alcoholism (which
produces a mild macrocytosis even in the absence of vitamin deficiency), apparently as a
direct toxic effect of alcohol specifically on the bone marrow.

[edit] Association with rapid red cell turnover and reticulocytosis

Mild macrocytocis is a common finding associated with rapid blood restoration or
production, since in general, "fresh" or newly-produced red cells (reticulocytes) are larger
than the mean (average) size, due to slow shrinkage of normal cells over a normal red cell
circulating lifetime. Thus, chronic obstructive pulmonary disease (COPD), in which
which red cells are rapidly produced in response to low oxygen levels in the blood, often
produces mild macrocytosis. Also, rapid blood replacement from the marrow after a
traumatic blood loss, or rapid red blood cell turnover from rapid hemolysis, also often
produces mild macrocytosis in the associated anemia. [1].

Megaloblastic Anaemia
In this group of anaemias the erythroblasts in the bone marrow show a delay of the
maturation of the nucleus relative to that of the cytoplasm. The delay in the maturation of
the nucleus is due to defective DNA synthesis. This may be caused by:

• Vitamin B12 deficiency

• Φολατε δεφιχιενχψ

• Αβνορµαλιτιεσ οφ ϖιτ Β12 ορ φολατε µεταβολισµ

• Οτηερ δεφεχτσ οφ ∆ΝΑ σψντηεσισ

Both vitamin B12 and folate are required for the synthesis of DNA. Folate is needed in its
tetrahydrofolate form (FH4) as a cofactor in DNA synthesis. Vitamin B12 is a cofactor
required for the conversion of homocysteine to methionine which enables cells to receive
FH4 for synthesis of methylene FH4, the coenzyme required for the conversion of
deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) in the
formation of DNA.
Vitamin B12 Deficiency
The natural source of B12 is from the diet. Vitamin B12 is synthesised only by bacteria
and is found in meat, fish, eggs, and milk, but not in plants, and it is not usually destroyed
by cooking. A normal diet contains a large excess of B12 compared with daily needs. B12
is combined with intrinsic factor (IF), a glycoprotein synthesised by gastric parietal cells.
The IF-B12 complex binds to a specific receptor protein for IF, cubulin, in the distal
ileum, where B12 is then absorbed.
In Western countries, B12 deficiency is usually caused by pernicious anaemia, an
autoimmune disorder. The majority of patients have IgG autoantibodies targeted against
gastric parietal cells and IF, leading to atrophy of the gastric mucosa with consequent
failure of IF production. Gastritis affecting the fundus is present with plasma cell and
lymphoid infiltration. The parietal and chief cells are replaced by mucin-secreting cells.
Achlorhydria (failure to produce hydrochloric acid) occurs and secretion of IF is absent
or almost absent.
Less commonly, it may also be caused by:

• veganism in which the diet lacks B12

• gastrectomy

• ileal resection

• small intestinal lesions, as in Crohn's disease

• stagnant loop syndrome

• tropical sprue

• fish tapeworm

• congenital malabsorption

The deficiency takes at least 2 years to develop - i.e. the time needed for body stores to
deplete at a rate of 1-2µg each day when there is no new B12 entering the body from the
diet.
Folate Deficiency
Humans are unable to synthesise folate and so require preformed folate as a vitamin in
the diet. It is found in green vegetables such as spinach broccoli, and offal, such as liver
and kidney. Cooking causes loss of 60-90% of the folate.
The main cause of folate deficiency is poor dietary intake, which may occur alone or
with excessive utilisation or malabsorption (Table 1). It may also be caused by antifolate
drugs.
Poor Dietary Intake Malabsorption

• Old age • Small bowel disease - but

effect is less than that of
• Poor social conditions anorexia
• Starvation • Gluten-induced enteropathy
• Alcohol excess • Tropical sprue
 • Anorexia:gastrointestinal
disease - e.g. partial
gastrectomy, coeliac
disease, Crohn's disease;
cancer
Excess Utilisation Folate Antagonists

• Anticonvulsants (phenytoin,
• Pregnancy and lactation primidone)
• Haemolytic anaemia • Sulphasalazine
• Myeloproliferative / • Methotrexate
malignant / inflammatory
disorders • Pyrimethamine

• Trimethoprim

Excess Urinary Folate Loss Mixed

• Congestive cardiac failure • Liver disease

• Chronic dialysis • Alcoholism

Table 1 Causes of folate deficiency

On a deficient diet, folate deficiency develops over about 4 months, but deficiency may
develop more rapidly in patients who have both a poor intake and excess utilisation of
folate, as in ITU patients.
Abnormalities of Vitamin B12 or Folate Metabolism
These include:

• Congenital deficiencies of enzymes concerned in B12 or folate metabolism or of

the serum transport protein for B12, transcobalamin II (TC II).

• Nitrous oxide anaesthesia

• Antifolate drug therapy, especially dihydrofolate (DHF) reductase inhibitors (e.g.

methotrexate, pyrimethamine)
Other defects of DNA synthesis
These include:

• Congenital deficiency of one or other enzyme concerned in purine or pyrimidine

synthesis, e.g. orotic aciduria
  Drug therapy inhibiting purine and pyrimidine synthesis (e.g. hydroxyurea,
cytosine arabinoside, 6-mercaptopurine, zidovudine (AZT))

 Some forms of AML and myelodysplasia

Clinical Features

 Onset: insidious

 Gradually progressive signs of anaemia

 Mild jaundice: excess Hb breakdown caused by ineffective erythropoiesis in

bone marrow

 Glossitis

 Angular stomatitis

 Weight loss: malabsorption caused by epithelial abnormality

 Purpura: result of thrombocytopenia

 Neuropathy (vitamin B12 deficiency only)

 Sterility

 Neural tube defects in the fetus (vitamin B12 or folate deficiency)

 Widespread melanin pigmentation: rarely

 Cardiovascular disease: due to raised serum homocysteine levels

Investigations

 Haematological findings:

Blood count: MCV (>96fl). May beHb, leucopenia, thrombocytopenia

Peripheral blood film: oval macrocytes and hypersegmented neutrophils (due to

retention of surplus nuclear material) with 6 lobes in the nucleus

 Bone marrow aspirate:

Typical features of megaloblastic erythropoiesis The immature red cells show

nuclear-cytoplasmic imbalance with enlarged abnormal nuclei and basophilic
cytoplasm
Not always necessary in straightforward megaloblastic anaemia and a low serum
vitamin B12
 • Serum bilirubin:  as a result of ineffective erythropoiesis or if destruction of
developing red cells is increased

 Serum vitamin B12:  (<160ng/l). Very low in pernicious anaemia. Can be assayed
using radioisotope dilution or immunological assays

 Serum folate: N / , and red cell folate is N /  owing to inhibition of normal

folate synthesis

 Autoantibodies:

Parietal cell antibodies in serum

IF antibodies in serum: diagnostic of pernicious anaemia
Also detected in gastric juice
Anti-gliadin and endomysial antibodies: folate deficiency

 Vitamin B12 absorption tests: Schilling test - patient swallows B12 labelled with
radioactive cobalt and absorption is usually measured in directly by quantifying
urinary excretion. Normal subjects excrete >10% of the radioactive dose. The test
is then repeated with IF added.
If excretion is now normal (malabsorption is corrected) = pernicious anaemia or
gastrectomy
If excretion is still abnormal = terminal ileum lesion or bacterial overgrowth.

 Endoscopy or barium meal and follow through

 Duodenal biopsy

Treatment
Most cases only require administering the appropriate vitamin (Table 2). However, it
is important not to give folate in vitamin B12 deficiency since the neuropathy may be
aggravated. B12 deficiency must be excluded before commencing large doses of folic
acid. In the elderly, correct any heart failure with diuretics and oral potassium
supplements given for 10 days. Avoid blood transfusion as it may cause circulatory
overload.
Vitamin B12
Folate Deficiency
Deficiency
Compound Hydroxycobalamin Folic acid
Route IM, PO, SL PO

Dose 1000g 5mg

 6 x 1000g over 2-3
Initial dose Daily for 4 mths
wks
Maintenanc
1000g every 3 mths Depends on underlying disease;
e
life-long therapy may be needed in
chronic inherited haemolytic
anaemias, myelofibrosis, renal
dialysis

Prophylacti
c Total gastrectomy Pregnancy, severe haemolytic
Ileal resection anaemias, dialysis, prematurity

Table 2 Treatment of megaloblastic anaemia

Course of Response to Correct Vitamin Therapy

 24-48hrs: patient feels better with increased appetite and well-being

 48hrs: marrow is normoblastic. However, giant metamyelocytes persist for up to

12 days

 2-3 days: reticulocyte response begins. Peaks at 6-7 days

 7-10 days: white cell and platelet counts return to normal

 Fortnight: Hb rises by 2-3g/dl each fortnight

(Back to top of page)

Non-Megaloblastic Macrocytic Anaemia

There are many non-megaloblastic causes of macrocytic anaemia. The exact mechanisms
creating macrocytes in each of these conditions is not clear. Increased lipid deposition on
the red cell membrane or alterations of erythrocyte maturation time in the marrow have
been suggested.
The causes of non-megaloblastic macrocytosis include:

