Anemia

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.

See basics of hematology, transfusion, and iron deficiency anemia for more information.

• Definition: a decrease in the absolute number of circulating RBCs
• WHO criteria for anemia ^[1]
  • Men: Hb < 13 g/dL
  • Women: Hb < 12 g/dL

References:^[2]

Anemia may be classified into several subtypes based on the following methods:

• Morphology/size of RBCs (the classification most widely used) ^[3]
• 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)	< 80	80–100	> 100
Mechanism	Insufficient hemoglobin production	Decreased blood volume and/or decreased erythropoiesis	Insufficient cell production and/or maturation Defective DNA synthesis Defective DNA repair
Differential diagnosis	Defective heme synthesis Iron deficiency anemia (the most common) Lead poisoning Anemia of chronic disease (late phase) Sideroblastic anemia Defective globin chain Thalassemia	Hemolytic anemia (reticulocyte count > 2%) Hemoglobinopathies Sickle cell anemia HbC disease Enzyme deficiencies Pyruvate kinase deficiency G6PD deficiency Membrane defects Paroxysmal nocturnal hemoglobinuria Hereditary spherocytosis Autoimmune hemolytic anemia Microangiopathic hemolytic anemia Macroangiopathic hemolytic anemia Infections Nonhemolytic (reticulocyte count < 2%) Blood loss Aplastic anemia Anemia of chronic kidney disease Iron deficiency anemia (early phase) Anemia of chronic disease (early phase)	Megaloblastic anemia Vitamin B12 deficiency Folate deficiency Medications Phenytoin Sulfa drugs Trimethoprim Hydroxyurea MTX 6-mercaptopurine Fanconi anemia Orotic aciduria Nonmegaloblastic anemia Liver disease Alcohol use Diamond-Blackfan anemia Myelodysplastic syndrome Hypothyroidism Multiple myeloma

Both iron deficiency anemia and anemia of chronic disease can manifest with normocytic anemia in the initial phase and microcytic anemia later on.

Bone marrow failure (e.g., due to myeloproliferative malignancy, myelodysplastic syndrome) can manifest with microcytic, normocytic, or macrocytic anemia.

The causes of microcytic anemia can be remembered with IRON LAST: IRON deficiency, Lead poisoning, Anemia of chronic disease, Sideroblastic anemia, Thalassemia.

References:^[4][2][5]

• Pallor; (e.g., on mucous membranes, conjunctivae)
• Exertional dyspnea; and fatigue
• Pica (craving for ice or dirt)
• Jaundice (in hemolytic anemia)
• Muscle cramps
• Worsening of angina pectoris
• Features of hyperdynamic state
  • Bounding pulses
  • Tachycardia/palpitations
  • Flow murmur
  • Pulsatile sound in the ear
• Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g., thalassemia, myelofibrosis).
  • Hepatosplenomegaly
  • Paravertebral mass
  • Widening of diploic spaces of the skull

Pulse acceleration is often the first sign of hemodynamically relevant blood loss.

References:^[5]

History

• 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 ^[6]

• Check iron studies (e.g., serum iron, ferritin, TIBC, % iron saturation)
  • Low ferritin: iron deficiency anemia (see diagnosis of iron deficiency anemia)
  • High/normal ferritin
    • High TIBC: iron deficiency anemia
    • Low/normal TIBC: consider other diagnoses
      • High CRP/ESR and/or history of chronic disease: anemia of chronic disease
      • Abnormal electrophoresis: thalassemia
      • Peripheral blood smear with basophilic stippling: lead poisoning, sideroblastic anemia, thalassemias, myelodysplastic syndromes
      • Bone marrow biopsy with ringed sideroblasts: sideroblastic anemia
  • Normal iron studies: workup for acute blood loss, hemolytic anemia, thalassemia, sideroblastic anemia
• Check reticulocyte count
  • Low reticulocyte count (< 2%) indicates ineffective or decreased RBC production.
    • Iron deficiency anemia
    • Anemia of chronic disease
    • Sideroblastic anemia
    • Lead poisoning
  • Normal/high: thalassemia (> 2 %)

	Serum laboratory results in microcytic anemia
	Iron	Ferritin	% Iron saturation	Transferrin or TIBC	Reticulocyte count	Red cell distribution width (RDW)
Iron deficiency	↓	↓	↓	↑	↓	↑
Anemia of chronic disease	↓	↑	Normal to ↓	↓	↓	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)

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)
    • Low EPO: anemia of chronic kidney disease
    • Normal/high EPO: aplastic anemia
    • Anemia of chronic disease
    • Malignancy (e.g., acute leukemia)
  • Normal/high reticulocyte count (> 2%)
    • Sign of hemolysis (e.g., ↓ haptoglobin, ↑ LDH, unconjugated bilirubin, schistocytes): hemolytic anemia
    • No sign of hemolysis: acute blood loss anemia

MCV > 100 fL = macrocytic anemia

• Check peripheral blood smear
  • Hypersegmented neutrophils (> 5 lobes) present: megaloblastic anemia
    • Normal methylmalonic acid, ↑ homocysteine levels in serum: folic acid deficiency
    • ↑ Methylmalonic acid, ↑ homocysteine levels in serum: vitamin B₁₂ deficiency
    • Orotic acid in urine: orotic aciduria
  • No hypersegmented neutrophils present: nonmegaloblastic anemia
    • Electrophoresis with ↑ HbF level: Diamond-Blackfan anemia (see above)
    • Dysplastic RBCs and/or WBCs: myelodysplastic syndrome
    • Abnormal TSH: hypothyroidism
    • Alcohol use
    • Liver disease

Serum methylmalonic acid level can be used to distinguish between folic acid deficiency (normal) and vitamin B₁₂ deficiency (high).

