anemia-causes-symptoms-diagnosis-differential-diagnosis-and other-details

Anemia: Causes, Symptoms, Diagnosis, Treatments and other details

Worldwide Anemia is the most common health issue in the general population. So we heard many times, he/she is Anemic! Certainly, we know the basics about anemia. So check out here if you want to know complete details about anemia- the causes of anemia, symptoms of anemia, how to diagnose anemia, how to treat it and many more.

What is Anemia?

Anemia means deficiency of hemoglobin in the blood due to either too few RBC or too little hemoglobin in the body. Clinically, Anemia is a bodily state when the hemoglobin level in the blood is below the reference range appropriate for that age and sex.

Level of hemoglobin differs with age and sex. The normal range of hemoglobin in a child is not the same as the normal range of hemoglobin of an adult. Similarly, the normal range of hemoglobin in a pregnant woman is not the same as in a non-pregnant woman. You will wonder to know that normal hemoglobin level differs with gender also. Usually, men have higher hemoglobin than women, and this is considered normal. So normal range of hemoglobin between men and women is different.

Generally, anemia is recognized in the laboratory if the hemoglobin level or hematocrit level is reduced than the expected normal range. Hematocrit levels are less useful than hemoglobin levels in assessing anemia. So if in the blood test report, it is seen that hemoglobin level is below the normal range, then it is considered as anemia.

WHO defines anemia as a hemoglobin level less than 130 gm/L (13 gm/dL) in men and less than 120gm /L (12 gm/dL) in women.

Other factors such as pregnancy and altitude affect hemoglobin levels in our body. So these factors we should consider to determine whether a person is anemic or not.

The clinical effect of anemia is reduced oxygen supply to the tissues of our body. So our blood supply needs to be increased in the tissue to cope up with the deficiency of oxygen in the tissue. But, when there is increased demand for oxygen, such as during exercise, then the deprivation of oxygen becomes more pronounced, and a crisis occurs.

A rapid appearance of anemia (such as due to blood loss) causes more severe symptoms than a gradually developing anemia. Because in gradually developing anemia, our body takes other mechanisms inside our body to cope up with the anemic environment.

Persons with cardiorespiratory disease (heart and lung disease) are more prone to develop symptoms of anemia. Because in the heart and lung disease, our body is already compromised, so coping with anemia becomes more difficult.

Now, what are the essential elements for red cell production? Because decreased production of red blood cell results in anemia. So red blood cell is a vital component to determine the severity of anemia. Let’s have a look about the essential elements for red blood cell production inside our body.

The important or critical elements for red cell production (erythropoiesis) are

  1. Erythropoietin production- It is a circulating hormone that stimulates red blood cell production when there is low oxygen state in our body.
  2. Iron availability
  3. The proliferative capacity of the bone marrow to produce more red blood cells- If the bone marrow fails to produce red blood cells as per demand, then anemia develops.
  4. Effective maturation of red cell precursors- Red blood cell needs maturation to be fully active, otherwise immature red blood cells are not effective in it’s function and destroy early within our body, so anemia results. So, effective maturation of red blood cell is vital.

All these parameters are used for the initial classification of anemia. Initial classification of anemia helps to determine the appropriate treatment for a particular anemic person, to monitor the response of the treatment and gives a basic idea about treatment outcome.

Causes of Anemia

It is very important to know the cause of anemia, because only then appropriate treatment can be given. Many factors lead to anemia, so it is not possible to tell the cause of anemia only by doing physical examination. Thorough medical evaluation and laboratory tests are needed to confirm the cause of anemia.

Causes of anemia are the following

Decreased or ineffective marrow production of red blood cells 

  • Lack of iron, vitamin B12, or folate.
  • Hypoplasia or myelodysplasia
  • Invasion of bone marrow by malignant (cancer) cells
  • Renal failure
  • Anemia of chronic diseases

Normal marrow production but increased removal of red blood cells

  • Blood loss
  • Hemolysis
  • Hypersplenism (Enlargement of the spleen)

Whatever the cause of anemia, the ultimate result is decreased red blood cell in the blood. So anemia develops.

Anemia Symptoms

Whatever the cause of anemia, as there is decreased RBC or decreased hemoglobin, so common symptoms appear that are usually same for different types of anemia. The severity of symptoms gives an indication that how severe the anemia is.

