Anemia

Anemia (also spelled anaemia) is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood,[3][4] or a lowered ability of the blood to carry oxygen.[5] When anemia comes on slowly, the symptoms are often vague and may include feeling tired, weakness, shortness of breath or a poor ability to exercise.[1] Anemia that comes on quickly often has greater symptoms, which may include confusion, feeling like one is going to pass out, loss of consciousness, or increased thirst.[1] Anemia must be significant before a person becomes noticeably pale.[1] Additional symptoms may occur depending on the underlying cause.[1]

The three main types of anemia are due to blood loss, decreased red blood cell production, and increased red blood cell breakdown.[1] Causes of blood loss include trauma and gastrointestinal bleeding, among others.[1] Causes of decreased production include iron deficiency, a lack of vitamin B12, thalassemia, and a number of neoplasms of the bone marrow.[1] Causes of increased breakdown include a number of genetic conditions such as sickle cell anemia, infections like malaria, and certain autoimmune diseases.[1] It can also be classified based on the size of red blood cells and amount of hemoglobin in each cell.[1] If the cells are small, it is microcytic anemia.[1] If they are large, it is macrocytic anemia while if they are normal sized, it is normocytic anemia.[1] Diagnosis in men is based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL), while in women, it must be less than 120 to 130 g/L (12 to 13 g/dL).[1][6] Further testing is then required to determine the cause.[1][7]

Certain groups of individuals, such as pregnant women, benefit from the use of iron pills for prevention.[1][8] Dietary supplementation, without determining the specific cause, is not recommended.[1] The use of blood transfusions is typically based on a person's signs and symptoms.[1] In those without symptoms, they are not recommended unless hemoglobin levels are less than 60 to 80 g/L (6 to 8 g/dL).[1][9] These recommendations may also apply to some people with acute bleeding.[1] Erythropoiesis-stimulating medications are only recommended in those with severe anemia.[9]

Anemia is the most common blood disorder, affecting about a third of the global population.[1][2] Iron-deficiency anemia affects nearly 1 billion people.[10] In 2013, anemia due to iron deficiency resulted in about 183,000 deaths – down from 213,000 deaths in 1990.[11] It is more common in women than men,[10] during pregnancy, and in children and the elderly.[1] Anemia increases costs of medical care and lowers a person's productivity through a decreased ability to work.[6] The name is derived from Ancient Greek: ἀναιμία anaimia, meaning "lack of blood", from ἀν- an-, "not" and αἷμα haima, "blood".[12]

Anemia
Other namesAnaemia
Iron deficiency anemia blood film
Blood from a person with iron-deficiency anemia
Pronunciation
  • /əˈniːmiə/
SpecialtyHematology
SymptomsFeeling tired, weakness, shortness of breath, feeling like passing out[1]
CausesBlood loss, decreased red blood cell production, increased red blood cell breakdown[1]
Diagnostic methodBlood hemoglobin measurement[1]
Frequency2.36 billion / 33% (2015)[2]

Signs and symptoms

Symptoms of anemia
Main symptoms that may appear in anemia[13]
Anemia
The hand of a person with severe anemia (on the left) compared to one without (on the right)

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.[14] 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 those with iron-deficiency anemia.[15]

Causes

Modified sickle cell 01
Figure shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin.[16]

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 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

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.

Blood loss

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.[26]
  • From the 6th week of pregnancy hormonal changes cause an increase in the mother's blood volume due to an increase in plasma.[27]

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.[28][29][30]

Diagnosis

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

Definitions

There are a number of definitions of anemia; reviews provide comparison and contrast of them.[36] A strict but broad definition is an absolute decrease in red blood cell mass,[37] however, a broader definition is a lowered ability of the blood to carry oxygen.[5] 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.[38]

It is difficult to directly measure RBC mass,[39] so the hematocrit (amount of RBCs) or the hemoglobin (Hb) in the blood are often used instead to indirectly estimate the value.[40] Hemotocrit; 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.[41] Different values are used in pregnancy and children.[41]

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.

