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. Anemia is the most common hematologic disorder seen in general medical practice. Risk factors include extremes of age, female gender, lactation, and pregnancy.

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 (GI) 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.

Gradual, prolonged bleeding

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

  • Excessive menstrual losses are a common cause in females.

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

  • Rare causes include hookworm, 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.

Nutrient deficiency or depletion

Iron deficiency anemia [8] [11] [12] [13]

  • The most common cause of anemia worldwide. It includes a range of underlying causes. Approximately 4% of women in the US between the ages of 20 and 49 years have been estimated to be iron deficient. [14] The formation of the heme moiety in Hb, myoglobin, and cytochrome requires iron; inadequate intake or absorption of iron, or excessive iron loss, leads to a microcytic anemia.

  • 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. There is a strong relationship between pica (a medical disorder in which children develop an appetite for non-nutritive substances) and iron deficiency.

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

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

  • Runner's anemia is caused by volume expansion accompanied by increased destruction of RBCs due to repetitive impact of the foot on the ground.

  • 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 [10]

  • 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 a megaloblastic anemia.

  • Causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, strict vegan diets), diminished breakdown of dietary vitamin B12 (due to pernicious anemia, previous gastric or intestinal surgery, atrophic gastritis), or malabsorption (gastric malabsorption, Crohn disease, celiac disease, bacterial overgrowth). A systematic review of the literature concluded that there is no clear evidence linking anemia to subnormal B12 levels in the geriatric population. [15]

Folate deficiency [10] [16]

  • 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 swollen, red, painful tongue; angular stomatitis; patchy hyperpigmentation of the skin and mucous membranes; a persistent mild pyrexia (in the absence of infection); and a megaloblastic anemia.

  • Common causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, 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 abuse 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 (TPN).

Acquired bone marrow disease

Myelodysplastic syndrome [17]

  • 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 (RDW) in the setting of macrocytic anemia in an older adult should raise this suspicion.

Leukemias

  • Acute lymphocytic leukemia, acute myelogenous 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 (AA) [18] [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.

  • Patients with paroxysmal nocturnal hemoglobinuria can develop aplastic anemia, although the mechanism is not known.

  • Definitive diagnosis is established following bone marrow aspiration and biopsy. In AA, characteristic findings include: [18]

    • Profoundly hypocellular marrow with a decrease in all elements; marrow space is composed of fat and marrow stroma

    • Residual hematopoietic cells that are morphologically normal

    • The absence of malignant infiltrates or fibrosis

    • Hematopoiesis is nonmegaloblastic.

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.

  • Medications exert a toxic effect on erythroid progenitor cells that is reversible once the medication is discontinued. Examples include antiepileptic medications (phenytoin, carbamazepine, valproate sodium), azathioprine, chloramphenicol (which can also cause aplastic anemia), sulfonamides, isoniazid, and procainamide.

  • Chronic acquired disease is caused by autoimmune diseases (e.g., systemic lupus erythematosus [SLE], 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.

  • Autoimmune diseases can also cause autoimmune hemolytic anemia.

Toxin exposure

Drugs

  • Certain drugs may produce immune-mediated or direct RBC hemolysis; interfere directly with DNA synthesis; impair the absorption, metabolism, or action of important DNA synthesis cofactors; or have a toxic effect on progenitor cells in the bone marrow.

  • A wide range of drugs are known to cause hemolytic anemia. Common examples 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).

  • Antifolates act by impairing folic acid function, and include methotrexate and trimethoprim. Anticonvulsants (phenytoin, phenobarbital, primidone) interfere with folate absorption. Other drugs that can decrease folate levels include oral contraceptives and cycloserine.

  • Drugs that interfere with vitamin B12 metabolism include p-aminosalicylic acid, metformin, colchicine, neomycin, and biguanides.

  • Drugs and chemicals that produce a toxic effect on a range of progenitor cells, producing aplastic anemia, 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 erythropoetin production include ACE inhibitors and angiotensin-II receptor blockers. [20]

Radiation exposure

  • Radiation exposure can produce a pancytopenia.

Lead toxicity

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

Alcohol abuse

  • 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.

