HEMOLYTIC ANEMIAS
Definition:
A hemolytic anemia is a reduction in
the number of circulating red cells resulting from their premature destruction.
Pathophysiology:
When the lifespan
is shortened , the circulating red cell mass and supply of O2 is decreased lead to increase erythropoietin and so
increase red cell mass.
When the rate of
destruction exceeds 8 times normal so hemolytic anemia results.
Site of Destruction:
Intravascularly, extravascularly or
more commonly in both sites .
Intravascular hemolysis :
When Hb
is released into the circulation it binds to haptoglobin .
- The plasma haptoglobin
level falls .
. - Haemoglobinuria and Haemosiderinuria
Compensatory Mechanism:
*Erythroid hyperplasia.
*Change in the myeloid /
erytheroid ratio
*Expansion of the marrow cavities of the
skull, vertebrae and long bones ,
causing marked skeletal
deformities.
. Pressure effects on nearby organs *
Pathological changes in haemolytic
anaemia:
increased red cell destruction Effects of Elevated unconjugated bilirubin -
- Reduced or absent
haptoglobins
. - Elevated methaemalbumin
. - Increased
urinary urobilinogen.
- Haemosiderinuria ( chronic intravascular haemolysis ).
- Reticuloendothelial
hyperplasia – hepatomegaly and splenomegaly.
Effect of increased red cell
production:
. Rise in reticulocyte count.
. Bone marrow expansion – hypercellularity .
Classification
* Extrinsic
factors ( e.g. antibody –complement mediated lysis or direct trauma).
* Membrane abnormality (
e. g congenital spherocytosis).
* Abnormalities of red cell metabolism ( e.g glucose –6
phosphate dehydrogenase -G6PD – deficiency).
* Disorders of haemoglobin ( e.g
thalassaemia or sickle cell
disease).
I –Red Cell Enzyme Deficiencies
The red cell has a very simple
metabolism ; it need little more than
supply of sugar from which it obtains energy by two metabolic routes.
1-The anaerobic Embden -
Meyerhof pathway
2-Aerobic pentose
phosphate pathway
Substances generated are:
*ATP , drive the anion membrane pumps
which remove sodium and water
from cell .
* 2-3
diphosphoglycerate alters the oxygen affinity of hemoglobin .
* NADH , maintaining the iron atom of hemoglobin in the
reduced (Fe) state.
* NADPH , important for maintaining sulphydry groups (-SH) in
the reduced state .
Glucose –6 Phosphate Dehydrogenase
Deficiency
. X- linked trait -
. - The disorder is
extremely heterogenous
-
There are two – types of G6PD – A and B
Type A Negro population.
Type B all population .
The gene for G6PD is located on the
long arm of the X- chromosome.
Affected males have very low or absent
activity in their red cells.Clinical features
G6PD deficiency may cause
. Drug induced hemolytic anemia.
. Favism.
. Neonatal jaundice .
. Chronic hemolysis .
Oxidant drugs
The most important offenders are the
sulphonamides and the anti malarials
primaquine and chlorquine.
Ingestion of the drug is followed
rapidly by intravascular haemolysis with fever , malaise , prostration and
passage of dark urine.
The haemoglobin (Hb) level falls
rapidly , accompanied by a marked reticulocytosis and the appearance of Heinz
bodies in many of the red cells.
Favism:
Acute haemolytic episodes following
ingestion of the fava beans.
Neonatal jaundice:
- Occur up to the
third week of life.
. - Leads to a full picture of kernicterus
Chronic haemolysis:
. - A few reported families
- The hemolysis in
such circumstances may be exacerbated
by drugs or intercurrent infection.
-Splenectomy is of only
limited value.
Diagnosis:
A simple assay for G6PD activity.
Pyruvate Kinase Deficiency
* Is the commonest enzyme deficiency in the Embden – Meyerhof pathway.
* Autosomal recessive disorder.
* Subnormal levels are
observed in the parents of affected children.
