Etiology

Anemia occurs when the production of red blood cells (RBCs) is decreased, the destruction of RBCs is accelerated, or there is a loss of RBCs due to bleeding. In many cases, a combination of these mechanisms is present.

Risk factors include extremes of age, female sex, lactation, and pregnancy.

Nutrient deficiency, acquired bone marrow disease, drugs, toxins, chronic systemic diseases and genetic diseases may all lead to reduced RBC production. The resulting anemia can be microcytic, hypoproliferative normocytic or macrocytic, depending on the cause.

Microvascular diseases, infections, drugs, and genetic disorders may cause hemolytic anemia.

Hemolytic anemias are a group of anemias resulting from increased destruction of RBCs with a resultant increase in circulating indirect bilirubin.[4][5] The resulting anemia can be microcytic or hyperproliferative normocytic, depending on the cause. 

Acute hemorrhage causes a normocytic anemia and reticulocytosis occurs within 6 hours of the onset of bleeding. By contrast, chronic slow bleeding causes microcytic anemia due to ongoing iron loss leading to deficiency.

Nutrient deficiency or depletion

Iron deficiency anemia[2][6][7]

  • The most common cause of anemia worldwide.

  • The formation of the heme moiety in hemoglobin, myoglobin, and cytochrome requires iron; inadequate intake or absorption of iron, or excessive iron loss, leads to a microcytic anemia.

  • At least 10% of women in the US between the ages of 12 and 49 years are iron deficient. 22% of Mexican-American women and 19% of non-Hispanic black women in the US are iron deficient.[8]

  • Signs of iron deficiency include koilonychia, angular cheilosis, glossitis, and thinning hair.

  • Inadequate iron intake: red meat provides the main source of heme iron, and iron deficiency is common in geographic regions where meat is sparse and there is poor dietary iron intake. Other sources of heme iron include white meats, fish, and seafood. Vegetarians are more prone to iron deficiency anemia because plants provide non-heme iron that is less readily absorbed. Beans, nuts, dried fruit, broccoli, and spinach are sources of iron.

  • Iron malabsorption occurs due to achlorhydria, gastric surgery, chronic pancreatitis, gallstones, destruction of small bowel absorptive area in chronic diseases such as celiac disease, intestinal wall edema in heart failure, or following extensive resection of the proximal small bowel.

  • Excessive iron loss: gradual prolonged bleeding due to any cause produces iron depletion, because two-thirds of the total body iron is contained in circulating hemoglobin (Hb). Menstruation and occult gastrointestinal bleeding are the most common causes. Hemoglobinuria (iron loss in the urine) is rare. The usual cause is paroxysmal nocturnal hemoglobinuria, but hemoglobinuria can occur following rapid intravascular hemolysis of any cause.

Vitamin B12 deficiency[9]

  • Vitamin B12 is an essential cofactor in DNA synthesis, which is obtained only from the diet or by supplementation.

  • Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs.

  • Deficiency produces neurologic disorders and megaloblastic anemia.

  • Decreased dietary intake may occur in chronic malnutrition, alcohol misuse, and strict vegan diets.

  • Diminished breakdown of dietary vitamin B12 may be due to pernicious anemia, previous gastric or intestinal surgery, or atrophic gastritis.

  • Malabsorption occurs in gastric malabsorption, Crohn disease, celiac disease and bacterial overgrowth.

Folate deficiency[9]

  • Folate is an essential cofactor in DNA synthesis, which is obtained only from the diet or by supplementation.

  • Dietary sources include green leafy vegetables, citrus fruits, and animal products.

  • Deficiency produces a range of signs, including a glossitis; angular stomatitis; patchy hyperpigmentation of the skin and mucous membranes; a persistent mild pyrexia (in the absence of infection); and megaloblastic anemia.

  • Common causes include decreased dietary intake (e.g., chronic malnutrition, alcohol misuse, dietary restriction of protein intake), impaired absorption (achlorhydria, celiac disease, tropical sprue, zinc deficiency, bacterial overgrowth), and increased folate requirement (infancy, pregnancy, lactation, malignancy).

  • Patients with vitamin B12 deficiency can have excessive renal folate excretion. Similarly, chronic alcohol misuse can lead to excessive biliary folate excretion.

  • Rarely, hypothyroidism and congenital enzyme deficiencies may impair folate metabolism.

Generalized malnutrition

  • Often causes iron deficiency.

  • Patients often have associated vitamin B12 and/or folate deficiency, in which case the resulting anemia is normocytic.

