Anemia

Anemias can also be described based on the RBC size and concentration of hemoglobin in them. If cell size is much smaller than normal, it is known as microcytic anemia. If it is much bigger than normal, then it is macrocytic anemia. Likewise, if the concentration of hemoglobin is much lower than normal, it is hypochromic anemia; if the concentration is much higher than normal, the RBCs are called hyperchromic.

Within the two broad categories of general causes of anemia, there are several types with different specific causes. Some of the most common types are summarized in the table below. See the sections below to read more about each one.

This article only addresses some of the more common causes of anemia, especially those that are not typically associated with white blood cell and platelet abnormalities. There are many other conditions that can, for various reasons, result in some level of anemia, such as:

• Bleeding—significant bleeding resulting from, for example, trauma or surgery (acute) or from gastrointestinal bleeding (ulcers) occurring over time (chronic)
• Leukemia (acute or chronic)
• Lymphoma
• Myelodysplastic syndrome
• Multiple myeloma
• Myeloproliferative neoplasms (e.g., myelofibrosis)
• Infections (e.g., HIV)

Though different types of anemia have different causes, the signs and symptoms can be very similar. Mild or moderate forms of anemia may cause few, if any, symptoms. Some of the most common symptoms are:

• General feeling of tiredness or weakness (fatigue)
• Lack of energy
• Pale skin (pallor)
• Dizziness
• Headaches

Other signs and symptoms that may develop as the anemia becomes more severe include a feeling of cold or numbness in hands and/or feet, shortness of breath, fast or irregular heartbeat, and chest pain.

Several routine laboratory tests may be used to help diagnose anemia as well as help to determine the underlying cause. These are listed below. Depending on the results of these, the medical history of the person, and signs and symptoms, other tests may be done as follow up to help diagnose the cause of anemia and to help guide treatment. (Click on the links for the different types of anemia at the top of this page to read about these specific tests.)

Complete Blood Count (CBC)
Anemia may first be detected when a routine test that counts the number and relative proportion of each of the different types of cells in the blood stream, called a complete blood count (CBC), is done during a health exam or as part of testing for other conditions. A CBC is often ordered as part of a yearly physical exam and helps to evaluate overall health and to screen for a wide variety of disorders.

With anemia, some of the components of the CBC that may show abnormal results include:

• RBC count—typically low
• Hemoglobin—low
• Hematocrit—low
• RBC indices—these include mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). They give a healthcare practitioner information about the size of the red blood cells and the amount and concentration of hemoglobin in RBCs present in someone's blood at that moment. For example, the size and hemoglobin concentration of RBCs can help with diagnosing anemia because those characteristics can vary for different kinds of anemia.

Blood Smear and Differential
If results of the CBC indicate anemia, it may be followed up with an examination of a blood smear or a differential, which counts white blood cells. The smear review can provide additional information, such as the shape of red blood cells and the presence of abnormal cells, which can help diagnose and classify anemia.

Reticulocyte Count
This test provides information on the number of relatively immature red blood cells in a person's blood sample. When someone has anemia (low RBC count, hemoglobin, and hematocrit), the results of this test can help determine the cause and/or help classify the type of anemia. For example, for a person with anemia, an inappropriately low reticulocyte count often indicates decrease in red blood cell production in the bone marrow.

Results from these tests may give clues as to the cause. Several other tests may be run to help determine the cause of the anemia and to guide treatment. See the individual discussions of the different types of anemia for more on these.

Iron deficiency anemia is a common type of anemia and it has many causes. Symptoms are related to the overall decrease in the number of red blood cells (RBCs) and the level of hemoglobin. If the iron deficiency anemia is mild to moderate, there may be no signs or symptoms. In addition to the most common signs and symptoms, there are some that are more unique to iron deficiency and may appear as iron stores in the body are chronically depleted. These may include:

• Brittle or spoon-shaped nails
• Swollen or sore tongue
• Cracks or ulcers at the corners of the mouth
• Difficulty in swallowing
• Craving to eat unusual non-food substances such as ice or dirt (also known as "pica")

Iron is an essential trace element and is necessary for the production of healthy RBCs. It is one component of heme, a part of hemoglobin, which is the protein in RBCs that binds to oxygen and allows RBCs to transport oxygen throughout the body. If not enough iron is taken in compared to what the body needs, then iron stored in the body begins to be used up. As iron stores are depleted, the body makes fewer RBCs with decreased amounts of hemoglobin in them, resulting in anemia.

