Anemia

Anemia is defined as a decrease in the number of circulating red blood cells (RBC), represented by a reduction in hemoglobin concentration (Hb), hematocrit (Hct), or RBC count. It is a common condition that can be caused by either inadequate RBC production, excessive RBC destruction, or blood loss. The most common cause is iron deficiency. Clinical features, if present, are mostly nonspecific and may include fatigue, dyspnea, conjunctival pallor, and tachycardia. Anemia is often an incidental finding made on CBC that requires further workup to determine the cause. The next best step is to obtain RBC indices, most importantly, the mean corpuscular volume (MCV), to distinguish between microcytic, normocytic, and macrocytic anemias based on the size of the RBCs. Size classification helps guide the next diagnostic step. A peripheral blood smear can serve to identify classic pathologic RBC forms. Reticulocyte count can serve to evaluate the bone marrow response. Since Hb levels initially remain normal in the setting of acute blood loss, it is important to monitor vital signs such as blood pressure and heart rate. Treatment depends on the form of anemia and may include supplementation (e.g., iron, vitamin B₁₂, and folate), discontinuation of causative agents (e.g., in aplastic anemia), and stopping the source of bleeding or treating the underlying condition (e.g. in anemia of chronic disease). Acute and/or severe cases of anemia may require the transfusion of packed red blood cells.

Classification by cell size

There are many ways to classify anemias (e.g. cell size, mechanism, acute vs. chronic, inherited vs. acquired, primary vs. secondary). Classification by cell size is how hematologists begin their diagnostic work-up, and therefore has the most practical application.

Microcytic anemia (MCV < 80 fL)

• Mechanism: insufficient hemoglobin production → decreased hemoglobin available for erythrocytes → microcytic, hypochromic anemia
• Types
  • Iron deficiency anemia (most common form of anemia)
  • Thalassemias
  • Acquired causes (e.g., lead poisoning)
  • Sideroblastic anemia
    • Rare disorder of heme synthesis that can be inherited; (e.g., X-linked sideroblastic anemia due to a δ-ALA-synthase gene defect) or acquired (lead exposure; , myelodysplastic syndromes, alcohol use disorder, vitamin B_6,, or copper deficiency, isoniazid)

Macrocytic anemia (MCV > 100 fL)

• Mechanism: insufficient cell production → more hemoglobin available for erythrocytes → macrocytic anemia
• Types
  • Megaloblastic
    • Vitamin B12 deficiency or folate deficiency
      • Folic acid and vitamin B₁₂ are essential for cell proliferation. Deficiencies may affect all cell lines (pancytopenia).
      • Folic acid deficiency manifests more quickly because the body's stores of folic acid last for only about 3 months; without any uptake while vitamin B₁₂ stores last up to 2–3 years.
    • Orotic aciduria
  • Non-megaloblastic
    • Reticulocytosis
    • Liver disease
    • Alcohol use
    • Myelodysplastic syndrome
    • Hypothyroidism
    • Multiple myeloma

Normocytic anemia (MCV 80–100 fL)

• Mechanism: decreased erythropoiesis or decreased blood volume
• Types
  • Hemolytic (See hemolytic anemias)
  • Non-hemolytic
    • Anemia of chronic disease; (ACD): anemia of chronic disease can also be microcytic.
    • Aplastic anemia
    • Anemia of chronic kidney disease
    • Bone marrow failure or disease (e.g., myeloproliferative neoplasms, myelodysplastic syndromes)
    • Blood loss

References:^[2][1][3]

• Exertional dyspnea and fatigue
• Pallor (most evident on mucous membranes, in particular, the conjunctiva)
• Muscle cramps
• Possibly tachycardia
• Bounding pulses; , palpitations, pulsatile sound in the ear
• Worsening of angina pectoris
• Features of extramedullary hematopoiesis in certain severe chronic anemias (e.g., thalassemia, myelofibrosis)
  • Hepatosplenomegaly
  • Paravertebral mass
  • Widening of diploic spaces of skull

Aplastic anemia

• Definition: Pancytopenia (anemia, thrombocytopenia, and leukocytopenia) with bone marrow insufficiency
• Etiology
  • Idiopathic (in >50%)
  • Inherited
    • Fanconi anemia is a hereditary autosomal recessive disorder due to a DNA crosslink repair defect that presents with the following features:
      • 50% develop acute myeloid leukemia or myelodysplastic syndromes in early adulthood
      • Skeletal and organ abnormalities: short stature, hypo- and hyperpigmentation, cafe-au-lait spots, microcephaly, developmental delay, thumb and forearm malformations; , kidney, GI, heart, eye, and ear abnormalities
      • Labs: pancytopenia
  • Medication side effects/toxicity
    • Carbamazepine, methimazole, NSAIDs, benzene, chloramphenicol, cytostatic drugs, propylthiouracil
  • Ionizing radiation
  • Viruses: parvovirus B19, hepatitis viruses, EBV, HIV
• Bone marrow biopsy
  • The findings of hypocellular fat-filled marrow with RBC of normal morphology is diagnostic for aplastic anemia.
• Treatment
  • Cessation of the offending agent or treatment for infection
  • Blood transfusions
  • Immunosuppressive therapy
  • Hematopoietic cell transplantation (HCT)

Drugs that can cause aplastic anemia: Can't Make New Blood Cells Properly = Carbamazepine, Methimazole, NSAIDs, Benzenes, Chloramphenicol, Propylthiouracil