WHO's Hemoglobin thresholds used to define anemia[42] (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, such as: ESR, ferritin, serum iron, transferrin, RBC folate level, serum vitamin B12, hemoglobin electrophoresis, renal function tests (e.g. serum creatinine) although the tests will depend on the clinical hypothesis that is being investigated. When the diagnosis remains difficult, a bone marrow examination allows direct examination of the precursors to red cells, although is rarely used as is painful, invasive and is hence reserved for cases where severe pathology needs to be determined or excluded.

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. Limitations of MCV include cases where the underlying cause is due to a combination of factors – such as iron deficiency (a cause of microcytosis) and vitamin B12 deficiency (a cause of macrocytosis) where the net result can be normocytic cells.

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 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 index shows inadequate production response to anemia.Reticulocyte production index shows appropriate response to anemia = ongoing hemolysis or blood loss without RBC production problem.
No clinical findings consistent with hemolysis or blood loss: pure disorder of production.Clinical findings and abnormal MCV: hemolysis or loss and chronic disorder of production*.Clinical findings and normal MCV= acute hemolysis or loss without adequate time for bone marrow production to compensate**.
Macrocytic anemia (MCV>100)Normocytic anemia (80<MCV<100)Microcytic anemia (MCV<80)

* 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 (MCV>100)Normocytic anemia (MCV 80–100)Microcytic anemia (MCV<80)
High reticulocyte countLow reticulocyte 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:

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.[44] 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.[45] 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.[46][47] 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).[48]

The Mentzer index (mean cell volume divided by the RBC count) predicts whether microcytic anemia may be due to iron deficiency or thallasemia, although it requires confirmation.[49]

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 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, 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.
    • 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.[50] 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.[51]

Normocytic

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

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),[52] or may be caused by eating various plants or other substances:

Hyperanemia

Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%.[55]

Refractory anemia

Refractory anemia, an anemia which does not respond to treatment,[56] is often seen secondary to myelodysplastic syndromes.[57] Iron deficiency anemia may also be refractory as a manifestation of gastrointestinal problems which disrupt iron absorption or cause occult bleeding. [58]

Transfusion dependent

Transfusion dependent anemia is a form of anemia where ongoing blood transfusion are required.[59] Most people with myelodysplastic syndrome develop this state at some point in time.[60] Beta thalassemia may also result in transfusion dependence.[61][62] Concerns from repeated blood transfusions include iron overload.[60] This iron overload may require chelation therapy.[63]

Treatments

Treatments for anemia depend 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 suffer from iron deficiency; one-third of them have the more severe form of the disorder, anemia.[64] 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 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.[65] 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, although since there is also concurrent iron deficiency and inflammation present, parenteral iron is advised to be taken concurrently.[66]

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 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.[67]

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).[1] 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).[9] Transfusing earlier does not improve survival.[68] Transfusions otherwise should only be undertaken in cases of cardiovascular instability.[69]

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 meets the individual person's needs.[70] They should not be used for mild or moderate anemia.[68] 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.[70][71]

Hyperbaric oxygen

Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric oxygen (HBO) by the Undersea and Hyperbaric Medical Society.[72][73] 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.[72] The beliefs of some religions (ex: Jehovah's Witnesses) may require they use the HBO method.[72] A 2005 review of the use of HBO in severe anemia found all publications reported positive results.[74]

Epidemiology

A moderate degree of iron-deficiency anemia affected approximately 610 million people worldwide or 8.8% of the population.[10] It is slightly more common in females (9.9%) than males (7.8%).[10] Mild iron deficiency anemia affects another 375 million.[10]

History

Evidence of anemia goes back more than 4000 years.[75]

References

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External links

External resources
Aplastic anemia

Aplastic anemia is a rare disease in which the body fails to produce blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anaemia causes a deficiency of all blood cell types: red blood cells, (white blood cells, and platelets).It is more frequent in people in their teens and twenties, but is also common among the elderly. It can be caused by heredity, immune disease, or exposure to chemicals, drugs, or radiation. However, in about half the cases, the cause is unknown.The definitive diagnosis is by bone marrow biopsy; normal bone marrow has 30–70% blood stem cells, but in aplastic anaemia, these cells are mostly gone and replaced by fat.First line treatment for aplastic anaemia consists of immunosuppressive drugs, typically either anti-lymphocyte globulin or anti-thymocyte globulin, combined with corticosteroids and ciclosporin. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related matched marrow donor.The disease is also known as the cause of death of Eleanor Roosevelt and Marie Curie.

Autoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs (RBCs originating from outside the person themselves, e.g. in the case of a blood transfusion). AIHA is a relatively rare condition, affecting one to three people per 100,000 per year. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.The terminology used in this disease is somewhat ambiguous. Although MeSH uses the term "autoimmune hemolytic anemia", some sources prefer the term "immunohemolytic anemia" so drug reactions can be included in this category. The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.

Diamond–Blackfan anemia

Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components (the platelets and the white blood cells), which are usually normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia.

A variety of other congenital abnormalities may also occur in DBA.

Erythropoietin

Erythropoietin (; EPO), also known as haematopoietin or haemopoietin, is a glycoprotein cytokine secreted by the kidney in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted sufficient to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any anemia, and hypoxemia due to chronic lung disease.

Erythropoietin is produced by interstitial fibroblasts in the kidney in close association with the peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood.

Exogenous erythropoietin, recombinant human erythropoietin (rhEPO) is produced by recombinant DNA technology in cell culture and are collectively called erythropoiesis-stimulating agents (ESA): two examples are epoetin alfa and epoetin beta. ESAs are used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Risks of therapy include death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided.

rhEPO has been used illicitly as a performance-enhancing drug. It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of posttranslational modification.

Fanconi anemia

Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia, and 90% develop bone marrow failure (the inability to produce blood cells) by age 40. About 60–75% of people have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% of people have some form of endocrine problems, with varying degrees of severity.

FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair via homologous recombination.Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is bone marrow transplant if a donor is available. Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as mitomycin C. The typical age of death was 30 years in 2000.FA occurs in about one per 130,000 births, with a higher frequency in Ashkenazi Jews in Israel and Afrikaners in South Africa. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. It should not be confused with Fanconi syndrome, a kidney disorder also named after Fanconi.

Folate deficiency

Folate deficiency is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. Anemia is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. It is characterized by the appearance of large-sized, abnormal red blood cells (megaloblasts), which form when there are inadequate stores of folic acid within the body.

Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase deficiency (G6PDD) is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.It is an X-linked recessive disorder that results in defective glucose-6-phosphate dehydrogenase enzyme. Red blood cell breakdown may be triggered by infections, certain medication, stress, or foods such as fava beans. Depending on the specific mutation the severity of the condition may vary. Diagnosis is based on symptoms and supported by blood tests and genetic testing.Avoiding triggers is important. Treatment of acute episodes may include medications for infection, stopping the offending medication, or blood transfusions. Jaundice in newborns may be treated with bili lights. It is recommended that people be tested for G6PDD before certain medications, such as primaquine, are taken.About 400 million people have the condition globally. It is particularly common in certain parts of Africa, Asia, the Mediterranean, and the Middle East. Males are affected more often than females. In 2015 it is believed to have resulted in 33,000 deaths. Carriers of the G6PDD allele may be partially protected against malaria.

Hemolytic anemia

Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular, but usually in the spleen). It has numerous possible consequences, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.

Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension.

Hereditary spherocytosis

Hereditary spherocytosis is an abnormality of red blood cells, or erythrocytes. The disorder is caused by mutations in genes relating to membrane proteins that allow for the erythrocytes to change shape. The abnormal erythrocytes are sphere-shaped (spherocytosis) rather than the normal biconcave disk shaped. Dysfunctional membrane proteins interfere with the cell's ability to be flexible to travel from the arteries to the smaller capillaries. This difference in shape also makes the red blood cells more prone to rupture. Cells with these dysfunctional proteins are degraded in the spleen. This shortage of erythrocytes results in hemolytic anemia.

It was first described in 1871. It is the most common cause of inherited hemolysis in European and North American Caucasian populations, with an incidence of 1 in 5000 births. The clinical severity of HS varies from symptom-free

carrier to severe hemolysis because the disorder exhibits incomplete penetrance in its expression.

Symptoms include anemia, jaundice, splenomegaly, and fatigue. Furthermore, the detritus of the broken-down blood cells – unconjugated or indirect bilirubin – accumulates in the gallbladder, and can cause pigmented gallstones to develop. In chronic patients, an infection or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms, a hemolytic crisis.

