Anemia

Anemia a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or
a lowered ability of the blood to carry oxygen. When anemia comes on slowly, the symptoms are
often vague and may include feeling tired, weakness, shortness of breath, and a poor ability to
exercise. When the anemia comes on quickly, symptoms may include confusion, feeling like one
is going to pass out, loss of consciousness, and increased thirst. Anemia must be significant
before a person becomes noticeably pale. Additional symptoms may occur depending on the
underlying cause. For people who require surgery, pre-operative anemia can increase the risk of
requiring a blood transfusion following surgery.
Anemia can be caused by blood loss, decreased red blood cell production, and increased red
blood cell breakdown. Causes of blood loss include trauma and gastrointestinal bleeding. Causes
of decreased production include iron deficiency, vitamin B12 deficiency, thalassemia, and a
number of neoplasms of the bone marrow. Causes of increased breakdown include genetic
conditions such as sickle cell anemia, infections such as malaria, and certain autoimmune
diseases. Anemia can also be classified based on the size of the red blood cells and amount of
hemoglobin in each cell. If the cells are small, it is called microcytic anemia; if they are large, it
is called macrocytic anemia; and if they are normal sized, it is called normocytic anemia.[1] The
diagnosis of anemia in men is based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL);
in women, it is less than 120 to 130 g/L (12 to 13 g/dL). Further testing is then required to
determine the cause.
Certain groups of individuals, such as pregnant women, benefit from the use of iron pills for
prevention. Dietary supplementation, without determining the specific cause, is not
recommended. The use of blood transfusions is typically based on a person's signs and
symptoms. In those without symptoms, they are not recommended unless hemoglobin levels are
less than 60 to 80 g/L (6 to 8 g/dL). These recommendations may also apply to some people with
acute bleeding. Erythropoiesis-stimulating medications are only recommended in those with
severe anemia.
Anemia is the most common blood disorder, affecting about a third of the global
population. Iron-deficiency anemia affects nearly 1 billion people. 

Signs and symptoms

Anemia goes undetected in many people and symptoms can be minor. The symptoms can be
related to an underlying cause or the anemia itself. Most commonly, people with anemia report
feelings of weakness or fatigue, and sometimes poor concentration. They may also
report shortness of breath on exertion.
In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of
the blood by increasing cardiac output. The patient may have symptoms related to this, such
as palpitations, angina (if pre-existing heart disease is present), intermittent claudication of the
legs, and symptoms of heart failure. On examination, the signs exhibited may
include pallor (pale skin, lining mucosa, conjunctiva and nail beds), but this is not a reliable sign.
A blue coloration of the sclera may be noticed in some cases of iron-deficiency anemia. There
may be signs of specific causes of anemia, e.g., koilonychia (in iron deficiency), jaundice (when
anemia results from abnormal break down of red blood cells – in hemolytic anemia), bone
deformities (found in thalassemia major) or leg ulcers (seen in sickle-cell disease). In severe
anemia, there may be signs of a hyperdynamic circulation: tachycardia (a fast heart
rate), bounding pulse, flow murmurs, and cardiac ventricular hypertrophy (enlargement). There
may be signs of heart failure. Pica, the consumption of non-food items such as ice, but also
paper, wax, or grass, and even hair or dirt, 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 academic performance in children of school age. Restless legs syndrome is
more common in people with iron-deficiency anemia than in the general population.

Causes
The causes of anemia may be classified as impaired red blood cell (RBC) production, increased
RBC destruction (hemolytic anemias), blood loss and fluid overload (hypervolemia). Several of
these may interplay to cause anemia. The most common cause of anemia is blood loss, but this
usually does not cause any lasting symptoms unless a relatively impaired RBC production
develops, in turn most commonly by iron deficiency.
Impaired production