Clinical feature:
. Presents in childhood -
- Anemia , jaundice and
splenomegaly , or sometimes even earlier as neonatal jaundice.
- The clinical course is
characterized by variable degree of anemia exacerbated by infection or other
stress.
- There is an increased
incidence of gallstones and bone changes.
Pyruvate Kinase Deficiency
* Is the commonest enzyme deficiency in the Embden – Meyerhof pathway.
* Autosomal recessive disorder.
* Subnormal levels are
observed in the parents of affected children.
Clinical feature:
. Presents in childhood -
- Anemia , jaundice and
splenomegaly , or sometimes even earlier as neonatal jaundice.
- The clinical course is
characterized by variable degree of anemia exacerbated by infection or other
stress.
- There is an increased
incidence of gallstones and bone changes.
Investigations :
Low or absent PK activity in red cells .
Treatment :
Splenectomy .
. Hemolytic crisis
are treated by blood transfusion .
II – Haemoglobinopathies
- Inherited disorders of hemoglobin structure
or its production .
- Human hemoglobin in a
globular protein , it consists
of a protein part , globin ,
combined with four hem groups .
- The globin fraction of normal adult hemoglobin (Hb A ) consists of four peptide chains , two (a) - chains and two (b) chains.
- Fetal hemoglobin (Hb F ) has two (a) chains and two (g) chains.
-
Normal adults have a minor hemoglobin (Hb A 2 ) with (a) chains and (d) chains .
- Inherited defect in the rate of synthesis
of one or more of the globin chains results in
under production of hemoglobin in unbalanced globin chain synthesis with perception of the chains which are
produced in
excess , and the formation of rigid inclusion
( Heinz bodies ) .
(A) Structural
Haemoglobinopathies
Three main types
Hemoglobin variants which
cause hemolytic alteration of the molecule configuration of Hb (sickling) of
Heinz body formation .
Abnormal hemoglobin with altered oxygen
carrying properties hereditary methemoglobinaemia or polycythemia.
Variant which are
synthesized at a reduced rate, (thalassaemia ).
(A) Sickling
disorders:
During deoxygenation the abnormal hemoglobin
molecule form linear stricks , causing the red cell to become deformed into a rigid
, sickle shape .
·
Sickle cells have
difficulty in passing through the microcirculation , this leads to blockage of
small vessels and tissue damage .
Sickling damage the red
cell membrane and leads to haemolysis .
Sickle cell anaemia (ss)
· - Severe , in capacitating , disorder
resulting in hemolytic anemia from about the third month of life .
- Chronic hemolytic anemia punctuated by
periodic exacerbations or crisis .
Diagnosis of sickling disorders :
1-The racial
background with typical
clinical and hematological
feature
2-Hematological
findings
3- A sickling test
4- Screening tests
5- The diagnosis should always be
confirmed by hemoglobin electrophoresis
Sickle cell disease crisis
1- Painful crises
- Results of either
diminished blood flow leading to tissue infarction or
sequestration of sickled erythrocytes in various organs .
- May be precipitated by
factors including infection , dehydration and exposure to low
temperatures .
·
- In the first year of
life a common presenting feature is
the painful swelling of the hands and feet (hand –foot- syndrome) .
- In older children and
adults , sever pain in the limbs and back associated with fever and prostration is the commonest presentation .
- 2-Aplastic crises
Rapidly falling hemoglobin level
together with an absent reticulocyte count .
-
3-Sequestration crisis
Pooling of sickled
erythrocytes may occur in
the spleen liver or lungs .
Life –threatening
complication seen in early
childhood .
Characterized by massive enlargement of the spleen together with a sharply falling
hemoglobin level and rising of the
reticulocyte count
Splenic infarction occurs
between 5 and 10 years of age so this complication is not seen in adults .
Occur in the liver in
adult life , leading to rapid enlargement together with a falling hemoglobin
level and a rise in reticulocyte count .
Occur in the lungs where
bilateral radiological changes associated with tachycardia , fever and profound
hypoxia may accompany a rapidly falling hemoglobin level .