Some of the causes of iron deficiency include:

• Chronic bleeding—if bleeding is excessive over a period of the time (chronic), the body's stored iron is gradually depleted and, as a result, the body cannot produce enough hemoglobin and red blood cells. In women, iron deficiency may be due to heavy menstrual periods or bleeding fibroids. In older women and in men, the bleeding is usually from disease of the intestines such as ulcers and cancer.
• Dietary deficiency—iron deficiency may be due to a diet poor in iron. Meat, poultry, fish, and iron-fortified foods or dark leafy greens and certain beans are good sources of iron. Children and pregnant or nursing women especially need more iron due to increased requirements. In pregnant women, lack of iron can lead to low birth weight babies and premature delivery. Women who are pregnant or planning to become pregnant routinely take iron supplements to prevent these complications. Newborns who are nursing from deficient mothers tend to have iron deficiency anemia as well.
• Absorption problem—certain conditions affect the absorption of iron from food in the gastrointestinal (GI) tract and over time can result in anemia. These include celiac disease, Crohn disease, intestinal surgery such as gastric bypass, and reduced stomach acid from taking prescription medications.

Laboratory Tests
Initial blood tests typically include a complete blood count (CBC). Results may show:

• Hemoglobin (Hb)—may be normal early in the disease but will decrease as anemia worsens
• Red blood cell indices—early on, the RBCs may be a normal size and color (normocytic, normochromic) but as the anemia progresses, the RBCs become smaller (microcytic) and paler (hypochromic) than normal.
  • Average size of RBCs (mean corpuscular volume, MCV)—decreased
  • Average amount of hemoglobin in RBCs (mean corpuscular hemoglobin, MCH)—decreased
  • Hemoglobin concentration (mean corpuscular hemoglobin concentration, MCHC)—decreased
  • Increased variation in the size of RBCs (red cell distribution width, RDW)

A blood smear may reveal RBCs that are smaller and paler than normal as well as RBCs that vary in size (anisocytosis) and shape (poikilocytosis).

If a healthcare provider suspects that someone's anemia is due to iron deficiency, several follow-up tests may be run to confirm the iron deficiency. These may include:

• Serum iron—the level of iron in someone's blood, which is usually decreased
• Ferritin—a protein used to store iron; the small quantity of ferritin that is released into the blood is a reflection of the amount of stored iron in the body and is usually low with iron deficiency anemia. It is considered to be the most specific test for identifying iron deficiency anemia, unless infection or inflammation are present.
• Transferrin and total iron-binding capacity (TIBC)—transferrin is a protein that binds to and carries iron through the blood; TIBC is a reflection of how much transferrin is available to bind to iron. In iron deficiency anemia, the transferrin level and TIBC are high.
• Reticulocyte count—reticulocytes are young, immature red blood cells; the number of reticulocytes in iron deficiency anemia is low because there is insufficient iron to produce new RBCs.
• Soluble transferrin receptor (sTfR)—this test is primarily ordered to help distinguish between anemia that is caused by iron deficiency and anemia that is caused by inflammation or a chronic illness. It may be ordered as an alternative to ferritin when a person has a chronic illness and/or inflammation is present or suspected. It will be high in iron deficiency.

If the iron deficiency is thought to be due to chronic blood loss, such as GI tract bleeding, then other tests and procedures may be performed. Laboratory tests that may be able to detect GI bleeding are the fecal occult blood test (FOBT) or fecal immunochemical test (FIT).