 Disturbance of proliferation and differentiation of stem cells

o Pure red cell aplasia
o Aplastic anemia affects all kinds of blood cells. Fanconi anemia is a
hereditary disorder or defect featuring aplastic anemia and various other
abnormalities.
o Anemia of kidney failure due to insufficient production of
the hormone erythropoietin
o Anemia of endocrine disorders
 Disturbance of proliferation and maturation of erythroblasts
o Pernicious anemia is a form of megaloblastic anemia due to vitamin
B12 deficiency dependent on impaired absorption of vitamin B12. Lack of
dietary B12 causes non-pernicious megaloblastic anemia
o Anemia of folate deficiency, as with vitamin B12, causes megaloblastic
anemia
 o Anemia of prematurity, by diminished erythropoietin response to
declining hematocrit levels, combined with blood loss from laboratory
testing, generally occurs in premature infants at two to six weeks of age.
o Iron deficiency anemia, resulting in deficient heme synthesis
o Thalassemias, causing deficient globin synthesis
o Congenital dyserythropoietic anemias, causing ineffective erythropoiesis
o Anemia of kidney failure (also causing stem cell dysfunction)
 Other mechanisms of impaired RBC production
o Myelophthisic anemia or myelophthisis is a severe type of anemia
resulting from the replacement of bone marrow by other materials, such
as malignant tumors, fibrosis, or granulomas.
o Myelodysplastic syndrome
o anemia of chronic inflammation
o Leukoerythroblastic anemia is caused by space-occupying lesions in
the bone marrow that prevent normal production of blood cells.
Increased destruction
Anemias of increased red blood cell destruction are generally classified as hemolytic anemias.
These are generally featuring jaundice and elevated lactate dehydrogenase levels.

 Intrinsic (intracorpuscular) abnormalities cause premature destruction. All of these,

except paroxysmal nocturnal hemoglobinuria, are hereditary genetic disorders.
o Hereditary spherocytosis is a hereditary defect that results in defects in the
RBC cell membrane, causing the erythrocytes to be sequestered and
destroyed by the spleen.
o Hereditary elliptocytosisis another defect in membrane skeleton proteins.
o Abetalipoproteinemia, causing defects in membrane lipids
o Enzyme deficiencies
 Pyruvate kinase and hexokinase deficiencies, causing
defect glycolysis
 Glucose-6-phosphate dehydrogenase
deficiency and glutathione synthetase deficiency, causing
increased oxidative stress
o Hemoglobinopathies
 Sickle cell anemia
 Hemoglobinopathies causing unstable hemoglobins
o Paroxysmal nocturnal hemoglobinuria
 Extrinsic (extracorpuscular) abnormalities
o Antibody-mediated
 Warm autoimmune hemolytic anemia is caused by
autoimmune attack against red blood cells, primarily by IgG.
It is the most common of the autoimmune hemolytic diseases.
It can be idiopathic, that is, without any known cause, drug-
associated or secondary to another disease such as systemic
 lupus erythematosus, or a malignancy, such as chronic
lymphocytic leukemia.
 Cold agglutinin hemolytic anemia is primarily mediated by
IgM. It can be idiopathic or result from an underlying
condition.
 Rh disease, one of the causes of hemolytic disease of the
newborn
 Transfusion reaction to blood transfusions
o Mechanical trauma to red blood cells
 Microangiopathic hemolytic anemias, including thrombotic
thrombocytopenic purpura and disseminated intravascular
coagulation
 Infections, including malaria
 Heart surgery
 Haemodialysis
Blood loss

 Anemia of prematurity, from frequent blood sampling for laboratory testing,

combined with insufficient RBC production
 Trauma or surgery, causing acute blood loss
 Gastrointestinal tract lesions, causing either acute bleeds (e.g. variceal lesions, peptic
ulcers) or chronic blood loss (e.g. angiodysplasia)
 Gynecologic disturbances, also generally causing chronic blood loss
 From menstruation, mostly among young women or older women who have fibroids
 Many type of cancers, including colorectal cancer and cancer of the urinary bladder,
may cause acute or chronic blood loss, especially at advanced stages
 Infection by intestinal nematodes feeding on blood, such as hookworms and the
whipworm Trichuris trichiura 
 Iatrogenic anemia, blood loss from repeated blood draws and medical procedures.
The roots of the words anemia and ischemia both refer to the basic idea of "lack of blood", but
anemia and ischemia are not the same thing in modern medical terminology. The
word anemia used alone implies widespread effects from blood that either is too scarce (e.g.,
blood loss) or is dysfunctional in its oxygen-supplying ability (due to whatever type of
hemoglobin or erythrocyte problem). In contrast, the word ischemia refers solely to the lack of
blood (poor perfusion). Thus ischemia in a body part can cause localized anemic effects within
those tissues.
Fluid overload
Fluid overload (hypervolemia) causes decreased hemoglobin concentration and apparent anemia:

