Anemia: Overview

Anemia is a condition in which individuals have low Hb levels, which can arise from  various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia may occur from blood loss, decreased RBC production such as in iron deficiency, or increased RBC destruction such as in hemolysis. Management is aimed at improving Hb levels and treating the underlying conditions.

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Overview

Definition

Anemia is a quantitative deficiency of Hb, the oxygen-carrying component of RBCs. Anemia is noted when Hb levels are approximately:

  • < 13.5 g/dL in adult males
  • < 12 g/dL in adult females 
  • < 11 g/dL in children

Normal levels can vary depending on the laboratory reference range.

Epidemiology

  • Found in patients of all ages, from infants to elderly
  • More common in women than in men
  • Prevalence:
    •  > 20% of individuals who are > 85 years of age
    • Mild iron deficiency anemia is common in women of reproductive age.
  • Hemoglobinopathies are more common in certain ethnicities:
    • Sickle cell disease: Black or African descent
    • Hereditary spherocytosis: European descent
    • Thalassemia: Mediterranean and Southeast Asian descent

Anatomy and physiology review

  • RBCs are produced in the bone marrow.
  • Pluripotent hematopoietic stem cells → common myeloid stem cell → proerythroblast → erythrocyte
  • RBC production is stimulated by erythropoietin, which is made in the kidneys.
  • RBCs are cleared through the spleen: Senescent, rigid, or abnormal RBCs unable to squeeze through the narrow splenic slits are retained and cleared.

Etiology

Anemia can be caused by:

  • Blood loss
  • Decreased RBC production
  • Increased RBC destruction

Classification of anemia according to etiology

Table: Classification of anemia according to etiology
EtiologyCategoriesTypes of anemia
Blood lossAcute
  • Trauma
  • Surgery
  • Postpartum hemorrhage
  • Severe epistaxis
Chronic
  • GI bleeding (upper or lower):
    • Peptic ulcer disease
    • Diverticular disease
    • Cancer
  • Heavy menstrual bleeding
Decreased RBC productionAbnormal proliferation or differentiation of stem cells
  • Aplastic anemia
  • Pure red cell aplasia
  • Anemia of renal failure (due to ↓ erythropoietin)
Defective DNA synthesis in erythroblasts
  • Vitamin B12 deficiency
  • Folate deficiency
Defective Hb synthesis
  • Defective heme synthesis:
    • Iron deficiency anemia
    • Lead poisoning
  • Defective globin chains:
    • Hemoglobinopathies, including sickle cell anemia
    • Thalassemias
Unknown or multiple mechanisms
  • Sideroblastic anemia
  • Anemia of chronic infections
Increased RBC destructionAbnormal Hb
  • Sickle cell anemia
  • Thalassemias
Enzyme deficiencies
  • Glucose-6-phosphate dehydrogenase (G6PD)
  • Glutathione synthetase
  • Pyruvate kinase
  • Hexokinase
Membrane disorders
  • Spherocytosis
  • Elliptocytosis
  • Paroxysmal nocturnal hemoglobinuria (PNH)
Immune-mediated
  • Autoimmune disease:
    • Idiopathic (primary)
    • Systemic lupus erythematosus
    • Malignant neoplasms
  • Drug-associated:
    • Antibiotics
    • NSAIDs
    • Anticancer agents
  • Transfusion reactions
Mechanical trauma to RBCs
  • Thrombotic thrombocytopenic purpura (TTP)
  • DIC
  • Cardiac trauma
Infections
  • Malaria
  • Hookworm

Classification

Anemia is most commonly classified into the subtype microcytic, normocytic, or macrocytic based on the size of the RBCs. MCV reflects the size of the RBCs and is reported on a CBC.

Anemia overview chart

Classification of anemia based on the MCV

Image by Lecturio.

