ANEMIAS
Dr. Nusrum Iqbal
Anemia due to marrow failure (Aplastic anemia)
Aplastic anemia is defined as pancytopenia with hypocellularity (aplasia) of the bone
marrow. It is an uncommon but serious condition
Aplastic anemia is due to a reduction in the number of pluripotential stem cell together
with a fault in those remaining or an immune reaction against them. Failure of one cell
line may occur
Evolution to myelodysplasia, paroxysmal nocturnal haemoglobinuria (PNH) or acute
myeloblastic leukaemia occurs in some cases
Causes
Immune mechanisms are probably responsible for most cases of idiopathic acquired
aplastic anemia
Activated cytotoxic T cells in blood and bone marrow are responsible for the bone
marrow failure
Drugs may cause marrow aplasia, including cytotoxic drugs such as busulphan and
doxorubicin
Causes
Some individuals develop aplasia due to sensitivity to non-cytotoxic drugs such as
chloramphenicol, gold, carbimazole, chlorpromazine, phenytoin, tolbutamide, nonsteroidal anti-inflammatory
Congenital aplastic anaemia are rare. Fanconi’s anemia is inherited as autosomal
recessive and is associated with skeletal, renal and central nervous system abnormalities
Causes of Aplastic Anaemia
Primary
Congenital e.g. Fanconi’s anemia
Idiopathic acquired (50% of cases)
Secondary
Chemicals, e.g. benzene
Drugs
Chemotherapeutic
idiosyncratic
Insecticides
Ionizing radiation
Infections
Viral, e.g. hepatitis, measles, HIV, Parvo
Other, e.g. tuberculosis
Pregnancy
Paroxysmal nocturnal hemoglobinuria
Clinical Features
Anemia
Bleeding
Infection
Ecchymoses
Bleeding gums and epistaxis
Mouth infections
Lymphadenopathy
Hepatosplenomegaly are rare
Investigations
The laboratory diagnosis is made on the basis of:
Pancytopenia
The virtual absence of reticulocytes
A hypocellular or aplastic bone marrow with increased fat spaces
Differential Diagnosis
Causes of pancytopenia
Aplastic anaemia
Drugs
Megaloblastic anaemia
Bone marrrow inflitration or replacement
Hodgkin’s and non-Hodgkin’s lymphoma
Acute leukoaemia
Myeloma
Secondary carcinoma
Myelofibrosis
Hypersplenism
Systemic lupus erythematosus
Disseminated tuberculosis
Paroxysmal nocturnal hemoglobinuria
Overwhelming sepsis
Treatment and Prognosis
The main danger is infection and stringent measures should be undertaken to avoid this
in a severely neutropenic patient immediate institution of broad-spectrum parenteral
antibiotics
Supportive care including transfusions of red cells platelets
Leucocyte-depleted red cell platelets should be given to prevent HLA
alloimmunization to minimize the risk of rejection of a bone marrow transplant to prevent
febrile transfusion reactions
Cause of the aplastic anemia must be eliminated if possible
Course of aplastic anemia can be variable
Treatment and Prognosis
A bad prognosis (i.e. severe aplastic anaemia) is associated with the presence of two of
the following three features:
Neutrophil count <0.5x109/L
Platelet count of <20x109/L
Reticulocyte count of <40x109/L
In severe aplastic anaemia, there is a very poor outcome without treatment.
Bone marrow transplantation is the treatment of choice for patietns under 20 years of
age
Treatment and Prognosis
Immunosuppression produces similar long-term survival.
Transplantation versus immuno-suppression is a contentious issue in the 20-45 age
range
Patients over the age of 45 are not eligible for bone marrow transplantation because of
the high risk of graft-versus-host disease
With matched transplants, the 3 year survival rate is up to 90%
Treatment and Prognosis
Immunosuppressive therapy is used for those pateints over the age of 45 years;
Antilymphocyte globulin (ALG) and cyclosporin are used alone or in combination.
