Anemia in Adults

Background

• Anemia is a condition of decreased hemoglobin (Hb) concentration compared to age-matched and gender-matched controls.
• World Health Organization (WHO) defines anemia (at sea level) as:
  • Hb < 13 g/dL (130 g/L) in male persons ≥ 15 years old
  • Hb < 12 g/dL (120 g/L) in nonpregnant female persons ≥ 15 years old or adolescents aged 12-14 years
  • Hb < 11.5 g/dL (115 g/L) in children aged 5-11 years
  • Hb < 11 g/dL (110 g/L) during pregnancy or in children aged 6-59 months
• Anemia is a common condition with an estimated prevalence of 27% world wide (1.93 billion people). In adults, anemia is particularly high during pregnancy (estimated prevalence of 42% world wide) and older adults age > 65 years (reported prevalence of 10%-24%).
• Maintenance of stable Hb concentration is governed by a balance between the ability of the bone marrow to produce red blood cells (RBCs) in response to blood loss, natural aging of RBCs, and RBC destruction. Anemia results when erythropoietic response (reticulocytosis) cannot compensate for normal or increased loss of RBCs in the circulation.
• Causes of anemia can be broadly classified according to non-hypoproliferative or hypoproliferative anemia, which is determined by degree of bone marrow response evaluated by the reticulocyte count.
  • Non-hypoproliferative anemia refers to RBC loss due to bleeding or hemolysis.
    • Hemolysis may occur as a result of intrinsic RBC defects due to abnormal RBC properties.
      • These include:
        • membrane/cytoskeletal defects (for example, hereditary spherocytosis)
        • hemoglobinopathies (for example, sickle cell disease)
        • enzymopathies (for example, glucose-6-phosphate dehydrogenase deficiency)
      • The majority of these conditions are inherited, except for paroxysmal nocturnal hemoglobinuria (an acquired membrane defect).
    • Hemolysis may occur as a result of extrinsic defects due to the destruction of normal RBCs.
      • These include:
        • mechanical damage to RBCs (for example, malfunctioning cardiac valve and ventricular assist devices)
        • microangiopathic hemolysis (for example, thrombotic thrombocytopenic purpura [TTP] and hemolytic uremic syndrome [HUS])
        • immunologic damage (for example, autoimmune hemolytic anemia)
        • damage to RBCs from infectious disease (for example, malaria and babesiosis)
        • metabolic/oxidant damage or hypersplenism
      • The majority of these conditions are acquired, except for rare congenital variants of TTP and HUS.
  • Hypoproliferative anemia refers to a decrease in RBC production and may occur due to:
    • deficiencies in nutrients that are required for adequate erythropoiesis such as iron, vitamin B12, or folate deficiency
    • organ dysfunction such as chronic kidney disease which leads to low erythropoietin levels, and endocrine disorders
    • bone marrow failure including pure red cell aplasia, congenital and acquired aplastic anemia, hematological malignancies, and bone marrow suppression and infiltration by conditions such as inflammation, infection, oncologic malignancies, and sarcoidosis