Microcytic anemia

Microcytic anemia is characterized by small RBCs with a low MCV. These features are usually due to a decreased Hb content within the RBCs. Causes include:

  • Iron deficiency anemia: 
    • The most common cause of anemia
    • Causes include:
      • Chronic GI blood loss
      • Chronic heavy menstrual bleeding
      • Malabsorption of iron in chronic GI disease (e.g., Crohn’s or celiac disease)
      • Insufficient dietary iron
      • Pregnancy
  • Thalassemia
  • Anemia of chronic disease (later stages)
  • Lead poisoning
  • Sideroblastic anemia

Mnemonic:

To remember the causes of microcytic anemia use the mnemonic TAILS:

  • Thalassemia
  • Anemia of chronic disease
  • Iron deficiency anemia
  • Lead poisoning
  • Sideroblastic anemia

Normocytic anemia

Normocytic anemias have a normal MCV. Often, the reticulocyte count is used to help narrow the differential diagnosis. (Reticulocytes are “new” blood cells in circulation, and their level reflects the rate of new RBC production.) Causes of normocytic anemia include:

Hemolytic anemias:

  • Will have a corrected reticulocyte count > 3%: indicates normally functioning bone marrow
  • Caused by intrinsic RBC defects:
    • Sickle cell disease
    • G6PD deficiency
    • PNH
    • Hereditary spherocytosis
  • Causes due to extrinsic defects:
    • Autoimmune hemolytic anemias (e.g., systemic lupus erythematosus)
    • Microangiopathic hemolytic anemia (e.g., TTP, hemolytic uremic syndrome (HUS), DIC)
    • Macroangiopathic hemolytic anemia (e.g., with prosthetic heart valves or aortic stenosis)
    • Infections (e.g., malaria)

Nonhemolytic anemias: 

  • Will have corrected reticulocyte count < 3%: indicates that the bone marrow is not responding to the stressor, leading to underproduction of RBCs
  • Causes:
    • Anemia of chronic disease (earlier stages), usually CKD
    • Anemia of congestive heart failure (CHF)
    • Anemia due to endocrine deficiency (e.g., hypothyroidism or adrenal insufficiency)
    • Diabetes mellitus
    • Obesity
    • Malignancy
    • Aplastic anemias
    • Blood loss < 1 week ago (bone marrow working properly, but has not yet had enough time to catch up with blood loss)

Macrocytic anemia

Macrocytic anemias have an elevated MCV, or large RCBs. Causes include: 

  • Megaloblastic anemias (the problem is within the bone marrow):
    • Deficiencies of vitamins needed for proper DNA synthesis (due to either insufficient dietary intake or malabsorption):
      • Vitamin B12 deficiency 
      • Folate deficiency
    • Rare causes:
      • Diamond-Blackfan anemia: a congenital erythroid aplasia that usually presents in infancy; WBCs and platelets are usually normal
      • Orotic aciduria: autosomal recessive disease presenting with physical and intellectual delays in infancy, resulting from defects in the metabolism of orotic acid 
  • Nonmegaloblastic anemias (the problem is outside the bone marrow); can be due to:
    • Liver disease
    • Alcohol use disorder
    • Reticulocytosis
    • Drugs (many)

Other ways to classify anemia

  • Acute or chronic 
  • Inherited or acquired defects
  • Primary or secondary

Clinical Presentation

History

Important details when considering a diagnosis of anemia:

  • History of eating disorder
  • History of gastric or intestinal surgery
  • Family history of hematologic diseases
  • Medications that cause or worsen bleeding
  • Medications that may cause hemolytic anemia
  • Travel history
  • Special diet that may lead to a vitamin deficiency (e.g., vegan)
  • Amount of alcohol use

Symptoms and physical exam findings

Symptoms develop based on the rate and severity of Hb decrease from baseline. Anemia is also often asymptomatic and found on laboratory studies only.