 Alcohol: most frequent cause of MCV in the absence of anaemia

 Liver disease

 Myxoedema

 Myelodysplastic syndromes
 • Cytotoxic drugs

• Aplastic anaemia

• Pregnancy

• Smoking

• Reticulocytosis

• Myeloma

• Neonatal

It is important to exclude B12 or folate deficiency before these diagnoses are made.
White cell and platelet counts are normal unless the underlying marrow disease affects
these. The red cells are circular rather than oval, hypersemented neutrophils are absent
and the marrow is normoblastic.
Red Cell Production and Anaemia
Anaemia is defined as a reduction in haemoglobin concentration. This varies between
sexes but is usually defined as a haemoglobin less than 13.5g/dl in males and 11.5 g/dl in
females. The reduction in haemoglobin is generally accompanied by a fall in the red cell
count and the packed cell volume or 'haematocrit'. Alterations in plasma volume will alter
haemoglobin concentrations. A reduction in plasma volume, as in dehydration, will cause
an artificial elevation of the haemoglobin concentration and may mask anaemia. An
increase in plasma volume, as in pregnancy, may cause an apparent anaemia. Anaemia is
not immediately apparent in acute major blood loss when the total blood volume is
reduced. It generally takes over 24 hours before anaemia is evident.
Clinical features of anaemia
These are very variable and depend on the speed of onset of the anaemia and the co-
existence of other medical conditions. In general, a slowly progressive anaemia may be
relatively asymptomatic and the patient may be able to adapt. However, co-existent
cardiac or pulmonary disease may exacerbate the symptoms. The symptoms that are
defined include lethargy, shortness of breath, exacerbation of angina. The physical signs
on examination of the patient are generally unreliable but it is possible that pallor of the
mucous membranes or, very rarely, koilonychia (spooning of nails) may be observed.
Classification of anaemia
There are many different causes of anaemia and 2 major classification systems exist; in
practice a combination of the two are used.
A – a classification based on the cause of the anaemia:
(i) those patients who have reduced production of red cells
(ii) patients whose red cells function poorly
(iii) situations where there is increased loss or destruction of red cells.
B – Classification of anaemia based on the size of red cells - the mean cell volume
(MCV); the normal range for this parameter is 80-100fl.
(i) macrocytic (large red cells)
(ii) normocytic (normal sized red cells)
(iii) microcytic (small red cells).
The second classification is widely used. It is practical because the vast majority of
peripheral blood counts measured in the United Kingdom are analysed on modern
electronic cell counters. These counters identify a number of parameters related to red
cell size, red cell number and the concentration of haemoglobin in red cells.
The macrocytic anaemias
Causes of a macrocytic anaemia (raised MCV) are listed below:
B12 and folate deficiency
Vitamin B12 and folic acid are closely involved in the production of DNA. Deficiency of
either one of these vitamins causes a macrocytic anaemia. Vitamin B12 is absorbed from
the ileum as a complex with intrinsic factor produced in the gastric parietal cells; folate
on the other hand is absorbed in the duodenum and jejunum. Deficiencies of either can
result from diseases of the site of absorption. Folic acid is widely distributed in food-
stuffs but vitamin B12 is confined to meat products. Consequently, vitamin B12
deficiency can be seen in strict vegans. In non-vegans the main cause of vitamin B12
deficiency is pernicious anaemia, which is an auto-immune condition with antibodies
being produced against gastric parietal cells in 90% and intrinsic factor in 70% of
patients. Folic acid deficiency can often be related to a poor diet or to malabsorption
within the gut, eg coeliac disease.
Alcoholism and liver disease
Many forms of liver disease, including alcoholic cirrhosis and, indeed, alcoholism per se,
can lead to a macrocytic anaemia. There is often co-existent folate deficiency.
Impaired red cell production
Aplastic anaemia, where there is bone marrow failure or myelodysplasia, where there is
ineffective red cell production, can both cause a macrocytic anaemia. The causes of
aplastic anaemia are varied but can include certain viruses, eg hepatitis B, excessive
doses of cytotoxic drugs or radiation, or idiosyncratic reactions to drugs. The treatment of
aplastic anaemia is either bone marrow transplantation or immunotherapy.
Myelodysplasia is a heterogeneous group of conditions which may be pre-leukaemic.
There is no satisfactory treatment for these conditions other than blood product support,
eg red cell transfusion. In some patients, cytotoxic therapy or bone marrow
transplantation may be indicated.
Haemolytic anaemias
There are many causes of haemolytic anaemia. Destruction of red cells may take place
either within the circulation (intra-vascular haemolysis) or outside the circulation mainly
in the spleen (extra-vascular haemolysis). In these conditions the reticulocyte count is
usually raised. Reticulocytes are large red cells, and so their presence in increased
numbers can cause a raised MCV. It is possible to have a haemolytic anaemia with a
normal MCV; in these cases the degree of reticulocytosis is less. The aetiology of
haemolytic anaemia may be divided into stimuli outside the red cell membrane, problems
within the red cell membrane and defects within the red cell itself. An example of a
haemolytic anaemia where the stimulus lies outside the red cell membrane is auto-
immune haemolytic anaemia. In these cases the direct Coomb's test is positive; i.e. there
is an antibody active against red cells, which is present in the plasma. This causes
increased destruction of red cells in the spleen. Auto-immune anaemia can be idiopathic,
i.e. without an identified precipitating cause or secondary to a lymphoma, an auto-
immune disease, eg. rheumatoid arthritis or systemic lupus erythematosus, (but these
diseases can also suppress red cell production); certain drugs induce auto-immune
haemolytic anaemia; more rarely it may occur in association with an infection.
An example of a haemolytic anaemia secondary to an inherent problem within the red
cell membrane is hereditary spherocytosis. This is a congenital condition that has a
Mendelian pattern of inheritance characterised by a chronic haemolytic anaemia but with
a negative direct Coomb's test. It is best treated by splenectomy.
An example of a chronic haemolytic anaemia due to an inherent problem within the red
cell is glucose 6 phosphate dehydrogenase deficiency. This is an x-linked condition and
therefore affects only males. It leads to a chronic haemolytic state which is exacerbated
by certain drugs, infection and the ingestion of favar beans. Treatment is avoidance of
precipitating agents.
Normochromic anaemia
Anaemia of chronic disease
Most chronic coexistent medical conditions can cause such an anaemia. The mechanism
is thought to be due to failure to use iron efficiently. Examples of chronic conditions
include chronic inflammatory diseases such as rheumatoid arthritis, chronic infections
including tuberculosis or malignancy. Some cases of anaemia of chronic disease are
hypochromic, microcytic, ie, low MCH, low MCV but with a normal ferritin.
Acute blood loss
As mentioned previously, acute major blood loss will cause a normochromic, normocytic
anaemia which becomes apparent after about 24 hours.
Mixed deficiency anaemia
There are rare cases of a mixed deficiency anaemia, eg. combined iron deficiency with
B12 or folate deficiency. The result is an anaemia which is normocytic.
Bone marrow failure
This may occur in individuals whose marrow is infiltrated by malignancy, are post-
chemotherapy or have chronic renal disease.
Microcytic anaemias
Causes of microcytic anaemia include:
Iron deficiency anaemia
This is the most common cause of anaemia in the UK. The most likely cause of iron
deficiency anaemia is chronic blood loss. In women this may be due to excessive periods
(menorrhagia) but overall it is usually due to chronic blood loss from the gastro-intestinal
tract. This may be due to any bleeding pathology in the gut. Blood loss of 4ml per day
will, in time, render an individual iron-deficient. The diagnosis of an iron deficiency
anaemia is confirmed by a reduced serum ferritin. Once it has been ascertained that the
patient has an iron deficient anaemia, then investigation to find the source of blood loss is
required. This usually involves investigation of the G1 tract with barium studies or
endoscopy. Treatment of the iron ferrous sulphate tablets, but it is important to remember
that the cause of the anaemia must be found.
Haemoglobinopathies, e.g., thalassaemia
The thalassaemias are a complicated group of conditions which are inherited. They are
prevalent in certain parts of the world including the Mediterranean basin, parts of Africa,
the Middle East, Indian sub-continent and South-East Asia. In the severe forms of the
disease the patient is chronically anaemic with a hypochromic, microcytic picture but a
raised red cell count. Treatment is by repeated transfusion which can cause iron overload.
Attention then needs to be given to the treatment of the iron overload, generally using
Desferrioxamine. In some patients bone marrow transplantation can be curative.
Other rare causes of a microcytic anaemia include lead poisoning and some types of
sideroblastic anaemia Sideroblastic anaemia is a rare condition which may be either
congenital when it usually occurs in males, or is secondary to certain drugs, particularly
those used to treat tuberculosis.
Anemia, like a fever, is a symptom of disease that requires investigation to determine the
underlying etiology. Often, practicing physicians overlook mild anemia. This is similar to
failing to seek the etiology of a fever. The purpose of this article is to provide a method
of determining the etiology of an anemia.
Anemia is strictly defined as a decrease in red blood cell (RBC) mass. Methods for
measuring RBC mass are time consuming, are expensive, and usually require transfusion
of radiolabeled erythrocytes. Thus, in practice, anemia is usually discovered and
quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and
hematocrit (Hct). These values should be interpreted cautiously because they are
concentrations affected by changes in plasma volume. For example, dehydration elevates
these values, and increased plasma volume in pregnancy can diminish them without
affecting the RBC mass.

Pathophysiology
Erythroid precursors develop in bone marrow at rates usually determined by the
requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid
precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to
normoblasts in a process requiring growth factors and cytokines. This process of
differentiation requires several days. Normally, erythroid precursors are released into
circulation as reticulocytes.
Reticulocytes remain in the circulation for approximately 1 day before reticulin is excised
by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation.
The mature erythrocyte remains in circulation for about 120 days before being engulfed
and destroyed by phagocytic cells of the reticuloendothelial system.
Erythrocytes are highly deformable and increase their diameter from 7 µm to 13 µm
when they traverse capillaries with a 3-µm diameter. They possess a negative charge on
their surface, which may serve to discourage phagocytosis. Because erythrocytes have no
nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and
pentose pathways for energy. Many enzymes required by the aerobic and anaerobic
glycolytic pathways decrease within the cell as it ages. In addition, the aging cell has a
decrease in potassium concentration and an increase in sodium concentration. These
factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan.
RBCs contain fluid Hb encased in a lipid membrane supported by a cytoskeleton.
Abnormalities of the membrane, the chemical composition of the Hb, or certain
glycolytic enzymes can reduce the lifespan of RBCs to cause anemia. Basically, only 3
causes of anemia exist: blood loss, increased RBC destruction (hemolysis), and decreased
production of RBCs. Each of these 3 causes includes a number of etiologies that require
specific and appropriate therapy. Often, the etiology can be determined if the RBCs are
altered in either size or shape or if they contain certain inclusion bodies. For example,
Plasmodium falciparum malaria is suggested by the presence of more than one ring form
in an RBC and produces pan-hemolysis of RBCs of all ages.

Frequency

United States
The prevalence of anemia in population studies of healthy nonpregnant people depends
on the Hb concentration chosen for the lower limit of normal values. The World Health
Organization chose 12.5 g/dL for both adult males and females. In the United States,
limits of 13.5 g/dL for men and 12.5 g/dL for women are probably more realistic. Using
these values, approximately 4% of men and 8% of women have values lower than those
cited. A significantly greater prevalence is observed in patient populations. Less
information is available regarding studies using RBC or Hct.

International
The prevalence of anemia in Canada and northern Europe is believed to be similar to that
in the United States. In underprivileged countries, limited studies of purportedly healthy
subjects show the prevalence of anemia to be 2-5 times greater than that in the United
States. Although geographic diseases, such as sickle cell anemia, thalassemia, malaria,
hookworm, and chronic infections, are responsible for a portion of the increase,
nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play
major roles in the increased prevalence of anemia. Populations with little meat in the diet
have a high incidence of iron deficiency anemia because heme iron is better absorbed
from food than inorganic iron.

Mortality/Morbidity
• The morbidity and mortality of anemias vary greatly depending on the etiology.

• Acute hemorrhage has variable mortality depending on the site of bleeding

(80% with aortic rupture, 30-50% with bleeding esophageal varices,
approximately 1% with benign peptic ulcers).

• Anemia from gastrointestinal bleeding may be the first evidence of an

intestinal malignancy.

• Sickle cell disease may be associated with frequent painful crises and a
shortened lifespan, or patients with sickle cell disease may remain
relatively asymptomatic with a nearly normal lifespan.

• Most patients with beta-0 homozygous thalassemia die during the second
or third decade of life unless they undergo bone marrow transplantation.

• Ηερεδιταρψ σπηεροχψτοσισ either may present with a severe hemolytic

anemia or may be asymptomatic with compensated hemolysis.

• Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may

manifest as chronic hemolytic anemia or exist without anemia until the
patient receives an oxidant medication.

• The 2-year fatality rate for severe aplastic anemia is 70% without bone
 marrow transplantation or a response to immunosuppressive therapy.

• Many symptoms associated with anemia are not caused by diminished RBC mass.
Patients with pernicious anemia are often asymptomatic when they are detected
incidentally with an Hb of 6 g/dL. In contrast, ice chewing, calf cramps, and
diminished capability to perform muscular work occur in iron-deficiency anemia
with an Hb of 10-11 g/dL because of depletion of iron-containing proteins other
than Hb.

• In addition, tolerance of anemia is proportional to the anemia's rate of

development. Symptoms and mortality associated with rapidly developing anemia
are more profound than in slowly developing anemia.