Signs and symptoms of anemia are the following

Tiredness, Fatigue, loss of stamina, lightheadedness, breathlessness, development or worsening of ischaemic symptoms such as angina or claudication.

As these symptoms are common in many medical conditions, so when these symptoms occur, it does not mean the person is anemic, there can be other reasons too for the development of these symptoms. So laboratory test is needed to confirm if these symptoms are due to anemia or not.

A person with anemia may not show all of the symptoms mentioned above. As severity of anemia increases, chances to get more symptoms increases.

Nonspecific Signs Of Anemia

The following are the non specific signs of anemia

  • Mucous membrane pallor
  • Tachypnoea (abnormally rapid breathing)
  • Raised jugular venous pressure
  • Tachycardia (an abnormally rapid heart rate)
  • Flow murmurs (an unusual sound that occurs when blood flows through the heart and surrounding arteries)
  • Ankle edema
  • Postural hypotension

Anemia Diagnosis

Approach to the patient:

The evaluation of anemia needs careful history and physical examination. Nutritional history related to drugs or alcohol intake and family history of anemia should always be assessed. Information regarding exposure to certain toxic agents or drugs and symptoms related to other disorders commonly associated with anemia is very important.

The signs and symptoms include bleeding, fatigue, malaise, weight loss, night sweats, fever, and various other symptoms are important to note. The physical examination may give clues about the cause of the anemia through findings of infection, blood in the stool, lymphadenopathy (enlarged lymph node), enlarged spleen (splenomegaly), or petechiae.

Splenomegaly and lymphadenopathy suggest an underlying lymphoproliferative disease, and petechiae suggest platelet dysfunction. If there are previous laboratory test reports, then it will be helpful to determine the time of appearance of anemia. It will give an indication that how long the anemia is present. More longer the duration, usually more severe the condition is. However, it is not always possible to determine the time of appearance of anemia.

In an anemic person, physical examination shows forceful heartbeat, strong peripheral pulses, and a systolic “flow” murmur. The doctor checks all these for a proper treatment management.

The skin and mucous membrane may be pale if the hemoglobin is less than 8 to 10 gm/dL or less than 80-100 g/L. To know if the mucous membrane or skin is pale, one needs to focus on areas where vessels are close to the surface, such as the mucous membranes, nail beds, palmar creases.

It is important to mention that if the palmar creases are lighter in color than the surrounding skin when you hyperextend your hand, then the hemoglobin level is usually less than 80 g/L or less than 8 g/dL. It is an important finding to note.

Anemia Clinical Diagnosis

  1. Iron deficiency anemia: It is the most common cause of anemia throughout the world. A thorough history of the gastrointestinal system is important because many times, blood loss in the gastrointestinal system is a cause of anemia. Also, if the woman is within the reproductive age and has menstrual periods, then anemia can be due to heavy periods (menorrhagia) in these women.
  2. A dietary history should assess the intake of iron and folate. These iron and folate can be deficient in our body according to our needs. Such as in pregnancy or during periods of rapid growth, we need more iron and folate. So then deficiency occurs if we do not increase our intake, as a result anemia develops.
  3. Past medical history is very important to determine the cause of anemia. Many diseases are associated with anemia, such as rheumatoid arthritis; Anemia occurs due to chronic diseases. Also, a history of previous surgery can lead to anemia. Such as resection of the stomach or small bowel may lead to malabsorption of iron and/or vitamin B12 and cause anemia.
  4. Family history is very important to know the cause of anemia. Many times, diseases like hemolytic anemias, hemoglobinopathies, hereditary spherocytosis comes from family. So these diseases certainly have some genetic connection. Pernicious anemia may also run in families.
  5. Drug history is also very important to know the cause of anemia. Several drugs like aspirin and other anti-inflammatory drugs cause blood loss, so anemia results from blood loss.  Drugs like sulphonamides cause hemolysis, as a result anemia develops. Drug chloramphenicol causes bone marrow depression, so bone marrow can not produce red blood cells and results anemia.

On examination and also through the general physical findings, there may be specific findings associated with the development of anemia. Such as a person is found to have a right iliac fossa mass due to underlying caecal carcinoma. It can be the cause of anemia in this person.

Hemolytic anemias can cause jaundice. So if a person has jaundice along with anemia, there is a high chance that the person has hemolytic anemia.

