Anemia

Anemia (/əˈniːmiə/; also spelled anaemia and anæmia; from Ancient Greek: ἀναιμία anaimia,
meaning lack of blood, from ἀν- an-, "not" + αἷμα haima, "blood") is a decrease in number of red
blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood.[1][2] However, it can
include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in
numerical development as in some other types of hemoglobin deficiency. Because hemoglobin
(found inside RBCs) normally carries oxygen from the lungs to the capillaries, 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.

Anemia is the most common disorder of the blood. The several kinds of anemia are produced by a
variety of underlying causes. It can be classified in a variety of ways, based on the morphology of
RBCs, underlying etiologic mechanisms, and discernible clinical spectra, to mention a few. The
three main classes 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).

Of the two major approaches to diagnosis, the "kinetic" approach involves evaluating production,
destruction and loss,[3] and the "morphologic" approach groups anemia by red blood cell size. The
morphologic approach uses a quickly available and low-cost lab test as its starting point (the MCV).
On the other hand, focusing early on the question of production may allow the clinician to expose
cases more rapidly where multiple causes of anemia coexist.

Signs and symptoms

Main symptoms that may appear in anemia[4]

Anemia goes undetermined in many people, and symptoms can be minor or vague. The signs and
symptoms can be related to the anemia itself, or the underlying cause.

Most commonly, people with anemia report feelings of weakness, or fatigue, general malaise and
sometimes poor concentration. They may also report dyspnea (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, mucosal linings and nail beds),
but this is not a reliable sign. 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 soil, 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.
Restless legs syndrome is more common in those with iron-deficiency anemia.

Diagnosis

Peripheral blood smear microscopy of a patient with iron-deficiency anemia

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 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.
WHO's Hemoglobin thresholds used to define anemia[5] (1 g/dL = 0.6206 mmol/L)
Age or gender group Hb threshold (g/dl) Hb threshold (mmol/l)
Children (0.5–5.0 yrs) 11.0 6.8
Children (5–12 yrs) 11.5 7.1
Teens (12–15 yrs) 12.0 7.4
Women, non-pregnant (>15yrs) 12.0 7.4
Women, pregnant 11.0 6.8
Men (>15yrs) 13.0 8.1

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.

Classification
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.

Production vs. destruction or loss

The "kinetic" approach to anemia yields arguably 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 guaiac-positive stool,
radiographic findings, or frank bleeding.

The following is a simplified schematic of this approach:

Anemia

Reticulocyte production Reticulocyte production index shows

index shows inadequate appropriate response to anemia =
production response to ongoing hemolysis or blood loss
anemia. without RBC production problem.

No clinical findings Clinical findings and Clinical findings and normal

consistent with abnormal MCV: MCV= acute hemolysis or
hemolysis or blood hemolysis or loss and loss without adequate time
loss: pure disorder of chronic disorder of for bone marrow production
production. production*. to compensate**.

Macrocytic anemia Normocytic anemia

Microcytic anemia (MCV<80)
(MCV>100) (80<MCV<100)

* 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.

Here is a schematic representation of how to consider anemia with MCV as the starting point:

Anemia

Macrocytic anemia Normocytic anemia

(MCV>100) (MCV 80–100) Microcytic anemia
(MCV<80)

High Low
reticulocyte reticulocyte
count count

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.

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
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.[6] 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.[7] 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.[8][9] 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).[10]

Macrocytic

 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.
 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.
 Methotrexate, zidovudine, and other drugs may inhibit DNA replication.

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.[11] 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.[12]

Normocytic

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 anemias.

Heinz body anemia

Heinz bodies form in the cytoplasm of RBCs and appear as small dark dots under the microscope.
Heinz body anemia has many causes, and some forms can be drug-induced. It is triggered in cats by
eating onions[13] or acetaminophen (paracetamol). It can be triggered in dogs by ingesting onions or
zinc, and in horses by ingesting dry 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,[14] is often seen secondary to
myelodysplastic syndromes.[15]

Iron deficiency anemia may also be refractory as a clinical manifestation of gastrointestinal

problems which disrupt iron metabolism. [16]

Causes
Broadly, 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 eventually. Indeed, 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.[17] (See Iron deficiency anemia)

Impaired production

 Disturbance of proliferation and differentiation of stem cells

o Pure red cell aplasia[18]
o Aplastic anemia[18] affects all kinds of blood cells. Fanconi anemia is a hereditary
disorder or defect featuring aplastic anemia and various other abnormalities.
o Anemia of renal failure[18] by insufficient erythropoietin production
o Anemia of endocrine disorders