• Race
• Certain races and ethnic groups have an increased prevalence of genetic factors
associated with certain anemias. Examples are hemoglobinopathies, thalassemia,
and G-6-PD deficiency. Each of these disorders has different morbidity and
mortality in different populations due to differences in the genetic abnormality
producing the disorder. For example, G-6-PD deficiency and thalassemia have
less morbidity in African Americans than in Sicilians because of differences in the
genetic fault. Conversely, sickle cell anemia has a greater morbidity and mortality
in African Americans than among Saudi Arabians.

• Race is a factor in nutritional anemias and anemia associated with chronic

untreated illnesses to the extent that socioeconomic advantages are distributed
along racial lines in a given area. Socioeconomic advantages affect diet and the
availability of health care and lead to a decreased prevalence of these types of
anemia.1, 2, 3 For instance, iron deficiency anemia is much more prevalent in third
world populations who have little meat in their diets than it is in populations of
the United States and northern Europe. Similarly, anemia of chronic disorders is
commonplace in populations with a high incidence of chronic infectious disease
(eg, malaria, tuberculosis, AIDS), and this is at least in part worsened by the
socioeconomic status of these populations and their access to adequate health
care.

Sex
• Overall, anemia is twice as prevalent in females as in males. This difference is
significantly greater during the childbearing years due to pregnancies and menses.

• Approximately 65% of body iron is incorporated into circulating Hb. Each gram
of Hb contains 3.46 mg of iron (1 mL of blood with Hb of 15 g/dL = 0.5 mg of
iron). Each healthy pregnancy depletes the mother of approximately 500 mg of
 iron. While a man must absorb about 1 mg of iron to maintain equilibrium, a
premenopausal woman must absorb an average of 2 mg daily. Further, because
women eat less food than men, they must be more than twice as efficient as men
in the absorption of sufficient iron to avoid iron deficiency.

• Women have a markedly lower incidence of anemia from X-linked anemias, such
as G-6-PD deficiency and sex-linked sideroblastic anemias.

Age
• Severe genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi
syndrome) are more commonly found in children because they do not survive to
adulthood.

• During the childbearing years, women are more likely to become iron deficient.

• Neoplasia increases in prevalence with each decade of life and can produce
anemia from bleeding, from the replacement of bone marrow with tumor, or from
the development of anemia associated with chronic disorders. Use of aspirin,
nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with
age and can produce gastrointestinal bleeding.

CLINICAL
Section 3 of 11

• Authors and Editors

• Ιντροδυχτιον

• Χλινιχαλ

• ∆ιφφερεντιαλσ

• Ωορκυπ

• Τρεατµεντ

• Μεδιχατιον

• Φολλοω−υπ

• Μισχελλανεουσ

• Μυλτιµεδια
 • Ρεφερενχεσ

History
Carefully obtain a history and perform a physical examination in every patient with
anemia because the findings usually provide important clues to the etiology of the
underlying disorder. From the standpoint of the investigation of the anemia, asking
questions in addition to those conventionally explored during a routine examination is
important. Areas of inquiry found valuable are briefly described below.

• Often, the duration of anemia can be established by obtaining a history of

previous blood examination and, if necessary, by acquiring those records.
Similarly, a history of rejection as a blood donor or prior prescription of
hematinics provides clues that anemia was detected previously.

• Obtain a careful family history not only for anemia but also for jaundice,
cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs. Carefully
document the patient's occupation, hobbies, prior medical treatment, drugs
(including over-the-counter medications and vitamins), and household exposures
to potentially noxious agents. Patients are unlikely to volunteer exposures to
tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically
queried.

• In searching for blood loss, carefully document pregnancies, abortions, and

menstrual loss. Estimates of menstrual losses are notoriously inaccurate if only
routine inquiry is made.

• Often, patients do not appreciate the significance of tarry stools. Changes in

bowel habits can be useful in uncovering neoplasms of the colon.

• Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or

overestimated from one patient to another. Obviously, seek a careful history of
gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias,
or diverticula.

• Abnormal urine color can occur in renal and hepatic disease and in hemolytic
anemia.

• A thorough dietary history is important in a patient who is anemic. This history

must include foods that the patient both eats and avoids as well as an estimate of
their quantity.

• A meal-by-meal description is necessary to obtain appropriate estimates.

 • Even then, patients frequently attempt to deceive the physician because of
embarrassment regarding dietary idiosyncrasies or financial restrictions. In
these circumstances, a close and concerned family member participating in
the dietary history can often be helpful because this person is usually more
objective than the patient.

• Specifically question patients regarding consumption of either clay or

laundry starch. This history will not be provided spontaneously. These
substances render iron less absorbable.

• Changes in body weight are important with regard to dietary intake and
can suggest the presence of malabsorption or an underlying wasting
disease of infectious, metabolic, or neoplastic origin.

• Nutritional deficiencies may be associated with unusual symptoms that can be

elicited by a history.

• Patients with iron deficiencies frequently chew or suck ice (pagophagia).

Occasionally, they complain of dysphasia, brittle fingernails, relative
impotence, fatigue, and cramps in the calves on climbing stairs that are out
of proportion to their anemia.

• In vitamin B-12 deficiency, early graying of the hair, a burning sensation

of the tongue, and a loss of proprioception are common.

• Suspect a loss of proprioception if the patient stumbles in the dark or must

look in order to put on pants in the morning.

• Paresthesia or unusual sensations frequently described as pain also occur

in pernicious anemia.

• Patients with folate deficiencies may have a sore tongue, cheilosis, and
symptoms associated with steatorrhea.

• Color, bulk, frequency, and odor of stools and whether the feces float or
sink can be helpful in detecting malabsorption. More sensitive questions to
detect steatorrhea include whether the toilet needs to be flushed more than
once to rid it of stool and whether an oily substance is floating on the
water surface after the first flush.

• Obtain a history of fever or identify the presence of fever because infections,

neoplasms, and collagen vascular disease can cause anemia. Similarly, the
occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of
either thrombocytopenia or other bleeding disorders; this may be an indication
either that more than one bone marrow lineage is involved or that coagulopathy is
a cause of the anemia because of bleeding.

• Cold intolerance can be an important symptom of hypothyroidism or lupus

 erythematosus, paroxysmal cold hemoglobinuria, and certain
macroglobulinemias.

• The relation of dark urine to either physical activity or time of day can be
important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria.

• Explore the presence or the absence of symptoms suggesting an underlying

disease, such as cardiac, hepatic, and renal disease; chronic infection;
endocrinopathy; or malignancy.

• Physical
• Too often, the physician rushes into the physical examination without looking at the
patient for an unusual habitus or appearance of underdevelopment, malnutrition, or
chronic illness. These findings can be important clues to the underlying etiology of
disease and provide information related to the duration of illness. The skin and
mucous membranes are often bypassed so that pallor, abnormal pigmentation, icterus,
spider nevi, petechiae, purpura, angiomas, ulcerations, palmar erythema, coarseness
of hair, puffiness of the face, thinning of the lateral aspects of the eyebrows, nail
defects, and a usually prominent venous pattern on the abdominal wall are missed in
the rush to examine the heart and the lungs.

• Examine optic fundi carefully but not at the expense of the conjunctivae and the
sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma
signs in the conjunctival vessels, or telangiectasia that can be helpful in planning
additional studies.

• Perform systematic examination for palpable enlargement of lymph nodes for

evidence of infection or neoplasia. Bilateral edema is useful in disclosing
underlying cardiac, renal, or hepatic disease, whereas unilateral edema may
portend lymphatic obstruction due to a malignancy that cannot be observed or
palpated.

• Carefully search for both hepatomegaly and splenomegaly. Their presence or

absence is important, as are the size, the tenderness, the firmness, and the
presence or the absence of nodules. In patients with chronic disorders, these
organs are firm, nontender, and nonnodular. In patients with carcinoma, they may
be hard and nodular. The patient with an acute infection usually has a palpably
softer and more tender organ.

• A rectal and pelvic examination cannot be neglected because tumor or infection of

these organs can be the cause of anemia.

• The neurologic examination should include tests of position sense and vibratory
sense, examination of the cranial nerves, and testing for tendon reflexes. The heart
should not be ignored because enlargement may provide evidence of the duration
 and the severity of the anemia, and murmurs may be the first evidence of a
bacterial endocarditis that could explain the etiology of the anemia.

Causes
Causes of anemia are numerous and multifaceted. A family history may be useful in
detecting hereditary etiology. Diet and exposure to drugs and chemicals can be useful. A
geographic history and a thorough knowledge of the patient's health can be important in
establishing an etiology.

• Genetic

• Hemoglobinopathies

• Thalassemias

• Enzyme abnormalities of the glycolytic pathways

• Defects of the RBC cytoskeleton

• Congenital dyserythropoietic anemia

• Rh null disease

• Hereditary xerocytosis

• Abetalipoproteinemia

• Fanconi anemia

• Nutritional

• Iron deficiency

• Vitamin B-12 deficiency

• Folate deficiency

• Starvation and generalized malnutrition

• Hemorrhage

• Immunologic - Antibody-mediated abnormalities

• Physical effects

• Trauma
 • Burns

• Frostbite

• Prosthetic valves and surfaces

• Drugs and chemicals

• Aplastic anemia

• Megaloblastic anemia

• Chronic diseases and malignancies

• Renal disease

• Hepatic disease

• Chronic infections

• Neoplasia

• Collagen vascular diseases

• Infections

• Viral - Hepatitis, infectious mononucleosis, cytomegalovirus

• Bacterial - Clostridia, gram-negative sepsis

• Protozoal - Malaria, leishmaniasis, toxoplasmosis

• Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

• DIFFERENTIALS
• Section 4 of 11

• Authors and Editors

• Ιντροδυχτιον

• Χλινιχαλ
 • ∆ιφφερεντιαλσ

• Ωορκυπ

• Τρεατµεντ

• Μεδιχατιον

• Φολλοω−υπ

• Μισχελλανεουσ

• Μυλτιµεδια

• Ρεφερενχεσ

•
Aplastic Anemia
Cooley Anemia
Hemolytic Anemia
Iron Deficiency Anemia
Low LDL Cholesterol (Hypobetalipoproteinemia)
Megaloblastic Anemia
Myelophthisic Anemia
Pernicious Anemia
Sickle Cell Anemia
Spur Cell Anemia
Thalassemia, Alpha
Thalassemia, Beta

• WORKUP
• Section 5 of 11

• Authors and Editors

• Ιντροδυχτιον

• Χλινιχαλ

• ∆ιφφερεντιαλσ

• Ωορκυπ

• Τρεατµεντ
 • Μεδιχατιον

• Φολλοω−υπ

• Μισχελλανεουσ

• Μυλτιµεδια

• Ρεφερενχεσ

Lab Studies
• The first step in the diagnosis of anemia is detection with reliable accurate tests so
that important clues to underlying disease are not overlooked and patients are not
subjected to unnecessary tests for and treatment of nonexistent anemia. Detection
of anemia involves the adoption of arbitrary criteria.

• The World Health Organization's criterion for anemia in adults is Hb

values less than 12.5 g/dL. Children aged 6 months to 6 years are
considered anemic at Hb levels less than 11 g/dL, and children aged 6-14
years are considered anemic when Hb levels are less than 12 g/dL. The
disadvantage of such arbitrary criteria is that a few healthy individuals fall
below the reference range, and some people with an underlying disorder
fall within the reference range for Hb concentration.

