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Anaemia of chronic disorders (ACD)
Many of the anaemias seen in clinical practice
occur in patents with systemic disorders and are the
result of a number of contributing factors.
It occurs in patients with a variety of chronic
inflammatory (infectious and non-infectious) and
malignant diseases.
Usually, both the erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP) are raised.
It may be complicated by additional features.
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The pathogenesis
1. The decreased release of iron from macrophages to
plasma and so to erythroblasts.
2. Reduced red cell lifespan
3. Inadequate erythropoietin response to anaemia.
4. Increased levels of various cytokines
• IL-l
• IL-6
• TNF ( increases apoptosis of bone marrow erythroid
cells.) will reduce erythropoietin secretion.
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ACD
The anaemia is corrected by the successful treatment of
the underlying disease.
It does not respond to iron therapy despite the low serum iron.
Responses to recombinant erythropoietin therapy may be
obtained (e,g. in rheumatoid arthritis or cancer).
In many conditions the anaemia is complicated by anaemia
from other causes (e.g. iron or folate deficiency, renal
failure, bone marrow infiltration, hypersplenism or
endocrine abnormality).
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Serum iron
The fall in serum iron results from an impaired
flow of iron from cells (including intestinal
mucosal cells, hepatocytes and macrophages) to
plasma.
This is due to increased secretion of hepcidin by
hepatocytes in response to inflammation.
Hepcidin inhibits release of iron from
macrophages and iron absorption
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Ferritin
A rise in serum ferritin occur as part of the acute-
phase response.
Increased lactoferrin, occurring in response to
inflammation and mediated by cytokines,
competes with transferrin for iron and forms a
complex, which is taken up by macrophages in the
liver and spleen.
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Anaemia of malignant diseases
Contributing factors include:
Anaemia of chronic disorders
Blood loss
Iron deficiency
Marrow infiltration (often associated with a leucoerythroblastic
picture)
Folate deficiency
Haemolysis
Marrow suppression from radiotherapy or chemotherapy
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Anaemia of malignant diseases
Microangiopathic haemolytic anaemia occurs with
mucin-secreting adenocarcinoma particularly of the
stomach, lung and breast.
Autoimmune haemolytic anaemia with malignant
lymphoma, CLL and rarely with other tumours.
There is also an association of pernicious anaemia with
carcinoma of the stomach.
11. 11
Peripheral blood film in metastatic mucin-secreting adenocarcinoma of
the stomach showing red cell polycrmasia and fragmentation and
thrombocytopenia, The patient had disseminated intravascular
coagulation,
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Anaemia of malignant diseases
The anaemia of malignant disease may
respond partly to erythropoietin.
Folic acid should only be given if there is
definite megaloblastic anaemia caused by the
deficiency; it might 'feed' the tumour.
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White cell changes
Leukaemoid reactions may
occur with tumours
showing widespread
necrosis and inflammation.
Hodgkin's disease is
associated with a variety of
white cell abnormalities
including eosinophilia,
monocytosis and
leucopenia.
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Haemostatic abnormalities
Patients with malignant disease may show either
thrombocytosis or thrombocytopenia.
Disseminated tumours, particularly mucin-secreting
adenocarcinomas, are associated with DIC and
generalized haemostatic failure.
Activation of fibrinolysis occurs in some patients
with carcinoma of the prostate.
Occasional patients with malignant disease have
spontaneous bruising or bleeding caused by an
acquired inhibitor of one or other coagulation factor,
most frequently factor VIII, or to a paraprotein
interfering with platelet function.
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Cancer patients have a high incidence (estimated at 15%) of
venous thromboembolism.
This is increased by surgery and some drugs
It is most common in ovarian, brain, pancreatic and colon
cancers.
It may be difficult to manage with oral anticoagulation because of
bleeding, interruptions with chemotherapy an thrombocytopenia,
anorexia or vomiting.
Liver disease and drug interactions can cause further
complications so daily low molecular weight heparin injections
may be preferable to warfarin.
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Rheumatoid arthritis
In patients with rheumatoid arthritis, the
anaemia of chronic disorders is proportional to
the severity of the disease.
It is complicated in some patients by iron
deficiency caused by gastrointestinal bleeding
related to therapy with salicylates, non-
steroidal anti-inflammatory agents or
corticosteroid.
Bleeding into inflamed joints may also be a
factor.
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Systemic lupus erythromatosus (SLE)
In systemic lupus erythematosus (SLE) there may be
anaemia of chronic disorders
50% of patients are leucopenic with reduced
neutrophil and lymphocyte counts
Renal impairment and drug-induced gastrointestinal
blood loss also contribute to the anaemia.
Autoimmune haemolytic anaemia occurs in 5% of
patients
There may be autoimmune thrombocytopenia also in
5% of patients.