Table: Clinical presentation of anemia
Body region/organ systemSymptomsPossible physical exam findings
General
  • Fatigue
  • Generalized weakness
  • Loss of appetite
  • Cold hands or feet
  • Restless legs
  • Pica (eating nonfood substances like ice or clay)
  • Pallor
  • Lymphadenopathy
Integumentary
  • Itching
  • Dry skin
  • Easy bruising
  • Pallor
  • Jaundice
  • Purpura
  • Nails with koilonychia (“spoon nails”)
Cardiorespiratory
  • Chest pain
  • Palpitations
  • Dyspnea
  • Tachycardia
  • Tachypnea
  • Orthostatic hypotension
  • Signs of CHF:
    • ↑ Jugular venous pressure
    • S3
    • Respiratory crackles
    • Ankle edema
Head, eyes, ears, nose, and throat (HEENT)Epistaxis
  • Pale conjunctiva
  • Atrophic glossitis
Neurologic
  • Headaches
  • Light-headedness
  • Paresthesias
  • Decreased sensation
  • Abnormal reflexes
GI/abdomen
  • Hematochezia/rectal bleeding
  • Melena
  • Diarrhea
  • Hematemesis
  • Hepatomegaly
  • Splenomegaly
  • Hemorrhoids
  • Rectal mass
Genitourinary
  • Hematuria
  • Heavy or frequent menstrual bleeding
  • Enlarged uterus

Diagnosis

The diagnostic process typically starts by assessing the CBC, MCV, and reticulocyte count, which are best evaluated simultaneously to start narrowing the differential diagnosis. Additional studies may be obtained on the basis of the patient’s clinical presentation.

Serologic studies

  • CBC findings: 
    • Decreased Hb (component of RBCs)
    • Decreased Hct (ratio of the volume of RBCs to the volume of blood, expressed as a percentage)
    • MCV: helps narrow the differential diagnosis
    • Pancytopenia: usually seen in megaloblastic anemia 
    • Factors that elevate Hb and may mask underlying anemia:
      • Smoking
      • Hemoconcentration due to hypovolemia
      • High altitude
  • Reticulocyte evaluation:
    • Reticulocyte count: 
      • Reticulocytes are immature RBCs in circulation
      • Can be expressed as a percentage of all RBCs or as an absolute number
    • ↑ Reticulocyte count indicates:
      • Hemolysis
      • Recovery from bleeding
      • Removal of a bone marrow insult (e.g., drug)
      • Repletion of deficient nutrients
    • Corrected reticulocyte counts: 
      • Reveals adequate versus inadequate bone marrow response
      • Calculation: Reticulocyte count × (patient’s Hct/reference Hct)
  • Iron studies: 
    • Includes: 
      • Serum iron
      • Transferrin and transferrin saturation
      • Ferritin
      • Total binding iron capacity
    • ↓ Level of total body iron → iron deficiency anemia
  • Laboratory tests when hemolytic anemia is suspected:
    • Haptoglobin: ↓ with hemolysis 
    • Lactate dehydrogenase: ↑ with hemolysis
    • Indirect bilirubin: ↑ with hemolysis 
    • Direct Coombs test: detects antibodies attached to RBCs, such as in erythroblastosis fetalis (due to Rh incompatibility)
    • Indirect Coombs test: detects antibodies against foreign RBCs, which are present in autoimmune hemolytic anemia 
  • Other serologic tests:
    • CMP: to evaluate renal and hepatic function
    • Thyroid-stimulating hormone (TSH)
    • Vitamin B12 level
    • Folate level

Peripheral blood smear

A peripheral blood smear can be helpfuling in establishing the underlying cause of an anemia.

Table: Abnormal RBC findings in a peripheral blood smear
AbnormalityDescriptionAssociated pathology
Sickle cellsSickle-shaped cells
  • Sickle cell anemia
Howell-Jolly bodiesPeripherally located purple bodies representing nuclear remnants of RBCs
  • Sickle cell anemia
  • Asplenia
Bite cells (degmacytes)RBCs with loss of semicircular portionsG6PD
Heinz bodiesRed-pink inclusions within RBCs representing aggregates of abnormal Hb
  • G6PD
  • Thalassemias
SpherocytesDense, small spherical cells with no central pallor
  • Hereditary spherocytosis
  • Autoimmune hemolytic anemia
SchistocytesIrregularly shaped RBC fragmentsDue to mechanical damage:
  • Microangiopathic hemolytic anemia
  • Macroangiopathic hemolytic anemia
NormoblastsNucleated RBCsSevere hemolysis
Target cells (codocytes)Bull’s-eye appearance (central area of hemoglobinization)
  • Hemoglobinopathies :
    • Thalassemia
    • HbC disease
  • Liver disease
  • Asplenia
Basophilic stipplingPurple-blue dots within RBCs representing ribosomal precipitates
  • Sideroblastic anemia
  • Lead poisoning
  • Thalassemias
Dacrocytes (teardrop cells)Teardrop-shaped RBCsDue to bone marrow infiltration:
  • Myelofibrosis
  • Myelodysplastic syndrome
MacroovalocytesLarge, oval-shaped erythrocytesMegaloblastic anemia