• Usually, US values are slightly higher. Anemia is suggested in males with

Hb levels less than 13.5 g/dL and in females with Hb levels less than 12.5
g/dL. Higher values are anticipated in individuals living in altitudes
significantly above sea level. Conditions with an increase in plasma
volume, such as during the last trimester of pregnancy, are associated with
lower values without an existent anemia because the red cell mass is
normal.

• Once the existence of anemia is established, investigate the pathogenesis. If an

adequate history has been taken and a physical examination has been performed,
the etiology may be obvious, and confirmatory studies and appropriate therapy
can be undertaken with a minimum of investigation. If this is not the case, initiate
a definite plan of investigation considering the cost to the patient along with a
determination of the etiology of the abnormality.

• A rational approach is to begin by examining the peripheral smear and laboratory

values obtained on the blood count. If the anemia is either microcytic (mean
corpuscular volume [MCV], <84) or macrocytic (MCV, >96) or if certain
abnormal RBCs or WBCs are observed in the blood smear, the investigative
approach can be limited (see Table 1, Table 2, and Table 3).
 • Presently, RBC cellular indices are computer calculated and automatically placed
on laboratory reports. The formulae for calculating these values follow (reference
ranges are in parentheses). RBC is per million cells.

• MCV = Hct X 10/RBC (84-96 fL)

• Mean corpuscular Hb (MCH) = Hb X 10/RBC (26-36 pg)

• Mean corpuscular Hb concentration (MCHC) = Hb X 10/Hct (32-36%)

• A rapid method of determining whether cellular indices are normocytic and

normochromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3
should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Deviation
from the calculated values suggests microcytosis, macrocytosis, or hypochromia
versus the presence of spherocytes (MCHC, >36).

• Table 1. Microcytic Hypochromic Anemia (MCV, <83; MCHC, <31)

S
Total Iron- Bone
Conditi eru
Binding Marr
on m Comment
Capacity ow
Iro
(TIBC) Iron
n
Iron
deficien ⇓ ⇑ 0 Responsive to iron therapy
cy
Chronic
inflamm ⇓ ⇓ ++ Unresponsive to iron therapy
ation
Thalass
Reticulocytosis and indirect
emia ⇑ N ++++
bilirubinemia
major
Thalass Elevation of A of fetal
emia N N ++ hemoglobin, target cells, and
minor poikilocytosis
Lead
poisonin N N ++ Basophilic stippling of RBCs
g
Siderobl
⇑ N ++++ Ring sideroblasts in marrow
astic
Hemogl
N N ++ Hemoglobin electrophoresis
obin

• ⇑ = increased, ⇓ = decreased, N = normal, 0 = absent, +'s indicate amount of

stainable iron in bone marrow specimens on a scale of 0-4.

Table 2. Macrocytic Anemia (MCV, >95)

Megaloblastic bone marrow
Nonmegaloblastic bone
marrow
Deficiency of vitamin B-12
Deficiency of folic acid
Drugs affecting DNA synthesis
Inherited disorders of DNA synthesis
Liver disease
Hypothyroidism and hypopituitarism
Accelerated erythropoiesis (reticulocytes)
Hypoplastic and aplastic anemia
Infiltrated bone marrow

Table 3. Various Forms of RBCs

Macr
Larger than normal (>8.5 µm diameter). See Table 2.
ocyte
Micro
Smaller than normal ( <7 µm diameter). See Table 1.
cyte
Hypo
Less hemoglobin in cell. Enlarged area of central pallor. See Table
chro
1.
mic
Spher Loss of central pallor, stains more densely, often microcytic.
ocyte Hereditary spherocytosis and certain acquired hemolytic anemias.
Targe Hypochromic with central "target" of hemoglobin. Liver disease,
t cell thalassemia, hemoglobin D, postsplenectomy.
Lepto Hypochromic cell with a normal diameter and decreased MCV.
cyte Thalassemia.
Ellipt Oval to cigar shaped. Hereditary elliptocytosis, certain anemias
ocyte (particularly vitamin B-12 and folate deficiency).
Schist Fragmented helmet- or triangular-shaped RBCs. Microangiopathic
ocyte anemia, artificial heart valves, uremia, malignant hypertension.
Stom
Slitlike area of central pallor in erythrocyte. Liver disease, acute
atocyt
alcoholism, malignancies, hereditary stomatocytosis, and artifact.
e
Tear-
shape Drop-shaped erythrocyte, often microcytic. Myelofibrosis and
d infiltration of marrow with tumor. Thalassemia.
RBCs
Acant
Five to 10 spicules of various lengths and at irregular interval on
hocyt
surface of RBCs.
e
Evenly distributed spicules on surface of RBCs, usually 10-30.
Echin
Uremia, peptic ulcer, gastric carcinoma, pyruvic kinase deficiency,
ocyte
preparative artifact.
Sickl Elongated cell with pointed ends. Hemoglobin S and certain types
e cell of hemoglobin C and l.

• In microcytic hypochromic anemia, seek a source of bleeding. The appropriate

laboratory tests are serum iron level and TIBC and either serum ferritin level or
stain of bone marrow specimen for iron. If the serum iron level is decreased and
TIBC is increased, a diagnosis of iron deficiency can be made, therapy can be
initiated, and a search for the cause of the iron deficiency can be started. If this
cannot be demonstrated, suspect each of the other causes of a microcytic anemia
listed in Table 1, and the order of investigation can be influenced by findings in
the history, physical examination, or peripheral smear.

• Similarly, a reasonable approach with macrocytic anemia is to determine if the

bone marrow aspirate is megaloblastic. If so, attempt to incriminate either vitamin
B-12 or folic acid deficiency with appropriate laboratory studies. Similar to the
establishment of a diagnosis of iron deficiency anemia, a diagnosis of vitamin B-
12 or folic acid deficiency does not stop with an abnormal laboratory value for
one of these vitamins. Prompt treatment can be instituted, but a continued search
for an underlying cause of the vitamin deficiency is indicated (see Pernicious
Anemia).

• When a normocytic normochromic anemia is encountered, classify the anemia

into 3 possible etiologies (ie, blood loss, hemolysis, decreased production). In
most anemias, one of these causes is the dominant factor. However, in certain
anemias, more than a single cause may play an important role. For example,
pernicious anemia is predominantly due to decreased production of erythrocytes,
 but hemolysis adds significantly to the severity of anemia.

• Blood loss

• Obviously, significant hemorrhage produces anemia. Immediately after

blood loss, the Hct cannot be used as a reliable method to determine the
quantity of lost blood because the patient loses plasma as well as RBCs.
After acute hemorrhage, the Hct falls for 24-48 hours until the plasma
volume is replaced. At that time, anemia is normochromic and normocytic
with normal cellular indices because the cells in the peripheral blood have
been produced prior to bleeding (see Iron Deficiency Anemia).

• If the patient had adequate iron stores, accelerated production of RBCs

occurs, so that 1 week after bleeding, a larger than normal number of
young RBCs and reticulocytes are circulating in the peripheral blood.
Because reticulocytes and young RBCs have a larger volume (MCV of
approximately 120), macrocytes may be observed in the peripheral smear,
and a slight increase in the MCV occurs.

• If hemorrhage was sufficient to deplete iron stores (1-2 L of blood, 500-

1000 mg of iron), newly formed erythrocytes are microcytic and
hypochromic and gradually replace normal erythrocytes in the circulation
that were produced prior to the induction of iron deficiency. Because
RBCs normally survive for 120 days in circulation, maximal changes in
the MCV and MCHC are not observed until that time. Iron deficiency and
the depletion of iron stores can be detected several weeks after bleeding by
measurements of the serum iron level and TIBC and/or special stains of
bone marrow specimens showing an absence of storage iron.

• Diagnosis of iron deficiency anemia in an adult in the United States should

be attributed to bleeding unless other causes can be proven. Aside from
recent multiparity, other causes are relatively uncommon and include
prolonged dietary idiosyncrasies (eg, clay eating, laundry starch
consumption, protein deprivation for several years), urinary loss of iron
due to intravascular hemolysis (eg, artificial aortic valves, paroxysmal
nocturnal hemoglobinuria), gastrectomy, and other upper gastrointestinal
surgery or disease.

• Diagnosis of iron deficiency anemia is made by demonstrating that the

patient has low serum iron levels and elevated TIBC, absence of stainable
iron in a bone marrow specimen, or both. A low serum ferritin level
provides confirmation of the diagnosis. The presence of microcytosis and
hypochromia is helpful but not diagnostic.

• Microcytic hypochromic anemia is observed with conditions other than

iron deficiency anemia. Certain types of these disorders are iron-
overloading states in which the administration of iron can be deleterious to
 the patient (see Table 1). Similarly, low serum iron levels can be observed
in chronic inflammatory states with normal body stores of iron. However,
in the latter, the TIBC is usually decreased rather than increased, and
stainable iron can be demonstrated in bone marrow aspirates. Whenever
the diagnosis of iron deficiency anemia is in doubt, follow-up blood work
after administration of iron to show correction of the anemia can be
helpful in confirming the diagnosis.

• The patient notices hemorrhage from most body organs. Epistaxis,

hemoptysis, or hematuria of sufficient degree to cause anemia is usually
reported to the physician long before iron deficiency ensues. However,
bleeding from either the uterus or the gastrointestinal tract may be
disregarded by the patient or be totally undetected until anemia becomes
profound and symptomatic.

• Menstrual bleeding among healthy females varies monthly from 10-250

mL. Unless the patient observes a change in menses, she relates that
menses are normal unless specific questions are asked. The presence of
clots, abdominal cramps, excessive gushing of blood upon removal of
tampons, the need for both tampons and pads, and the use of an unusual
number of pads or tampons can be used to determine if menstrual bleeding
may be sufficient to induce iron deficiency anemia.

• Gastrointestinal bleeding is the other occult cause of anemia due to blood

loss. If hemorrhage is profuse, it is usually detected before evidence of
iron deficiency anemia occurs because hematochezia or melena causes the
patient to seek medical attention. However, if the bleeding occurs slowly,
it is usually undetected until anemia ensues because stools appear normal.

• Every patient with iron deficiency anemia should have a stool examination
for occult blood. A positive result necessitates a careful search of the
gastrointestinal tract to identify the site of bleeding. Unfortunately, a
negative result does not exclude gastrointestinal blood loss because
bleeding can be intermittent and require several examinations for
detection. Also, less than 20-30 mL of blood in the stool per day may go
undetected due to the insensitivity of the test. The 2 methods used to
detect small daily losses of blood from the gut are as follows: (1) placing
the patient on a meat-free diet for several days and using more sensitive
methods, such as a benzidine test, and (2) labeling the patient's RBCs with
chromium 51 and collecting stool specimens for the detection of the
radioisotope.

• Investigate gastrointestinal bleeding by endoscopy and radiographic

studies (see Procedures).

• Hemolysis (increased RBC destruction)

 • A normal RBC survives in the circulation for 120 days. If the erythrocytic
lifespan is shortened significantly ( <40 d), the patient has a hemolytic
disorder that may be demonstrated by showing increased production of
erythrocytes, increased destruction, or both. The former is revealed most
readily by the presence of sustained reticulocytosis and the latter by the
occurrence of indirect bilirubinemia (see Table 4, below).

• Other laboratory tests are available to detect hemolysis, but they are either
more expensive or less reliable.

