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. Anaemia is the most common haematological disorder seen in general medical practice. Risk factors include extremes of age, female sex, lactation, and pregnancy.

Nutrient deficiency, acquired bone marrow disease, genetic disorders, drugs, toxins, and chronic systemic diseases may all lead to reduced RBC production.

Haemolytic anaemias are a group of anaemias resulting from increased destruction of RBCs with a resultant increase in circulating indirect bilirubin.[9][10][11] Clinical jaundice appears once bilirubin levels rise above 34.2 to 68.4 mmol/L (2-4 mg/dL). Additional disease-specific symptoms may also be present. The resulting anaemia can be microcytic or hyperproliferative normocytic, depending on the cause. 

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. The irregular-shaped RBC fragments produced by this process are called schistocytes and can be seen on a peripheral blood smear.

Haemodilution can occur following expansion of plasma volume. This drop in haemoglobin concentration is known as ‘dilutional anaemia’. This is often iatrogenic (e.g., following intravenous fluid administration) and may result in unnecessary transfusions.

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 (GI) 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.

Gradual, prolonged bleeding

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

  • Excessive menstrual losses are a common cause in females.

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

  • Rare causes include hookworm, cows' 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.

Nutrient deficiency or depletion

Iron deficiency anaemia[6][12][13][14][15]

  • The most common cause of anaemia worldwide. It includes a range of underlying causes. Approximately 4% of women in the US aged between 20 and 49 years have been estimated to be iron deficient.[16] 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.

  • Meat provides the main source of haem iron, and iron deficiency is common in geographical 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 coeliac disease, or following extensive resection of the proximal small bowel.

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

  • Haemoglobinuria (iron loss in the urine) is rare. The usual cause is paroxysmal nocturnal haemoglobinuria, but haemoglobinuria can occur following rapid intravascular haemolysis of any cause.

  • Pregnancy increases physiological demand on iron, which is needed for fetal brain and placental development.

Vitamin B12 deficiency[8]

  • Vitamin B12 is an essential co-factor in DNA synthesis, being obtained only from the diet or by supplementation. Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs. Deficiency produces neurological disorders and a megaloblastic anaemia.

  • Causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, strict vegan diets), diminished breakdown of dietary vitamin B12 (due to pernicious anaemia, previous gastric or intestinal surgery, atrophic gastritis), or malabsorption (gastric malabsorption, Crohn's disease, coeliac disease, bacterial overgrowth). One systematic review concluded that there is no clear evidence linking anaemia to subnormal B12 levels in the geriatric population.[17]

Folate deficiency[8][18]

  • Folate is an essential co-factor in DNA synthesis, being 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 anaemia.

  • Common causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, dietary restriction of protein intake), impaired absorption (achlorhydria, coeliac 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.

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 (TPN).

Acquired bone marrow disease

Myelodysplastic syndrome[19]

  • 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.

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

Leukaemias

  • Acute lymphocytic leukaemia, acute myelogenous leukaemia, and chronic myelogenous 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 (AA)[20][21]

  • 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.

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

  • Definitive diagnosis is established following bone marrow aspiration and biopsy. In AA, characteristic findings include the following:[20]

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

    • Residual haematopoietic cells that are morphologically normal

    • The absence of malignant infiltrates or fibrosis

    • Haematopoiesis is non-megaloblastic.

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. 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 anti-epileptic medications (phenytoin, carbamazepine, valproate sodium), azathioprine, chloramphenicol (which can also cause aplastic anaemia), 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. The cause is unknown.

  • Autoimmune diseases can also cause autoimmune haemolytic anaemia.

Toxin exposure

Drugs

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

  • A wide range of drugs are known to cause haemolytic anaemia. 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 analogues (6-mercaptopurine, tioguanine, aciclovir), pyrimidine analogues (5-fluorouracil, azacitidine, zidovudine), and ribonucleotide reductase inhibitors (hydroxycarbamide, 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 anaemia, 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 erythropoetin production include ACE inhibitors and angiotensin-II receptor blockers.[22]

Radiation exposure

  • Radiation exposure can produce a pancytopenia.