 General causes of hypervolemia include excessive sodium or fluid intake, sodium or

water retention and fluid shift into the intravascular space.
 From the 6th week of pregnancy hormonal changes cause an increase in the mother's
blood volume due to an increase in plasma.[3
Intestinal inflammation
Certain gastrointestinal disorders can cause anemia. The mechanisms involved are multifactorial
and not limited to malabsorption but mainly related to chronic intestinal inflammation, which
causes dysregulation of hepcidin that leads to decreased access of iron to the circulation.

 Helicobacter pylori infection.
 Gluten-related disorders: untreated celiac disease and non-celiac gluten sensitivity.
Anemia can be the only manifestation of celiac disease, in absence of gastrointestinal
or any other symptoms.
 Inflammatory bowel disease.

Diagnosis
Definitions
There are a number of definitions of anemia; reviews provide comparison and contrast of them.
[43]
 A strict but broad definition is an absolute decrease in red blood cell mass, however, a broader
definition is a lowered ability of the blood to carry oxygen. An operational definition is a
decrease in whole-blood hemoglobin concentration of more than 2 standard deviations below
the mean of an age- and sex-matched reference range.
It is difficult to directly measure RBC mass, so the hematocrit (amount of RBCs) or
the hemoglobin (Hb) in the blood are often used instead to indirectly estimate the value.
Hematocrit; however, is concentration dependent and is therefore not completely accurate. For
example, during pregnancy a woman's RBC mass is normal but because of an increase in blood
volume the hemoglobin and hematocrit are diluted and thus decreased. Another example would
be bleeding where the RBC mass would decrease but the concentrations of hemoglobin and
hematocrit initially remains normal until fluids shift from other areas of the body to the
intravascular space.
The anemia is also classified by severity into mild (110 g/L to normal), moderate (80 g/L to 110
g/L), and severe anemia (less than 80 g/L) in adult males and adult non pregnant
females. Different values are used in pregnancy and children.

Testing
Anemia is typically diagnosed on a complete blood count. 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 it 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.

TYPES OF ANAEMIA
Microcytic
Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which
could be caused by several etiologies:

 Heme synthesis defect
o Iron deficiency anemia (microcytosis is not always present)
o Anemia of chronic disease (more commonly presenting as normocytic
anemia)
 Globin synthesis defect
o Alpha-, and beta-thalassemia
o HbE syndrome
o HbC syndrome
o Various other unstable hemoglobin diseases
 Sideroblastic defect
o Hereditary sideroblastic anemia
o Acquired sideroblastic anemia, including lead toxicity
o 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 due to insufficient dietary intake or absorption of iron to

meet the body's needs. Infants, toddlers, and pregnant women have higher than
average needs. Increased iron intake is also needed to offset blood losses due to
digestive tract issues, frequent blood donations, or heavy menstrual periods. 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, 12% of all women of
childbearing age have iron deficiency, compared with only 2% of adult men. The
incidence is as high as 20% among African American and Mexican American
women. Studies have shown iron deficiency without anemia causes poor school
performance and lower IQ in teenage girls, although this may be due to
socioeconomic factors. Iron deficiency is the most prevalent deficiency state on a
worldwide basis. It is sometimes the cause of abnormal fissuring of the angular
(corner) sections of the lips (angular stomatitis).
 In the United States, the most common cause of iron deficiency is bleeding or blood
loss, usually from the gastrointestinal tract. Fecal occult blood testing, upper
endoscopy and lower endoscopy should be performed to identify bleeding lesions. In
older men and women, the chances are higher that bleeding from the gastrointestinal
tract could be due to colon polyps or colorectal cancer.
 Worldwide, the most common cause of iron deficiency anemia is parasitic infestation
(hookworms, amebiasis, schistosomiasis and whipworms).
Macrocytic Anaemia