A test for Helicobacter pylori may detect a bacterium that can cause ulcers in the GI tract that may be a cause of chronic bleeding. If any of these tests are positive or if it is strongly suspected that a GI bleed exists, then procedures such as endoscopy or colonoscopy may be done to find the location of the bleeding so that it can be treated.

Treatment
Treatment of iron deficiency typically involves iron supplements and/or a change in diet. Vitamin C also helps with iron absorption. However, if iron-deficiency is suspected to result from abnormal blood loss, further testing is often required to determine the reason for the bleeding. People with severe iron deficiency may require a transfusion of blood cells or iron therapy through intravenous (IV) or injections. When the underlying cause is found and treated, then the anemia usually resolves.

Pernicious anemia is a condition in which the body doesn't absorb enough vitamin B12 to make enough red blood cells (RBCs). This happens when the body doesn't make enough of a substance called "intrinsic factor." Intrinsic factor is a protein produced by cells in the stomach lining that bind to vitamin B12 and allow it to be absorbed in the small intestine. Without enough intrinsic factor, the body cannot absorb vitamin B12 from the diet and cannot produce enough normal RBCs, which leads to anemia. In addition to lack of intrinsic factor, other causes of vitamin B12 deficiency and anemia include dietary deficiency and conditions that affect absorption of the vitamin from the small intestine such as surgery, certain drugs, digestive disorders (celiac disease, Crohn disease), and infections. Of these, pernicious anemia is the most common cause of B12 deficiency.

Vitamin B12 deficiency can result in general symptoms of anemia as well as nerve problems. These may include:

• Numbness and tingling that start first in the hands and feet (from nerve damage)
• Muscle weakness
• Slow reflexes
• Loss of balance
• Unsteady walking
• Confusion, memory loss, depression, and/or dementia in severe cases

Folic acid is another B vitamin, and deficiency in this vitamin may also lead to anemia. Folic acid, also known as folate, is found in many foods, especially in green, leafy vegetables. Folic acid is added to most grain products in the United States so that deficiency in folic acid is rarely seen in the U.S. nowadays. Folic acid is needed during pregnancy for normal development of the brain and spinal cord. It is important for women considering pregnancy to take appropriate amounts of folate supplements before they get pregnant and during pregnancy to make sure that they are not folate-deficient.

Anemia resulting from vitamin B12 or folate deficiency are often referred to as "megaloblastic anemia" because red blood cells are larger than normal. A lack of these vitamins does not allow RBCs to develop normally, which leads to their large size. This results in a reduced number of abnormally large RBCs and anemia.

Laboratory Tests
Symptoms of anemia will usually be investigated initially with a complete blood count (CBC) and differential. In pernicious anemia, other causes of vitamin B12 deficiency, or folate deficiency, these usually reveal:

• A low hemoglobin level
• Red cell indices—the mean corpuscular volume (MCV), which is the average size of RBCs, is high. Mean corpuscular hemoglobin (MCH) is also high, but mean corpuscular hemoglobin concentration (MCHC) is typically normal.
• A blood smear will reveal RBCs that are abnormally large and oval-shaped.
• The numbers of neutrophils (a type of white blood cell) and platelets may also be decreased.

Additional tests are usually done to make the diagnosis. Some of these include:

• Vitamin B12 level—blood level may be low when deficient in B12
• Folic acid level—blood level may be low if deficient in this B vitamin
• Methylmalonic acid (MMA)—may be high with vitamin B12 deficiency
• Homocysteine—may be high with either folate or vitamin B deficiency
• Reticulocyte count—the number of young RBCs, or reticulocytes, is low
• Antibodies against intrinsic factor and/or parietal cell—may be present in pernicious anemia

Sometimes a bone marrow aspiration or biopsy may be performed to see if the marrow appearance is consistent with megaloblastic anemia and to rule out other bone marrow disorders that may also cause anemia with larger RBCs.

Treatment
Treatment in these conditions involves supplementation with the vitamin that is deficient. If the cause of deficiency is the inability to absorb vitamin B12 from the digestive tract, then the vitamin may be given as injections. Treatment of underlying causes such as a digestive disorder or infection may help to resolve the anemia.