  • Associated copper deficiency is rare, but should be considered in patients on prolonged total parenteral nutrition.

Blood loss

Acute hemorrhage

  • Any acute hemorrhage can cause a normocytic anemia. A reticulocytosis is seen within 6 hours of the onset of bleeding. By contrast, chronic slow bleeding leads to ongoing iron loss and produces a microcytic anemia due to iron deficiency.

  • The most common causes are trauma (including gunshot wounds, major fractures, or crush injuries), acute gastrointestinal bleeding, rupture of a vascular aneurysm (especially abdominal aortic aneurysm), and recent surgery.

  • Patients are at increased risk of hemorrhage if they are taking anticoagulant therapy, have an underlying defect in hemostasis, or have a consumptive or dilutional coagulopathy following repeated blood transfusions.

  • The American Gastroenterology Association recommends that a gastrointestinal cause be considered in all patients with iron deficiency anemia in the absence of an obvious cause.[10]

Gradual, prolonged bleeding

  • Bleeding due to any cause produces iron depletion, because two-thirds of the total body iron is contained in circulating Hb.

  • Excessive menstrual losses are a common cause in females.

  • The gastrointestinal tract is a common site of bleeding. Common causes include hemorrhoids, salicylate ingestion, peptic ulcer disease, hiatal hernia, diverticular disease, neoplastic disease, and ulcerative colitis.

  • Hookworm (Necator americanus) infection is rare in developed countries but is a significant cause of iron-deficiency anemia in low and middle-income countries.[11]

  • Rare causes include cows' milk allergy in infants, Meckel diverticulum, schistosomiasis, trichuriasis, and hereditary hemorrhagic telangiectasia.

Rare sources of blood loss from other sites include pulmonary bleeding (seen in idiopathic pulmonary hemosiderosis and Goodpasture syndrome), blood donation, and self-harm. In addition, any underlying disorder that impairs hemostasis increases the risk of bleeding and iron deficiency anemia.

Chronic systemic disease

Anemia of chronic disease[7][12]

  • Usually causes a mild hypoproliferative normocytic anemia. Coexisting iron deficiency produces a microcytic anemia.

  • It is caused by chronic inflammation. Proinflammatory cytokines, especially interleukin-6 (IL-6), trigger a cascade of events, mediated via upregulation of hepcidin, that decrease RBC production (by lowering serum iron and erythropoietin levels) and increase RBC destruction (by stimulating erythrophagocytosis and oxygen free radical formation).[13]

  • Common underlying processes include infection, neoplasms, autoimmune reactions, and injury to tissue from trauma or major surgery.

  • These underlying processes may coexist.

Chronic kidney disease[14]

  • Produces a normocytic or microcytic anemia. The etiology is complex and multifactorial. Decreased erythropoietin production, accumulation of erythropoiesis inhibitors, and secondary hyperparathyroidism all contribute.

  • Chronic blood loss, inflammation, and nutritional deficiency cause an iron deficiency anemia. Patients often need to reduce their protein intake, which leads to decreased meat in the diet and poor iron intake. Poor iron absorption may also occur. Erythropoietin therapy and chronic inflammation can cause functional iron deficiency, produced by an inability to mobilize iron stores effectively.

Chronic liver disease

  • A mild to moderate nonmegaloblastic macrocytic anemia is produced by a combination of intravascular dilution due to volume overload, increased RBC destruction, and impaired bone marrow compensatory responses.

Hypothyroidism

  • Causes a mild hypoproliferative normocytic anemia due to the loss of the stimulatory effect of thyroid hormones on erythropoiesis.

Heart failure

  • Up to one third of patients with heart failure have anemia. Anemia of chronic disease, iron deficiency, hemodilution, and adverse effects of medication may all contribute.[15]

Inflammatory bowel disease

  • Anemia associated with inflammatory bowel disease is often due to a combination of iron deficiency and anemia of chronic disease.[16]

Hypogonadism

  • Testosterone increases production of hematopoietic growth factors, and iron bioavailability, and primary hypogonadism may cause anemia in older men.

Malignancies

  • Patients with cancer are up to 5 times more likely to have anemia compared with healthy, age-matched populations (49.7% vs 11.9% in one study). Folate, B12, serum iron, and transferrin saturation were lower, but ferritin, which is an acute phase reactant, was higher in cancer patients compared with controls. Anemia was more prevalent in metastatic than nonmetastatic disease.[17]

Acquired bone marrow disease

Myelodysplastic syndrome[18]

  • A heterogeneous group of clonal stem cell disorders. Uncontrolled proliferation and clonal expansion of neoplastic multipotential hematopoietic stem cells compromise the production of normal cells, producing a range of cytopenias.