• Table 4. Classification of the Hemolytic Disorders

Hereditary Acquired

Hereditary
spherocytos
is
Hereditary
elliptocytos
is
Hemoglobi
nopathies
Thalassemi
Intraco as Vitamin B-12 and folic acid deficiency
rpuscu Congenital Paroxysmal nocturnal
lar dyserythrop Hemoglobinuria
defect oietic Severe iron deficiency
anemias
Hereditary
RBC
enzymatic
deficiencies
Rarer
hereditary
abnormaliti
es
Extrac Physical agents: Burns, cold exposure
orpusc Traumatic: Prosthetic heart valves, march
ular hemoglobinemia, DIC, graft rejection
defect Chemicals: Drugs and venoms
Infectious agents: Malaria, toxoplasmosis,
mononucleosis, hepatitis, primary atypical
pneumonia, clostridial infections, bartonellosis,
leishmaniasis
 Hepatic and renal disease
Collagen vascular disease
Malignancies: Particularly hematologic neoplasia
Transfusion of incompatible blood
Hemolytic disease of the newborn
Cold hemagglutinin
disease
Autoimmune hemolytic anemia Thrombotic
thrombocytopenic purpura (TTP) and hemolytic
uremic syndrome (HUS)

• Anemia solely due to hemolysis does not occur until RBCs are being
destroyed at 6-8 times the normal rate, reducing the mean RBC lifespan to
less than 20 days because of the bone marrow's capacity to undergo 6-fold
hypertrophy and hyperplasia. Thus, if the clinician relies on the presence
of anemia to detect hemolytic states, the clinician misses most of them
and, perhaps, an important clue to an underlying disorder. On the contrary,
if reticulocytosis and indirect bilirubinemia are used to detect hemolytic
states, they are usually found when the mean lifespan is less than 40-50
days. More sophisticated methods, such as measurements of RBC lifespan,
are required to detect less severe shortening of erythrocyte lifespan (50-
100 d) and are only occasionally needed in clinical practice.

• All patients with both reticulocytosis and indirect bilirubinemia have a

hemolytic disorder. All patients with sustained reticulocytosis have a
hemolytic disorder. Unfortunately, the contrary is not the case, and
significant hemolysis can occur without reticulocytosis if the bone marrow
is unable to produce cells at an accelerated rate (eg, pernicious anemia,
leukemia, aplasia). A single demonstration of an elevated reticulocyte
count is insufficient to establish a diagnosis of hemolysis because transient
reticulocytosis may occur without hemolysis (eg, in the treatment of iron
deficiency anemia).

• Almost all patients with indirect bilirubinemia have a hemolytic disorder.

In adults, the exception is patients with Gilbert disease. These patients can
be distinguished from those with hemolytic disorders and those who have
no other obvious stigmata of hemolysis (eg, anemia, reticulocytosis,
Coombs test) by having the patient fast for 3 days. In Gilbert disease,
indirect bilirubin doubles with starvation, whereas in hemolytic disorders,
it does not. Once the presence of hemolysis has been established, the
etiology of the increased rate of RBC destruction can be sought.

• All causes of hemolytic disorders are either hereditary or acquired.

Similarly, they are due to either an intrinsic abnormality of the RBC
(intracorpuscular defect) or external factors that shorten the erythrocyte
lifespan (extracorpuscular). Using this nomenclature, only 4 groups of
hemolytic disorders are possible—hereditary intracorpuscular, hereditary
 extracorpuscular, acquired intracorpuscular, and acquired
extracorpuscular.

• All hereditary hemolytic disorders are due to intracorpuscular defects, and

most acquired disorders are due to extracorpuscular abnormalities (see
Table 4). Hereditary etiologies of hemolytic disease are suggested strongly
in any patient with a family history of anemia, jaundice, cholelithiasis, or
splenectomy. Whenever possible, family members, particularly parents,
siblings, and children, should undergo a hematologic examination,
including hemogram with reticulocyte count, indirect bilirubin
determination, and careful examination of the peripheral smear.

• If a specific hereditary hemolytic disorder (eg, hereditary spherocytosis,

hemoglobinopathy) is suggested in a patient, examine blood from family
members for that entity by appropriate laboratory methods. Establishment
of a hemolytic defect in other closely related family members permits a
presumptive diagnosis of hereditary intracorpuscular hemolytic disorder in
the patient. Showing a similar RBC abnormality (eg, spherocytes,
abnormal Hb, G-6-PD deficiency) among family members establishes the
basic etiology. Once the probability of a hereditary hemolytic disorder is
established, a planned approach to determine the definitive abnormality is
usually simple.

• A careful examination of the peripheral smear may reveal spherocytes in

hereditary spherocytosis; ovalocytes in hereditary elliptocytosis; sickle
cells in patients with major hemoglobinopathies associated with sickle Hb;
target cells in patients with Hb C or E disease; and marked poikilocytosis
with target cells, microcytes, and hypochromic RBCs in thalassemia.

• Even in certain rare disorders, abnormal erythrocyte morphology may

provide an important clue. Examples are acanthocytosis in
abetalipoproteinemia, stomatocytosis in the hereditary disorder of this
name, and numerous target cells in lecithin cholesterol acyltransferase
deficiency. Other laboratory studies of value in the hereditary hemolytic
disorders include the following:4

• Hereditary spherocytosis - MCHC greater than 36%, incubated

osmotic fragility studies autohemolysis in oxalate, and detection of
the underlying molecular defect

• Hemoglobinopathies - Sickle cell preparation, Hb electrophoresis

at one or more pH, heat denaturation test for unstable Hbs, oxygen
disassociation for Hbs with abnormal oxygen affinity

• Thalassemia - A2 and fetal Hb, Hb electrophoresis,

characterization of the molecular defect, quantification of alpha
and beta chains
 • Congenital dyserythropoietic anemias - Demonstration of
abnormalities of erythroid precursors in bone marrow aspirates,
positive acid hemolysis (Ham) test with normal result of sucrose
hemolysis test in one form of this disease (hereditary erythroblastic
multinuclearity with a positive acidified serum test [HEMPAS])

• Hereditary RBC enzymatic deficiencies - Specific RBC enzyme

assay

• In clinical practice, approximately 90% of hereditary RBC enzymatic

deficiencies with significant clinical manifestations are either G-6-PD
deficiencies or abnormalities of pyruvic kinase. The age at which a
hemolytic disorder is detected is not always helpful in determining
whether the disorder is hereditary. Although the abnormality is inherited,
congenital manifestations may be unusual. An infant with sickle cell
anemia or beta thalassemia appears healthy at birth. Clinical
manifestations usually do not occur in infants younger than 6 months
because fetal Hb has not been replaced by adult Hb until that age. Most
patients with G-6-PD deficiency have no manifestations of the erythrocyte
enzymatic abnormality until they receive an oxidant drug.

• Usually, thalassemia minor is not detected until a routine hemogram is

performed, and, then, it is often mistaken for iron deficiency anemia
because of the microcytosis and hypochromia. Thus, the physician dealing
with adult patients must be as aware of these disorders as the pediatrician.

• The most commonplace of the hereditary disorders is G-6-PD deficiency

because it occurs in 10% of the African American population living in the
United States. In this population, G-6-PD deficiency usually remains
undetected until oxidant drugs are administered. Then, it produces a mild-
to-moderate hemolytic anemia that is transient in nature. In white
populations of Mediterranean derivation, G-6-PD deficiency can produce
a chronic hemolytic anemia without exposure to drugs. Exposure to
oxidant drugs can produce lethal hemolysis.

• Acquired hemolytic disorders occur in a large number of disease states

and can vary considerably in severity. In addition, hemolysis may be
observed as a result of physical injury to the RBC or following exposure
to drugs, chemicals, or venoms. In many patients, the etiology of the
hemolytic disorder is apparent because of other manifestations of the
disease (eg, infections, collagen vascular disease).

• A confirmed positive Coombs test result can be extremely helpful in this

group of disorders. It provides assurance that the hemolytic disorder is an
acquired extracorpuscular defect and limits it to the group of disorders
associated with autoimmune hemolytic anemia. They include the
following:
 • Drug-dependent antibodies (eg, to penicillin, quinidine, alpha
methyldopa)

• Coexistence of an underlying disease (eg, hematologic

malignancies, lupus erythematosus, certain viral infections)

• Idiopathic groups in which an underlying disease cannot be

demonstrated

• Usually, the acquired hemolytic disorders with intracorpuscular defects

are not difficult to diagnose. Vitamin B-12 and folic acid deficiencies are
associated with macrocytic anemia, the presence of hypersegmented
polymorphonuclear leukocytes in the peripheral smear, megaloblastic
bone marrow, physical findings of the underlying cause of the deficiency
state, and abnormal serum levels for the deficient vitamin.

• Iron deficiency in the United States is rarely of sufficient severity to cause

significant hemolysis and is merely mentioned herein for the sake of
completeness.

• Paroxysmal nocturnal hemoglobinuria is diagnosed only if the physician

considers it in the differential diagnosis, and it may manifest by either a
pancytopenia or a hemoglobinuria. However, a sugar-water test can help
exclude this cause of hemolysis.

• The major diagnostic problem encountered with hemolytic disorders is

when the known causes for hemolysis have been excluded by history,
physical examination, and laboratory studies; the Coombs test result is
negative; and not enough family members can be tested to differentiate
between hereditary intracorpuscular hemolytic disorders and acquired
extracorpuscular defects.

• A donor cell chromium survival study can be helpful in differentiating

between a hereditary hemolytic disorder and an acquired hemolytic
disorder. Labeled RBCs from a healthy blood donor of a compatible blood
group allow for a normal survival rate in patients with hereditary
hemolytic disease and a shortened lifespan in those with an acquired
extracorpuscular defect.

• Decreased RBC production

• Diminished production of RBCs is suggested in all patients without

evidence of either blood loss or hemolysis. Thus, a patient with anemia
without evidence of bleeding or iron deficiency with normal indirect
bilirubin and normal or decreased reticulocyte count probably has a defect
in the production of erythrocytes. Many of these patients have
pancytopenia or other abnormalities of the leukocytes or the platelets that
can be detected with an examination of a peripheral smear. When this
 group of disorders is suspected, the most important laboratory test is a
bone marrow biopsy and aspiration (see Procedures). The bone marrow
biopsy permits categorization of these disorders into 3 separate groups: (1)
aplastic or hypoplastic, (2) hyperplastic, and (3) bone marrow replaced
with nonhematopoietic elements (infiltration of bone marrow) (see Image
1).

• Drugs or chemicals commonly cause the aplastic and hypoplastic group of

disorders. Certain types of these causative agents are dose related and others are
idiosyncratic. Any human exposed to a sufficient dose of inorganic arsenic,
benzene, radiation, or the usual chemotherapeutic agents used for treatment of
neoplastic diseases develops bone marrow depression with pancytopenia.
Conversely, among the idiosyncratic agents, only an occasional human exposed to
these drugs has an untoward reaction resulting in suppression of 1 or more of the
formed elements of bone marrow (1:100 to 1:millions). With certain types of
these drugs, pancytopenia is more common, whereas with others, suppression of
one cell line is usually observed. Thus, chloramphenicol may produce
pancytopenia, whereas a granulocytopenia is more frequently observed with
toxicity to sulfonamides or antithyroid drugs.

• The idiosyncratic causes of bone marrow suppression include multiple drugs in

each of the categories that can be prefixed with anti- (eg, antibiotics,
antimicrobials, anticonvulsants, antihistamines). The other idiosyncratic causes of
known etiology are viral hepatitis and paroxysmal nocturnal hemoglobinuria. In
approximately one half of patients presenting with aplastic anemia, a definite
etiology cannot be established, and the anemia must be regarded as idiopathic.