For more on this, see the article on Vitamin B12 and Folate Deficiency.

Aplastic anemia is a rare disease caused by a decrease in the number of all types of blood cells that bone marrow produces. Normally, the bone marrow produces a sufficient number of new red blood cells (RBCs), white blood cells (WBCs), and platelets for normal body function. Each type of cell enters the blood, circulates, and then dies within a certain time frame. For example, the normal lifespan of RBCs is about 120 days. If the bone marrow is not able to produce enough blood cells to replace those that die, a number of symptoms, including those due to anemia, may result. This form of anemia can be severe or even fatal.

Symptoms of aplastic anemia can appear abruptly or can develop more slowly. Some general symptoms that are common to different types of anemia may appear first and are due to the decrease in number of RBCs.

Some additional signs and symptoms that occur with aplastic anemia include those due to decreased platelets:

• Prolonged bleeding
• Frequent nosebleeds and bleeding gums
• Easy bruising
• Pinpoint red spots on skin
• Blood in the stool
• Heavy menstrual bleeding

There may also be signs and symptoms due to a low WBC count:

• Increased frequency and severity of infections
• Fever

Causes of aplastic anemia usually have to do with damage to the stem cells in the bone marrow that are responsible for blood cell production. Some factors that may be involved with bone marrow damage and that can lead to aplastic anemia include:

• Exposure to toxic substances like arsenic, benzene (found in gasoline), or pesticides
• Cancer therapy (radiation or chemotherapy)
• Autoimmune disorders such as lupus or rheumatoid arthritis
• Viral infections such as hepatitis, HIV, EBV, or CMV
• Medicines such as chloramphenicol (an antibiotic rarely used in the U.S.)

Rarely, aplastic anemia is due to an inherited (genetic) disorder such as Fanconi anemia. For more on this rare blood condition, see the Fanconi Anemia Research web site. Other genetic disorders leading to aplastic anemia include Shwachman-Diamond syndrome and dyskeratosis congenita.

Laboratory Tests
The initial test for anemia, the complete blood count (CBC), may reveal many abnormal results.

• Hemoglobin and/or hematocrit may be low.
• RBC and WBC counts are low.
• Platelet count is low.
• Red blood cell indices are usually normal.
• The differential white blood count shows a decrease in most types of cells but not lymphocytes.

Some additional tests that may be performed to help determine the type and cause of anemia include:

• Reticulocyte count—result is low
• Erythropoietin—usually increased in aplastic anemia
• Bone marrow aspiration or biopsy will show a decrease in the number of all types of cells.
• Tests for infections such as hepatitis, HIV, EBV, CMV help to determine the cause.
• Tests for arsenic (a heavy metal) and other toxins
• Iron tests or tests for vitamin B12 may be done to rule out other causes.
• ANA—to determine if the cause is autoimmune disease

Treatment
A physical examination or complete medical history may reveal possible causes for aplastic anemia, such as exposure to toxins or certain drugs (e.g., chloramphenicol) or prior treatment for cancer. Some cases of aplastic anemia are temporary while others have lasting damage to the bone marrow. Therefore, the treatment depends on the cause. Reducing or eliminating exposure to certain toxins or drugs may help resolve the condition. Medications may be given to stimulate bone marrow production, to treat infections, or to suppress the immune system in cases of autoimmune disorders. Blood transfusions and a bone marrow transplant may be needed in severe cases.

Rarely, anemia is due to problems that cause the red blood cells (RBCs) to die or be destroyed prematurely. Normally, RBCs live in the blood for about four months. In hemolytic anemia, this time is shortened, sometimes to only a few days. The bone marrow is not able to produce new RBCs quickly enough to replace those that have been destroyed, leading to a decreased number of RBCs in the blood, which in turn leads to a diminished capacity to supply oxygen to tissues throughout the body. This results in the typical symptoms of anemia.