On a blood smear, Howell-Jolly bodies may be seen within red blood cells. Primary treatment for patients with symptomatic HS has been total splenectomy, which eliminates the hemolytic process, allowing normal hemoglobin, reticulocyte and bilirubin levels.

Acute cases can threaten to cause hypoxia through anemia and acute kernicterus through high blood levels of bilirubin, particularly in newborns. Most cases can be detected soon after birth. An adult with this disease should have their children tested, although the presence of the disease in children is usually noticed soon after birth. Occasionally, the disease will go unnoticed until the child is about 4 or 5 years of age. A person may also be a carrier of the disease and show no signs or symptoms of the disease. Other symptoms may include abdominal pain that could lead to the removal of the spleen and/or gallbladder.

Spherocytosis patients who are heterozygous for a hemochromatosis gene may suffer from iron overload, despite the hemochromatosis genes being recessive.

Iron-deficiency anemia

Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise. Anemia that comes on quickly often has more severe symptoms, including: confusion, feeling like one is going to pass out or increased thirst. Anemia is typically significant before a person becomes noticeably pale. Children with iron deficiency anemia may have problems with growth and development . There may be additional symptoms depending on the underlying cause.Iron-deficiency anemia is caused by blood loss, insufficient dietary intake, or poor absorption of iron from food. Sources of blood loss can include heavy periods, childbirth, uterine fibroids, stomach ulcers, colon cancer, and urinary tract bleeding. Poor absorption of iron from food may occur as a result of an intestinal disorder such as inflammatory bowel disease or celiac disease, or surgery such as a gastric bypass. In the developing world, parasitic worms, malaria, and HIV/AIDS increase the risk of iron deficiency anemia. Diagnosis is confirmed by blood tests.Iron deficiency anemia can be prevented by eating a diet containing sufficient amounts of iron or by iron supplementation. Foods high in iron include meat, nuts, spinach, and foods made with iron-fortified flour. Treatment may include dietary changes and dealing with underlying causes, for example medical treatment for parasites or surgery for ulcers. Iron supplements and vitamin C may be recommended. Severe cases may be treated with blood transfusions or iron injections.Iron-deficiency anemia affected about 1.48 billion people in 2015. A lack of dietary iron is estimated to cause approximately half of all anemia cases globally. Women and young children are most commonly affected. In 2015 anemia due to iron deficiency resulted in about 54,000 deaths – down from 213,000 deaths in 1990.

Iron deficiency

Iron deficiency, or sideropaenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key component of the hemoglobin protein, acting as a transport medium for electrons within the cells in the form of cytochromes, and facilitating oxygen enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and death.Total body iron averages approximately 3.8 g in men and 2.3 g in women. In blood plasma, iron is carried tightly bound to the protein transferrin. There are several mechanisms that control human iron metabolism and safeguard against iron deficiency. The main regulatory mechanism is situated in the gastrointestinal tract. When loss of iron is not sufficiently compensated by adequate intake of iron from the diet, a state of iron deficiency develops over time. When this state is uncorrected, it leads to iron-deficiency anemia. Before anemia occurs, the medical condition of iron deficiency without anemia is called latent iron deficiency (LID) or iron-deficient erythropoiesis (IDE).

Untreated iron deficiency can lead to iron-deficiency anemia, a common type of anemia. Anemia is a condition characterized by inadequate red blood cells (erythrocytes) or hemoglobin. When the body lacks sufficient amounts of iron, production of the protein hemoglobin is reduced. Hemoglobin binds to oxygen, enabling red blood cells to supply oxygenated blood throughout the body. Children, pre-menopausal women (women of child-bearing age) and people with poor diet are most susceptible to the disease. Most cases of iron-deficiency anemia are mild, but if not treated it can cause problems like fast or irregular heartbeat, complications during pregnancy, and delayed growth in infants and children that could impact their cognitive development and their behavior.

Macrocytic anemia

The term 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 red blood cells (erythrocytes) are larger than their normal volume. The normal erythrocyte volume in humans is about 80 to 100 femtoliters (fL= 10−15 L). In metric terms the size is given in equivalent cubic micrometers (1 μm3 = 1 fL). The condition of having erythrocytes which (on average) are too large, is called macrocytosis. In contrast, in microcytic anemia, the erythrocytes are smaller than normal.

