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Etiology of Anemia

By Alan E. Lichtin, MD, Cleveland Clinic;Cleveland Clinic Lerner College of Medicine

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Anemia is a decrease in the number of RBCs, Hct, or Hb content.

The RBC mass represents the balance between production and destruction or loss of RBCs. Thus, anemia can result from one or more of 3 basic mechanisms (see Classification of Anemia by Cause):

  • Blood loss

  • Deficient erythropoiesis

  • Excessive hemolysis (RBC destruction)

Classification of Anemia by Cause



Blood loss


GI bleeding





Bladder tumors

Cancer or polyps in GI tract

Heavy menstrual bleeding

Kidney tumors

Ulcers in the stomach or small intestine

Deficient erythropoiesis*


Iron deficiency

Iron-transport deficiency

Iron utilization defect

Iron reutilization defect

Thalassemias (also classified under excessive hemolysis due to intrinsic RBC defects)


Aplastic anemia


In kidney disease

In endocrine failure (thyroid, pituitary)

In protein depletion




Copper deficiency

Folate deficiency

Vitamin B12 deficiency

Vitamin C deficiency

Excessive hemolysis due to extrinsic RBC defects

Reticuloendothelial hyperactivity with splenomegaly


Immunologic abnormalities

Autoimmune hemolysis

Cold antibody hemolysis (paroxysmal cold hemoglobinuria)

Warm antibody hemolysis

Isoimmune (isoagglutinin) hemolysis

Mechanical injury



Excessive hemolysis due to intrinsic RBC defects

Membrane alterations, acquired


Paroxysmal nocturnal hemoglobinuria


Membrane alterations, congenital

Hereditary elliptocytosis

Hereditary spherocytosis

Metabolic disorders (inherited enzyme deficiencies)

Embden-Meyerhof pathway defects

G6PD deficiency


Hb C disease

Hb E disease

Hb S-C disease

Hb S–β-thalassemia disease

Sickle cell disease (Hb S)

Thalassemias (β,β-δ, and α)

*Classified according to RBC indices.

Blood loss can be acute or chronic. Anemia does not develop until several hours after acute blood loss, when interstitial fluid diffuses into the intravascular space and dilutes the remaining RBC mass. During the first few hours, however, levels of polymorphonuclear granulocytes, platelets, and, in severe hemorrhage, immature WBCs and normoblasts may rise. Chronic blood loss results in anemia if loss is more rapid than can be replaced or, more commonly, if accelerated erythropoiesis depletes body iron stores (see Iron Deficiency Anemia).

Deficient erythropoiesis (see Overview of Decreased Erythropoiesis) has myriad causes. Complete cessation of erythropoiesis results in a decline in RBCs of about 7 to 10%/wk (1%/day). Impaired erythropoiesis, even if not sufficient to decrease the numbers of RBCs, often causes abnormal RBC size and shape.

Excessive hemolysis (see Overview of Hemolytic Anemia) can be caused by intrinsic abnormalities of RBCs or by extrinsic factors, such as the presence of antibodies on their surface, that lead to their early destruction. An enlarged spleen sequesters and destroys RBCs more rapidly than normal. Some causes of hemolysis deform as well as destroy RBCs. Excessive hemolysis does not normally decrease reticulocyte production unless iron or other essential nutrients are depleted.

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