Anemia (/əˈniːmiə/; also spelled anaemia and anæmia; from Ancient Greek: ἀναιμία anaimia, meaning lack of 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 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.

Anemia is the most common disorder of the blood. There are several kinds of anemia, produced by a variety of underlying causes. Anemia can be classified in a variety of ways, based on the morphology of RBCs, underlying etiologic mechanisms, and discernible clinical spectra, to mention a few. The three main classes of anemia include excessive blood loss (acutely such as a hemorrhage or chronically through low-volume loss), excessive blood cell destruction (hemolysis) or deficient red blood cell production (ineffective hematopoiesis).

There are two major approaches to diagnosis: the "kinetic" approach which involves evaluating production, destruction and loss,^[3] and the "morphologic" approach which 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[link]

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 non-specific symptoms of a feeling 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 preexisting 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 based items 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.

Restless legs syndrome is more common in those with iron-deficiency anemia.

Less common symptoms may include swelling of the legs or arms, chronic heartburn, vague bruises, vomiting, increased sweating, and blood in stool.

Diagnosis[link]

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.

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[link]

Red blood cell size[link]

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[link]

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 guaiac-positive stool, radiographic findings, or frank bleeding.

The following is a simplified schematic of this approach:

* 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:

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[link]

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

• Heme synthesis defect
  • Iron deficiency anemia
  • Anemia of chronic disease (more commonly presenting as normocytic anemia)
• Globin synthesis defect
  • alpha-, and beta-thalassemia
  • HbE syndrome
  • HbC syndrome
  • and various other unstable hemoglobin diseases
• Sideroblastic defect
  • Hereditary sideroblastic anemia
  • Acquired sideroblastic anemia, including lead toxicity
  • Reversible sideroblastic anemia

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 and Mexican American women.^[7] Studies have shown that 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. Iron deficiency 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 polyp or colorectal cancer.
• Worldwide, the most common cause of iron deficiency anemia is parasitic infestation (hookworm, amebiasis, schistosomiasis and whipworm).^[10]

Macrocytic[link]

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

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.^[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[link]

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[link]

When two or more 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 ^[13] 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.

Heinz body anemia[link]

Heinz bodies form in the cytoplasm of RBCs and appear like small dark dots under the microscope. There are many causes of Heinz body anemia, and some forms can be drug induced. It is triggered in cats by eating onions^[14] or acetaminophen (paracetamol). It can be triggered in dogs by ingesting onions or zinc, and in horses by ingesting dry red maple leaves.

Hyperanemia[link]

Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%.

Refractory anemia[link]

Refractory anemia is an anemia which does not respond to treatment.^[15] It is often seen secondary to myelodysplastic syndromes.^[16]

Iron deficiency anemia may also be refractory as a clinical manifestation of gastrointestinal problems which disrupt iron metabolism. ^[17]

Grading[link]

WHO Grading of anemia:^[18][19]

• Grade 1 (Mild Anemia): 10 g/dl - cutoff point for ages
• Grade 2 (Moderate Anemia): 7-10 g/dl
• Grade 3 (Severe Anemia): below 7 g/dl

National Cancer Institute Grading of Anemia:^[20]

• Grade 0 (within normal limits) 12.0–16.0 g/dl for women and 14.0–18.0 g/ dl for men
• Grade 1 (Mild) 10 g/dl to levels within normal limits
• Grade 2 (Moderate) 8.0–10.0 g/dl
• Grade 3 (Severe) 6.5–7.9 g/dl
• Grade 4 (Life threatening) <6.5 g/dl

Causes[link]

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 doesn't cause any lasting symptoms unless a relatively impaired RBC production develops, in turn most commonly by iron deficiency.^[21] (See Iron deficiency anemia)

Impaired production[link]

• Disturbance of proliferation and differentiation of stem cells.
  • Pure red cell aplasia^[22]
  • Aplastic anemia,^[22] affecting all kinds of blood cells. Fanconi anemia is a hereditary disorder or defect featuring aplastic anemia and various other abnormalities.
  • Anemia of renal failure,^[22] by insufficient erythropoietin production
  • Anemia of endocrine disorders