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 of these factors work to the opposite effect of larger cell size, to finally result in a total blood hemoglobin concentration that is less than normal (i.e., anemia).

Macrocytic anemia is not a disease in the sense of having a single pathology but, rather, is a condition. As such, it is the class name for a set of pathologies that all produce somewhat the same red blood cell abnormality. Different pathologies result in macrocytic-type anemias. Some of these pathologies produce slightly different sets of appearances in blood cells that are detectable from red and white cell morphology, and others are only detectable with chemical testing.

Megaloblastic anemia

Megaloblastic anemia is an anemia (of macrocytic classification) that results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis.

Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias.

The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Loss of micronutrients may also be a cause. Copper deficiency resulting from an excess of zinc from unusually high oral consumption of zinc-containing denture-fixation creams has been found to be a cause.Megaloblastic anemia not due to hypovitaminosis may be caused by antimetabolites that poison DNA production directly, such as some chemotherapeutic or antimicrobial agents (for example azathioprine or trimethoprim).

The pathological state of megaloblastosis is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow and also by hypersegmented neutrophils (defined as the presence of neutrophils with six or more lobes or the presence of more than 3% of neutrophils with at least five lobes). These hypersegmented neutrophils can be detected in the peripheral blood (using a diagnostic smear of a blood sample).

Myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells. Early on, there are typically no symptoms. Later symptoms may include feeling tired, shortness of breath, easy bleeding, or frequent infections. Some types may develop into acute myeloid leukemia.Risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. Problems with blood cell formation result in some combination of low red blood cells, low platelets, and low white blood cells. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in the blood cells and bone marrow.Treatments may include supportive care, drug therapy, and stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medication lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor.About seven per 100,000 people are affected with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976.

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to the presence of defective surface protein DAF on the red blood cell, which normally functions to inhibit such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. Other key features of the disease, such as the high incidence of blood clot formation, are incompletely understood.PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to the absence of protective proteins on the membrane). It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority of affected people have the telltale red urine in the morning that originally gave the condition its name.Allogeneic bone marrow transplantation is the only cure, but has significant rates of additional medical problems and death. The monoclonal antibody eculizumab reduces the need for blood transfusions and improves quality of life for those affected by PNH. Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to the extent that it may be equivalent to that of the general population. Eculizumab costs at least $440,000 for a single year of treatment and has been reported as one of the world's most expensive drugs.

Sickle cell disease

Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle cell crisis"), anemia, swelling in the hands and feet, bacterial infections and stroke. Long-term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.Sickle cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent. This gene occurs in chromosome 11. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. An attack can be set off by temperature changes, stress, dehydration and high altitude. A person with a single abnormal copy does not usually have symptoms and is said to have sickle cell trait. Such people are also referred to as carriers. Diagnosis is by a blood test, and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation and pain medication. Other measures may include blood transfusion and the medication hydroxycarbamide (hydroxyurea). A small percentage of people can be cured by a transplant of bone marrow cells.As of 2015, about 4.4 million people have sickle cell disease, while an additional 43 million have sickle cell trait. About 80% of sickle cell disease cases are believed to occur in Sub-Saharan Africa. It also occurs relatively frequently in parts of India, the Arabian Peninsula and among people of African origin living in other parts of the world. In 2015, it resulted in about 114,800 deaths. The condition was first described in the medical literature by the American physician James B. Herrick in 1910. In 1949, the genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954, the protective effect against malaria of sickle cell trait was described.

Sideroblastic anemia

Sideroblastic anemia or sideroachrestic anemia is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need in order to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can develop into hematological malignancies (especially acute myeloid leukemia).

Sideroblasts (sidero- + -blast) are nucleated erythroblasts (precursors to mature red blood cells) with granules of iron accumulated in the mitochondria surrounding the nucleus. Normally, sideroblasts are present in the bone marrow, and enter the circulation after maturing into a normal erythrocyte. The presence of sideroblasts per se does not define sideroblastic anemia. Only the finding of ring (or ringed) sideroblasts characterizes sideroblastic anemia.

