HEMOLYTIC ANEMIAS
HA
Hemolysis : an increased rate of RBC destruction with a
shortening of the normal life span of the cell from the normal
120 days to as little as a few days in severe hemolysis. The
marrow can increase erythrocyte production 6-8 fold so mild
degrees of hemolysis are not associated with anemia.
Severe hemolysis can lead to a rapid and profound fall in Hb,
and be life threatening. It is suspected when polychromatic
cells are seen on the blood film (reticulocytes).
It is usually associated with raised blood unconjugated bilirubin
and splenomegaly .
Hemolysis can be caused by inherited or acquired
disorders.
Diagnosis of the cause of the hemolysis is made
according to the family history; clinical features and
red cell morphology that together will indicate what
further laboratory tests are required.
Marrow examination is generally unnecessary.
• The child with hemolysis may be pale with fluctuating
jaundice (usually mild) and splenomegaly.
• Pigment gallstones may complicate the disorder ,HA
should always be excluded in a child with stones.
• Aplastic crises may occur, usually precipitated by
parvovirus infection which leads to reticulocytopenia and
anemia. Parvovirus infection typically produces severe
anemia sometimes requiring transfusion, and a modest
thrombocytopenia and leucopenia.
Hemolytic anemia
The major categories of HA are:
1-Immunemediated.
2-Membrane defect (Spherocytosis).
3-Enzyme defect(G6PD def).
4-Hb defect (SCA,Thalassemia).
Membrane defects
Hereditary spherocytosis (HS)
HS
It is caused by a defect in the skeleton of the RBC
membrane that generally affects the spectrin
component.
The characteristic finding is increased numbers of
spherocytes in the peripheral blood. It is
inherited as A.D in 75% of cases, other cases
inheritant as A.R or new mutation.
Pathology
In AD type the defect may be in either beta
spectrin,ankyrin or protein 3. In AR form the defect is
in either -protein or protein 4-2.
This defect affect the RBC skeleton leading to budding
of RBC memb, This bud is removed rapidly by the RES
leading to loss of RBC surface area.The stretching
ability of the RBC is very limited which lead to RBC
rupture.
The spherocyte have no easy transit through the
splenic cord because of its shape this will affect
glucose metabolism and decrease pH of RBC.
A, polychromatic cell; B, microspherocyte
Clinical pictures
1-May be asymptomatic with mild anemia & discovered
accidentally.
2-The severe form may be started at early infancy with neonatal
jaundice, severe anemia , splenomegaly & chronic blood
transfusion.
3-Clinical pictures of complication, which are:
A-Bone marrow aplasia after Parvo virus B19 infection.
This v. infect erythroid cells in the BM & with arrest in
development. The aplasia last for 10-14 days during which
time the Hb drops by 50% with reticulocytopenia.
B-Hyper hemolysis after some viral infection lead to increasing
anemia, reticulocytosis &jaundice.
C-Delayed growth and sexual developments.
D-Pigmented gallstones.
Laboratory diagnosis
1-CBC:A-anemia.
B-high MCHC>36.
C-high retic. count.
D-normal MCH & MCV.
E-spherocytes in peripheral blood.
2-Incubated osmotic fragility test is elevated.
3-High indirect bilirubin.
4-Decrease habtoglobin.
5-Membrane protein analysis for difficult cases
Management
1-In mild anemia with normal growth and development,we only
observe the child and limit the intervention to folic acid tablet
1 mg/day.
2-Splenectomy for any child with chronic anemia or growth
failure but we should defer it till the age of 5 yr to minimize
the risk of sepsis & we should vaccinate the child by
pneumococcal , H. influenza & menengiococcal vaccines at
least 2 weeks before splenectomy & give the child
prophylactic penicillin after splenectomy until at least 18 yr of
age.
In some reports,partial splenectomy appears to improve the
anemia & maintain splenic function.
3-Elective cholecystectomy for symptomatic gallstones.
Glucose-6-phosphate
dehydrogenase(G6PD)
deficiency
G6PD deficiency is the most common RBC metabolic disorder. It is
usually transmitted in an X-linked recessive fashion.
Defects. The two prototypic forms are:
The A- variant is found mainly in the black population and is
associated with an isoenzyme that deteriorates rapidly (it
has a half-life of 13 days).
The Mediterranean variant is found mainly in individuals of
Greek and Italian descent and is associated with almost
complete absence of enzyme activity, even in young cells,
due to extreme instability (it has a half-life of several hours).
Pathogenesis
G6PD-deficient cells do not generate an amount of reduced
glutathione that is sufficient to protect the RBCs from oxidant
agents.
Exposed sulfhydryl groups of Hb are oxidized, predisposing the
molecule to denaturation.
The heme and globin moieties dissociate, with the globin
precipitating as Heinz bodies.
The damaged RBCs are then removed by the RES; severely
damaged cells may lyse intravascularly.
HA results from oxidative damage to the RBCs
as consequence of the loss of the protective
effect of the enzyme G6PD.
The prevalence of G6PD def. is related to the
prevalence of malaria as in Africa, it also high
in mediterranean area.The incidence of P
falceparum parasite is lower in G6PD def.
patients.