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 erythrocyte morphology.

Bone marrow biopsy

• 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:
  • Aplastic anemia
  • Myelodysplastic syndromes
  • Myeloproliferative neoplasm
  • Malignant invasion of the bone marrow

References:^[4][2][7][8]

• Description: pancytopenia caused by bone marrow insufficiency ^[11]
• Etiology
  • 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 ^[12][13]
    • 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
  • Fatigue, malaise
  • Pallor
  • Purpura, petechiae, mucosal bleeding
  • Infection
• Diagnostics
  • CBC:
    • Pancytopenia (in contrast to aplastic crisis characterized by anemia only)
    • Normocytic or macrocytic anemia
  • Reticulocyte count: low
  • EPO level: high
  • Bone marrow biopsy findings
    • Hypocellular fat-filled marrow (dry bone marrow tap)
    • RBCs normal morphology
• Treatment
  • Cessation of the causative agent
  • Supportive therapy
    • Treatment of infections
    • Blood transfusion
    • Platelet transfusion
  • Bone marrow stimulants (e.g., GM-CSF)
  • Immunosuppressive therapy
    • Cyclosporine
    • Antithymocyte globulin (ATG)
    • Tacrolimus
    • Eltrombopag
    • Alemtuzumab
  • Consider hematopoietic cell transplantation (HCT) in young patients. ^[14]

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

References: ^{[15][16][17][18][19]}

• Description: anemia due to chronic inflammation
• Epidemiology: second most common anemia ^[20]
• 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
• Etiology
  • Inflammation (e.g., rheumatoid arthritis, systemic lupus erythematosus)
  • Malignancy (e.g., lung cancer, breast cancer, lymphoma)
  • Chronic infections (e.g., tuberculosis)
  • Chronic kidney disease
• Diagnostics
  • CBC: normocytic anemia (early phase) → microcytic anemia (later phase)
  • Low iron
  • Low iron saturation
  • Low TIBC
  • Elevated serum ferritin
  • Low reticulocyte count
• Treatment:
  • Treat the underlying cause
  • Blood transfusion if required (see transfusion for indications for blood transfusion)
  • EPO in chronic incurable diseases (e.g., chronic kidney disease)

References:^[21]

• Description: : anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria ^[22]
• Etiology
  • Inherited: X-linked sideroblastic anemia due to a δ-ALA-synthase gene defect
  • Acquired
    • Vitamin B₆ deficiency
    • Lead poisoning
    • Alcohol use disorder
    • Drugs (e.g., chloramphenicol, isoniazid , linezolid)
    • Copper deficiency
    • Myelodysplastic syndrome
    • Malignancy
• Diagnostics
  • CBC: microcytic anemia
  • Serum iron studies
    • High ferritin
    • High iron
    • High transferrin saturation
    • Normal/low TIBC
  • Peripheral blood smear
    • Basophilic stippling of RBCs
    • Normocytes/macrocytes (more common in acquired etiologies)
  • Prussian blue staining of bone marrow: ringed sideroblasts
• Treatment
  • Cessation of the offending agent
  • Pyridoxine (B₆) supplementation (a cofactor for δ-ALA synthase)

References: ^[8]

• Description: normocytic, normochromic anemia characterized by a severe reduction in circulating reticulocytes and marked reduction or absence of erythroid precursors in the bone marrow ^[23]
• Pathophysiology: : thought to be related to abnormal T-cell function and IgG antibodies that target erythroblasts and erythropoietin
• Etiology
  • Acquired: most often idiopathic, but can be associated with
    • Thymoma
    • Myelodysplastic syndrome
    • Drugs (e.g., phenytoin, chloramphenicol)
    • Parvovirus B19 infection
    • Autoimmune disorders (e.g., type 1 diabetes, thyroiditis, rheumatoid arthritis)
  • 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)
      • Short stature, webbed neck
      • Upper extremity malformations (e.g., triphalangeal thumbs)
      • Microcephaly, micrognathia
      • Hypertelorism, flat nasal bridge, cleft palate
    • Electrophoresis
      • Elevated HbF levels
      • Low total Hb levels
• Diagnosis
  • Low reticulocyte count
  • Bone marrow biopsy shows marked reduction or absence of erythroid precursors.
• 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:^{[24][15][16][17][18][19][25][26][23]}