Aetiology
Anaemia 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 disorders may all lead to reduced RBC production. The resulting anaemia can be microcytic, hypoproliferative normocytic or macrocytic, depending on the cause.
Microvascular diseases, infections, drugs, and genetic disorders may cause haemolytic anaemia.
Haemolytic anaemias are a group of anaemias resulting from increased destruction of RBCs with a resultant increase in circulating indirect bilirubin.[10][11] The resulting anaemia can be microcytic or hyperproliferative normocytic, depending on the cause.
Acute haemorrhage causes a normocytic anaemia and reticulocytosis occurs within 6 hours of the onset of bleeding. By contrast, chronic slow bleeding causes microcytic anaemia due to ongoing iron loss leading to deficiency.
Nutrient deficiency or depletion
Iron deficiency anaemia[4][12][13]
The most common cause of anaemia worldwide.
The formation of the haem moiety in haemoglobin, myoglobin, and cytochrome requires iron; inadequate intake or absorption of iron, or excessive iron loss, leads to a microcytic anaemia.
At least 10% of women in the US aged between 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.[14]
Signs of iron deficiency include koilonychia, angular cheilosis, glossitis, extreme fatigue, breathlessness, and thinning hair.
Red meat is the main source of haem iron; iron deficiency is common in geographical regions where meat is sparse and there is poor dietary iron of other sources of haem iron (e.g., white meats, fish, and seafood). Vegetarians are more prone to iron deficiency anaemia because plants provide non-haem iron that is less readily absorbed. Beans, nuts, dried fruit, broccoli, and spinach are sources of iron.
Iron malabsorption due to atrophic gastritis (probably because of the impairment of iron absorption that accompanies all causes of achlorhydria), gastric surgery, chronic pancreatitis, gallstones, destruction of small bowel absorptive area in chronic diseases such as coeliac disease, intestinal wall oedema in heart failure, or following extensive resection of the proximal small bowel.[13]
Gradual prolonged bleeding due to any cause produces iron depletion, because two-thirds of the total body iron is contained in circulating haemoglobin (Hb). Common causes include menstruation and chronic/occult gastrointestinal bleeding.[13][15] Haemoglobinuria (iron loss in the urine) is rare. Urinary losses of iron can occur in paroxysmal nocturnal haemoglobinuria, or following rapid intravascular haemolysis of any cause.[16]
Iron deficiency anaemia has been reported to be more common in children with dental caries.[17][18][19]
Vitamin B12 deficiency
Vitamin B12, an essential co-factor in DNA synthesis, is obtained only from the diet or by supplementation.[20]
Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs.
Vitamin B12 deficiency produces neurological disorders and megaloblastic anaemia.
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 anaemia, previous gastric or intestinal surgery, or atrophic gastritis
Malabsorption occurs in gastric malabsorption, Crohn's disease, coeliac disease and bacterial overgrowth.
Vitamin B12 deficiency may be caused by certain medicines (e.g., colchicine, proton pump inhibitors, H2-receptor antagonists, metformin) and the recreational use of nitrous oxide.[21]
Folate deficiency
Folate is an essential co-factor in DNA synthesis, being obtained only from the diet or by supplementation.[20]
Dietary sources include green leafy vegetables, citrus fruits, and animal products.[20]
Deficiency produces a range of signs, including glossitis, angular stomatitis, patchy hyperpigmentation of the skin and mucous membranes, a persistent mild pyrexia (in the absence of infection), and megaloblastic anaemia.
Common causes of folate deficiency include decreased dietary intake (e.g., chronic malnutrition, alcohol misuse, dietary restriction of protein intake), impaired absorption (achlorhydria, coeliac disease, tropical sprue, zinc deficiency, bacterial overgrowth), and increased folate requirement (infancy, pregnancy, lactation, malignancy).[20]
Patients with vitamin B12 deficiency can have excessive renal folate excretion. Similarly, chronic alcohol misuse can lead to excessive biliary folate excretion.[20]
Rarely, hypothyroidism and congenital enzyme deficiencies may impair folate metabolism.[20]
Generalised malnutrition
Often causes iron deficiency.
Patients often have associated vitamin B12 and/or folate deficiency, in which case the resulting anaemia is normocytic.
Associated copper deficiency is rare, but should be considered in patients on prolonged total parenteral nutrition.
Blood loss
Acute haemorrhage
Any acute haemorrhage can cause a normocytic anaemia. 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 anaemia 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 haemorrhage if they are taking anticoagulant therapy, have an underlying defect in haemostasis, or have a consumptive or dilutional coagulopathy following repeated blood transfusions.
A gastrointestinal cause be considered in all patients with iron deficiency anaemia in the absence of an obvious cause.[22]
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 loss is a common cause in females.
The gastrointestinal tract is a common site of bleeding. Common causes include haemorrhoids, 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 anaemia in low and middle-income countries.[23]
Rare causes include cow milk allergy in infants, Meckel's diverticulum, schistosomiasis, trichuriasis, and hereditary haemorrhagic telangiectasia.