Vitamin B12 deficiency often causes nerve (neurological) issues such as peripheral neuropathy, dementia, and signs of subacute combined degeneration of the cord. So if a person shows these nerve issues and have anemia, there is high chance that the anemia in this person is due to vitamin B12 deficiency.

Sickle cell anemia may cause leg ulcers, stroke, or features of pulmonary hypertension (lung hypertension). So if a person shows these signs along with anemia, there is high chance that the person may have sickle cell anemia.

Anemia can be the result of different factors playing simultaneously; that is, it is multifactorial (more than one factor is present as the cause of anemia). So there may be a lack of specific signs and symptoms. Still, despite that, anemia may be present.

Anemia Lab Tests

For anemia Full Blood Count is done. The MCV blood test most accurately indicates size of the red cells in the full blood count. Commonly when anemia is present, then

  1. A normal MCV ( also called normocytic anemia) suggests either anemia is due to acute blood loss or the anemia due to chronic diseases known as the anemia of inflammation.
  2. A low MCV ( also called microcytic anemia) suggests iron deficiency or thalassemia or sometimes anemia of chronic disease or anemia of inflammation.
  3. A high MCV ( also called macrocytic anemia) suggests vitamin B12 deficiency or folate deficiency, or myelodysplasia.

When MCV is normal (76-100fl), or MCV is low ( less than 76 fl), then it is important to look for blood film and reticulocyte count.

If there is a high reticulocyte count, it can be due to bleeding or hemolysis.

Laboratory Tests in Anemia Diagnosis

Now, lets have a look about all the laboratory tests that are needed for anemia diagnosis.

  1. Complete blood count test (CBC)

 A. Red blood cell count- Hemoglobin, Hematocrit, Reticulocyte count

 B. Red blood cell indices- Mean cell volume (MCV), Mean cell hemoglobin (MCH), Mean cell hemoglobin concentration (MCHC), Red cell distribution width (RDW)

C. White blood cell count – Cell differential count, Nuclear segmentation of neutrophils

D. Platelet Count

E. Cell morphology- Cell size, Hemoglobin content, Anisocytosis, Poikilocytosis, Polychromasia

2. Iron supply studies

  A. Serum iron

  B. Total iron-binding capacity

   C. Serum ferritin

3. Marrow examination

  A. Aspirate – M/ E ratio (ratio of myeloid to erythroid precursors), Cell morphology, Iron stain

  B. Biopsy – Cellularity, Morphology

Several physiologic factors affect complete blood count, such as age, sex, pregnancy, smoking, and altitude. High-normal hemoglobin may be seen when the person lives at altitude or smoke heavily. All these factors must be considered in anemia diagnosis.

The MCHC reflects defects in hemoglobin synthesis.

Peripheral blood smear gives important information about defects in red cell production, variation in cell size (Anisocytosis), variation in cell shape (Poikilocytosis). 

The degree of anisocytosis correlates with increases in the RDW or the range of cell sizes. 

Poikilocytosis suggests a defect in the maturation of red cell precursors in the bone marrow or indicates the fragmentation of circulating red cells.

Anemia Types

Types of anemia or functional classification of anemia is

  1. Bone marrow production defects ( hypoproliferation)
  2. Red cell maturation defects (ineffective erythropoiesis)
  3. Decreased red cell survival (blood loss or hemolysis)

In hypoproliferative anemia, there is typically a low reticulocyte production index together with little or no change in red cell morphology that is normochromic normocytic anemia.

Maturation disorder typically has a slight to moderately elevated reticulocyte production index that is either macrocytic or macrocytic.

Increased red cell destruction due to hemolysis leads to an increase in reticulocyte production index to at least three times normal when sufficient iron is available.

A reticulocyte production index of more than 2.5 indicates that hemolysis is most likely occurred.

A reticulocyte production index less than 2 indicates hypoproliferative anemia or maturation disorder anemia.

Hypoproliferative Anemia

At least 75 percent of all anemia cases are hypoproliferative. In this type, the bone marrow, erythroid marrow fails to proliferate to produce red blood cells, so anemia develops. Majority of cases, hypoproliferative anemia occurs due to mild to moderate iron deficiency or inflammation. Hypoproliferative anemia also results from bone marrow damage, iron deficiency, inadequate erythropoietin stimulation. Inadequate erythropoietin stimulation can occur due to improper renal function, inflammatory cytokines like interleukin 1 that suppress erythropoietin production, or reduced tissue demand for oxygen due to metabolic disease such as hypothyroidism.