  • Usually due to acquired chromosomal abnormalities, but can be caused by chemotherapy or radiation therapy.

  • The anemia is a nonmegaloblastic macrocytic anemia, but the peripheral blood smear may show hypersegmented neutrophils similar to those seen in megaloblastic macrocytic anemias. A normal random distribution of red cell width in the setting of macrocytic anemia in an older adult should raise this suspicion.

Leukemias

  • Acute lymphocytic leukemia, acute myeloid leukemia, and chronic myelogenous leukemia are caused by the uncontrolled proliferation and clonal expansion of abnormal progenitor cells. These diseases affect progenitor cells at different stages of the differentiation process, but all cause anemia by compromising the production of normal RBCs.

Infiltration of the bone marrow by secondary malignancy

  • Metastasis of solid tumors to the bone marrow can cause anemia by infiltration of the marrow space. Any tumor can metastasize to the bone marrow, but the most commonly seen are neuroblastoma in children, and breast, prostate, and lung cancer in adults. Metastasis to the bone marrow is a poor prognostic sign.

Aplastic anemia[19]

  • A disorder of stem cell failure, leading to pancytopenia in the absence of splenomegaly.

  • Can be due to an inherited bone marrow failure syndrome or acquired (induced by a variety of disorders, e.g., autoimmune or toxic) where immune mechanisms with local activation of interferon gamma may be a common etiologic pathway.

  • Affected patients typically present with recurrent infections due to neutropenia, bleeding episodes due to thrombocytopenia, and, less often, fatigue due to anemia.

  • Toxic causes include benzene, dipyrone, chloramphenicol, penicillamine, and gold.

  • Definitive diagnosis is established following bone marrow aspiration and biopsy.

Pure red cell aplasia

  • Caused by congenital or acquired impairment of erythroid progenitor cells.

  • Acquired forms can be self-limited or chronic.

  • Self-limited acquired disease can be caused by infections or medications. The most common infectious cause is parvovirus B19. Other infectious causes include infectious mononucleosis, viral hepatitis, malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.

  • Certain medications exert a toxic effect on erythroid progenitor cells that is reversible once the medication is discontinued. Examples include phenytoin, carbamazepine, sodium valproate, azathioprine, chloramphenicol, sulfonamides, isoniazid, and procainamide.

  • Chronic acquired disease is caused by autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, polyarteritis nodosa, scleroderma), persistent infection (persistent parvovirus B19 infection in immunosuppressed patients, chronic active hepatitis), and thymomas.

  • Congenital forms are produced by in-utero damage of erythroid progenitor cells. The cause is unknown.

Toxin exposure

Drugs

  • Drugs may cause anemia through multiple mechanisms, including: immune-mediated or direct RBC hemolysis; interference with DNA synthesis; impaired absorption, metabolism, or action of important DNA synthesis cofactors; or a toxic effect on progenitor cells in the bone marrow.

  • Hemolytic anemia: common culprits include penicillin, methyldopa, levodopa, quinidines, cephalosporins, and some non-steroidal anti-inflammatory drugs (NSAIDs).

  • Drugs that directly interfere with DNA synthesis include purine analogs (6-mercaptopurine, 6-thioguanine, acyclovir), pyrimidine analogs (5-fluorouracil, 5-azacytidine, zidovudine), and ribonucleotide reductase inhibitors (hydroxyurea, cytarabine arabinoside).

  • Drugs that affect DNA synthesis cofactors include: methotrexate and trimethoprim (impair folic acid function); phenytoin, phenobarbital and primidone (interfere with folate absorption); and p-aminosalicylic acid, metformin, colchicine, and neomycin (interfere with B12 metabolism).

  • Drugs and chemicals that produce a toxic effect on a range of progenitor cells include benzene, chloramphenicol, penicillamine, and gold.

  • Drugs that produce a toxic effect on erythroid progenitor cells, producing pure red cell aplasia, include antiepileptic medications (phenytoin, carbamazepine, valproate sodium), azathioprine, chloramphenicol (which can also cause aplastic anemia), sulfonamides, isoniazid, and procainamide.

  • Drugs that inhibit erythroid stimulation and suppress erythropoietin production include ACE inhibitors and angiotensin-II receptor blockers.[20]

Radiation exposure

  • Radiation exposure can produce a pancytopenia.