Evaluation

• Patients may be asymptomatic due to development of anemia over weeks or months, allowing the body to compensate for lower oxygen carrying capacity.
• There is no specific Hb concentration that leads to development of symptoms, but most patients will present with symptoms when Hb drops to < 7 g/dL (70 g/L). However, patients with conditions of limited cardiac function (for example, heart failure or coronary artery disease) may present with symptoms of anemia at a higher Hb level than those with normal cardiac function.
• General signs and symptoms of anemia:
  • Symptoms of anemia are related to lack of oxygen delivery and include, fatigue, listlessness, shortness of breath, chest pain, decreased exercise tolerance, dizziness, syncope (if anemia is significant), headache, and palpitations.
  • Signs associated with anemia include, paleness of mucous membranes, resting tachycardia, hypotension, and tachypnea.
  • Signs and symptoms of hemolytic anemia include, jaundice, scleral icterus, dark urine, hepatosplenomegaly, splenic fullness, and in severe cases, angina, fever, pallor, tachycardia, signs of heart failure, and hemoglobinuria.
• Additional clinical presentation will depend on the underlying cause contributing to anemia.
• Physical exam should include assessment of orthostatic vital signs, which is important because patient at rest may appear hemodynamically stable but may become severely hypotensive with standing and assessment of location and severity of bleeding if bleeding is suspected.
• Two complementary diagnostic approaches to identify the cause of anemia:
  • Kinetic approach categorizes anemias based on the reticulocyte count and addresses the mechanism(s) responsible for the fall in Hb concentration. According to this approach, anemia can result from:
    • decreased RBC production (inappropriate reticulocyte response)
    • increase in RBC destruction (appropriate reticulocyte response)
    • blood loss (appropriate reticulocyte response)
  • Morphologic approach categorizes anemias by alterations in RBC size (mean corpuscular volume [MCV]).
• After the diagnosis of anemia is made, perform further diagnostic testing, starting with the reticulocyte count (kinetic approach) and followed by the MCV (morphologic approach). .
  • Kinetic approach:
    • If reticulocyte response is normal, assess for hemolysis (extracorpuscular or intracorpuscular) or bleeding.
      • Test for markers of hemolysis including low haptoglobin, elevated serum lactate dehydrogenase, elevated aspartate aminotransferase, and elevated bilirubin.
      • Examine a peripheral smear for presence of schistocytes, bite cells, sickle cells or spherocytes.
      • Consider direct antiglobulin test to rule out autoimmune hemolytic anemia.
      • Additional tests will depend on the clinic context.
    • If reticulocyte response is inappropriate and tests for hemolysis are negative, consider the mean cell volume.
  • Morphologic approach:
    • Microcytic (MCV < 80 femtoliter [fL]):
      • Determine if anemia is caused by iron deficiency, thalassemia, anemia of inflammation, or hereditary spherocytosis. Initial testing should include evaluation of serum ferritin level (as well as other iron studies) to determine if iron deficiency is present.
      • Presence of thalassemia may be confirmed by Hb electrophoresis (beta-thalassemia) or DNA sequencing (alpha-thalassemia).
    • Macrocytic (MCV > 100 fL)
      • If reticulocyte count is elevated (reticulocytes are larger than mature RBCs and may increase the MCV), consider hemolysis or blood loss.
      • If reticulocyte count is inappropriately low, consider:
        • vitamin B12 and folate levels to rule out nutritional deficiency
        • liver function tests
        • thyroid function tests
        • screening for alcohol use disorder
        • bone marrow examination for myelodysplastic syndrome (and other primary hematologic disease)
    • Normocytic
      • Rule out bleeding (especially in the acute setting before development of iron deficiency and microcytosis).
      • If retriculocyte count is inappropriately low, consider:
        • serum iron studies and C-reactive protein to assess for anemia of inflammation
        • blood urea nitrogen and creatinine to assess for anemia of chronic kidney disease
        • thyroid function tests
        • testosterone in male adults
        • serum protein electrophoresis to assess for plasma cell dycrasia
        • bone marrow examination for myelodysplastic syndrome (and other primary hematological disease) and anemia of marrow infiltration (for example, leukemia, multiple myeloma, solid tumors, and scarring)
      • Take into consideration that:
        • almost all anemias are normocytic during the early stages of the disorder
        • existence of multiple causes (for example, iron deficiency and liver disease or iron deficiency with vitamin B12 deficiency) can result in normocytic anemia
        • partial treatment of megaloblastic anemia such as, vitamin B12 deficiency or folate deficiency can result in normocytic anemia

Management

• Initial management is dependent on patient clinical status:
  • Patients who are bleeding:
    • Control bleeding. This may involve surgery, gastroenterology, or involvement of specialist such as interventional radiology.
    • In patients with hemodynamic instability, ongoing bleeding, or tissue hypoxia, transfuse RBCs (Strong recommendation).
  • Patients who are hemodynamically stable:
    • Not all patients require immediate management.
    • Indications for transfusion (excluding those with acute coronary syndrome, severe thrombocytopenia [patients with hematological or oncological conditions at risk of bleeding], and those with chronic transfusion-dependent anemia):
      • Transfusion is not indicated until Hb level drops to 7 g/dL (70 g/L) or less (Strong recommendation).
      • For patients having orthopedic surgery or cardiac surgery or have pre-existing cardiovascular disease, transfuse RBCs when Hb level is ≤ 8 g/dL (80 g/L) (Strong recommendation).
• Management of chronic anemia:
  • Treat underlying conditions contributing to anemia.
  • Other approaches to manage anemia:
    • Nutritional supplementation to correct deficiency such as iron deficiency, vitamin B12 deficiency, and folate deficiency to support erythropoiesis.
    • Administration of erythropoiesis stimulating agents (ESAs) for the treatment of anemia associated conditions such as inflammation, chronic kidney disease, and cancer.
    • If anemia involves severe/massive splenomegaly, splenic irradiation as palliative treatment and splenectomy to relieve symptoms of severe/massive splenomegaly and cytopenias. Specific indications for splenectomy depend on the clinical context.
    • Hematopoietic stem cell transplantation (HSCT) to restore hematopoiesis after high-dose cytotoxic therapy for malignancy (autologous or allogeneic HSCT) or to correct congenital or acquired defects in blood cell production and/or immune function (allogeneic HSCT).