• Whenever possible, a cause for the aplastic anemia should be uncovered because
cessation of exposure may lead to recovery. Identification of the offending agent
is likewise important in determining the prognosis.

• Chances of survival are poorer for patients with idiosyncratic aplasia caused by
chloramphenicol and viral hepatitis and better when paroxysmal nocturnal
hemoglobinuria or anti-insecticides are the probable etiology. The prognosis for
idiopathic aplasia lies between these 2 extremes, with an untreated mortality rate
of approximately 60-70% within 2 years after diagnosis.

• Rare causes of anemia due to a hypoplastic bone marrow include familial

disorders and the acquired pure red cell aplasias. The latter are characterized by a
virtual absence of erythroid precursors in the bone marrow with normal numbers
of granulocytic precursors and megakaryocytes.

• Among patients with a hyperplastic bone marrow and decreased production of

RBCs, one group has an excellent prognosis, and the other is unresponsive,
refractory to therapy, and has a relatively poor prognosis. The former includes
patients with disorders of relative bone marrow failure due to nutritional
deficiency in whom proper treatment with vitamin B-12, folic acid, or iron leads
 to a correction of anemia once the appropriate etiology is established. Drugs
acting as an antifolic antagonist or inhibitor of DNA synthesis can produce similar
effects. The second group includes patients with an idiopathic hyperplasia that
may respond partially to pyridoxine therapy in pharmacologic doses but, more
frequently, does not. These patients have ringed sideroblasts in the bone marrow
indicating an inappropriate use of iron in the mitochondria for heme synthesis.

• Certain patients with marrow hyperplasia may have refractory anemia for years,
but some of the group eventually develop acute myelogenous leukemia.

• Rare causes of diminished erythrocyte production with hyperplastic bone marrow

include hereditary orotic aminoaciduria and erythremic myelosis.

• Infiltration of the bone marrow with fibrous tissue, neoplastic cells, or other cells
that replace normal hematopoietic tissue can diminish the production of RBCs,
granulocytes, and platelets. The diagnosis of myelofibrosis or neoplastic
involvement of bone marrow is often suggested by evidence of myeloid
metaplasia in the peripheral smear (ie, erythroid and granulocyte precursors).
Replacement of bone marrow with nonhemopoietic cells leads to activation of
fetal sites of blood production in organs, such as the liver and the spleen, with
release of abnormally shaped erythrocytes and normoblasts, immature
granulocytes and normoblasts, immature granulocytes, and large platelets into the
peripheral blood. Myeloid metaplasia does not occur in aplastic disease. Thus, its
presence in a patient who is anemic suggests bone marrow infiltration, even
before the biopsy specimen is obtained.

• Imaging Studies
• Imaging studies are useful in the workup for anemia when a neoplastic etiology is
suggested. They permit discovery of the neoplasm or centrally located adenopathy.
Occasionally, they are useful in detecting or confirming the existence of
splenomegaly.

• Procedures
• Investigate gastrointestinal bleeding by endoscopy and radiographic studies to
identify the bleeding site. However, even these methods may leave a source of
gastrointestinal bleeding undetected because these procedures do not detect the
bleeding site or the lesion if small. Examples of these causes include coagulation
abnormalities induced by aspirin or platelet dysfunction, hookworm infestation,
hemangiomas of the small bowel, lymphosarcoma and other tumors, adenomas of
 the gallbladder, and self-administration of anticoagulants.

• Bone marrow aspirates and biopsy findings are particularly useful in establishing
the etiology of anemia in patients with decreased production of RBCs. They help
differentiate aplasia; megaloblastic hyperplasia; and infiltration of marrow with
neoplasia, myelodysplasia, and myelofibrosis. In addition, they lead to a definitive
histologic diagnosis of leukemias, lymphomas, myelomas, and metastatic
carcinomas. These procedures are less useful in detecting hemolytic anemia
(except to detect lymphoma or leukemia), and they are less useful in diagnosing
congenital dyserythropoietic anemia, in which they reveal the multinuclearity of
erythroid precursors. Iron stains of the bone marrow aspirate can be used to
document the existence of iron deficiency anemia or the sideroblastic anemias.

IRON DEFICIENCY ANAEMIA

LABORATORY FINDINGS
Peripheral Blood

• Normal or decreased reticulocytes reflect impaired marrow response to anaemia

in absence of iron.
Sequential Stages in the Development of Iron Deficiency

• Normal indices, no anaemia, and depleted iron stores, indicated by decreased

serum ferritin and marrow haemosiderin - early iron deficiency

• Normocytic, normochromic anaemia follows complete depletion of iron stores;

variable anisocytosis and poikilocytosis

• Microcytic, hypochromic anaemia indicates late iron deficiency.

Bone Marrow

• Decreased or absent stainable iron (haemosiderin) is the earliest indicator of iron

depletion; it precedes anaemia. Stainable marrow iron indicates storage iron.

• Variable cellularity - there is a poor correlation between the severity of anaemia

and the degree of erythroid hyperplasia.

• Decreased sideroblasts, which are iron-containing normoblasts

Other Laboratory Findings*

• Decreased serum ferritin - this is the earliest indicator of iron depletion, usually
corresponding to marrow iron stores. This might be normal in the presence of
accompanying chronic disease, liver disease, or malignant neoplasm.11
 • Increased iron binding capacity - this occurs only after storage iron is completely
depleted. The iron binding capacity is a measure of serum transferrin.

• Decreased serum iron and transferrin saturation (<16% early, <10% late)

• Increased free erythrocyte protoporphyrin - this provides the same information as

transferrin saturation but is a slower and more stable indicator of iron storage.
Laboratory Findings of Underlying Disease

• See diseases and conditions discussed above.

Megaloblastic Anaemia - Peripheral Blood

FOLIC ACID DEFICIENCY

top
LABORATORY FINDINGS
Peripheral Blood

• Findings identical to those in vitamin B12 deficiency

Bone Marrow

• Findings identical to those in vitamin B12 deficiency

Other Laboratory Findings

• Decreased serum folate - this is the most sensitive

indicator of folate deficiency, falling within a month
of deficient intake (Fig. 8-1). This falls many weeks
before megaloblastic anaemia appears. Serum folate
levels may change abruptly with changes in diet.
 • Decreased RBC folate - this appears after 3 months - 4
months of folate deficiency (Fig. 8-1). RBC folate is
an index of tissue folate stores.

• When folate stores are depleted, megaloblastic

anaemia occurs.

• Findings of ineffective erythropoiesis - increased

serum iron, unconjugated bilirubin, and LDH1

• Normal gastric acid; normal Schilling test; normal

serum vitamin B12
Laboratory Findings of Impaired Intestinal Absorption or Its
Causes

• Gluten enteropathy

• Lymphoma

• Amyloidosis

• Scleroderma

• Whipple's disease

ANAEMIA OF CHRONIC DISEASE

top
LABORATORY FINDINGS
Peripheral Blood

• Normochromic, normocytic anaemia (8 g/dl - 12 g/dl;

occasionally <7 g/dl); many patients have
microcytosis (MCV < 80um3) and hypochromia
(mean corpuscular haemoglobin concentration
(MCHC) <31 g/dl)

• Usually normal reticulocyte count; may occasionally

be reduced or slightly increased
Bone Marrow

• Normal cellularity and maturation

• Increased bone marrow RE iron - reflects impaired

 marrow utilisation of stored iron. The increase in
storage iron in the presence of decreased serum iron
and marrow sideroblasts is characteristic of this
disorder.

• Decreased sideroblasts

Other Laboratory Findings

• Decreased serum iron - characteristic finding;

precedes anaemia

• Decreased transferrin, which is usually measured as

total iron binding capacity - occurs after the decrease
in serum iron. This contrasts with increased total iron
binding capacity in iron deficiency.

• Decreased transferrin saturation (mean 15% range

10% - 25%); not as low as in iron deficiency

• Normal or increased serum ferritin - because ferritin

increases in inflammatory disorders, the level is
disproportionately elevated for the amount of marrow
iron.11 This contracts with decreased ferritin in iron
deficiency.
Laboratory Findings of Underlying Disease

• See diseases discussed above.

ANAEMIA OF CHRONIC RENAL

INSUFFICIENCY
top
LABORATORY FINDINGS
Peripheral Blood

• Normochromic, normocytic anaemia (haemoglobin 5

g/dl - 10 g/dl) - characteristic finding

• Microcytic anaemia occurs when there is iron

deficiency due to bleeding seconary to various platelet
dysfunctions. It may also be due to iron loss in
haemodialysis fluid.
 • Macrocytic anaemia - due to loss of folate in
haemodialysis fluid

• Occasional burr or helmet cells

• Acanthocytes and schistocytes, especially in

haemolytic-uremic syndrome

• Usually normal reticulocyte count; might be slightly

decreaed; a moderate increase in reticulocytes may
occur with higher blood urea nitrogen (BUN) levels.
Bone Marrow

• Normal bone marrow appearance; might appear

somewhat hypoplastic
Other Laboratory Findings

• Usually normal serum iron, total iron binding

capacity, transferring saturation; these may all be
decreased if iron deficiency occurs.

• Laboratory findings of chronic renal insufficiency

ANAEMIA OF HYPOMETABOLISM
top
LABORATORY FINDINGS

• Normocytic, normochromic anaemia (>10 g/dl) -

characteristic of hypothyroidism

• Microcytic, hypochromic anaemia is a consequence of

uterine bleeding in hypothyroidism

• Laboratory findings of anterior pituitary insufficiency,

hypothyroidism, Addison's disease, or seconary
testicular failure

HEREDITARY SPHEROCYTOSIS
top
LABORATORY FINDINGS
Peripheral Blood

• Increased spherocytes with decreased cell diameter

(microspherocytes)

• Normocytic, or slightly microcytic, hyperchromic

(MCHC 36 g/dl - 40 g/dl) anaemia (haemoglobin
{Hb} 9 g/dl - 12 g/dl) - the increased MCHC reflects
cell membrane loss

• Increased reticulocytes (5% - 20%) - reflects marrow

response to RBC destruction

• Macrocytes and polychromatophilia reflect

reticulocytosis.

• Increased RBC distribution width and anisocytosis

reflect two RBC populations.
Bone Marrow

• Normoblastic hyperplasia

• Hypoplasia may occur in the presence of an aplastic

crisis.

• Megaloblasts may occur with complicating folate

deficiency, which may supervene in any severe
chronic haemolytic anaemia. This is the result of
accelerated folic acid utilisation and DNA synthesis in
response to normoblastic hyperplasia.

• Moderate haemosiderin deposits

Other Laboratory Findings

• Indicators of extravascular haemolysis - increased

LDH (especially LDH1 and LDH2)1 unconjugated
(indirect) bilirubin, urine haemosiderin; decreased or
absent serum haptoglobin.

• Negative Coomb s' test

Increased Osmotic Fragility Test

Splenomegaly in Hereditary Spherocytosis

GLUCOSE-6-PHOSPHATE
DEHYDROGENASE DEFICIENCY
top
LABORATORY FINDINGS
Diagnostic Laboatory Tests
No Haematologic Findings in the Absence of haemolysis
Haematologic Findings in the Prescence of Haemolysis
Phase 1

• Acute haemolysis (1 day - 3 days after oxidative drug

exposure)

• Normocytic, normochromic anaemia - rapid occurrence,

severe indicators of haemolysis - increased LDH,
unconjugated bilirubin, reticulocytes; decreased
haptoglobin

• Increased Heinz bodies (characteristic feature),

basophillic stippling, polychromatophilia

• Fragmented RBC and spherocytes, if haemolysis is

severe

• Marrow shows normoblastic hyperplasia.