• Disturbance of proliferation and maturation of erythroblasts
  • Pernicious anemia^[22] is a form of megaloblastic anemia due to vitamin B₁₂ deficiency dependent on impaired absorption of vitamin B₁₂.
  • Anemia of folic acid deficiency.^[22] As with vitamin B₁₂, it causes megaloblastic anemia
  • Anemia of prematurity, by diminished erythropoietin response to declining hematocrit levels, combined with blood loss from laboratory testing. It generally occurs in premature infants at 2 to 6 weeks of age.
  • Iron deficiency anemia, resulting in deficient heme synthesis^[22]
  • thalassemias, causing deficient globin synthesis^[22]
  • Congenital dyserythropoietic anemias, causing ineffective erythropoiesis
  • Anemia of renal failure^[22] (also causing stem cell dysfunction)

• Other mechanisms of impaired RBC production
  • Myelophthisic anemia^[22] or myelophthisis is a severe type of anemia resulting from the replacement of bone marrow by other materials, such as malignant tumors or granulomas.
  • Myelodysplastic syndrome^[22]
  • anemia of chronic inflammation^[22]

Increased destruction[link]

Anemias of increased red blood cell destruction are generally classified as hemolytic anemias. These are generally featuring jaundice and elevated LDH levels.

• Intrinsic (intracorpuscular) abnormalities,^[22] where there the red blood cells have defects that cause premature destruction. All of these, except paroxysmal nocturnal hemoglobinuria, are hereditary genetic disorders.^[23]
  • Hereditary spherocytosis^[22] is a hereditary defect that results in defects in the RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by the spleen.
  • Hereditary elliptocytosis,^[22] another defect in membrane skeleton proteins
  • Abetalipoproteinemia,^[22] causing defects in membrane lipids
  • Enzyme deficiencies
    • Pyruvate kinase and hexokinase deficiencies,^[22] causing defect glycolysis
    • Glucose-6-phosphate dehydrogenase deficiency and glutathione synthetase deficiency,^[22] causing increased oxidative stress
  • Hemoglobinopathies
    • Sickle cell anemia^[22]
    • Hemoglobinopathies causing unstable hemoglobins^[22]
  • Paroxysmal nocturnal hemoglobinuria^[22]

• Extrinsic (extracorpuscular) abnormalities
  • Antibody-mediated
    • Warm autoimmune hemolytic anemia is an anemia caused by autoimmune attack against red blood cells, primarily by IgG. It is the most common of the autoimmune hemolytic diseases.^[24] 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 (CLL)^[25][25]
    • Cold agglutinin hemolytic anemia is primarily mediated by IgM. It can be idiopathic^[26] or result from an underlying condition.
    • Rh disease,^[22] one of the causes of hemolytic disease of the newborn
    • Transfusion reaction to blood transfusions^[22]
  • Mechanical trauma to red cells
    • Microangiopathic hemolytic anemias, including thrombotic thrombocytopenic purpura and disseminated intravascular coagulation^[22]
    • Infections, including malaria^[22]
    • heart surgery

Blood loss[link]

• Anemia of prematurity from frequent blood sampling for laboratory testing, combined with insufficient RBC production.
• Trauma^[22] or surgery, causing acute blood loss
• Gastrointestinal tract lesions,^[22] causing a rather chronic blood loss
• Gynecologic disturbances,^[22] also generally causing chronic blood loss
• From menstruation, mostly among young women

Fluid overload[link]

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.^[27]
• Anemia of pregnancy is anemia that is induced by blood volume expansion experienced in pregnancy.

Treatments[link]

Treatments for anemia depend on severity and cause.

Iron deficiency from nutritional causes is rare in 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 oral iron supplementation with ferrous sulfate, ferrous fumarate, or ferrous gluconate. When taking iron supplements, it is very common to experience stomach upset and/or darkening of the feces. 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.

Vitamin supplements given orally (folic acid) or intramuscularly (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.

Blood transfusions[link]

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.

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.^{[28][29][30][31]}

In addition, at least two retrospective studies have shown increases in adverse clinical outcomes in critically ill patients that underwent more aggressive transfusion strategies.^[32][33]

Hyperbaric oxygen[link]

Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric oxygen (HBO) by the Undersea and Hyperbaric Medical Society.^[34][35] 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 are factors.^[34] The beliefs of some religions (ex: Jehovah's Witnesses) may require they use the HBO method.^[34]

In 2002, Van Meter reviewed the publications surrounding the use of HBO in severe anemia and found that all publications report a positive result.^[36]

References[link]

External links[link]

• National Anemia Action Council (USA)