Lead toxicity

  • Occupational or home exposure. Anemia can occur because lead competes with zinc, an important cofactor in heme synthesis. Some patients also have a concurrent iron deficiency anemia.

Alcohol misuse

  • Long-term alcohol intake directly suppresses the bone marrow, independent of any concurrent liver disease or vitamin deficiency. The effect resolves only after months of abstinence, and may persist even after normalization of vitamin B12 and folate levels.

Immune reactions

Autoimmune hemolytic anemia[21][22]

  • RBCs are attacked by autoantibodies and targeted for extravascular destruction. This usually occurs either as part of other autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, or scleroderma) or in relation to a lymphoproliferative disorder (usually non-Hodgkin lymphoma or chronic lymphocytic leukemia).

  • Autoimmune diseases can also cause pure red cell aplasia.

Alloimmune hemolytic anemia

  • Can be caused by transfusion reactions, usually due to ABO incompatibility.

Infections

Hemolytic anemia

  • A range of infections can produce a hemolytic anemia, including cytomegalovirus, infectious mononucleosis, and toxoplasmosis. Leishmaniasis produces combined RBC hemolysis, bone marrow suppression, and blood loss.

Pure red cell aplasia

  • Causes of pure red cell aplasia include parvovirus B19, infectious mononucleosis, viral hepatitis, malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.[23]

Genetic disorders

Thalassemias[24][25]

  • A group of autosomal-recessive genetic conditions that result in decreased or absent production of the alpha-globin (alpha-thalassemia) or beta-globin (beta-thalassemia) chains in the Hb molecule. The decreased or absent globin production results in impairment of erythropoiesis. Increased RBC destruction occurs, producing hemolytic anemia.

  • Disease severity depends on the underlying mutations and ranges from asymptomatic to severe, transfusion-dependent anemia with skeletal changes.

Sickle cell anemia[24]

  • A hemolytic anemia caused by an autosomal-recessive single gene defect in the beta chain of Hb (HbA), which results in sickle cell Hb. RBCs containing sickle cell Hb become rigid and are distorted into a crescent shape.

  • Patients are prone to episodes of vaso-occlusion due to the rigid, deformed RBCs, and a prothrombotic state created by the accompanying leukocytosis, which increases cytokine release.

  • Persistent pain in the abdomen, chest, or skeleton and dactylitis are the key presenting symptoms.

Hereditary spherocytosis

  • A hemolytic anemia caused by an autosomal-dominant inherited abnormality of RBCs that produces defects in the skeletal proteins of the red cell membrane. As a result, RBCs lose their biconcave structure and become spherical (spherocytes). Spherocytes are fragile, and are selectively removed and destroyed by the spleen. Increased RBC destruction leads to anemia with hyperbilirubinemia and splenomegaly.

  • Disease severity ranges from asymptomatic to a transfusion-dependent anemia with jaundice, depending on the severity of the underlying membrane defect.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency[26]

  • An inherited (X-linked) hemolytic anemia due to an enzyme deficiency that is common among populations originating from parts of the world where malaria is or was common, such as sub-Saharan Africa, Asia, the Mediterranean region, and the Middle East.

  • G6PD catalyzes a reaction that is linked to the generation of reduced glutathione. RBCs rely solely on reduced glutathione as an antioxidant defense, so deficiency of G6PD increases RBC destruction.

  • The severity of the disease varies, depending on the severity of the underlying mutation. Most patients are asymptomatic. Symptomatic disease produces episodes of acute hemolysis, with pallor and jaundice, following exposure to oxidant stress.

  • Triggers include fava beans (favism), sulfa drugs, aspirin, nitrofurantoin, naphthalene, and febrile illness. The resulting hemolysis is usually self-limited. Life-threatening symptoms are more common with the Mediterranean variant.

Congenital bone marrow failure syndromes

  • Fanconi anemia is the most common. It is usually autosomal recessive, but can also be X-linked. Mutations in 13 genes have been identified. The genes code for proteins that form a nuclear complex involved in the DNA damage response. However, the precise mechanisms by which the mutations produce bone marrow failure are not known.

Microvascular disease

Microangiopathic hemolytic anemias are often considered as a group. They produce a hyperproliferative normocytic anemia.

The underlying disease process produces endothelial damage and activates the coagulation cascade, leading to fibrin deposition on the damaged endothelial surfaces. In small vessels, the endothelial fibrin causes mechanical fragmentation and shearing of RBCs, leading to hemolysis. The irregular-shaped RBC fragments produced by this process are called schistocytes and can be seen on a peripheral blood smear.