Lead toxicity

  • Occurs after occupational or home exposure to lead. Anaemia can occur because lead competes with zinc, an important co-factor in haem synthesis. Some patients also have a concurrent iron deficiency anaemia.

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 normalisation of vitamin B12 and folate levels.

Chronic systemic disease

Anaemia of chronic disease[6][23]

  • Can be a mild hypoproliferative normocytic anaemia or, in severe cases, a microcytic anaemia when co-existing with iron deficiency anaemia. 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).[24]

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

Chronic kidney disease[25]

  • Produces a normocytic or microcytic anaemia. The aetiology is complex and multifactorial. The main cause is decreased erythropoietin production, leading to decreased RBC production and a hypoproliferative normocytic anaemia. 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.[26]

  • Other causes of anaemia may also be present. Secondary hyperparathyroidism exacerbates anaemia in patients with renal failure, but the mechanism is unclear. Concurrent hyperparathyroidism should also be addressed, as treatment improves the management of anaemia in this setting.[26] Chronic blood loss, inflammation, and nutritional deficiency cause an iron deficiency anaemia (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 mobilise iron stores effectively.

Chronic liver disease

  • A mild to moderate non-megaloblastic macrocytic anaemia 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 anaemia due to the loss of the stimulatory effect of thyroid hormones on erythropoiesis.

Immune reactions

Autoimmune haemolytic anaemia[27][28]

  • 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's lymphoma or chronic lymphocytic leukaemia).

  • Autoimmune diseases can also cause pure red cell aplasia.

Alloimmune haemolytic anaemia

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

Infections

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.

Causes of pure red cell aplasia include parvovirus B19, infectious mononucleosis, viral hepatitis, malaria,[29] respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.

Genetic disorders

Thalassaemias[30][31]

  • Haemolytic anaemias. 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) chains in the Hb molecule. The decreased or absent globin production results in impairment of erythropoiesis. Increased RBC destruction occurs, producing haemolytic anaemia.

  • Alpha-thalassaemia has at least four distinct forms: silent carrier (one affected alpha-globin gene), which does not cause anaemia; alpha-thalassaemia trait (two affected alpha-globin genes); Hb H disease (typically three affected alpha-globin genes); and Hb Bart hydrops fetalis syndrome (typically deletion of all four 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-thalassaemia trait.[32]

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

Sickle cell anaemia[30]

  • 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 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 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[33]

  • 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.

  • G6PD catalyses a reaction that is linked to the generation of reduced glutathione, a key antioxidant defence of the cell. Deficiency of the enzyme renders cells vulnerable to oxidant damage towards the end of their lifespan. 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 oxidant 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. 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 characterised 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, anaemia, neutropenia (which can be intermittent), and skeletal abnormalities. About 90% of patients harbour mutations in a gene known as the SBDS gene, but the relationship of the mutations to bone marrow failure is not understood.

Microvascular disease

Haemolytic uraemic syndrome (HUS)[34]

  • Damage to the endothelium of the glomerular bed produces haemolytic anaemia (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)[34][35]

  • 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[36] or severe infection; severe obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae, retained dead fetus syndrome); malignancies (acute myelocytic leukaemia or metastatic mucin-secreting adenocarcinoma); major vascular disorders (haemangiomas, large aortic aneurysms); and severe toxic or immunological reactions.

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

Thrombotic thrombocytopenic purpura (TTP)[34][37]

  • 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.

  • A haemolytic anaemia 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.

Haemangiomas[34]

  • 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[38]

  • 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 anaemia, if it occurs, is usually mild.

Other causes

Pregnancy[39]

  • Anaemia 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, anaemia in pregnancy is defined as an Hb <10 g/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.[40]

  • 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 programme for anaemia in pregnancy in terms of reduced maternal and infant morbidity.[41]

Thermal burns

  • Patients with burns affecting more than 10% of the body's surface area can develop a haemolytic anaemia due to intravascular haemolysis 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.[42]

Hospital-acquired anaemia

  • New-onset anaemia in hospitalised patients with previously normal haemoglobin. 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.[43]

Use of this content is subject to our disclaimer