Erythropoiesis,
Haemoglobin and Anaemia
Erythropoiesis, the formation of red cells (erythrocytes), occurs in the
red bone marrow of adults and the liver and spleen of the fetus. It can also
occur in the liver and spleen of adults following bone marrow damage.
Erythropoiesis is primarily controlled by erythropoietin,
a glycoprotein hormone secreted primarily by the kidneys in response to
hypoxia; about 10–15% is produced by the liver, the major source for the fetus.
Other factors such as corticosteroids and growth hormones can also stimulate erythropoiesis.
Erythropoiesis begins when uncommitted stem cells commit to the
erythrocyte lineage and under the influence of erythropoietin transform into
rapidly growing precursor cells (colony forming unit erythroid cells, CFU-E)
and then proerythroblasts (Figure 6). These large cells are packed with
ribosomes, and it is here that haemoglobin synthesis begins. Development and
maturation proceeds through early (basophilic), intermediate (polychromatic) and
finally late (orthochromatic) erythroblasts (or normoblasts) of
decreasing size. As cell division ceases, ribosomal content decreases and
haemoglobin increases. The late erythroblast finally loses its nucleus to
become a reticulocyte, a young erythrocyte still retaining
the vestiges of a ribosomal reticulum. Reticulocytes enter the blood and, as they age, the reticulum
disappears and the characteristic biconcave shape develops. About 2 × 1011
erythrocytes are produced from the marrow each day, and normally 1–2% of circulating
red cells are reticulocytes. This increases when erythropoiesis is enhanced,
for example by increased erythropoietin due to hypoxia associated with
respiratory disease or altitude. This can greatly increase erythrocyte numbers
(polycythaemia) and haematocrit. Conversely, erythropoietin levels may
fall in kidney disease, chronic inflammation and liver cirrhosis, resulting in
anaemia.
Erythrocytes are destroyed by macrophages in the liver and spleen
after ∼120
days. The spleen also sequesters and eradicates defective erythrocytes. The
haem group is split from haemoglobin and
converted to biliverdin and then bilirubin. The iron is con-
served and recycled via transferrin, an iron transport protein, or
stored in ferritin. Bilirubin is a brown–yellow compound that is
excreted in the bile. An increased rate of haemoglobin breakdown results in
excess bilirubin, which stains the tissues (jaundice).
Haemoglobin has four subunits, each containing a polypeptide globin
chain and an iron-containing porphyrin, haem, which are synthesized
separately. Haem is synthesized from succinic acid and glycine in the
mitochondria, and contains one atom of iron in the ferrous state (Fe2+).
One molecule of haemoglobin has therefore four atoms of iron, and binds four
molecules of O2. There are several
types of haemoglobin, relating to the globin chains; the haem moiety is
unchanged. Adult haemoglobin (Hb A) has two α and two β chains. Fetal
haemoglobin (Hb F) has two γ chains in place of the β chains, and a high
affinity for O2. Haemoglobinopathies are due to abnormal
haemoglobins.
Sickle cell anaemia occurs in 10% of the Black population, and is
caused by substitution of a glutamic acid by valine in the β chain; this
haemoglobin is called Hb S. At a low Po2 Hb S gels, causing
deformation (sickling) of the erythrocyte. The cell is less flexible and
prone to fragmentation, and there is an increased rate of breakdown by
macrophages. Heterozygous patients with less than 40% Hb S normally have no symptoms
(sickle cell trait). Homozygous patients with more than 70% Hb S develop
full sickle cell anaemia, with acute episodes of pain resulting from
blockage of blood vessels, congestion of liver and spleen with red cells, and
leg ulcers.
Thalassaemia involves defective synthesis of α- or β-globin
chains. Several genes are involved. In β thalassaemia there are fewer or no β
chains available, so α chains bind to γ (Hb F) or δ chains (Hb A2). Thalassaemia major (severe β
thalassaemia) causes severe anaemia, and regular transfusions are required,
leading to iron overload. In heterozygous β thalassaemia minor there are no
symptoms, although erythrocytes are microcytic and hypochromic, i.e. mean cell volume (MCV), mean
cell haemoglobin content (MCH) and mean cell haemoglobin concentration (MCHC)
are reduced. In α thalassaemia there are fewer or no α chains. In the
latter case haemoglobin does not bind O2, and infants do not survive
(hydrops fetalis). When some α chains are present, patients surviving as
adults may produce some Hb H (four β chains); this precipitates in the red
cells which are then destroyed in the spleen.
Anaemia
Blood loss (e.g. haemorrhage, heavy menstruation) or chronic disease
(e.g. infection, tumours, renal failure) may simply reduce the number of
erythrocytes. When these have a normal MCV and MCH (see Chapter 5), this is
termed normocytic normochromic anaemia.
Iron deficiency is the most common cause of anemia. The dietary
requirement for iron is small, as the body has an efficient recycling system,
but is increased with significant blood loss. Women have a higher requirement
for dietary iron than men because of men- struation, and also during pregnancy.
Iron deficiency causes defective haemoglobin formation and a microcytic
hypochromic anaemia (reduced MCV and MCH).
Vitamin B12 (cobalamin) and folate are required for maturation
of erythroblasts, and deficiencies of either cause megaloblastic anaemia.
The erythroblasts are unusually large (megaloblasts), and mature as
erythrocytes with a high MCV and MCH, although MCHC is normal. Erythrocyte
numbers are greatly reduced, and rate of destruction increased. Folate
deficiency is mostly related to poor diet, particularly in the elderly or poor;
folate is commonly given with iron during pregnancy. Alcoholism and some
anticonvulsant drugs (e.g. phenytoin) impairs folate utilization. Pernicious
anaemia is caused by defective absorption of vitamin B12 from
the gut, where it is transported as a complex with intrinsic factor produced by
the gastric mucosa. Damage to the latter results in pernicious anaemia. B12
deficiency can also occur in strict vegans. Aplastic anaemia results
from aplastic (non-functional) bone marrow and causes pancytopenia (reduced
red, white and platelet cell count). It is dangerous but uncommon. It can be
caused by drugs (particularly anticancer), radiation, infections (e.g. viral
hepatitis, TB) and pregnancy, where it has a 90% mortality. A rare inherited
condition, Fanconi’s anaemia, involves defective stem cell production and differentiation.
Haemolytic anaemia involves an excessive rate of erythrocyte
destruction, and thus causes jaundice. Causes include blood transfusion
mismatch, haemolytic anaemia of the newborn (see Chapter 9), abnormal
erythrocyte fragility and haemoglobins, and autoimmune, liver and hereditary
diseases. In hereditary haemolytic anaemia (familial spherocytosis)
erythrocytes are more spheroid and fragile, and are rapidly destroyed in the
spleen. It is relatively common, affecting 1 in 5000 Caucasians. Jaundice is
common at birth but may appear after several years. Aplastic anaemia may occur
after infections, and megaloblastic anaemia from folate deficiency as a result
of high bone marrow activity.