Rare sources of blood loss from other sites include pulmonary bleeding (seen in idiopathic pulmonary haemosiderosis and Goodpasture's syndrome), blood donation, and self-harm. In addition, any underlying disorder that impairs haemostasis increases the risk of bleeding and iron deficiency anaemia.
Chronic systemic disease
Anaemia of chronic disease[12][24][25]
Usually causes a mild hypoproliferative normocytic anaemia. Co-existing iron deficiency produces a microcytic anaemia.[26]
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).[25][27]
Common underlying processes include infection, neoplasms, autoimmune reactions, and injury to tissue from trauma or major surgery.
These underlying processes may co-exist.
Chronic kidney disease[28]
Produces a normocytic or microcytic anaemia. The aetiology 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 anaemia. 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 mobilise iron stores effectively.
Chronic liver disease
A mild to moderate non-megaloblastic macrocytic anaemia 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 anaemia due to the loss of the stimulatory effect of thyroid hormones on erythropoiesis.
Overt hypothyroidism may be associated with maternal anaemia in pregnancy.[29][30]
Heart failure
Up to one third of patients with heart failure have anaemia. Anaemia of chronic disease, iron deficiency, hemodilution, and adverse effects of medication may all contribute.[31]
Inflammatory bowel disease
Anaemia associated with inflammatory bowel disease is often due to a combination of iron deficiency and anaemia of chronic disease.[32]
Hypogonadism
Malignancies
Acquired bone marrow disease
Myelodysplastic syndrome[37]
A heterogeneous group of clonal stem cell disorders. Uncontrolled proliferation and clonal expansion of neoplastic multipotential haematopoietic 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 radiotherapy.[38]
The anaemia is a non-megaloblastic macrocytic anaemia, but the peripheral blood smear may show hypersegmented neutrophils similar to those seen in megaloblastic macrocytic anaemias. A normal random distribution of red cell width in the setting of macrocytic anaemia in an older adult should raise this suspicion.
Leukaemias
Acute lymphoblastic leukaemia, acute myeloid leukaemia, and chronic myeloid leukaemia 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 anaemia by compromising the production of normal RBCs.
Infiltration of the bone marrow by secondary malignancy
Metastasis of solid tumours to the bone marrow can cause anaemia by infiltration of the marrow space. Any tumour can metastasise 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 anaemia[39]
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 aetiological pathway.
Affected patients typically present with recurrent infections due to neutropenia, bleeding episodes due to thrombocytopenia, and, less often, fatigue due to anaemia.
Toxic causes include benzene, dipyrone, chloramphenicol, penicillamine, and gold.
Can manifest as an immune-related haematological adverse drug event of immune checkpoint inhibitors in patients with cancer.[40]
Definitive diagnosis is established following bone marrow aspiration and trephine biopsy.
Pure red cell aplasia
Caused by congenital or acquired impairment of erythroid progenitor cells.
Acquired forms can be self-limiting or chronic.
Self-limiting acquired disease can be caused by infections or medications. One of the most common infectious causes 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, sulphonamides, 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.
Toxin exposure
Drugs and chemicals
Drugs may cause anaemia through multiple mechanisms, including: immune-mediated or direct RBC haemolysis; interference with DNA synthesis; impaired absorption, metabolism, or action of important DNA synthesis co-factors; or a toxic effect on progenitor cells in the bone marrow.
Penicillin, methyldopa, levodopa, quinidines, cephalosporins, and some non-steroidal anti-inflammatory drugs (NSAIDs) can cause haemolytic anaemia.
Drugs that directly interfere with DNA synthesis include purine analogues (6-mercaptopurine, tioguanine, aciclovir), pyrimidine analogues (5-fluorouracil, azacitidine, zidovudine), and ribonucleotide reductase inhibitors (hydroxycarbamide, cytarabine arabinoside).
Drugs that affect DNA synthesis co-factors 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 anti-epileptic medications (phenytoin, carbamazepine, sodium valproate), azathioprine, chloramphenicol (which can also cause aplastic anaemia), sulfonamides, isoniazid, and procainamide.
Drugs that inhibit erythroid stimulation and suppress erythropoietin production include angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers.[41]
Radiation exposure
Radiation exposure can produce a pancytopenia.
Lead toxicity
Occupational or home exposure to lead can cause anaemia. Some patients have a concurrent iron deficiency anaemia.[42]
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 normalisation of vitamin B12 and folate levels.
Immune reactions
Autoimmune haemolytic anaemia[43][44]
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, scleroderma) or in relation to a lymphoproliferative disorder (usually non-Hodgkin's lymphoma or chronic lymphocytic leukaemia).[44]
Autoimmune diseases can also cause pure red cell aplasia.
Alloimmune haemolytic anaemia
Can be caused by transfusion reactions, usually due to ABO incompatibility.