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The lupus anticoagulant interferes with blood
coagulation by altering the binding of coagulation
factors to platelet phospholipid and predisposes to
both arterial and venous thrombosis and
recurrent abortions.
Tests for antinuclear factor (ANF) and anti-DNA
antibodies are usually positive.
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Anaemia of chronic renal failure
A normocytic normochromic anaemia is
present in most patients with chronic
renal failure.
Generally, there is a 2 g/dL fall in
haemoglobin level for every 10 mmol/L
rise in blood urea.
There is impaired red cell production as a
result of defective erythropoietin
secretion.
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Uraemic serum has also been shown to contain
factors that inhibit proliferation of erythroid
progenitors.
Variable shortening of red cell lifespan occurs
In severe uraemia the red cells show
abnormalities including acanthocytosis and burr
cells.
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Increased red cell 2,3-DPG levels in response to the
anaemia result in decreased oxygen affinity and a shift of
the haemoglobin oxygen dissociation curve to the right.
Hyperphosphataemia result in decreased oxygen affinity
and a shift of the haemoglobin oxygen dissociation
curve to the right.
The patient's symptoms are therefore relatively mild for
the degree of anaemia.
Patients with polycystic kidneys usually have retained
erythropoietin production and may have less severe
anaemia for the degree of renal failure.
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Other contributory factors
Bone marrow suppression secondary to
uraemia
↓ RBCs survival
Uraemia cause platelets dysfunction
leading to anaemia secondary to blood
loss
Iron, folate loss during dialysis →
anemia
Aluminum toxicity
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Erythropoietin therapy has been found to
correct the anaemia in patients on dialysis or in
chronic renal failure, providing that iron and folate
deficiency have been corrected.
The dosage of erythropoietin usually required is
50-150 units/kg three times a week intravenously
or by subcutaneous infusion.
A poor response to erythropoietin suggests
iron or folate deficiency, infection, aluminium
toxicity (inhibits erythropoiesis) .
28. 28
Peripheral blood film in chronic renal failure showing red cell acanthocytosis
and numerous burr' cells.
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Platelet and coagulation
abnormalities
Platelets dysfunction occur in CRF secondary to
uraemia
HUS & TTP are associated with thrombocytopenia
Nephrotic syndrome is associated with thrombosis.
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Immune complex-mediated thrombocytopenia
Occurs in some patients with acute nephritis and
also following renal allografts.
Renal allografts may also lead to polycythaemia in
10-15%of patients.
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chronic liver disease is associated with anaemia that is
mildly macrocytic and often accompanied by target cells,
mainly as a result of increased cholesterol in the
membrane.
Contributing factors to the anaemia may include blood
loss (e.g. bleeding varices) with iron deficiency,
dietary folate deficiency and direct suppression of
haemopoiesis by alcohol.
Alcohol may have an inhibiting effect on folate
metabolism and is occasionally associated with (ring)
sideroblastic changes which disappear when alcohol is
withdrawn.
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Haemolytic anaemia may occur in patients with alcohol
intoxication
autoimmune haemolytic anaemia is found in some
patients with chronic immune hepatitis.
Haemolysis may also occur in end-stage liver disease
because of abnormal red cell membranes resulting
from lipid changes.
Viral hepatitis (usually non-A, non-B, non-C) is
associated with aplastic anaemia.
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Coagulation abnormalities
The acquired coagulation abnormalities
associated with liver disease are:
Deficiencies of vitamin K-dependent factors and, in severe
disease of factor V and fibrinogen.
Abnormalities of platelet function may also be present.
Dysfibrinogenaemia with abnormal fibrin polymerization may
occur .
A consumptive coagulopathy may be superimposed.
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Hypothyroidism
T3 and T4 potentiate the action of erythropoietin
A moderate anaemia is usual and may be caused
by lack of thyroxine.
There is also a reduced oxygen need and thus
reduced erythropoietin secretion.
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The anaemia is often macrocytic and the mean
corpuscular volume (MCV) falls with thyroxine
therapy.
Autoimmune thyroid disease, especially
myxoedema or Hashimoto's disease, is
associated with pernicious anaemia.
Iron deficiency may also be present, particularly
in women with menorrhagia.
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Malaria
Normochromic, normocytic anaemia is a
common manifestation of malaria
Haemolytic or anaemia of chronic disease
Both parasitized and non-parasitized red
cells lose deformability and the high shear
rates in the spleen enhance their removal by
the spleen
erythropoiesis, dyserythropoiesis, and
ineffective erythropoiesis
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Malaria
In the worst cases, DIC occurs and intravascular
haemolysis is marked with haemoglobinuria
Thrombocytopenia is commonly found in acute
malaria
Patients with chronic malaria have an anaemia of
chronic disorders;
hypersplenism may contribute to the anaemia
and result in moderate thrombocytopenia and
neutropenia
