Anemia

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Anemia can be defined as a reduction in the mass of circulating red cells; it is detected by analysis of peripheral blood (low haemoglobin, low red cell count, low haematocrit).

To compensate for the lack of oxygen-carrying capacity, several changes take place in anaemia.
Biochemical changes in red cells reduce the affinity of haemoglobin for oxygen, and there is increased cardiac output, together with attempted increased red cell production.

The causes of anaemia can be classified according to aetiology.
In clinical practice the most common cause is iron deficiency, followed by the anaemia of chronic disorders and deficiency of vitamins B12 and folate.
All of the other causes are much less common.

Chronic blood loss is the most common cause of iron-deficiency anaemia

IRON DEFICIENCY ANAEMIA:

Iron deficiency is the most common cause of anaemia The main causes of iron-deficiency anaemia are impaired intake, excessive blood loss (most common cause in adults), or increased demand (e.g. pregnancy and lactation).

The peripheral blood shows a hypochromic microcytic pattern.
There is a low total serum iron and increased total iron-binding capacity; a decreased serum ferritin level reflects reduced total body iron stores.

In addition to signs and symptoms of anaemia, some patients with iron-deficiency anaemia may develop angular cheilitis, atrophic glossitis, oesophageal webs, koilonychia and brittle nails.

MEGALOBLASTIC ANAEMIA:

Megaloblastic anaemia is the result of impaired DNA synthesis in marrow precursor cells. This type of anaemia is due to deficiency of vitamin B12 and folic acid.

Vitamin B12 is normally absorbed from the diet by binding to intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells.
The B12-IF complex binds to cells in the terminal ileum, where B12 is absorbed.
The most common cause of B12 deficiency is lack of production of IF, resulting in pernicious anaemia. In the stomach this is associated with autoimmune atrophic gastritis or can occur after surgical gastrectomy.
Disease or surgical removal of the absorption site in the terminal ileum may also cause B12 deficiency.

Folic acid deficiency is most commonly due to inadequate dietary intake (folic acid is normally found in vegetables, meat and eggs).
Deficiency is commonly encountered in alcoholics and in patients with malabsorption.

In the marrow, lack of B12 or folate causes development of abnormally large red-cell precursors (megaloblasts),} which develop into abnormally large red cells (macrocytes). Patients have anaemia, neutropenia and thrombocytopenia.

In vitamin B12 deficiency, but not folate deficiency, neurological disease may occur, with the development of sub-acute combined degeneration of the spinal cord.

APLASTIC ANAEMIA:

In aplastic anaemia there has been failure of marrow stem cells.
Patients develop a pancytopenia and have a severe life-threatening disease.
The marrow is depopulated of cells and is replaced by fat.
Many cases are idiopathic, but others follow a known insult to the marrow.

In contrast to aplastic anaemia, in which all formed elements of blood are affected, pure red-cell aplasia is characterized by suppression of red-cell progenitor cells. Patients develop anaemia, but other formed elements of marrow are unaffected.

There are three groups:

acute self-limited red-cell aplasia, which occurs after parvovirus infection or exposure to certain toxins.
chronic acquired red-cell aplasia, which is autoimmune and may be associated with thymomas.
chronic constitutional red-cell aplasia, which is due to a hereditary defect in progenitor cells.

ANAEMIA OF CHRONIC ILLNESS:

Anaemia of chronic disorders is the second most common cause of anaemia

Patients with underlying diseases such as non-organ-specific autoimmune diseases (e.g. rheumatoid disease and SLE), chronic infective diseases (e.g. tuberculosis, malaria, schistosomiasis), or neoplasia (lymphoma and some carcinomas) may develop a normochromic or hypochromic anaemia.

There are three main abnormalities found in such anaemias: iron stored in macrophages is not released for use in bone marrow, circulating red cells have a reduced life span, and the marrow shows lack of response to erythropoietin.

Serum iron and serum iron binding capacity are low, but serum ferritin is normal or raised (compare iron-deficiency anaemia.