Additional tests based on clinical presentation

  • Copper level for deficiency 
  • Hb electrophoresis
  • Serum protein electrophoresis
  • EGD and colonoscopy: to assess for occult source of GI bleeding, especially > 50 years of age
  • Bone marrow biopsy:
    • Important to consider if other cell lines abnormal 
      • Leukopenia
      • Thrombocytopenia
    • Abnormal findings
      • Ringed sideroblasts: sideroblastic anemia or lead poisoning 
      • Hypocellular bone marrow (dry bone marrow tap): aplastic anemia
      • > 20% blasts: leukemia 

Management

Restore blood counts

  • Allow the body to replenish its own RBCs:
    • Supplementation of missing nutrients
    • Stop pathologic bleeding.
    • Treat underlying disease.
  • Transfusion of RBCs to maintain Hb
    • > 7 g/dL in a majority of patients
    • > 8 g/dL in patients with cardiovascular disease

Educate the patient regarding lifestyle

If lifestyle factors are thought to be contributing to the anemia, education can be provided regarding:

  • Alcohol use
  • Smoking
  • Adequate dietary intake and supplementation

Treat the underlying cause

  • Oral nutrient replacement for nutrient deficiencies:
    • Iron
    • Vitamin B12
    • Folate
  • Address malabsorption issues (e.g., celiac sprue).
  • Treat source of bleeding if pathologic, for example:
    • Malignancy:
      • Endometrial cancer
      • Colon, gastric, or other GI malignancy
    • Peptic ulcer disease
    • Inflammatory bowel disease (e.g., ulcerative colitis)
    • Severe diverticular disease 
  • Treat underlying chronic diseases, as possible (e.g., consider erythropoietin injection for CKD).
  • Treat endocrinopathies, if present (e.g., levothyroxine for hypothyroidism).
  • Evaluate benefits and risks of long-term medications that may worsen anemia.

Comparison of Common Types of Anemia

Nonhemolytic anemias

  • Iron deficiency anemia: most common type of anemia worldwide. Iron deficiency anemia is due to a decreased supply of iron, an increased loss of iron (e.g., through unrecognized GI bleeding), or an increased demand for iron (e.g., pregnancy). Treatment is with supplementation and/or managing the underlying contributing disease.
  • Thalassemia: hereditary cause of microcytic, hypochromic anemia. Thalassemia is a deficiency in either the alpha (⍺) or beta (𝛽) globin chains resulting in both ineffective erythropoiesis and hemolysis. Clinical presentations range from asymptomatic carriers to severe anemia with shortened life expectancy.
  • Megaloblastic anemia: subset of macrocytic anemia that arises because of impaired nucleic acid synthesis in erythroid precursors: This impaired synthesis leads to ineffective RBC production and intramedullary hemolysis. The most common causes are vitamin B12 and folic acid deficiencies, which can be due to low dietary intake, underlying malabsorptive conditions, and medications. Clinical presentation includes anemia, GI symptoms, and neurologic manifestations.
  • Sickle cell anemia (sickle cell disease (SCD)): inherited autosomal recessive Hb due to a single point mutation in the beta-globin gene. The abnormal Hb polymerizes when it becomes deoxygenated, leading to sickle-shaped deformation of the RBCs. These sickled RBCs are hemolyzed easily and cause microvascular obstruction with associated organ ischemia, severe pain crises, and systemic complications. Sickle cells can usually be seen on a peripheral blood smear.
  • Sideroblastic anemia: This heterogeneous group of bone marrow disorders is characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ring-like distribution around the nucleus (ring sideroblasts). Sideroblastic anemias may be due to inherited defects in heme synthesis or can be acquired through alcoholism, lead poisoning, medications, and vitamin deficiencies. Serum iron levels are typically elevated. 

