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. 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.
- Definition: a decrease in the absolute number of circulating RBCs; exact cutoffs vary from source to source.
- WHO criteria for anemia 
- Revised WHO/National Cancer Institute 
- American Society of Hematology 
- US National Health and Nutrition Examination Survey: children aged 12–35 months: Hb < 11 g/dL
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
- RBC proliferation: hypoproliferative (decreased RBC production) vs. hyperproliferative (increased RBC destruction or blood loss)
|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
- Growth impairment (chronic anemia)
- Worsening of angina pectoris
- Features of hyperdynamic state
- 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.
- Check CBC to confirm anemia and assess severity.
- Based on MCV, classify into microcytic, macrocytic, and normocytic anemia.
- Order initial tests to evaluate the underlying cause of anemia.
- Microcytic anemia: iron panel to evaluate for iron deficiency anemia; further evaluation depends on iron panel findings.
Macrocytic anemia: peripheral blood smear to differentiate megaloblastic anemia from nonmegaloblastic anemia.
- Megaloblastic anemia: serum B12 and folate levels and, if necessary, serum homocysteine and methylmalonic acid levels to identify vitamin B12 deficiency and/or folate deficiency
- Nonmegaloblastic anemia: reticulocyte count to differentiate macrocytosis due to hemolysis/blood loss (high reticulocyte count) from macrocytosis due to drugs, alcohol, myelodysplastic syndromes, or pure red cell aplasia (low reticulocyte count).
- Normocytic anemia: reticulocyte count to assess bone marrow response.
- Consider advanced diagnostics such as hemoglobin electrophoresis and bone marrow aspirate and biopsy as needed and with the guidance of a hematologist.
Initial test to confirm and classify anemia.
- RBC indices: MCV is the most important parameter in the diagnostic workup of anemia.
- Based on MCV, further testing should be performed to determine the underlying cause.
- Abnormalities in platelet count, WBC count, and WBC differential may provide signs of the underlying diagnosis. 
Microcytic anemia (MCV < 80 fL) 
- Iron studies: initial investigation for microcytic anemia
Peripheral blood smear (PBS), reticulocyte count, RDW: not routinely required to evaluate microcytic anemia because findings are often nonspecific
- PBS findings may suggest a specific etiology.
- Reticulocyte count
- RDW: typically high in iron deficiency anemia and sideroblastic anemia
- Hemoglobin electrophoresis: obtain if serum iron levels, TIBC, and TfS are normal or elevated
- Bone marrow biopsy: consider if the following are identified 
- Serum lead level: consider in patients with basophilic stippling but no ringed sideroblasts on PBS (see )
|Serum laboratory findings in microcytic anemia|
|Transferrin or TIBC||Reticulocyte count|| |
|Anemia of chronic disease||↓||↑||Normal to ↓||↓||↓||Normal|
|Normal to ↑*||Normal to ↑*||Normal to ↑*||Normal to ↓*||↑||Normal (occasionally ↑)|
|Pregnancy or use of oral contraceptive pills||Normal to ↓||Normal||↓||↑||Normal||Normal|
|* If there is iron overload (e.g., due to multiple transfusions, ineffective erythropoiesis, increased GI iron absorption)|
Basophilic stippling on peripheral blood smear suggests lead poisoning or sideroblastic anemia. Because ringed sideroblasts are not usually seen in lead poisoning, they can help to distinguish between this condition and sideroblastic anemia.
Macrocytic anemia (MCV > 100 fL) 
- Peripheral blood smear (PBS): initial investigation for macrocytic anemia to look for megaloblastic changes (hypersegmented neutrophils)
Evaluation of megaloblastic macrocytic anemia
- Vitamin B12 and folate levels: obtain in all patients with megaloblastic changes on PBS. 