MYELODYSPLASTIC SYNDROMES:

Myelodysplastic syndromes cause refractory anaemia and predispose to leukaemia

Myelodysplastic syndromes are diseases of late adult life, in which there is production of abnormal clones of marrow stem cells.
The products of abnormal clones are defective and prematurely destroyed; thus, depending on severity, anaemia and pancytopenia may develop.
The presence of genetically abnormal clones in the marrow predisposes to the development of leukaemia in about 40% of cases. The main problem is an indolent anaemia that requires treatment with transfusions over several years but does not respond to administering haematinics (refractory anaemia).

Histologically the marrow shows normal or increased cellularity with megaloblastic cells. Abnormal red-cell precursors containing iron (ringed sideroblasts) may be seen, and abnormal myeloblasts may be found. Based on the numbers of myeloblasts and abnormal red-cell precursors, five sub-types of myelodysplasia have been defined in a French-American-British (FAB) classification.

SIDEROBLASTIC ANAEMIA:

Sideroblastic anaemias are characterized by defective haem synthesis in red-cell precursors}

The sideroblastic anaemias are characterized by abnormal red-cell progenitor cells that accumulate excess iron in their cytoplasm, forming cells termed ring sideroblasts.
These cells have defective haem synthesis and result in anaemia.

There are two main groups of disease:

Secondary sideroblastic anaemias, which are drug- related (isoniazid), toxic-related (lead, alcoholism) or neoplasia-related (haematological malignancies).
Primary sideroblastic anaemia (myelodysplastic syndrome).

LEUKOERYTHROBLASTIC ANAEMIA:

Marrow infiltration may result in leukoerythroblastic anaemia

Extensive infiltration of the bone marrow may cause obliteration of normal haemopoietic elements.
Extramedullary haemopoiesis then commonly develops.
Patients develop leukoerythroblastic anaemia, which is characterized by circulating erythroblasts and primitive white cells.

The main conditions causing extensive infiltration of bone marrow are disseminated carcinoma, disseminated lymphoma and myelofibrosis.
A leukoerythroblastic picture may also develop after massive haemorrhage, severe haemolysis and severe infections.

HEMOLYTIC ANEMIA: (HEREDITARY SPHEROCYTOSIS,G-6-P-D-D, AND THALASSAEMIA)

Haemolytic anaemia is characterized by reduced red-cell survival in the blood

Chronic increased red-cell destruction causes development of anaemia with increased reticulocytes in blood, splenomegaly, erythroid hyperplasia resulting in expansion of bone marrow, and unconjugated hyperbilirubinaemia.

The main causes are:

Intrinsic red cell defects
Membrane defects, e.g. hereditary spherocytosis.
Enzyme defects, e.g. glucose-6-phosphate dehydrogenase deficiency.
Abnormal haemoglobin synthesis of thalassaemia, sickle cell disease.

Extrinsic factors damaging red cells, are mainly immune and trauma.

Haemolytic anaemia may be caused by membrane defects in red cells.
The most common disease is hereditary spherocytosis.
Red cells have an abnormal cell-membrane-associated cytoskeleton, which is caused by abnormalities of the red-cell membrane-bracing proteins ankyrin, spectrin or band 4.2 protein.
In some cases a defect in one of the spectrin genes has been documented.

Patients with this disease have jaundice, splenomegaly and haemolytic anaemia.
Red cells are spherical on blood film and are abnormally fragile, undergoing lysis in the spleen.
There is expansion of the haemopoietic marrow and splenomegaly.
Splenectomy is performed to prevent haemolysis.

Enzyme defects in red cells may predispose to haemolysis

Haemolytic anaemia may also be caused by enzyme defects that render red cells susceptible to damage by oxidant stress.
Glucose-6-phosphate dehydrogenase deficiency is an X-linked condition, in which haemolytic crises are precipitated by infections or administration of certain drugs (quinine, phenacetin, aspirin).
Pyruvate kinase deficiency causes a chronic haemolytic anaemia.

