Anaemia of chronic

disorders
 Introduction
• The anaemia of chronic disease (ACD) is a common
normochromic or mildly hypochromic anaemia that occurs in
patients with a systemic disease

• It is not due to marrow replacement by tumour, bleeding,

haemolysis
 Causes of the anaemia of chronic disorders.
• Chronic infl ammatory diseases
• Infections (e.g. pulmonary abscess,
• tuberculosis, osteomyelitis, pneumonia,
• bacterial endocarditis)
• Non - infectious (e.g. rheumatoid arthritis,
• systemic lupus erythematosus and other
• connective tissue diseases, sarcoidosis,
• Crohn ’ s disease, Gaucher ’ s disease)
• Malignant diseases
• Carcinoma, lymphoma, sarcom
 Characteristic features
• Normochromic, normocytic or mildly hypochromic (MCV rarely
< 75 fL)
• Mild and non - progressive anaemia (haemoglobin rarely < 9.0
g/dL) – the severity being related to the severity of the disease.
• Both the serum iron and TIBC are reduced.
• The serum ferritin is normal or raised.
• Bone marrow storage (reticuloendothelial) iron is normal but
erythroblast iron is reduced
• The plasma levels of TNF - α , IL - 1 (IL - 1 α and IL - 1 β ) and IL -
6 are raised.
 Pathogenesis
key factors
• inflammation,
• infection
• Malignancy is an increased level of hepcidin
• Hepcidin binds to ferroportin and the complex serves to prevent
transmembrane iron transport
• The body utilizes this mechanism to reduce the supply of iron to
microorganisms
• reduction of iron absorption from the intestine and the sequestration
of iron within macrophages
• reducing supply of iron to developing erythrocytes.
 Pathogenesis
• Increased levels of inflammatory cytokines, including
interleukin (IL) - 1, IL - 6, tumour necrosis factor (TNF) and
transforming growth factor (TGF) - β .
• These interact with accessory marrow stromal cells and
with the erythroid progenitors themselves to reduce their
sensitivity to erythropoietin.
• In this way, the marrow is attempting to aid the
recruitment of pluripotent stem cells to produce white
blood cells in order to combat infection/inflammation and
possibly malignancy
 Treatment
• The severity of the anaemia correlates with the activity and
severity of the underlying chronic disease
• Successful therapy of this leads to a reduction in the levels
of the mediator cytokines, increased erythropoietin
production and reduced inhibition of erythropoiesis.
• Correction of the anaemia may take weeks or months.
• Pharmacological doses of recombinant erythropoietin have
been used successfully to improve anaemia in patients with
rheumatoid arthritis, cancer and myeloma
APLASTIC ANEMIA
 Introduction
• Aplastic anemia is a rare but potentially fatal bone marrow
failure syndrome
• First case report In 1888
• Patient presented with severe anemia, neutropenia, and a
yellow hypocellular marrow on postmortem examination
• Features include pancytopenia, reticulocytopenia, bone
marrow hypocellularity, and depletion of hematopoietic stem
cells
 PATHOPHYSIOLOGY OF BONE MARROW
FAILURE
• destruction of hematopoietic stem cells due to injury by drugs,
chemicals, radiation, viruses, or autoimmune mechanisms
• premature senescence and apoptosis of hematopoietic stem cells due
to mutations
• Ineffective hematopoiesis due to stem cell mutations or vitamin B12or
folate deficiency
• disruption of the bone marrow microenvironment that supports
hematopoiesis
• decreased production of hematopoietic growth factors or related
hormones;
• loss of normal hematopoietic tissue due to infiltration of the marrow
space with abnormal cells.
 Acquired Aplastic Anemia
• Idiopathic (70% of acquired cases)
• Secondary (10-15% of acquired cases)
• Cytotoxic drugs
• Benzene
• Radiation
• Idiosyncratic
• Chemicals
• Insecticides
• Cutting/lubricating oils
 Acquired Aplastic Anemia
• Viruses
• Epstein-Barr virus