Other complications
Infection
Pneumococcal infections , and prophylactic
penicillin together with vaccination should be considered . Salmonella
osteomyelitis .
Renal damage
o
Impairment of tubular function
o
Infarction leading to hematuria
o
Papillary necrosis and
o Nephrotic
syndrome
Chronic leg ulceration.
Aseptic bone necrosis
Priapism .
Gallstones
Pulmonay
Management : Between crises
o Folic acid
o Any infections treated promptly
o Painful crises should be
treated with rest ,
hydration , and adequate analgesia .
o Hospitalization may be required
for sever crises
o Hemoglobin level and
reticulocyte count must be
performed at least daily during severe crises
Routine blood transfusion is unnecessary
.
o Transfusion may be indicated , if
the hemoglobin falls much below its usual level.
o Vaso occlusive complications of
sickling are prevented if the proportion of HbS – containing cells is reduced
to less than 30% .
o Sodium cyanate increase O2 affinity of
HBS but it’s long tern use results in neurotoxicity , extra – corporeal
treatment of the sickeled red blood cells with cyanate is now available and useful.
. Prevention
1-Genetic counseling
Pre- natal diagnosis and
termination of pregnancy 2-
(B) The B-
thalassaemias
Thalassaemia Major , Cooley’s Anaemia
Sever form .
Manifest in infancy .
Prognosis is grave .
Many fail to survive into
adult life .
The children stunted .
Anemia is usually severe .
Jaundice is mild.
Splenomegaly is often .
. Enlargement of the liver
. Erythrocytes very deficient in hemoglobin with great variation
in shape and size , target cells are quite common and basophilic stippling.
Leucocytosis .
Platelet count is normal .
The reticulocytes count is
raised .
.The bone marrow usually
shows a normoblastic hyperplasia expand the marrow cavities with great widening
of the diploe and very prominent vertical striations are to be seen on X- ray
as hair on end and mongoloid appearance.
The spleen usually is greatly
enlarged .
Thalassaemia minor and Minima
Benign condition -
- Detected incidentally in apparently normal individuals mild
anaemia.
- Most of these patients are completely symptoms – free.
The haemoglobin level may be in the
normal range. -
The blood film appearances are similar
in type to those of thalassaemia major but are much less marked .
.% - The reticulocyte count is rarely over 5
. Only small amounts of haemoglobin F are found
. High levels of haemoglobin A2 -
thalassaemias a
Haemoglobin Barts – Hydrops Fetalis
Syndrome:
. - This condition is incompatible with life
- The only chains
synthesized are g and b
chains.
. -The clinical picture is
of hydrops fetalis
- Haematological picture is of severe thalassaemic syndrome.
Haemoglobin H –Disease:
Is a B –chain tetramer .
. The B- chian tetramer
is unstable and becomes
precipitated within the erythrocytes
These cause membrane
damage .
. Are important cause of
the premature erythrocyte
destruction .
Enhanced by oxidant drugs .
The results of splenectomy
are difficult to assess .
Many avoid the use of any
oxidant drugs .
Management of the Thalassaemias
In the very mild or silent forms of
thalassaemia no treatment is usually indicated.
Folate supplements are
therefore usually given.
General medical care.
Prompt treatment for any
episode of infection.
In the more severe forms of homozygous
B- thalassaemia , periodic blood transfusion is the only way of maintaining a
reasonable haemoglobin concentration ®hyper transfusion .
super transfusion
Splenectomy is usually
only contemplated in children with severe B- thalassaemia , indication :
evidence of excessive erythrocyte destruction .
sequestration .
Population screening and
genetic counseling .
Problem of iron overload :
Excess iron deposition in all organs which
result in tissue hemosiderosis (2ry hemochromatosis ), with the clinical
picture of :
-1-Hepatic dysfunction
-2-Growith failure
-3-Cardiac complications
Treatment of iron overload :
Chelation therapy by desferroxamine (Desferal )
given by small mechanical infusion pump of 1.5 gm over a period of 8-12 hours
, 3- 5 times /week.
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