Chronic systemic disease

Anemia of chronic disease [8] [21]

  • Can be a mild hypoproliferative normocytic anemia or, in severe cases, a microcytic anemia when coexisting with iron deficiency 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). [22]

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

Chronic kidney disease [23]

  • Produces a normocytic or microcytic anemia. The etiology is complex and multifactorial. The main cause is decreased erythropoietin production, leading to decreased RBC production and a hypoproliferative normocytic anemia. Inhibitors of erythropoiesis accumulate, further exacerbating the effects of decreased erythropoietin. Serum ferritin may be elevated in chronic kidney disease, but patients should still receive concurrent iron supplementation with erythropoietin-stimulating agent (ESA) therapy as long as serum ferritin is <500 micrograms/L. [24]

  • Other causes of anemia may also be present. Secondary hyperparathyroidism exacerbates anemia in patients with renal failure, but the mechanism is unclear. Concurrent hyperparathyroidism should also be addressed, as treatment improves the management of anemia in this setting. [24] Chronic blood loss, inflammation, and nutritional deficiency cause an iron deficiency anemia (which would be microcytic rather than normocytic). 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 a common feature of a range of liver diseases, and 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.

Immune reactions

Autoimmune hemolytic anemia [25]

  • RBCs are attacked by autoantibodies and targeted for extravascular destruction. This usually occurs either as part of other autoimmune conditions (e.g., SLE, 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

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

Causes of pure red cell aplasia include parvovirus B19, infectious mononucleosis, viral hepatitis, malaria, [26] respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.

Genetic disorders

Thalassemias [27] [28]

  • Hemolytic anemias. 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.

  • Alpha-thalassemia has at least 4 distinct forms: silent carrier (one affected alpha-globin gene), which does not cause anemia; alpha-thalassemia trait (2 affected alpha-globin genes); Hb H disease (typically 3 affected alpha-globin genes); and Hb Bart hydrops fetalis syndrome (typically deletion of all 4 alpha-globin genes), which is incompatible with life. Polymerase chain reaction (PCR) DNA testing and Southern blot analysis may be used to determine the specific defect in alpha-thalassemia trait. [29]

  • Beta-thalassemia is classified as silent carrier, beta-thalassemia minor, beta-thalassemia intermedia, or beta-thalassemia major, depending on the clinical and hematological features. Disease severity depends on the underlying mutation, and ranges from asymptomatic (in silent carriers and beta-thalassemia minor) to a severe transfusion-dependent anemia with skeletal changes (beta-thalassemia major). Note that in the presence of iron deficiency, a normal HbA2 does not exclude beta-thalassemia trait. Genetic testing is not typically performed as increases in hemoglobin F are readily seen on electrophoresis.

Sickle cell anemia [27]

  • 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 to 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 [30]

  • 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, a key antioxidant defense of the cell. Deficiency of the enzyme renders cells vulnerable to oxidant damage toward the end of their lifespan. 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.

  • Dyskeratosis congenita is characterized by the triad of abnormal nails, reticulated skin rash, and leukoplakia. X-linked, autosomal-dominant, and autosomal-recessive inheritance patterns have been observed. The genetic defects all decrease telomerase function. Telomeres maintain chromosomal stability, and the bone marrow is heavily dependent on telomere preservation to support its high rate of cell proliferation. Loss of telomerase produces bone marrow failure.

  • Shwachman-Diamond syndrome is a rare autosomal-recessive disease that produces exocrine pancreatic dysfunction, anemia, neutropenia (which can be intermittent), and skeletal abnormalities. About 90% of patients harbor mutations in a gene known as the SBDS gene, but the relationship of the mutations to bone marrow failure is not understood.

Microvascular disease

Hemolytic uremic syndrome (HUS) [31]

  • Damage to the endothelium of the glomerular bed produces hemolytic anemia (due to fragmentation and shearing of RBCs), thrombocytopenia (due to platelet consumption), 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) [31] [32]

  • 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 [33] 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.

  • A hemolytic anemia is produced by fragmentation and shearing of RBCs against clots in the small vessels.

Thrombotic thrombocytopenic purpura (TTP) [31] [34]

  • 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.

  • A hemolytic anemia is produced by fragmentation and shearing of RBCs against clots in the small vessels. 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 (CNS) symptoms and renal disease.

Hemangiomas [31]

  • Vascular tumors that occur as a result of abnormal angiogenesis and overproliferation of blood vessels. They occur in a wide range of locations, ranging from obvious superficial lesions to internal organs.

  • 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 [35]

  • 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 [36]

  • Anemia in pregnancy may be due to a dilutional effect, as the plasma volume expands out of proportion to the RBC mass. To account for this effect, anemia in pregnancy is defined as an Hb <10g/dL. Iron deficiency is the cause in 95% of cases, due to an increase in demand for iron, and one third of women will have either iron deficiency or folate deficiency by the third trimester. [37]

  • Despite being an important problem in pregnancy with effective treatment available, 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. [38]

Thermal burns

  • Patients with burns affecting more than 10% of the body's surface area can develop a 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. [39]

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 erythropoesis. HAA is associated with increased morbidity and length of hospital stay. [40]

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