Haemolysis may be caused by mechanical destruction of red cells

Mechanical damage to red cells may lead to reduced life span and haemolysis.

There are three main groups of mechanical haemolysis:

Macroangiopathic. Prosthetic cardiac valves.
Microangiopathic. Fragmentation by fibrin strands in small vessels, as seen in disseminated intravascular coagulation.
In this condition there is activation of the coagulation system in small vessels, causing microthrombi.
This results in depletion of coagulation factors and platelets (increased risk of bleeding) and in mechanical fragmentation of red cells (haemolysis).
Splenic. Hypersplenism caused by enlargement of the spleen is associated with haemolysis.
Red cells are sequestered in the spleen and are prematurely destroyed.

Spherocytes are abnormal red cells which have a convex instead of a bi-concave shape.
In a normal blood film, the centre of red cells is slightly paler than the periphery.
In spherocytes, the centre of the cell is darker than the periphery.
Such cells are abnormally fragile and prone to haemolysis.

Thalassaemia syndromes are caused by defective synthesis of the alpha- or beta-globin chains of haemoglobin.
Disease is inherited and is common in the Mediterranean, Middle and Far East, and Southeast Asia, where carrier rates of 10-15% are found.
The main pathological features are the consequence of increased requirements for red-cell production (caused by red-cell destruction):

Increased intramedullary haemopoiesis causes deformed bones (increased size and bossing of the skull).
Increased extramedullary haemopoiesis causes hepatosplenomegaly.
Consequences of excess iron deposition in tissues, derived from transfusions with haemolysis (affects heart, liver and pancreas).

In severe forms of disease there is a hypochromic microcytic anaemia associated with haemolysis of red cells. The most severe form of disease is that which results from abnormality of the beta-globin chain.

Normal adult haemoglobin (HbA) is composed of 2 alpha-globin chains and 2 beta-globin chains (alpha2 beta2). In thalassaemia, one or more of the genes responsible for synthesis of a- or b-globin chains is abnormal. Depending on which chain is affected, an a thalassaemia or beta thalassaemia results.

SICKLE-CELL ANAEMIA:

In sickle-cell disease a point mutation in the gene coding for the beta-globin chain results in an abnormal form of haemoglobin, termed HbS (alpha2 betaS2).
This form of haemoglobin polymerizes at low oxygen saturations, causing abnormal rigidity and deformity of red cells, which assume a sickle shape.
As a result, red cells are abnormally fragile (undergoing haemolysis), and sludge in small vessels (causing vascular occlusion).

In sickle-cell trait, individuals are heterozygous for the beta-globin gene abnormality and 30% of the haemoglobin is HbS, resulting in no significant clinical abnormality.

In patients with sickle-cell disease (homozygous for the abnormal b-globin gene), over 80% of haemoglobin is HbS, the rest being HbF and HbA2.
There are three patterns of acute deterioration, termed sickle-cell crises:

1 Sequestration crises. In the early years of sickle-cell anaemia, sudden pooling of red cells in the spleen may develop, causing a rapid fall in haemoglobin concentration, which can lead to death.

2 Infarctive crises. Obstruction of small blood vessels occurs, leading to infarcts. Commonly affected tissues are bone (especially femoral head), spleen (leading to splenic atrophy), and skin (leading to ankle ulcers).

3 Aplastic crises. Splenic atrophy caused by infarction predisposes to infection leading to depression of red-cell production. This precipitates a rapid fall in haemoglobin concentration in the face of continued haemolysis.

In addition to development of crises, abnormalities occur in many organs. Other mutations of the beta-globin gene form haemoglobins C, D and E, which also result in haemolysis.

Changes in Circulating White Cells in Blood Haemolysis may be caused by immune-mediated destruction of red cells in autoimmune haemolytic anaemias.

Antibodies binding to antigens on red cells may cause premature destruction of red cells. The three main types of disease in which this happens are warm-antibody haemolytic anaemia (80% of cases), cold-antibody haemolytic anaemia (20% of cases) and isoantibody haemolytic anaemia (rare).

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