Hemolytic uremic syndrome[27]

  • Damage to the endothelium of the glomerular bed produces hemolytic anemia, thrombocytopenia and nephropathy.

  • Causes include verotoxins, produced by Escherichia coli; neuraminidase, produced by streptococcal species; inherited defects in proteins that control complement; and drugs (cyclosporine and some chemotherapy agents).

Disseminated intravascular coagulation (DIC)[28]

  • An acquired syndrome produced by activation of coagulation pathways, resulting in the formation of intravascular thrombi and the depletion of platelets and coagulation factors.

  • DIC can be triggered by major trauma; burns; organ failure (pancreatitis, acute liver failure); sepsis or severe infection; severe obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae, retained dead fetus syndrome); malignancies (acute myelocytic leukemia or metastatic mucin-secreting adenocarcinoma); major vascular disorders (hemangiomas, large aortic aneurysms); and severe toxic or immunologic reactions.

Thrombotic thrombocytopenic purpura[29][30] 

  • A clinical syndrome of microangiopathic hemolytic anemia and thrombocytopenic purpura.

  • Believed to be due to the production of abnormally large von Willebrand factor (vWF) multimers. The abnormal vWF triggers aggregation of circulating platelets at sites of high intravascular shear stress, which in turn results in thrombi in the microvasculature system.

  • Thrombocytopenia is produced by excessive consumption of platelets; purpura and other signs of bleeding appear in a small proportion of patients. Thrombus formation in the microvasculature also produces severe central nervous system symptoms and renal disease.

Hemangiomas[31]

  • Vascular tumors that occur as a result of abnormal angiogenesis and overproliferation of blood vessels. These range from obvious superficial lesions to internal organ hemangiomas.

  • A local consumptive coagulopathy (Kasabach-Merritt syndrome) can occur as a complication, leading to thrombus formation and thrombocytopenia. Shearing and fragmentation of RBCs against the clots in the small vessels of the hemangiomas can lead to a hemolytic anemia.

  • Kasabach-Merritt syndrome can also produce DIC in severe cases.

Malignant hypertension

  • A hypertensive emergency with systolic BP >210 mmHg and diastolic BP >130 mmHg, associated with rapid deterioration of vital organ function. Common causes include untreated essential hypertension, renal disease, eclampsia, use of sympathomimetic drugs, and use of monoamine oxidase inhibitors. The disease is more common in older people, males, and those of black ethnicity.

  • Causes endothelial injury and endothelial fibrin deposition. Mechanical RBC shearing and fragmentation, resulting from high pressures and fibrin in the small vessels, produces hemolytic anemia.

Prosthetic valves and surfaces[32]

  • The shear stresses and turbulence created by the foreign surface cause shearing and fragmentation of RBCs. Improved prosthetics have reduced the incidence of this complication, and the anemia, if it occurs, is usually mild.

Other causes

Pregnancy

  • Anemia in pregnancy is common, with a prevalence of 2.1% in the US.[33] Prevalence is highest in non-Hispanic black women and teenagers.[33] Worldwide, 38% of pregnant women are anemic.[34]

  • Pregnancy increases physiologic demand on iron, which is needed for fetal brain and placental development. In addition, the plasma volume expands out of proportion to the RBC mass causing hemodilution.

  • Iron deficiency in pregnancy is associated with an increased risk of maternal and perinatal morbidity and mortality.[35]

  • Anemia may be due to a dilutional effect, as the plasma volume expands out of proportion to the RBC mass.

  • Despite being an important problem in pregnancy that can be effectively treated, there is a lack of high-quality evidence on the benefits of a national screening program for anemia in pregnancy in terms of reduced maternal and infant morbidity.[36]

Thermal burns

  • Patients with burns affecting more than 10% of the body's surface area can develop hemolytic anemia due to intravascular hemolysis of RBCs (at the site of the burn and systemically), loss of red cell mass due to thrombus formation, and damage to RBCs from systemically released proteases and oxygen free radicals.[37]

Hospital-acquired anemia

  • New-onset anemia in hospitalized patients with previously normal hemoglobin. Hospital-acquired anemia (HAA) is typically related to increased phlebotomy and iatrogenic blood loss from invasive procedures or hemodilution. Acute inflammatory response to illness decreases compensatory erythropoiesis. HAA is associated with increased morbidity and length of hospital stay.[38]

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