- Clinical science
Anemia is defined as a decrease in the quantity 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 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. Once anemia has been established, the mean corpuscular volume (MCV) should be checked to distinguish between microcytic, normocytic, and macrocytic anemia and to determine the next diagnostic steps. A peripheral blood smear allows for the identification of pathologic RBC forms. Reticulocyte count can also be used to evaluate the bone marrow response. Treatment depends on the form of anemia and underlying condition. Acute and/or severe cases of anemia may require transfusion of packed red blood cells.
Anemia may be classified into several subtypes based on the following methods:
- Morphology/size of RBCs (the classification most widely used) 
- Time course: acute vs. chronic
- Inheritance: inherited vs. acquired
- Etiology: primary vs. secondary
|Classification of anemia by morphology|
|Microcytic anemia||Normocytic anemia||Macrocytic anemia|
|MCV (fL)|| || || |
|Mechanism|| || |
|Differential diagnosis|| |
- Pallor; (e.g., on mucous membranes, conjunctivae)
- Exertional dyspnea; and fatigue
- (craving for ice or dirt)
- Jaundice (in hemolytic anemia)
- Muscle cramps
- Worsening of angina pectoris
- Features of hyperdynamic state
- Bounding pulses
- Pulsatile sound in the ear
- Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g., , ).
Pulse acceleration is often the first sign of hemodynamically relevant blood loss.
- Bleeding (e.g., recent surgery/trauma, menorrhagia, melena)
- Chronic disease (e.g., rheumatoid arthritis, underlying malignancy)
- Medication (e.g., recent isoniazid use)
- Family history of inherited anemias or hemophilia
- Alcohol use
Complete blood count (CBC) with RBC indices
- MCV is the most important initial test in the diagnostic workup.
- Based on RBC size, further testing should be performed to determine the underlying cause.
MCV < 80 fL = microcytic anemia 
- Check iron studies (e.g., serum iron, ferritin, TIBC, % iron saturation)
- Low ferritin: (see )
- High/normal ferritin
- Normal iron studies: workup for acute blood loss, , thalassemia, sideroblastic anemia
- Check reticulocyte count
|Serum laboratory results in microcytic anemia|
|Iron||Ferritin||% Iron saturation||Transferrin or TIBC||Reticulocyte count|| |
|Anemia of chronic disease||↓||↑||Normal to ↓||↓||↓||Normal|
|Normal to ↑*||Normal to ↑*||Normal to ↑*||Normal to ↓*||Normal or ↑||Normal (occasionally ↑)|
|* If iron overload is present (e.g., due to multiple transfusions, ineffective erythropoiesis, ↑ GI iron absorption)|
Basophilic stippling on peripheral blood smear suggests lead poisoning or sideroblastic anemia. Ringed sideroblasts are usually not seen in lead poisoning and can be used to distinguish between it and sideroblastic anemia.
MCV 80–100 fL = normocytic anemia
- Check iron studies (see above)
- Check reticulocyte count to evaluate bone marrow response
- Low reticulocyte count (< 2%) shows ineffective or decreased RBC production (hypoproliferative anemia)
- Normal/high reticulocyte count (> 2%)
MCV > 100 fL = macrocytic anemia
- Check peripheral blood smear
- Hypersegmented neutrophils (> 5 lobes) present: megaloblastic anemia
- No hypersegmented neutrophils present: nonmegaloblastic anemia
- Manual examination of a peripheral blood sample under a microscope
- May reveal classic pathologic RBC forms, which can be used to identify certain types of anemia that automated RBC indices cannot (e.g., schistocytes in hemolytic anemia)
- See .
- Manual examination of bone marrow aspirate sample under a microscope
- Rarely used in the workup of anemia
- Indications include pancytopenia and/or abnormal cells on the CBC or peripheral blood smear (e.g., blasts)
- Prussian blue staining if sideroblastic anemia is suspected (see above)
- Can be used to diagnose:
- Treat underlying cause (e.g., iron supplementation for IDA, EPO for chronic kidney disease, vitamin B6 for sideroblastic anemia , bleeding cessation with surgical or interventional procedures in case of active bleeding)
- Blood transfusion with RBCs: See “transfusion thresholds” in .
- Bone marrow transplantation may be indicated in severe cases (e.g., aplastic anemia, bone marrow failure). 
- IV access
- IV fluid resuscitation if the patient is hypotensive or tachycardic
- Type and screen with cross-matching.
- Consent patient for blood transfusion.
- Consider indications for transfusion of packed RBCs (see also transfusion) 
- Consider transfusion of other blood components, if indicated (e.g., platelets , fresh frozen plasma ).
- Identify and treat the underlying cause.
- Serial blood pressure monitoring, continuous pulse oximetry
- Supplemental oxygen as needed
- Description: pancytopenia caused by bone marrow insufficiency 
Idiopathic in > 50% of cases
- Possibly immune-mediated
- May follow acute hepatitis (hepatitis-associated aplastic anemia)
- Medication side effects: carbamazepine, methimazole, NSAIDs, chloramphenicol, propylthiouracil, sulfa drugs, cytostatic drugs (esp. alkylating agents and antimetabolites)
- Toxins: benzene, cleaning solvents, insecticides, toluene
- Ionizing radiation
- Viruses: parvovirus B19, HBV, EBV, CMV, HIV
Fanconi anemia 
- Hereditary autosomal recessive disorder due to a DNA crosslink repair defect resulting in bone marrow failure
- 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
- Laboratory tests show pancytopenia and normocytic or macrocytic anemia.
- ∼ 50% of patients with Fanconi anemia will develop acute myeloid leukemia or myelodysplastic syndromes in early adulthood.
- Idiopathic in > 50% of cases
- Clinical features
- Cessation of the causative agent
- Supportive therapy
- Bone marrow stimulants (e.g., GM-CSF)
- Immunosuppressive therapy
- Consider hematopoietic cell transplantation (HCT) in young patients. 
Agents that can cause aplastic anemia: Can't Make New Blood Cells Properly = Carbamazepine, Methimazole, NSAIDs, Benzenes, Chloramphenicol, Propylthiouracil
- Description: anemia due to chronic inflammation
- Epidemiology: second most common anemia 
Pathophysiology: inflammation → increase in cytokines (esp. IL-6) and hepcidin → results in the outcomes listed below:
- Reduced iron release from macrophages in the reticuloendothelial system and reduced intestinal iron absorption → reduced iron available systemically
- Reduced response (of production) to erythropoietin (EPO) and relative reduction of EPO levels → reduced RBC synthesis
- Reduced erythrocyte survival and lifespan
- Description: : anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria 
- Description: normocytic, normochromic anemia characterized by a severe reduction in circulating reticulocytes and marked reduction or absence of erythroid precursors in the bone marrow 
- Pathophysiology: : thought to be related to abnormal T-cell function and IgG antibodies that target erythroblasts and erythropoietin
- Acquired: most often idiopathic, but can be associated with
Congenital: Diamond-Blackfan anemia (DBA)
- Intrinsic defect of erythroid progenitor cells → increased apoptosis
- Rapid onset of macrocytic (non-megaloblastic) anemia in infancy (usually diagnosed within the first year of life)
- Additional clinical features (physical abnormalities manifest in ∼ 50% of patients)