ALG alone produces a hematological recovery in 50-60%, 80% in patietns also receiving
cyclosporin
Levels of haemopoietic growth factors are normal or increased in most patients with
aplastic anemia, and are ineffective as primary treatment
Treatment and Prognosis
Androgens (e.g. oxymethalone) are sometimes useful in patients not responding to
immunosuppression in patients with moderately severe aplastic anaemia
Steroids have little activity in severe aplastic anaemia are used for serum sickness due
to ALG. Also used to treat children with congenital pure red cell aplasia (diamondbalckfan syndrome)
Adult pure red cell aplasia is associated with a thymoma in 30% of cases and
thymectomy may induce a remission
HEMOLYTIC ANEMIAS
Haemolytic anemias are caused by increased destruction of red cells
Breakdown of normal red cells occurs in the macrophages of the bone marrow, liver
and spleen
Consequences of Haemolysis
The bone marrow can increase its output by six to eight times by increasing the
proportion of cells committed to erythropoiesis (erythroid hyperplasia) by expanding the
volume of active marrow
Immature red cells (reticulocytes) are released prematurely. These cells are larger than
mature cells stain light blue on a peripheral blood film
Sites ofHaemolysis
Extravascular haemolysis
The red cells are removed from the circulation by macrophages in the
reticuloendothelial system, particularly the spleen
Sites of Haemolysis
Intravascular Haemolysis
When red cells are rapidly destroyed within the circulation, haemoglobin is liberated
Excess free plasma Hb is filtered by the renal glomerulus and enters the urine
In the renal tubular cell, Hb is broken down and becomes deposited in the cells as
haemosiderin
Some of the free plasma Hb is oxidized to methaemoglobin, which dissociates into
ferrihaem and globin. Plasma haemopexin binds ferrihaem
The
liver plays an important role in removing Hb bound to hepatoglobin and
haemopexin and any remaining free Hb
Evidence for Haemolysis
Increased red cell breakdown leads to:
Elevated serum bilirubin (unconjugated)
Excess urinary urobilinogen (resulting from bilirubin breakdown in the intestine
Reduced plasma haptoglobin
Raised serum lactic dehydrogenase (LDH)
Evidence for Haemolysis
Increased red cell production leads to:
Reticulocytosis
Erythroid hyperplasia of the bone marrow
Evidence of abnormal red cell in some haemolytic anaemias:
Spherocytes
Sickle cells
Red cell fragments
Demonstration of shortened red cell life-span
Red cell survival studes using 51Cr-labbled red cells are useful in complicated cases,
and for quantitation of the severity of haemolysis
Causes of Hemolytic Anaemia
Inherited
Red cell membrane defect
Hereditary spherocytosis
Hereditary elliptocytosis
Haemoglobin abnormalities
Thalasaemia
Sickle cell disease
Metabolic defects
Glucose-6-phosphate
Dehydrogenase deficiency
Pyruvate kinase deficiency
Causes of Hemolytic Anemia
Acquired
Immune
Autoimmune
Warm
cold
Alloimune
Hemolytic transfusion
Reactions
Hemolytic disease of the new born
After allogeneic bone marrow or organ transplantation
Drug-induced
Causes of Haemolytic Anaemia
Acquired
Non-immune
Acquired membrane defects
Paroxysmal nocturnal haemoglobinuria
Mechanical
Microangiopathic haemolytic anaemia
Valve prosthesis
March haemoglobinuria
Secondary to systemic disease:
Renal and liver failure
Causes of Hemolytic Anaemia
Miscellaneous
Infections, e.g. malaria,
Clostridium welchii
Drugs and chemicals causing damage to the red cell membrane or oxidative hemolysis
Hypersplenism
Burns
Red cell membrane defects
The normal red cell membrane consists of a lipid bilayer crossed by integral proteins
with an underlying lattice of proteins (or cytoskeleton), spectrin, actin, ankyrin and
protein 4.1, attached to integral proteins
Hereditary Spherocytosis (HS)
Surface-to-volume ratio decrease, the cells become spherocytic. Spherocytes are more
rigid and less deformable than normal red cells. They are unable to pass through the
splenic microcirculation and they die
Deficiency in the structural protein spectrin quantitative defects in other membrane
proteins have been identified
Abnormal red cell membrane associated with increased permeability to sodium
Hereditary Spherocytosis (HS)
HS is the most common inherited hemolytic anemia in northern Europeans, affecting 1
in 5000
25% of patients autosomal dominant
HS is due to a defect in the red cell membrane, resulting in the cells losing part of the
cell membrane as they pass through the spleen
Clinical Features
Jaundice at birth
Some patients may go through life with no symptoms and are detected only during
family studies
Anemia, splenomegaly ulcers on the leg course of the disease may be interrupted
by aplastic, hemolytic and megaloblastic
Aplastic anemia usually occurs after infections, parvovirus megaloblastic anemia
is the result of folate depletion
Chronic hemolysis leads to the formation of pigment gallstones
Investigations
Anaemia: mild, but occasionally can be severe
Blood film: this shows spherocytes and reticulocytes
Hemolysis: is evident (e.g. the serum bilirubin and urinary urobilinogen will be raised

Osmotic fragility: when red cells are placed in solutions of increasing hypotonicity,
they take in water, swell, and eventually useful to confirm a suspicion of spherocytosis on
a blood film
Direct antiglobulin (Coombs’) test: negative in spherocytosis
Treatment
The spleen, which is the site of cell destruction, should be removed in all but the
mildest cases
Raised bilirubin and especially the presence of gallstones should encourage
splenectomy
Best to postpone splenectomy until after child-hood
Splenectomy should be preceeded by pneumococcal and Hib immunization and
followed by lifelong penicillin prophylaxis
Folate levels should be monitored, or folic acid can be given prophylactically
Hereditary Elliptocytosis
This disorder of the red cell membrane is inherited in an autosomal dominant manner
and has a prevalence of 1 in 2500 in Caucasians
Red cells are elipiptical owing to spectrin and other protein abnormaliteis
Hereditary Stomatocytosis
Stomatocytes are red cells in which the pale central area appears slit-like.
There presence in large numbers may occur in a hereditary haemolytic anaemia
associated with a membrane defect, but excess alcohol intake is also a common cause