Anemia of chronic disease

• Second most common form of anemia
• Etiology
  • Inflammation (e.g., rheumatoid arthritis, systemic lupus erythematosus)
  • Malignancy (e.g., lung cancer, breast cancer, lymphoma)
  • Infection (e.g., tuberculosis)
• Pathophysiology: In chronic disease or inflammation, anemia is mediated through cytokines and, more importantly, hepcidin , which causes:
  1. Reduced iron uptake (and release) from macrophages in reticuloendothelial system and reduced intestinal absorption
  2. Reduced response (of production) to erythropoietin (EPO) and relative reduction of EPO levels → reduced synthesis
  3. Reduced erythrocyte survival and lifespan
  4. Results in normocytic or microcytic anemia
• Treatment: treat underlying cause

Pure red cell aplasia

• Definition: normocytic normochromic anemia with severe reduction in the number of reticulocytes in the peripheral blood and marked reduction or absence of erythroid precursors from the bone marrow.
• Etiology
  • Congenital
    • Diamond-Blackfan anemia (DBA) is a congenital pure red blood cell aplasia that presents in infancy with the following features:
      • Macrocytic (non-megaloblastic) anemia in infancy or early childhood (usually diagnosed before one year of age)
      • Pallor in infancy
      • Congenital malformations (50%): microcephaly, hypertelorism, flat nasal bridge, micrognathia, short stature, webbed neck, cleft palate, and triphalangeal thumbs
      • Electrophoresis reveals elevated fetal Hb levels
  • Acquired: most often idiopathic, but can be associated with a number of conditions, such as:
    • Thymoma
    • Myelodysplastic syndrome
    • Drugs (e.g., phenytoin, chloramphenicol)
    • Parvovirus B19 infection
    • Autoimmune disorders (e.g., type 1 diabetes, thyroiditis, rheumatoid arthritis)
• Pathophysiology: : not well-understood, but it is thought to be related to abnormal T-cell function and IgG antibodies that target erythroblasts and erythropoietin
• Treatment
  • Treatment of the underlying cause (e.g., cessation of possible offending agents, thymectomy)
  • Red blood cell transfusion for symptomatic patients
  • Immunosuppressive and/or cytotoxic agents (e.g., glucocorticoids, cyclosporine, cyclophosphamide)

References:^{[4][5][6][7][8][9][10][11][12][13]}

The diagnosis of anemia is made based on hemoglobin, hematocrit, or RBC count. After determining that anemia is present, workup for the cause of anemia is required.

History

• Bleeding (history of recent trauma or surgery, menorrhagia, melena, hematemesis)
• Hemolysis (jaundice, gallstones)
• Chronic diseases
• Medications
• Family history (e.g., inherited anemias and hemophilia)
• Social history (alcohol)

Complete blood count (CBC) with the RBC indices

MCV is the most important test in the diagnostic workup. Based on RBC size, further tests should be ordered to determine the diagnosis.

MCV < 80 fL = microcytic anemia

• Iron studies: serum iron, ferritin , transferrin/total iron binding capacity (TIBC), % iron saturation
• Reticulocyte count
• If iron studies are normal: workup for hemolytic anemia
• If iron deficiency is suspected: further workup for causes of bleeding
• If thalassemia is suspected: hemoglobin electrophoresis
• If sideroblastic anemia is suspected: cell staining with Prussian blue reveals ringed sideroblasts (for more information on staining, see Prussian blue reaction)

	Serum Iron	Serum Ferritin	% Iron saturation	Transferrin/TIBC	Reticulocyte count	Red cell distribution width (RDW)
Iron deficiency	↓	↓	↓	↑	↓	↑
Anemia of chronic disease	↓	↑	↓	↓	↓	Normal
Thalassemia	Normal to ↑*	Normal to ↑*	Normal to ↑*	Normal to ↓*	Normal or ↑	Normal (occasionally ↑)
Sideroblastic anemia	↑	↑	↑	↓	↓	↑
* If iron overload is present (e.g., due to multiple transfusions, ineffective erythropoiesis, ↑ GI iron absorption)

MCV 80–100 fL = normocytic anemia

• Reticulocyte count: evaluate bone marrow response
  • Low reticulocyte count: ineffective or decreased RBC production; , e.g., chronic renal failure; , aplastic anemia (look for possible causative agents; see “Subtypes and variants” above), ACD, and cancer/dysplasia (e.g., acute leukemia)
  • High reticulocyte count: increased RBC destruction (hemolysis) or blood loss
  • Normal or elevated reticulocyte count: acute blood loss and hemolysis

MCV > 100 fL = macrocytic anemia

• Folate and/or vitamin B₁₂ levels: decreased levels may cause megaloblastic anemia:
  • Appearance of hypersegmented neutrophils (megaloblastic) on peripheral blood smear
  • ↓ Reticulocytes, ↑ iron
  • Bone marrow (not required): erythroid hyperplasia
  • In vitamin B₁₂ deficiency: workup for causes such as type A gastritis and ileal disease (e.g., Crohn's disease)
• Evaluate for myelodysplastic syndromes
• Evaluate other cell lines (may also be affected)

Peripheral blood smear

• May reveal classic pathologic RBC forms that can be used to identify certain types of anemia → see erythrocyte morphology

Bone marrow biopsy

• Invasive procedure that is rarely used in the workup of anemia
• Indications include pancytopenia and the finding of abnormal cells on the complete blood count or the peripheral blood smear such as blasts.
• Anemia accompanied by one of those findings may be caused by aplastic anemia, myelodysplastic syndromes, myeloproliferative neoplasm, or malignancy replacing the bone marrow.

References:^{[2][1][14][15]}