Ring sideroblasts are named so because iron-laden mitochondria form a ring around the nucleus. It is a subtype of basophilic granules of the erythrocyte, but which can only be seen in bone marrow. To count a cell as a ring sideroblast, the ring must encircle a third or more of the nucleus and contain five or more iron granules, according to the 2008 WHO classification of the tumors of the hematopoietic and lymphoid tissues.The WHO International Working Group on Morphology of MDS (IWGM-MDS) defined three types of sideroblasts:

Type 1 sideroblasts: fewer than 5 siderotic granules in the cytoplasm

Type 2 sideroblasts: 5 or more siderotic granules, but not in a perinuclear distribution

Type 3 or ring sideroblasts: 5 or more granules in a perinuclear position, surrounding the nucleus or encompassing at least one third of the nuclear circumference.Type 1 and type 2 are found in Non-sideroblastic anemias. Type 3 is found only in Sideroblastic anemia.

Thalassemia

Thalassemias are inherited blood disorders characterized by abnormal hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells). Anemia can result in feeling tired and pale skin. There may also be bone problems, an enlarged spleen, yellowish skin, and dark urine. Slow growth may occur in children.Thalassemias are genetic disorders inherited from a person's parents. There are two main types, alpha thalassemia and beta thalassemia. The severity of alpha and beta thalassemia depends on how many of the four genes for alpha globin or two genes for beta globin are missing. Diagnosis is typically by blood tests including a complete blood count, special hemoglobin tests, and genetic tests. Diagnosis may occur before birth through prenatal testing.Treatment depends on the type and severity. Treatment for those with more severe disease often includes regular blood transfusions, iron chelation, and folic acid. Iron chelation may be done with deferoxamine or deferasirox. Occasionally, a bone marrow transplant may be an option. Complications may include iron overload from the transfusions with resulting heart or liver disease, infections, and osteoporosis. If the spleen becomes overly enlarged, surgical removal may be required.As of 2013, thalassemia occurs in about 280 million people, with about 439,000 having severe disease. It is most common among people of Italian, Greek, Middle Eastern, South Asian, and African descent. Males and females have similar rates of disease. It resulted in 16,800 deaths in 2015, down from 36,000 deaths in 1990. Those who have minor degrees of thalassemia, similar to those with sickle-cell trait, have some protection against malaria, explaining why they are more common in regions of the world where malaria exists.

Vitamin B12 deficiency anemia

Vitamin B12 deficiency anemia, of which pernicious anemia is a type, is a disease in which not enough red blood cells are produced due to a deficiency of vitamin B12. The most common initial symptom is feeling tired. Other symptoms may include shortness of breath, pale skin, chest pain, numbness in the hands and feet, poor balance, a smooth red tongue, poor reflexes, depression and confusion. Without treatment some of these problems may become permanent.Pernicious anemia refers to anemia that results from lack of intrinsic factor. Lack of intrinsic factor is most commonly due to an autoimmune attack on the cells that create it in the stomach. It can also occur following the surgical removal of part of the stomach or from an inherited disorder. Other causes of low vitamin B12 include not enough dietary intake (such as in a vegan diet), celiac disease, or tapeworm infection. When suspected, diagnosis is made by blood and, occasionally, bone marrow tests. Blood tests may show fewer but larger red blood cells, low numbers of young red blood cells, low levels of vitamin B12, and antibodies to intrinsic factor.Because pernicious anemia is due to a lack of intrinsic factor, it is not preventable. Vitamin B12 deficiency due to other causes may be prevented with a balanced diet or with supplements. Pernicious anemia can be easily treated with either injections or pills of vitamin B12. If the symptoms are severe, injections are typically recommended initially. For those who have trouble swallowing pills, a nasal spray is available. Often, treatment is lifelong.Pernicious anemia due to autoimmune problems occurs in about one per 1000 people. Among those over the age of 60, about 2% have the condition. It more commonly affects people of northern European descent. Women are more commonly affected than men. With proper treatment, most people live normal lives. Due to a higher risk of stomach cancer, those with pernicious anemia should be checked regularly for this. The first clear description was by Thomas Addison in 1849. The term "pernicious" means "deadly", and was used as before the availability of treatment the disease was often fatal.

Diseases of red blood cells (D50–69,74, 280–287)
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