 Disturbance of proliferation and maturation of erythroblasts

o Pernicious anemia[18] 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 folic acid deficiency,[18] 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[18]
o thalassemias, causing deficient globin synthesis[18]
o Congenital dyserythropoietic anemias, causing ineffective erythropoiesis
o Anemia of renal failure[18] (also causing stem cell dysfunction)

 Other mechanisms of impaired RBC production

o Myelophthisic anemia[18] or myelophthisis is a severe type of anemia resulting from
the replacement of bone marrow by other materials, such as malignant tumors or
granulomas.
o Myelodysplastic syndrome[18]
o anemia of chronic inflammation[18]

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[18] cause premature destruction. All of these, except

paroxysmal nocturnal hemoglobinuria, are hereditary genetic disorders.[19]
o Hereditary spherocytosis[18] 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 elliptocytosis[18] is another defect in membrane skeleton proteins.
o Abetalipoproteinemia,[18] causing defects in membrane lipids
o Enzyme deficiencies
 Pyruvate kinase and hexokinase deficiencies,[18] causing defect glycolysis
 Glucose-6-phosphate dehydrogenase deficiency and glutathione synthetase
deficiency,[18] causing increased oxidative stress
o Hemoglobinopathies
 Sickle cell anemia[18]
 Hemoglobinopathies causing unstable hemoglobins[18]
o Paroxysmal nocturnal hemoglobinuria[18]

 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.[20] 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.[21][21]
 Cold agglutinin hemolytic anemia is primarily mediated by IgM. It can be
idiopathic[22] or result from an underlying condition.
 Rh disease,[18] one of the causes of hemolytic disease of the newborn
 Transfusion reaction to blood transfusions[18]
o Mechanical trauma to red cells
 Microangiopathic hemolytic anemias, including thrombotic
thrombocytopenic purpura and disseminated intravascular coagulation[18]
 Infections, including malaria[18]
 Heart surgery

Blood loss
  Anemia of prematurity from frequent blood sampling for laboratory testing, combined with
insufficient RBC production
 Trauma[18] or surgery, causing acute blood loss
 Gastrointestinal tract lesions,[18] causing a rather chronic blood loss
 Gynecologic disturbances,[18] also generally causing chronic blood loss
 From menstruation, mostly among young women

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.[23]
 Anemia of pregnancy is induced by blood volume expansion experienced in pregnancy.

Treatments
Treatments for anemia depend on severity and cause.

Oral Iron

Iron deficiency from nutritional causes is rare in men and postmenopausal 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 oral iron
supplementation with ferrous sulfate, ferrous fumarate, or ferrous gluconate. When taking iron
supplements, stomach upset and/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 anemias of chronic disease, associated with chemotherapy, or associated with renal disease, some
clinicians prescribe recombinant erythropoietin or epoetin alfa, to stimulate RBC production.

Parenteral 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
can be used. 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

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. Blood does have risks associated, such as disease transmission and host
incompatibility, even in cases where crossmatching was correctly undertaken. Each unit of blood is
only equivalent to 200–250 mg iron, thus requiring several units per patient to replete iron stores.
Increasingly, physicians are using parenteral iron both to conserve a finite resource, for improved
patient outcomes but also to reduce costs to the hospital.

In severe, acute bleeding, transfusions of donated blood are often lifesaving. Improvements in
battlefield casualty survival are 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.

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.[24][25][26][27]

In addition, at least two retrospective studies have shown increases in adverse clinical outcomes in
critically ill patients who underwent more aggressive transfusion strategies.[28][29]

Hyperbaric oxygen

Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric oxygen
(HBO) by the Undersea and Hyperbaric Medical Society.[30][31] 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.[30] The beliefs of some religions (ex:
Jehovah's Witnesses) may require they use the HBO method.[30]

In 2002, Van Meter reviewed the publications surrounding the use of HBO in severe anemia and
found all publications reported positive results.[32]

Vitamin supplements given orally (folic acid) or intramuscularly (vitamin B12) will replace specific
deficiencies.

Erythropoiesis-stimulating agent

The motive for the administration of an erythropoiesis-stimulating agent (ESA) is to maintain

hemoglobin at the lowest level that both minimizes transfusions and best meets individual patient
needs.[33] Medical speciality professional organizations do not recommend the use of ESAs to
chronic kidney disease patients who do not have hemoglobin levels greater than 10 g/dL and do not
have anemia symptoms.[33][34]