- Serum homocysteine and methylmalonic acid levels: obtain in patients with borderline serum vitamin B12 and/or folate levels
- Bone marrow biopsy: consider if any of the following are present 
- Additional evaluation: : consider urine orotic acid levels if orotic aciduria is suspected (extremely rare)
Evaluation of nonmegaloblastic macrocytic anemia 
Reticulocyte count: in all patients with nonmegaloblastic macrocytic anemia to evaluate bone marrow response
- Normal/low reticulocyte count (< 2%)
- High reticulocyte count (> 2%)
- Additional evaluation: consider the following if reticulocyte count and metabolic panels are normal and there is no history of drug/alcohol use
Normocytic anemia (MCV 80–100 fL) 
Reticulocyte count: in all patients with normocytic anemia to evaluate bone marrow response
Normal/low reticulocyte count (< 2%) indicates ineffective or decreased RBC production (hypoproliferative anemia)
- Iron studies: to evaluate for iron deficiency anemia and/or anemia of chronic disease (see microcytic anemia)
- Vitamin B12 and folate levels (see megaloblastic macrocytic anemia)
- Basic metabolic panel (BMP), LFTs, thyroid studies: if iron studies and B12 and folate levels are normal 
- Serum erythropoietin levels: consider if BUN and/or creatinine levels are abnormal 
- High reticulocyte count (> 2%) 
- Normal/low reticulocyte count (< 2%) indicates ineffective or decreased RBC production (hypoproliferative anemia)
- Bone marrow aspirate and biopsy: consider in hypoproliferative anemia with normal nutritional assays and metabolic panels 
Peripheral blood smear
- 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:
- Imaging is not routinely indicated for the workup of anemia unless bleeding is suspected.
- Consider endoscopy and/or colonoscopy in patients with anemia and positive FOBT.
- Consider abdominal ultrasound to evaluate for hypersplenism, liver disease, or renal disease.
- Consider CT and/or PET scan if malignancy is suspected.
- Identify and treat the underlying cause
- Blood transfusion with RBCs for severe anemia:
- Consider hospital admission or observation in: 
- Bone marrow transplantation may be indicated in certain cases (e.g., aplastic anemia).
- IV access
- IV fluid resuscitation if the patient is hypotensive or tachycardic
- Type and screen with crossmatching
- Consent patient for blood transfusion.
- Obtain blood for further diagnostic workup of anemia before initiating transfusion.
- Consider indications for transfusion of packed RBCs.
- Consider transfusion of other blood components, if indicated (e.g., platelets, fresh frozen plasma; see transfusion).
- Identify and treat the underlying cause.
- Serial blood pressure monitoring, continuous pulse oximetry
- Supplemental oxygen as needed
- Idiopathic in > 50% of cases
- 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: 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. 
- Clinical features
- Cessation of the causative agent
- Supportive therapy
- Bone marrow stimulants (e.g., GM-CSF, eltrombopag)
- 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
- Congenital: Diamond-Blackfan anemia (DBA): see below
Diamond-Blackfan anemia 
- Additional clinical features: physical abnormalities manifest in ∼50% of affected individuals
- Treatment 
- Increased risk of malignancy: acute myelogenous leukemia, myelodysplastic syndrome, solid tumors (e.g., colon cancer, osteogenic sarcoma)
- Treatment-associated complications: iron overload due to repeated transfusions, corticosteroid-induced hyperglycemia
- Endocrine dysfunction: adrenal insufficiency, hypogonadism, vitamin D deficiency
- Description: acute anemia due to blood loss
- Etiology: any cause of bleeding can cause acute blood loss anemia
- Clinical features: May be asymptomatic or have symptoms of anemia (see above) 
- Routine laboratory studies
- Imaging: Modality depends on the pretest probability of the suspected site of bleeding.
- CT of soft tissue if there is concern for intramuscular bleeding.
- Abdominal/pelvic CT if there is concern for intra-abdominal bleeding.
- Chest radiography and/or chest CT if there is concern for a pulmonary source (See “Diagnostics” in pleural effusion and in hemothorax).
- Endoscopy and/or colonoscopy if there is concern for a GI bleed. (See ''Diagnostics'' in gastrointestinal bleeding)
- Identify and treat the underlying cause
- Blood transfusion
Hemoglobin and hematocrit levels can initially be normal in acute hemorrhage, even if there has already been significant blood loss. They will eventually decrease after plasma volume has been restored either spontaneously or via IV fluid resuscitation.