The half life of the enz in normal RBC is 60 days,the mature RBC
cannot synthesize the enz. The younger RBCs are relatively more
resistant to hemolysis .
The deficient RBC hemolysed when exposed to exogenous
factors.The particles of the denaturated Hb,Heinz body,attach to
the cell membrane causing irreversible damage and lysis, most of
lysis occur intravascularly causing hemoglobinemia &
hemoglobinuria.
There may be an extravascular hemolysis which explain the
splenomegaly in some cases.
Favism is the classical cause of acute hemolysis in G6PD def. Fava
bean contain the beta glycosides vicine & convicine These substances
may undergo auto-oxidation as part of their metabolism, producing
free O2 radicals.
Acute hemolysis that occurs upon exposure to Fava is characterized by:
1-unpredictable(only 25%of adult at risk develop
hemolysis).
2-Influence of dose and body weight.
3-Maturity of the bean.
4-Quality of bean(raw beans more than cooked, frozen or
canned
beans)
5-The activity of beta glucosidases in the bean & intestinal
mucosa.
Drug induced hemolysis
Many drugs and chemicals have been associated with
hemolysis in G6PD def patient,These substances have
the ability to stimulate the pentose phosphate PW in
RBC which can lead to oxidation of NADPH .
Infection-caused hemolysis
During the process of phagocytosis of bacteria there is a
release of peroxides by the phagocytosing granules,
these peroxides lead to release of O radicals.
Clinical presentation
There are three primary clinical
presentation:
1-Neonatal jaundice.
2-Acute hemolysis beyond the neonatal
period.
3-Chronic hemolysis (congenital nonspherocytic HA).
1-Neonatal jaundice:
Acute hemolysis is characterized by onset of jaundice
on the first few days of life that is out of the
proportion to the degree of anemia. All infant with
G6PD def develop NJ.
NJ in G6PD def neonate may be an exaggerated
physiological j or may be due to acute hemolysis
caused by inciting agent like inf., drugs, naphthalene
ball used in stored cloth diapers in developing
country.
2-Acute hemolysis:
Most pt with G6PD def. are asymptomatic until
exposed to inciting agent at which time they may
develop hemolysis.The onset of hemolysis is usually
within 24-48 hr of exposure. The initial manifestation
may include abdominal pain,vomiting or diarrhea,tea
colored urine (hemoglobinuria),Jaundice, pallor with
symptoms of anemia.
Examination usually reveals: anemia , jaundice
splenomegaly and hepatomegaly & in severe case
symptom of heart failure.
Lab.finding in acute hemolysis include:
1-Normochromic normocytic anemia with anisopoikilocytosis,
with few spherocyte .
2-Reticulocytosis.
3-Presence of bite cells (RBC bitten by macrophages).
4-Presence of hemigoast cells(RBC with uneven Hb distribution).
5-By using supravital stain we find inclusion bodies called Heinz
body(denatured Hb).
6-Low serum haptoglobin.
7-High uncong. bilirubin.
8-Hemoglobinuria .
9- hemoglobinemia.
Diagnosis of G6PD def
1-Antenatal diagnosis can be made by performing
G6PD assay on amniotic fl cells or from chorionic villi
biopsy and DNA assay.
2-Screening test:semiquantitative test,this test should
not be done during acute hemolysis because it lead
to normal value.The usual cut of deficiency value is
<30% of normal activity.
3-Quantitative assay: done several weeks after acute
hemolysis when reticulocyte return to normal.
4-G6PD electrophoresis.
Differential diagnosis:
1-AIHA.
2-Malaria induced hemolysis.
3-Hepatitis
Management of acute severe hemolysis
1-Removal of the inciting agent.
2-Brisk hydration to ensure adequate urine output.
3-blood transfusion.
4-Folic acid tablet 1mg/d for one month.
3-Chronic hemolysis
Small minority of pt develop chronic H.Clinically all pts are
male,presented with:
1-Neonatal j with anemia.
2-Jaundice and anemia.
3-splenomegaly.
4-Gallstone.
5-Acute hemolysis after exposure to oxidative agent.
Lab. Finding:
1-CBC:anemia,reticulocytosis & polychromasia.
2-Low haptoglobin.
3-Hyberbilirubinemia.
Management
1-Folic acid administration.
2-Blood transfusion if indicated.
Drugs induce hemolysis in G6PD:
ANALGESICS/ANTIPYRETICS acetophenetidin , amidopyrine
,aspirin ,phenacetin, probenicid .
ANTIMALARIALS chloroquine, hydroxychloroquine mepacrine,
pamaquine, pentaquine, primaquine, quinine, quinocide
SULFONAMIDES/SULFONES dapsone, sulfacetamide,
sulfamethoxypyrimidine, sulfanilamide ,sulfapyridine
sulfasalazine ,sulfisoxazole .
ANTIBACTERIAL chloramphenicol, cotrimoxazole, furazolidone,
nalidixic acid, nitrofurantoin nitrofurazone , paraaminosalicylic acid.
MISCELLANEOUS alpha-methyldopa, ascorbic acid dimercaprol
(BAL), hydralazine , methylene blue ,nalidixic acid
,naphthalene, vitamin K (water soluble)