Infections
Haemolytic anaemia
A range of infections can produce a haemolytic anaemia, including cytomegalovirus, infectious mononucleosis, and toxoplasmosis. Leishmaniasis produces combined RBC haemolysis, 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.[45]
Genetic disorders
A group of autosomal-recessive genetic conditions that result in decreased or absent production of the alpha-globin (alpha-thalassaemia) or beta-globin (beta-thalassaemia) chain in the Hb molecule. The decreased or absent globin production results in impairment of erythropoiesis. Increased RBC destruction occurs, producing haemolytic anaemia.
Disease severity depends on the underlying mutations and ranges from asymptomatic to severe, transfusion-dependent anaemia with skeletal changes.
Sickle cell anaemia[46]
A haemolytic anaemia 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 haemolytic anaemia 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 anaemia with hyperbilirubinaemia and splenomegaly.
Disease severity ranges from asymptomatic to a transfusion-dependent anaemia with jaundice, depending on the severity of the underlying membrane defect.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency[48][49]
An inherited (X-linked) haemolytic anaemia 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.[48][49]
G6PD catalyses a reaction that is linked to the generation of reduced glutathione. RBCs rely solely on reduced glutathione as an antioxidant defence, 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 haemolysis, with pallor and jaundice, following exposure to oxidative stress.
Triggers include fava beans (favism), sulfa drugs, aspirin, nitrofurantoin, naphthalene, and febrile illness. The resulting haemolysis is usually self-limiting. Life-threatening symptoms are more common with the Mediterranean variant.
Congenital bone marrow failure syndromes
Fanconi anaemia is the most common. It is usually autosomal recessive, but can also be X-linked. Caused by pathogenic variants in >20 DNA repair pathway genes.[50]
Microvascular disease
Microangiopathic haemolytic anaemias are often considered as a group. They produce a hyperproliferative normocytic anaemia.
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 haemolysis.[51] The irregular-shaped RBC fragments (schistocytes) can be seen on a peripheral blood smear.
Haemolytic uraemic syndrome[52]
Damage to the endothelium of the glomerular bed produces haemolytic anaemia, thrombocytopenia and nephropathy.
Causes include verotoxins, produced by Escherichia coli; neuraminidase, produced by streptococcal species; inherited defects in proteins that control complement; and drugs (e.g., cyclosporine, quinine). Novel targeted and immunomodulatory therapies have been implicated.[53]
Disseminated intravascular coagulation (DIC)[54]
An acquired syndrome produced by activation of coagulation pathways, resulting in the formation of intravascular thrombi and the depletion of platelets and coagulation factors.[54]
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 myeloid leukaemia or metastatic mucin-secreting adenocarcinoma); major vascular disorders (haemangiomas, large aortic aneurysms); and severe toxic or immunological reactions.
Thrombotic thrombocytopenic purpura[55][56]
A clinical syndrome of microangiopathic haemolytic anaemia 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.
Haemangiomas[57]
Vascular tumours that occur as a result of abnormal angiogenesis and overproliferation of blood vessels. These range from obvious superficial lesions to internal organ haemangiomas.
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 haemangiomas can lead to a haemolytic anaemia.
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 haemolytic anaemia.
Prosthetic valves and surfaces[58]
The shear stresses and turbulence created by the foreign surface cause shearing and fragmentation of RBCs.[58]
Improved prosthetics have reduced the incidence of this complication, and the anaemia, if it occurs, is usually mild.
Other causes
Pregnancy
Anaemia in pregnancy is common, with a prevalence of 2.1% in the US.[59] Prevalence is highest in non-Hispanic black women and teenagers.[59] Worldwide, 38% of pregnant women are anaemic.[60]
Pregnancy increases physiological demand for iron, which is needed for fetal brain and placental development. In addition, the plasma volume expands out of proportion to the RBC mass causing haemodilution.
Iron deficiency in pregnancy is associated with an increased risk of maternal and perinatal morbidity and mortality.[61]
Anaemia may be due to a dilutional effect, as the plasma volume expands out of proportion to the RBC mass.
Overt hypothyroidism may be associated with maternal anaemia in pregnancy.[29][30]
Despite anaemia being an important treatable problem in pregnancy, there is a lack of high-quality evidence demonstrating reduced maternal and infant morbidity attributable to national screening.[62]
Thermal burns
Patients with burns affecting >10% of the body's surface area can develop haemolytic anaemia due to intravascular haemolysis of RBCs (at the site of the burn and systemically), loss of RBC mass due to thrombus formation, and damage to RBCs from systemically released proteases and oxygen free radicals.[63]
Hospital-acquired anaemia
New-onset anaemia in hospitalised patients with previously normal haemoglobin levels. Hospital-acquired anaemia (HAA) is typically related to increased phlebotomy and iatrogenic blood loss from invasive procedures or haemodilution.
Acute inflammatory response to illness decreases compensatory erythropoiesis. HAA is associated with increased morbidity and length of hospital stay.[64]
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