Key laboratory tests that help distinguish various forms of hypoproliferative anemia are- serum iron, iron-binding capacity, evaluation of renal function, evaluation of thyroid function, marrow biopsy or marrow aspirated to detect marrow damage or infiltrative disease, serum ferritin to assess iron stores.

Anemia due to acute or chronic inflammation shows low serum iron, TIBC normal or low, percent transferrin saturation low, serum ferritin normal or high.

Anemia for mild to moderate iron deficiency show – low serum iron, low serum ferritin, low percent transferrin saturation, high TIBC.

Marrow damaged by drugs, infiltrative diseases such as leukemia, lymphoma, or marrow aplasia can be diagnosed from the peripheral blood and bone marrow morphology. In case of infiltrative disease or fibrosis, a marrow biopsy is needed.

Maturation Disorders Anemia

Maturation disorder anemia occurs due to vitamin B12 or folic acid deficiency, drug damage such as methotrexate or alkylating agents, damage by alcohol, or myelodysplasia. Severe iron deficiency also leads to maturation disorder anemia. Abnormalities or defect in heme synthesis or globin synthesis of hemoglobin also causes maturation disorder anemia.

Here it is important to mention that if the iron deficiency anemia is mild or moderate, then anemia is hypoproliferative anemia. But if iron deficiency anemia is severe and prolonged, then anemia is a maturation disorder anemia.

Blood Loss or Hemolytic Anemia

Hemolytic anemia shows red cell production indices more than 2.5 times normal.

Acute blood loss does not show an increased reticulocyte production index.

Anemia due to chronic blood loss may show iron deficiency.

After a rapid hemorrhage, our body replaces the fluid portion of plasma within 1-3 days. Still, it results in a low concentration of RBC. If bleeding does not occur again, then RBC concentration in the blood usually comes to normal within 3-6 weeks.

Hemolytic anemia occurs due to fragile RBC. Different reasons can cause an RBC to be fragile, so RBC easily ruptures when they go through the capillaries, especially through the spleen. The number of RBC produced in the body may be normal, but the fragile RBC has a shorter life span inside our body. Due to their shorter life span, the destruction of these RBC is more than RBC production, so serious anemia results.

Hemolytic anemia can be due to intravascular hemolysis or due to extravascular hemolysis. 

Intravascular hemolysis occurs in paroxysmal nocturnal hemoglobinuria.

Hemoglobinopathies such as sickle cell disease and thalassemia may also cause hemolytic anemia.

There may be autoimmune hemolysis, also disorder of hemoglobin molecule or disorder in red cell membrane cause hemolytic anemia. But in these cases, there is life long history of anemia.

People with chronic hemolytic disease such as hereditary spherocytosis not only show anemia but may also show symptomatic bilirubin gallstone or enlarged spleen due to prolonged red cell destruction.

Careful family history, medical history, laboratory tests, specialized laboratory tests such as hemoglobin electrophoresis, screen for red cell enzyme, etc., can help to diagnose the cause behind hemolytic anemia. Also, a direct or indirect antiglobulin test or a cold agglutinin titer can detect the presence of hemolytic antibodies or complement-mediated red cell destruction.

Anemia Treatment

Treatment of anemia is based upon the cause that causes anemia. So if the nutritional deficit is the reason, such as lack of iron, vitamin B12, and folic acid, then supplementation of these elements (iron, vitamin B12, folic acid) cures anemia.

Suppose the anemia is due to bone marrow suppression caused by a drug. In that case, withdrawing the drug and taking another drug as an alternative that does not cause bone marrow suppression is the treatment.

If anemia is due to an infiltrative lesion in the bone marrow, then treatment of that lesion is needed.

If anemia is due to hemolysis, then the cause of hemolysis needs to be determined, and treatment should be initiated accordingly.

Usually, treatment of anemia is initiated after determining the cause. But in many cases, for severe anemia, blood transfusion is done before determining the cause of anemia as a life-saving measure.

Treating the cause of anemia is of utmost important. We will discuss the treatment of anemia according to the reason separately.


  1. William’s Hematology Book, 9th Edition
  2. Harrison’s Principles of Internal Medicine 20th edition
  3. Davidson’s Principles and Practice of Medicine,23rd Edition

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