 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 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.
o Pernicious anemia is caused by a lack of intrinsic factor, which is required
to absorb vitamin B12 from food. A lack of intrinsic factor may arise from
an autoimmune condition targeting the parietal cells (atrophic gastritis)
that produce intrinsic factor or against intrinsic factor itself. These lead to
poor absorption of vitamin B12.
o Macrocytic anemia can also be caused by removal of the functional
portion of the stomach, such as during gastric bypass surgery, leading to
reduced vitamin B12/folate absorption. Therefore, one must always be
aware of anemia following this procedure.
 Hypothyroidism
 Alcoholism commonly causes a macrocytosis, although not specifically anemia.
Other types of liver disease can also cause macrocytosis.
 Drugs such as methotrexate, zidovudine, and other substances may inhibit DNA
replication such as heavy metals
Macrocytic anemia can be further divided into "megaloblastic anemia" or "nonmegaloblastic
macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis
with preserved RNA synthesis, which results in restricted cell division of the progenitor cells.
The megaloblastic anemias often present with neutrophil hypersegmentation (six to 10 lobes).
The nonmegaloblastic macrocytic anemias have different etiologies (i.e. unimpaired DNA globin
synthesis,) which occur, for example, in alcoholism. In addition to the nonspecific 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.[57] 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 isolate the curative substance
chemically and ultimately were able to isolate the vitamin B12 from the liver. All three shared the
1934 Nobel Prize in Medicine.

Normocytic Anaemia
Normocytic anemia occurs when the overall hemoglobin levels are decreased, but the red blood
cell size (mean corpuscular volume) remains normal. Causes include:

 Acute blood loss
 Anemia of chronic disease
 Aplastic anemia (bone marrow failure)
 Hemolytic anemia
Dimorphic
A dimorphic appearance on a peripheral blood smear occurs when there are two simultaneous
populations of red blood cells, typically of different size and hemoglobin content (this last
feature affecting the color of the red blood cell on a stained peripheral blood smear). For
example, a person recently transfused for iron deficiency would have small, pale, iron deficient
red blood cells (RBCs) and the donor RBCs of normal size and color. Similarly, a person
transfused for severe folate or vitamin B12 deficiency would have two cell populations, but, in
this case, the patient's RBCs would be larger and paler than the donor's RBCs. A person with
sideroblastic anemia (a defect in heme synthesis, commonly caused by alcoholism, but also
drugs/toxins, nutritional deficiencies, a few acquired and rare congenital diseases) can have a
dimorphic smear from the sideroblastic anemia alone. Evidence for multiple causes appears with
an elevated RBC distribution width (RDW), indicating a wider-than-normal range of red cell
sizes, also seen in common nutritional anemia.
Heinz body anemia
Heinz bodies form in the cytoplasm of RBCs and appear as small dark dots under the
microscope. In animals, Heinz body anemia has many causes. It may be drug-induced, for
example in cats and dogs by acetaminophen (paracetamol), or may be caused by eating various
plants or other substances:

In cats and dogs after eating either raw or cooked plants from the genus Allium, for
example, onions or garlic.
 In dogs after ingestion of zinc, for example, after eating U.S. pennies minted after
1982.
 In horses which eat dry or wilted red maple leaves.
Hyperanemia
Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%.
Refractory anemia
Refractory anemia, an anemia which does not respond to treatment, is often seen secondary
to myelodysplastic syndromes. Iron deficiency anemia may also be refractory as a manifestation
of gastrointestinal problems which disrupt iron absorption or cause occult bleeding. 
Transfusion dependent
Transfusion dependent anemia is a form of anemia where ongoing blood transfusion are
required. Most people with myelodysplastic syndrome develop this state at some point in time.
Beta thalassemia may also result in transfusion dependence. Concerns from repeated blood
transfusions include iron overload. This iron overload may require chelation therapy.

Treatment
Treatment for anemia depends on cause and severity. Vitamin supplements given orally (folic
acid or vitamin B12) or intramuscularly (vitamin B12) will replace specific deficiencies.