Depending on the cause, hemolytic anemia can be chronic, developing and lasting over a long period or lifetime, or may be acute. The various forms can have a wide range of signs and symptoms. See the discussions of the various types below for more on this.

The different causes of hemolytic anemia fall into two main categories:

• Inherited forms in which a gene or genes are passed from one generation to the next that result in abnormal RBCs or hemoglobin
• Acquired forms in which some factor results in the early destruction of RBCs

Inherited Hemolytic Anemia
Two of the most common causes of inherited hemolytic anemia are sickle cell anemia and thalassemia:

Sickle cell anemia is a disorder where the body makes abnormal hemoglobin, which in turn causes red blood cells to become crescent-shaped, sickle cells under certain conditions. The "trait" (when you carry one mutated gene from one of your parents) can cause minor difficulties; the "disease" (when you carry two mutated genes, one from each of your parents) causes severe clinical problems. Misshapen blood cells are unstable (leading to hemolysis) and can block blood vessels, causing pain and anemia. Newborns are usually screened for sickle cell anemia, particularly those of African descent, because they are more likely to possess the inherited trait. Sometimes screening is done prenatally on a sample of amniotic fluid. Follow-up tests for hemoglobin variants may be performed to confirm a diagnosis. Treatment is usually based on the type, frequency, and severity of symptoms.

Thalassemia is an inherited blood disorder where there is an imbalance in hemoglobin globin chain production that results in anemia and smaller red blood cells. Only in its most severe form do the RBCs break apart (hemolysis) and have a shortened life span. This "beta major" form (also called Cooley's anemia) may result in growth problems, jaundice, and severe anemia. In milder forms, there is no significant hemolysis. This "beta minor" form (sometimes called beta thal trait) causes a mild anemia and no obvious symptoms.

Other less common types of inherited forms of hemolytic anemia include:

• Hereditary spherocytosis—results in abnormally shaped RBCs (so called spherocytes) that may be seen on a blood smear. These cells are very rigid, cannot pass through the spleen as normal red cells would, and thus get destroyed prematurely.
• Hereditary elliptocytosis—another cause of abnormally oval-shaped RBCs seen on a blood smear.
• Glucose-6-phospate dehydrogenase (G6PD) deficiency—G6PD is an enzyme that is necessary for RBC survival and, if deficient, RBCs come into contact with certain substances in the blood, the cells rupture and get destroyed. Those substances could include naphthalene, antimalarial medications, or fava beans. G6PD deficiency may be diagnosed with a test for its activity.
• Pyruvate kinase deficiency—pyruvate kinase is another enzyme important for RBC survival and its deficiency causes significant anemia. It is a rare disease that may be diagnosed with a test for the enzyme activity.

Laboratory Tests
Since some of these inherited forms may have mild symptoms, they may first be detected on a routine complete blood count (CBC) and blood smear, which can reveal various abnormal results that give clues as to the cause. Follow-up tests are then usually performed to make a diagnosis. Some of these include:

• Hemoglobinopathy evaluation
• DNA analysis—not routinely done but can be used to help diagnose hemoglobin variants, thalassemia, and to determine carrier status
• G6PD test—to detect deficiency in this enzyme
• Osmotic fragility test—detects RBCs that are more fragile than normal, which may be found in hereditary spherocytosis

These genetic disorders cannot be cured, but often the symptoms resulting from the anemia may be alleviated with treatment as necessary.

Acquired Hemolytic Anemia
Some of the conditions or factors involved in acquired forms of hemolytic anemia include:

• Autoimmune disorders—conditions in which the body produces antibodies against its own red blood cells; it is not well understood why this may happen, but it accounts for about half of all cases of hemolytic anemia. Certain diseases such as lupus, HIV and hepatitis can increase a person's risk for it.
• Transfusion reaction—result of blood donor-recipient incompatibility; this occurs very rarely, but when it does, it can have some serious complications. For more on this, see the article on Transfusion Medicine.
• Infections, such as malaria and infectious mononucleosis (mono)
• Mother-baby blood group incompatibility—may result in hemolytic disease of the newborn
• Medications—certain medications such as penicillin can trigger the body to produce antibodies directed against RBCs or cause the direct destruction of RBCs.
• Physical destruction of RBCs by, for example, an artificial heart valve or cardiac bypass machine used during open-heart surgery
• Paroxysmal Nocturnal Hemoglobinuria (PNH)—a rare condition in which the different types of blood cells including RBCs, white blood cells, and platelets are abnormal due to lack of certain surface proteins; because the RBCs are defective, the body destroys them earlier than the normal lifespan. This disease occurs due to a change or mutation in a gene called PIGA in the stem cells that make blood. Though it is a genetic disorder, it is not passed from one generation to the next (it is not an inherited condition). Those affected will often pass dark urine due to the hemoglobin released by destroyed RBCs being cleared from the body by the kidneys. This is most noticeable first thing in the morning when urine is most concentrated. For more on this, see this Genetic Home Reference webpage.

Laboratory Tests
Hemolytic anemias are often first identified by signs and symptoms, during physical examination, and by medical history. A medical history can reveal, for example, a recent transfusion, treatment with penicillin, or cardiac surgery. A CBC and/or blood smear may show various abnormal results. Depending on those findings, additional follow-up tests may be performed. Some of these may include:

• Tests for autoantibodies for suspected autoimmune disorders
• Direct antiglobulin test (DAT) in the case of transfusion reaction, mother-baby blood type incompatibility, or autoimmune hemolytic anemia
• Haptoglobin—usually low
• Reticulocyte count—typically high
• Flow cytometry for suspected PNH

Treatment
Treatments for hemolytic anemia are as varied as the causes. However, the goals are the same: to treat the underlying cause of the anemia, to decrease or stop the destruction of RBCs, and to increase the RBC count and/or hemoglobin level to alleviate symptoms. This may involve, for example:

• Drugs used to suppress production of autoantibodies that destroy RBCs
• Blood transfusions to increase the number of healthy RBCs
• Bone marrow transplant—to increase production of normal RBCs
• Avoiding triggers that cause the anemia such as the cold in some forms of autoimmune hemolytic anemia or fava beans, naphthalene and certain medicines for those with G6PD deficiency.

Some chronic (long-term) illnesses can cause anemia. Often, anemia caused by chronic diseases goes undetected until a routine test such as a complete blood count (CBC) reveals abnormal results. Several follow-up tests may be used to determine the underlying cause. There are many chronic conditions and diseases that can result in anemia. Some examples of these include:

• Kidney disease—red blood cells are produced by the bone marrow in response to a hormone called erythropoietin, made primarily by the kidneys. Chronic kidney disease can cause anemia resulting from too little production of this hormone; the anemia can be treated by giving erythropoietin injections.
• Anemia of chronic disease—whenever there are chronic diseases that stimulate the body's inflammatory response, the ability of the bone marrow to respond to erythropoietin is decreased, mainly due to impairment in body iron regulation. For example, rheumatoid arthritis (a severe form of joint disease caused by the body attacking its own joints, called an autoimmune disease) can cause anemia by this mechanism. Other diseases that can produce anemia in the same way include chronic infections such as HIV or tuberculosis (TB).

Laboratory Tests
A number of tests may be used as follow up to abnormal results of initial tests such as a CBC and blood smear to determine the underlying cause of chronic anemia. Some of these may include:

• Reticulocyte count—will typically be low
• Comprehensive metabolic panel (CMP)—used to detect evidence of chronic disorders

Tests for anemia of chronic disease may include:

• Tests for inflammation such as CRP
• Erythropoietin—is typically mildly increased
• Tests for infections such as HIV and TB
• Iron and transferrin (TIBC)—are typically both low
• Soluble transferrin receptor (sTfR)—is typically normal or low

Treatment
Treatment of anemia due to chronic conditions usually involves determining and/or resolving the underlying disease. Blood transfusions may be used to treat the condition in the short term.