Phase 2

• Recovery (5 days - 15 days after oxidative drug

 exposure)

• Reticulocytosis (8% - 12%)

• Macrocytes reflect reticulocytosis.

• Increase in Hb and haematocrit over earlier values

• Absent haptoglobin reflects chronic haemolysis.

Phase 3

• Resistance (more than 7 days - 10 days after oxidative

drug exposure)

• Haemolysis stops and anaemia disappears.

• Young cells produced in response to haemolysis have

nearly normal levels of enzyme and are relatively
resistance to haemolysis. This phase continues as long as
the same dose of the drug is administered.

•
Πψρυϖατε κινασε δεφιχιενχψ αν αυτοσοµαλ
ρεχεσσιϖε δισορδερ χαυσινγ πολψχηροµασια,
ανισοχψτοσισ, ποικιλοχψτοσισ ωιτη βυρρ χελλσ ανδ
αχαντηοχψτεσ, ανδ ΝΡΒΧσ.
Ρεδυχεδ ΑΤΠ φορµατιον χαυσεσ ΡΒΧ µεµβρανε
ριγιδιτψ, ρεσυλτινγ ιν ηεµολψσισ. Σψµπτοµσ αρε
υσυαλλψ µιλδ ασ ινχρεασεδ 2,3−∆ΠΓ χαυσεσ α ριγητ
σηιφτ οφ τηε 02−δισσοχιατιον χυρϖε.
Περσονσ ηοµοζψγοτε φορ ΠΚ δεφιχιενχψ σηοω σεϖερε
ανεµια ανδ αρε υσυαλλψ δισχοϖερεδ ιν χηιλδηοοδ.
Σπλενοµεγαλψ, χηολελιτηιασισ ανδ ϕαυνδιχε αρε
φρεθυεντ.ΠΡΙςΑΤΕ
∀ΤΨΠΕ=ΠΙΧΤ;ΑΛΤ=∀0100090000034χ00000003001χ000
00000000400000003010600050000000χ025α1δδφ1707000
000φχ020000000000000000040000002δ01000008000000φ
α0200000000000000000000040000002δ0101001χ000000φ
β020χ00090000000000900100000000000202024δ53205361
6ε73205365726966000α0027008α0100000000φφφφφφφφ78
δ31300040000002δ010200030000000000

ΤΗΕ ΤΗΑΛΑΣΣΕΜΙΑΣ
ΗΨΠΕΡΛΙΝΚ ∴λ
∀τοπ∀0100090000034χ00000003001χ00000000000400000
003010600050000000χ029502110207000000φχ0200000000
00000000040000002δ01000008000000φα020000000000000
0000000040000002δ0101001χ000000φβ020χ000900000000
00900100000000000202024δ532053616ε732053657269660
00α0027008α0100000000φφφφφφφφ78δ31300040000002δ0
10200030000000000ΗΨΠΕΡΛΙΝΚ ∴λ
∀τοπ∀ΗΨΠΕΡΛΙΝΚ ∴λ ∀τοπ∀τοπ

∆εφινιτιον
Ηερεδιταρψ δισορδερσ χηαραχτεριζεδ βψ δεφεχτιϖε
προδυχτιον οφ ηεµογλοβιν, ωηιχη λεαδσ το ανεµια.

Χαυσεσ ανδ ρισκσ

Αν ιµβαλανχε ιν τηε αλπηα ανδ βετα προτειν γλοβιν
χηαινσ νεχεσσαρψ φορ τηε προδυχτιον οφ ηεµογλοβιν
ισ χαυσεδ βψ τηε ινηεριτανχε οφ α δεφεχτιϖε γενε.
Τηερε αρε τωο τψπεσ, αλπηα τηαλασσεµια ανδ βετα
τηαλασσεµια. Γενεσ µυστ βε ινηεριτεδ φροµ βοτη
παρεντσ το αχθυιρε τηε δισεασε. Ιφ ονε γενε ισ
ινηεριτεδ, τηε περσον ωιλλ βε α χαρριερ οφ τηε
δισεασε βυτ ωιλλ νοτ ηαϖε σψµπτοµσ. Αλπηα
τηαλασσεµιασ οχχυρσ ιν πεοπλε φροµ σουτηεαστ
Ασια ανδ Χηινα, ανδ αρε χαυσεδ βψ δελετιον οφ α γενε
ορ γενεσ φροµ τηε γλοβιν χηαιν. Τηε µοστ σεϖερε φορµ
οφ αλπηα τηαλασσεµια χαυσεσ α στιλλβορν φετυσ ασ
α ρεσυλτ οφ ηψδροπσ φεταλισ.
Βετα τηαλασσεµια οχχυρσ ιν πεοπλε οφ
Μεδιτερρανεαν οριγιν, ανδ το α λεσσερ εξτεντ,
Χηινεσε, οτηερ Ασιανσ, ανδ βλαχκσ. Ιτ ισ χαυσεδ βψ α
µυτατιον ιν τηε γλοβιν χηαιν. Αφφεχτεδ χηιλδρεν αρε
νορµαλ ατ βιρτη βυτ δεϖελοπ ανεµια δυρινγ τηε φιρστ
ψεαρ οφ λιφε. Γροωτη φαιλυρε, βονε δεφορµιτιεσ, ανδ
ενλαργεδ λιϖερ ανδ σπλεεν αρε σοµε οφ τηε προβλεµσ
τηατ χαν οχχυρ. Βλοοδ τρανσφυσιονσ µαψ µοδιφψ
σοµε οφ τηε δισεασε µανιφεστατιον, βυτ ιρον
οϖερλοαδ φροµ τηε τρανσφυσιονσ χαν χαυσε δαµαγε
το τηε ηεαρτ, λιϖερ, ανδ ενδοχρινε σψστεµσ. Α µιλδερ
φορµ οφ τηε δισεασε, τηαλασσεµια µινορ, προδυχεσ
ιρον−δεφιχιεντ αππεαρινγ βλοοδ χελλσ, ωιτη νο
σψµπτοµσ. Ρισκ φαχτορσ ινχλυδε α φαµιλψ ηιστορψ
οφ τηαλασσεµια ανδ αν ετηνιχ βαχκγρουνδ
συσχεπτιβλε το τηε δισεασε. Τηε ινχιδενχε ϖαριεσ
ωιδελψ τηρουγηουτ τηε ωορλδ.

ΛΑΒΟΡΑΤΟΡΨ ΦΙΝ∆ΙΝΓΣ
Βετα−τηαλασσεµια Μινορ
Περιπηεραλ Βλοοδ
• Ταργετ χελλσ, πολψχηροµατοπηιλια, βασοπηιλιχ
στιππλινγ, οχχασιοναλ νυχλεατεδ ΡΒΧ, ανισοχψτοσισ,
ποικιλοχψτοσισ
• Σλιγητ ηψποχηροµιχ (ΜΧΗ 20 πγ−22πγ), µιχροχψτιχ
(ΜΧς 50 υµ3 − 70 υµ3) αναεµια (ηαεµογλοβιν 9 γ/δλ −
11 γ/δλ), ωιτη νορµαλ το ινχρεασεδ ΡΒΧ (>5.7
µιλλιον/υλ)
• Ινχρεασεδ ρετιχυλοχψτεσ (2% − 10%)
Βονε Μαρροω
• Σλιγητ νορµοβλαστιχ ηψπερπλασια; αβυνδαντ ιρον
δεποσιτσ
Οτηερ Λαβορατορψ Φινδινγσ
• Ελεχτροπηορεσισ σηοωσ ινχρεασεδ ΗβΑ2 (3.5% −
8%); ινχρεασεδ ΗβΦ (1% − 5%) ιν 50% οφ πατιεντσ;
ινχρεασεδ ΗβΑ2 ισ διαγνοστιχ
• ∆εχρεασεδ οσµοτιχ φραγιλιτψ; τηισ ηασ βεεν υσεδ ασ
α ραπιδ σχρεενινγ τεστ
• Νορµαλ το ινχρεασεδ σερυµ ιρον; νορµαλ σερυµ
φερριτιν

Image 1b
Βετα−τηαλασσεµια Μαϕορ
Περιπηεραλ Βλοοδ
• Μαρκεδ ανισοχψτοσισ, ποικιλοχψτοσισ, ταργετ
χελλσ (10% − 35%), σπηεροχψτεσ, φραγµεντεδ ΡΒΧ;
οχχασιοναλ νυχλεατεδ ΡΒΧ, βασοπηιλιχ στιππλινγ,
σιδεροχψτεσ; ινχλυσιον βοδιεσ ρεπρεσεντινγ
αγγρεγατεδ αλπηα χηαινσ
• Μαρκεδ ηψποχηροµιχ, µιχροχψτιχ αναεµια (Ηβ 2.5
γ/δλ − 6.5 γ/δλ)
• Ινχρεασεδ ρετιχυλοχψτεσ (4% − 10%) − τηισ ινχρεασε
ισ λοωερ τηαν τηατ ωηιχη νορµαλλψ οχχυρσ ωιτη
σεϖερε αναεµια ανδ ινδιχατεσ ιναδεθυατε µαρροω
ρεσπονσε
• Ινχρεασεδ ωηιτε βλοοδ χελλ (ΩΒΧ) χουντ (10,000/υλ −
25,000/υλ) ωιτη οχχασιοναλ ιµµατυρε γρανυλοχψτεσ
• Οχχασιοναλ τηροµβοχψτοπενια − ρεφλεχτσ εφφεχτ οφ
σεχονδαρψ ηψπερσπλενισµ
Βονε Μαρροω
• Μαρκεδ νορµοβλαστιχ ηψπερπλασια ωιτη ποορ
ηαεµογλοβινισατιον; βασοπηιλιχ στιππλινγ; αβυνδαντ
ιρον δεποσιτσ; ΡΒΧ χψτοπλασµιχ ινχλυσιονσ, ωηιχη
αρε φρεε αλπηα χηαινσ; χλινιχαλ σεϖεριτψ
χορρελατεσ ωιτη αµουντ οφ αλπηα−χηαιν
πρεχιπιτατιον
Οτηερ Λαβορατορψ Φινδινγσ
• Ελεχτροπηορεσισ σηοωσ ΗβΦ 10% − 100% δεχρεασεδ
ορ αβσεντ ΗβΑ; ΗβΑ2 1% − 8%
• ∆εχρεασεδ οσµοτιχ φραγιλιτψ
• Φινδινγσ οφ ηαεµολψσισ − ινχρεασεδ υνχονϕυγατεδ
βιλιρυβιν, ινχρεασεδ Λ∆Η, δεχρεασεδ ηαπτογλοβιν
• Ινχρεασεδ σερυµ ιρον ανδ τρανσφερριν σατυρατιον
• ∆εχρεασεδ σερυµ φολατε − ρεφλεχτσ ινχρεασεδ
µαρροω υτιλισατιον οφ φολατε
ΗΨΠΕΡΛΙΝΚ
∀ηττπ://ωωω.βλοοδλινε.νετ/στοριεσ/στορψΡεαδερ∃2344
∀Τηαλασσεµια Ιµαγε Σεριεσ(Λινκ το Ιµαγε
σουρχε)ΒΛΟΟ∆ΛΙΝΕ
Haemoglobin H (Link to image source)The blood film
shows hypchromia, microcytosis, and target
cells. HbH disease is due to deletion of three out
of four alpha globin genes, resulting in an
anaemia which varies from mild to severe.