Oral iron
Nutritional iron deficiency is common in developing nations. An estimated two-thirds of children
and of women of childbearing age in most developing nations are estimated to have iron
deficiency without anemia; one-third of them have iron deficiency with anemia.[71] Iron
deficiency due to inadequate dietary iron intake is rare in men and postmenopausal women. The
diagnosis of iron deficiency mandates a search for potential sources of blood loss, such as
gastrointestinal bleeding from ulcers or colon cancer.
Mild to moderate iron-deficiency anemia is treated by oral iron supplementation with ferrous
sulfate, ferrous fumarate, or ferrous gluconate. Daily iron supplements have been shown to be
effective in reducing anemia in women of childbearing age. When taking iron supplements,
stomach upset or darkening of the feces are commonly experienced. The stomach upset can be
alleviated by taking the iron with food; however, this decreases the amount of iron
absorbed. Vitamin C aids in the body's ability to absorb iron, so taking oral iron supplements
with orange juice is of benefit.
In the anemia of chronic kidney disease, recombinant erythropoietin or epoetin alfa is
recommended to stimulate RBC production, and if iron deficiency and inflammation are also
present, concurrent parenteral iron is also recommended.
Injectable iron
In cases where oral iron has either proven ineffective, would be too slow (for example, pre-
operatively) or where absorption is impeded (for example in cases of inflammation), parenteral
iron preparations can be used. Parenteral iron can improve iron stores rapidly and is also
effective for treating people with postpartum haemorrhage, inflammatory bowel disease, and
chronic heart failure. The body can absorb up to 6 mg iron daily from the gastrointestinal tract.
In many cases the patient has a deficit of over 1,000 mg of iron which would require several
months to replace. This can be given concurrently with erythropoietin to ensure sufficient iron
for increased rates of erythropoiesis.
Blood transfusions
Blood transfusions in those without symptoms is not recommended until the hemoglobin is
below 60 to 80 g/L (6 to 8 g/dL). In those with coronary artery disease who are not actively
bleeding transfusions are only recommended when the hemoglobin is below 70 to 80g/L (7 to 8
g/dL). Transfusing earlier does not improve survival. Transfusions otherwise should only be
undertaken in cases of cardiovascular instability.
A 2012 review concluded that when considering blood transfusions for anaemia in people with
advanced cancer who have fatigue and breathlessness (not related to cancer treatment or
haemorrhage), consideration should be given to whether there are alternative strategies can be
tried before a blood transfusion.
Erythropoiesis-stimulating agents
The objective for the administration of an erythropoiesis-stimulating agent (ESA) is to maintain
hemoglobin at the lowest level that both minimizes transfusions and meets the individual
person's needs. They should not be used for mild or moderate anemia. They are not
recommended in people with chronic kidney disease unless hemoglobin levels are less than 10
g/dL or they have symptoms of anemia. Their use should be along with parenteral iron. The 2020
Cochrane Anaesthesia Review Group review of Erythropoietin plus iron versus control treatment
including placebo or iron for preoperative anaemic adults undergoing non‐cardiac
surgery demonstrated that patients were much less likely to require red cell transfusion and in
those transfused, the volumes were unchanged (mean difference -0.09, 95% CI -0.23 to 0.05).
Pre-op Hb concentration was increased in those receiving ‘high dose’ EPO, but not ‘low dose’.
Hyperbaric oxygen
Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric
oxygen (HBO) by the Undersea and Hyperbaric Medical Society. The use of HBO is indicated
when oxygen delivery to tissue is not sufficient in patients who cannot be given blood
transfusions for medical or religious reasons. HBO may be used for medical reasons when threat
of blood product incompatibility or concern for transmissible disease are factors. The beliefs of
some religions (ex: Jehovah's Witnesses) may require they use the HBO method. A 2005 review
of the use of HBO in severe anemia found all publications reported positive results.
Pre-operative anemia
An estimated 30% of adults who require non-cardiac surgery have anemia. In order to determine
an appropriate pre-operative treatment, it is suggested that the cause of anemia be first
determined. There is moderate level medical evidence that supports a combination of iron
supplementation and erythropoietin treatment to help reduce the requirement for red blood cell
transfusions after surgery in those who have pre-operative anemia.