• Hepatitis virus (non-A, non-B, non-C, non-G)
• Human immunodeficiency virus
• Miscellaneous conditions
• Paroxysmal nocturnal hemoglobinuria
• Autoimmune diseases
• Pregnancy
 Pathophysiology
Depletion of hematopoietic stem and progenitor cells from the
bone marrow may be due to
• direct damage to stem cells
• immune damage to stem cells
• other unknown mechanisms.
• direct mechanism, a cytotoxic drug, chemical, radiation, or
virus damages the DNA of the stem and progenitor cells,
causing apoptosis and cytolysis
• immune mechanism, exposure to certain drugs, chemicals,
viruses, causes an autoimmune cytotoxic T lymphocyte attack
that destroys the stem and progenitor cells
 Clinical Findings
• Symptoms vary in acquired aplastic anemia
• the disorder can range from very severe to mild or asymptomatic.
• Patients usually present with pallor, fatigue, and weakness.
• Severe anemia can result in serious cardiac complications, including
cardiac failure and death.
• Petechiae, bruising, epistaxis, bleeding gums, menorrhagia, retinal
hemorrhages, intestinal bleeding.
• Fever and bacterial or fungal infections are unusual at initial
presentation but may occur after prolonged periods of neutropenia.
• Splenomegaly and hepatomegaly are absent
 Laboratory Findings
• Pancytopenia is typical
• Hypocellular bone marrow plus at least two of
the following:
• Neutrophils (× 109/L) 0.5-1.5
• Platelets (× 109/L) 20-50
• Hb ≤10 g/dL plus reticulocytes <30 × 109/L
Normal bone marrow tissue section Hypoplastic bone marrow tissue
 Inherited Aplastic Anemia
• Patients with inherited aplastic anemia usually show
manifestations of the disorder at an early age and may have
physical malformations.
• The three inherited diseases for which bone marrow failure
and pancytopenia
• Fanconi anemia,
• dyskeratosis congenita,
• Shwachman-Diamond syndrome
 Fanconi Anemia
• Fanconi anemia (FA) is a chromosome instability disorder
characterized by aplastic anemia, physical abnormalities, and
cancer susceptibility.
• It was first described by Fanconi in 1927 in three brothers with
skin pigmentation, short stature, and hypogonadism.
• FA occurs at a rate of 1 per 33,000.
• The carrier rate is 1 in 300 in the United States and Europe,
with a threefold higher incidence in Ashkenazi Jews and South
African Africaners
• FA is the most common of the inherited aplastic anemias.
 Clinical Findings
• Physical malformations may be present at birth
• Hematologic abnormalities may first appear during childhood or
adulthood
• These anomalies vary considerably
• malformations of the thumbs
• radial hypoplasia
• microcephaly
• hip dislocation and scoliosis
• skin pigmentation (hyperpigmentation or hypopigmentation)
• short stature;
• abnormalities of the eyes, kidneys, and genitals
 Genetics and Pathophysiology
• FA is caused by biallelic mutations or deletions in one of 13 genes:
• FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE,
FANCF, FANCG (also called XRCC9), FANCI, FANCJ (also called
BRIP1/BACH1), FANCL, FANCM, and FANCN (also called PALB2)
• The mode of inheritance is autosomal recessive
• except for FANCB, which is X-linked.
• Mutations in the FANCA gene occur with the highest frequency.
• The relationship between mutations in the FA genes and disease
pathology is not clear
 Treatment
• Supportive treatment for cytopenia includes transfusions and
administration of androgens and cytokines (G-CSF and GM-CSF)
• Currently the only curative treatment for cytopenia is a bone marrow
transplant, preferably from a mutationnegative, HLA-identical sibling
• Because of the underlying genetic defect and the bone marrow
transplant conditioning regimens, patients still have an increased risk
of developing secondary malignancies even after successful
transplantation.
• Gene therapy has been attempted in clinical trials but has not been
successful