SICKLE-CELL DISEASE
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Sickle cell disease is an inherited blood
disorder in which there is a substitutive defect in
the formation of hemoglobin in the red blood
cells, producing a distinctive disease process.
This disease was first scientifically recorded in
1910 by Dr. James Herrick. While examining the
blood of a young West Indian student, he
observed that many of the red blood cells were
elongated with a curved shape instead of the
normal round configuration. It was after similar
repeated observations by other investigators
that the descriptive term "sickle cell anemia"
was used to describe this disease.

In sickle cell anemia, there is an alteration in the

arrangement of the hemoglobin molecular
structure. At the sixth position in each beta
chain where the amino acid, glutamate should
normally be incorporated, it is replaced by
another amino acid, valine. This small change in
the molecule results in great changes in its
physical and chemical characteristics, so that in
certain stressful conditions when the body is
deprived of oxygen, the red cells then assume a
crescent, banana, or sickle shape. This particular
shape of the red cells makes its travel through
the smaller blood vessels extremely difficult,
producings an obstruction by creating a "log-
jam", which may result in tissue and ultimately
organ damage. Because of the abnormal
hemoglobin and the shape of the red cells, they
are quickly destroyed. This, combined with an
inability of the body to produce sufficient
numbers of new cells, produces a state of
anemia.

The term sickle cell disease refers to all the

clinically significant sickling disorders, since the
degree of anemia may be variable and many
potentially dangerous episodes can occur
without an increase in the severity of the
anemia.

ΠΡΙςΑΤΕ
∀ΤΨΠΕ=ΠΙΧΤ;ΑΛΤ=∀0100090000034χ00000003001χ000
00000000400000003010600050000000χ0254104117070000
00φχ020000000000000000040000002δ01000008000000φα0
200000000000000000000040000002δ0101001χ000000φβ02
0χ00090000000000900100000000000202024δ532053616ε7
3205365726966000α0027008α0100000000φφφφφφφφ78δ31
300040000002δ010200030000000000
Ωελχοµε το τηε ΗΨΠΕΡΛΙΝΚ
∀ηττπ://ωωω.δεπτ.µεδ.υµν.εδυ/µεδιχινε/Χλινιχαλ_σερϖι
χεσ/Σιχκλε_Χελλ_∆ισεασε_Προγραµ/βοδψ_σιχκλε_χελ
λ_δισεασε_προγραµ.ητµλ∀Σιχκλε Χελλ ∆ισεασε
Προγραµ οφ τηε Υνιϖερσιτψ οφ Μιννεσοτα Ηεαλτη
Σψστεµ (ΥΜΗΣ).
ΛΑΒΟΡΑΤΟΡΨ ΦΙΝ∆ΙΝΓΣ
Σιχκλε Χελλ Τραιτ (ΗβΑΣ ∆ισεασε)
• Νορµαλ περιπηεραλ σµεαρ ανδ βονε µαρροω
• Νο αναεµια
• Ποσιτιϖε σιχκλε χελλ τεστ − ωηεν µορε τηαν
25% ΗβΣ ισ πρεσεντ, σιχκλινγ οφ ΡΒΧ µαψ βε
δεµονστρατεδ ιν α βλοοδ συσπενσιον βψ δεοξψγενατιον
οφ τηε βλοοδ
• Ποσιτιϖε σολυβιλιτψ τεστ φορ ΗβΣ − σιχκλε
τεστ Ηβ ισ ινσολυβλε ιν α πηοσπηατε βυφφερ σολυτιον
• Ηβ ελεχτροπηορεσισ − ΗβΑ 70% − 80%; ΗβΣ 30%
− 40%; ΗβΦ <2%. Πρεπονδερανχε οφ ΗβΑ οϖερ ΗβΣ ισ
α πρερεθυισιτε φορ τηισ διαγνοσισ. (Τηε ρεϖερσε
οχχυρσ ιν σιχκλε χελλ βετα−τηαλασσεµια)
• Λοω φιξεδ υρινε σπεχιφιχ γραϖιτψ ανδ
ηαεµατυρια οχχυρ ασ α ρεσυλτ οφ ρεναλ µεδυλλαρψ
µιχροινφαρχτσ.
Σιχκλε Χελλ Αναεµια (ΗβΣΣ ∆ισεασε)
Περιπηεραλ Βλοοδ
• Σιχκλε χελλσ, οϖαλοχψτεσ, µαρκεδ
ποικιλοχψτοσισ, ανισοχψτοσισ, νυχλεατεδ ΡΒΧ,
Ηοωελλ−ϑολλψ βοδιεσ, ταργετ χελλσ, σπηεροχψτεσ,
πολψχηροµατοπηιλια, στιππλεδ ΡΒΧ, σιδεροχψτεσ.
Τηεσε αβνορµαλ χελλσ αππεαρ ιν τηε χιρχυλατιον
βεχαυσε τηε ινφαρχτεδ σπλεεν ισ νο λονγερ αβλε το
ρεµοϖε τηεµ φροµ τηε χιρχυλατιον.
• Νορµοχψτιχ, νορµοχηροµιχ αναεµια (Ηβ 5 γ/δλ −
11 γ/δλ)
• Ινχρεασεδ ρετιχυλοχψτεσ (5% − 30%) −
δεχρεασεδ δυρινγ απλαστιχ χρισισ
• Ινχρεασεδ ΩΒΧ ωιτη λεφτ σηιφτ (10,000/υλ −
30,000/υλ) − δοεσ νοτ νεχεσσαριλψ σιγνιφψ αν
ινφεχτιον
• Ινχρεασεδ πλατελετσ (300,000/υλ − 500,000/υλ−
µαψ φαλλ δυρινγ αν ινφαρχτιϖε χρισισ
Βονε Μαρροω
• Ηψπερπλασια οφ αλλ ελεµεντσ βυτ εσπεχιαλλψ
οφ ΡΒΧ πρεχυρσορσ
• Ινχρεασεδ ιρον δεποσιτσ
Οτηερ Λαβορατορψ Φινδινγσ
• Ποσιτιϖε σιχκλε χελλ τεστ − ΡΒΧ τρανσφορµ το
σιχκλεδ φορµ ιν αν οξψγεν−ποορ ενϖιρονµεντ
• Ποσιτιϖε σολυβιλιτψ τεστ φορ ΗβΣ − σιχκλε
χελλ Ηβ ισ ινσολυβλε ιν α πηοσπηατε βυφφερ σολυτιον

• Ηβ ελεχτροπηορεσισ − ΗβΣ 80% − 100% − 100%,

ΗβΦ 0% − 20%; βεχαυσε τηερε ισ νο νορµαλ βετα
πολψπεπτιδε χηαιν, τηερε ισ νο ΗβΑ.
• Φινδινγσ οφ ηαεµολψσισ − ινχρεασεδ
υνχονϕυγατεδ (ινδιρεχτ) βιλιρυβιν, Λ∆Η (εσπεχιαλλψ
Λ∆Η1 ανδ Λ∆Η2), υρινε ηαεµοσιδεριν; δεχρεασεδ σερυµ
ηαπτογλοβιν
• ∆εχρεασεδ σεδιµεντατιον ρατε −ρεφλεχτσ
φαιλυρε οφ σιχκλε χελλσ το υνδεργο ρουλεαυξ
φορµατιον
• ∆εχρεασεδ οσµοτιχ φραγιλιτψ− τηε σιχκλε ΡΒΧ
ρεσιστ ηαεµολψσισ βψ ηψποτονιχ σαλτ σολυτιονσ
• Ινχρεασεδ σερυµ αλκαλινε πηοσπηατασε−
ρεσυλτ οφ βονε ανδ λιϖερ ινφαρχτσ
• Ηαεµατυρια ανδ φιξεδ υρινε σπεχιφιχ γραϖιτψ
(1.010−1.020)− δυε το ρεπεατεδ µιχροινφαρχτσ ιν τηε
ρεναλ µεδυλλα
• Λαβορατορψ φινδινγσ οφ χοµπλιχατιονσ:
ινφαρχτιον οφ λυνγσ, σπλεεν, κιδνεψσ; οστεοµψελιτισ,
υσυαλλψ δυε το σαλµονελλα; ιρον δεφιχιενχψ αναεµια
(δεχρεασεδ φερριτιν ανδ ΜΧς)
ΗβΣΧ ∆ισεασε
• Περιπηεραλ βλοοδ−σιχκλε χελλσ, µαψ ταργετ
χελλσ (20%−85%); ΗβΧ χρψσταλσ ιν 1%−2% οφ ΡΒΧ,
εσπεχιαλλψ φολλοωινγ σπλενεχτοµψ
• Μιλδ ανεµια
• Σλιγητ ρετιχυλοχψτισισ (αβουτ 3%)
• Ηαεµογλοβιν ελεχτροπηορεσισ− ΗβΣ 40%−50%,
ΗβΧ 40% − 50%, ΗβΦ 2%−15%,
• ΗβΑ αβσεντ
Σιχκλε Χελλ Β−Τηαλασσεµια ∆ισεασε
• Μανψ ταργετ χελλσ (20%−40%)
• Ηψποχηροµιχ, µιχροχψτιχ αναεµια
• Ηβ ελεχτροπηορεσισ−χοµπλετε βετα−χηαιν
συππρεσσιον: ΗβΣ50%−80%, ΗβΦ 2%−30%,ΗβΑ2 >3.6%;
ινχοµπλετε Βετα−χηαιν συππρεσσιον:ΗβΣ 50%−80%,
ΗβΦ 2%−20%, ΗβΑ 15%−35%, ΗβΑ2 >3.6%
• Οτηερ λαβορατορψ φινδινγσ αρε τηοσε οφ ΗβΣΣ
δισεασε.

ΗΑΕΜΟΓΛΟΒΙΝ Χ ∆ΙΣΕΑΣΕ
Haemoglobin C disease (link to image source)
Glutamine in the 6th position of the beta globin chain is replaced by lysine. In the
homozygous state (HbC disease), mild anaemia and splenomegaly is present. The
condition is found in Africa and the Middle East.

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LABORATORY FINDINGS
HbAC Trait

• Peripheral blood- moderately increased number of target

cells (5%-30%)

• Hb electrophoresis- HbA 55%-70%, HbC 30%-45%,

HbA2 slightly increased
HbCC Disease
Peripheral Blood

• Many target cells (about 90%), variable

microspherocytes,polychcromatophilia, a few RBC
contain tetragonal HbC crystals. The cryatals increase up
to 10% following splenectomy and after incubation in 3%
NaCl.

• Mild normocytic anemia (Hb 8 g/dl-12 g/dl)

Bone Marrow

• Normoblastic hyperplasia

Other Laboratory Findings

• Haemoglobin electrophoresis - HbC 95% - 100%, HbF

0% - 5%, HbA absent
• Findings of slight haemolysis - increased reticulocytes
(2% - 10%), LDH, unconjugated bilirubin

• Osmotic fragility test shows two cell populations; target

cells have decreased fragility and microspherocytes have
increased fragility.
HbSC Disease

• See Sickle Cell Disease.