Hemolytic anemias

Hemolytic anemias are result of the destruction or premature clearance of RBCs. Specifically, they can be due to either damage caused by a narrowed vascular lumen (intravascular hemolysis) or increased splenic clearance (extravascular hemolysis). Splenic clearance can result from intrinsic abnormalities of the RBCs (e.g., abnormal membranes, enzymes, or Hb) or extrinsic antibody coating by the immune system (e.g., ABO incompatibility). 

Examples of hemolytic anemias include:

  • Hereditary spherocytosis (HS): caused by a cytoskeletal protein deficiency in the RBC membrane. This deficiency results in loss of membrane stability and deformability of the RBC, causing its spherical shape (spherocyte). These cells are predisposed to splenic degradation, leading to extravascular hemolysis. Physical findings include jaundice and splenomegaly, while laboratory tests are consistent with hemolytic anemia. The definitive treatment for HS is splenectomy.
  • G6PD deficiency: This X-linked recessive intravascular hemolytic anemia is due to an inherited abnormality in the RBC enzyme G6PD, which generates nicotinamide adenosine dinucleotide phosphate (NADPH), protecting RBCs from oxidative injury. Patients have episodic hemolysis when cells encounter oxidative stressors.
  • Aplastic anemia (AA): rare life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow, in the absence of any abnormal cells, reflecting damage to the hematopoietic stem cells (HSCs). Aplastic anemia can be acquired or inherited. Multiple causes are known, including autoimmune damage to HSCs, medications, chemicals, whole-body radiation, viral infections, immune diseases, pregnancy, Fanconi anemia, and Down syndrome.
  • Autoimmune hemolytic anemia: rare type of hemolytic anemia characterized by the production of autoantibodies directed against RBCs, leading to the destruction of these cells in the spleen. Autoimmune hemolytic anemia is categorized as “warm” or “cold,” depending on the thermal reactivity of the autoantibodies. The etiology is diverse and includes infections, autoimmune diseases, lymphoproliferative disorders, and drugs.
  • Paroxysmal nocturnal hemoglobinuria (PNH): rare and serious acquired chronic hemolytic anemia (HA) with periodic exacerbations. PNH often follows a diagnosis of bone marrow failure/aplastic anemia, but it can also arise de novo. The underlying defect is a somatic mutation in a multipotent hematopoietic stem cell of the X-linked PIGA gene, followed by clonal expansion of the mutated stem cells. These abnormal RBCs undergo mostly intravascular hemolysis and may form a part of a unique clinical triad that also includes pancytopenia and venous thrombosis.

References

  1. Auerbach, M. (2021). Causes and diagnosis of iron deficiency anemia in adults. UpToDate. Retrieved April 21, 2021, from https://www.uptodate.com/contents/causes-and-diagnosis-of-iron-deficiency-and-iron-deficiency-anemia-in-adults
  2. Means, R.T. (2021). Diagnostic approach to anemia in adults. UpToDate. Retrieved April 21, 2021, from https://www.uptodate.com/contents/diagnostic-approach-to-anemia-in-adults
  3. Despotovic, J.M. (2021). Overview of hemolytic anemias in children. UpToDate. Retrieved April 21, 2021, from https://www.uptodate.com/contents/overview-of-hemolytic-anemias-in-children
  4. Camaschella, C., Weiss, G. (2020). Anemia of chronic disease/anemia of inflammation. UpToDate. Retrieved April 21, 2021, from https://www.uptodate.com/contents/anemia-of-chronic-disease-anemia-of-inflammation
  5. Brodsky, R.A. (2021). Diagnosis of hemolytic anemia in adults. UpToDate. Retrieved April 21, 2021, from https://www.uptodate.com/contents/diagnosis-of-hemolytic-anemia-in-adults
  6. Turner, J., Parsi, M. (2021). Anemia. StatPearls. Retrieved April 28, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/17527/ 
  7. Aster, J.C. (2005). Red blood cell and bleeding disorders. In Kumar, V., Abbas, A.K., Fausto, N. (Eds). Robbins and Cotran Pathologic Basis of Disease, 7th ed., pp. 622–649.

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