3. • inherited or acquired
• acute or more chronic
• intravascular or extravascular
• Intracorpuscular causes or to extracorpuscular
causes
4. • The clinical presentation of a patient with
anemia is greatly influenced in the first place
by whether the onset is abrupt or gradual.
• A patient with autoimmune HA or with favism
may be a medical emergency, whereas a
patient with mild hereditary spherocytosis or
with cold agglutinin disease may be diagnosed
after years.
5.
6. • Hemolysis regularly produces an increase in
unconjugated bilirubin and aspartate
aminotransferase (AST) in the serum;
urobilinogen will be increased in both urine and
stool.
• If hemolysis is mainly intravascular, the telltale
sign is hemoglobinuria (often associated with
hemosiderinuria); in the serum,is hemoglobin,
lactate dehydrogenase (LDH) is increased, and
haptoglobin is reduced.
7. • the bilirubin level may be normal or only
mildly elevated.
• increase in reticulocytes
• increased mean corpuscular volume (MCV)
polychromasia
• Red cell destruction is a potent stimulus for
erythropoiesis, which is mediated by
erythropoietin (EPO) produced by the kidney.
8. • chronic intravascular hemolysis, the persistent
hemoglobinuria will cause considerable iron
loss, needing replacement.
• chronic extravascular hemolysis, the opposite
problem, iron overload, is more common,
especially if the patient needs frequent blood
transfusions
9. INHERITED HEMOLYTIC ANEMIAS
• three essential components in the red cell: (1)
hemoglobin(2) the membrane-cytoskeleton
complex, and (3) the metabolic machinery.
11. • The main cytoskeletal protein is spectrin, the
basic unit of which is a dimer of α-spectrin
and β-spectrin.
12. Hereditary spherocytosis (HS)
• presence of numerous spherocytes in the
peripheral blood
• red cells were abnormally susceptible to lysis
in hypotonic media.
• the presence of osmotic fragility became the
main diagnostic test for HS.
13.
14. • Severe cases may present in infancy with
severe anemia,
• whereas mild cases may present in young
adults or even later in life.
• The main clinical findings are jaundice, an
enlarged spleen, and often gallstones;
15. • In milder cases, hemolysis is often
compensated (see above), and this may cause
variation in time even in the same patient,
due to the fact that intercurrent conditions
(e.g., pregnancy, infection) may cause
decompensation.
• The anemia is usually normocytic
• An increased mean corpuscular hemoglobin
concentration (MCHC)
16. • spleen itself is a major site of destruction
• transit through the splenic circulation makes
the defective red cells more spherocytic and,
therefore, accelerates their demise.
• Investigations: osmotic fragility, the acid
glycerol lysis test, the eosin-5′-maleimide
(EMA)–binding test, and SDS-gel
electrophoresis of membrane proteins;
17. TREATMENT
• We do not have a causal treatment for HS
• In mild cases, avoid splenectomy.
• Delay splenectomy until puberty in moderate
cases or until 4–6 years of age in severe cases.
• Antipneumococcal vaccination before
splenectomy.
• Along with splenectomy, cholecystectomy should
not be regarded as automatic; it should be
carried out, usually by the laparoscopic approach,
when clinically indicated.
20. Hereditary elliptocytosis (HE)
• Elliptical RBCS
• Alpha and beta spectrin mutation
• Recommended management are similar to
those outlined above for HS. Although the
spleen may not have the specific role it has in
HS, in severe cases, splenectomy may be
beneficial. The prevalence of HE causing
clinical disease is similar to that of HS
21. • an in-frame deletion of nine amino acids in
the SLC4A1 gene encoding band 3, causing the
Southeast Asia ovalocytosis.
22. Disorders of Cation Transport
• autosomal dominant inheritance
• increased intracellular sodium in red cells, with
concomitant loss of potassium
• high serum K+ (pseudohyperkalemia).
• In patients from some families, the cation transport
disturbance is associated with gain of water; as a
result, the red cells are overhydrated (low MCHC), and
on
• a blood smear, the normally round-shaped central
pallor is replaced by a linear-shaped central pallor,
which has earned this disorder the name
stomatocytosis
23. • In patients from other families, instead, the
red cells are dehydrated (high MCHC), and
their consequent rigidity has earned this
disorder the name xerocytosis.
• the primary defect may be in a cation
transporter; indeed, xerocytosis results from
mutations in PIEZO1
24. • in other patients with stomatocytosis, mutations
are found in other genes also related to solute
transport (Table 129-3), including SLC4A1
(encoding band3), the Rhesus gene RHAG, and
the glucose transporter gene SLC2A1 responsible
for a special form called cryohydrocytosis.
• in stomatocytosis, splenectomy is strongly
contraindicated because it has been followed in a
significant proportion of cases by severe
thromboembolic complications
26. Abnormalities of the glycolytic
pathway
• Pyruvate kinase deficiency The clinical picture of
homozygous (or compound biallelic) PK deficiency is
that of an HA that often presents in the newborn with
neonatal jaundice; the jaundice persists, and it is
usually associated with a very high reticulocytosis.
• anemia is remarkably well tolerated,
• because the metabolic block at the last step in
glycolysis causes an increase in bisphosphoglycerate
(or DPG); thus, the oxygen delivery to the tissues is
enhanced, a remarkable compensatory feat.
27. • The management of PK deficiency is mainly
supportive.
• oral folic acid supplements.
• Blood transfusion should be used as
necessary, and iron chelation may have to be
added if the blood transfusion requirement is
high
• severe disease, splenectomy may be beneficial
28. Abnormalities of redox metabolism
• Glucose 6-phosphate
dehydrogenase (G6PD) deficiency
• it is the only source of NADPH, which directly and
via glutathione (GSH) defends these cells against
oxidative stress.
• an intracorpuscular cause and an
extracorpuscular
• G6PD deficiency resistace to Plasmodium
falciparum malaria
29. • increased risk of developing neonatal jaundice
(NNJ) and a risk of developing acute HA (AHA)
when challenged by a number of oxidative
agents.
• NNJ related to G6PD deficiency is very rarely
present at birth; the peak incidence of clinical
onset is between day 2 and day 3, and in most
cases, the anemia is not severe.
30. • NNJ can be very severe in some G6PD-deficient
babies, especially in association with prematurity,
infection, and/or environmental factors (such as
naphthalene-camphor balls, which are used in
babies’ bedding and clothing), and the risk of
severe NNJ is also increased by the coexistence of
a monoallelic or biallelic mutation in the uridyl
transferase gene (UGT1A1; the same mutations
are associated with Gilbert’s syndrome).
• If inadequately managed, NNJ associated with
G6PD deficiency can produce kernicterus and
permanent neurologic damage
31. • AHA can develop as a result of three types of
triggers: (1) fava beans, (2) infections, and (3)
drugs.
• The onset can be extremely abrupt, especially
with favism in children.
• The anemia is moderate to extremely severe,
usually normocytic and normochromic, and
due partly to intravascular hemolysis;
32. • hemoglobinemia, hemoglobinuria, high LDH, and
low or absent plasma haptoglobin.
• anisocytosis, polychromasia, and spherocytes
typical of hemolytic anemias.
• The most typical feature of G6PD deficiency is the
presence of bizarre poikilocytes, with red cells
that appear to have unevenly distributed
hemoglobin (“hemighosts”) and red cells that
appear to have had parts of them bitten away
(“bite cells” or blister cells”)
33.
34. • supravital staining with methyl violet, which, if
done promptly, reveals the presence of Heinz
bodies (consisting of precipitates of denatured
hemoglobin and hemichromes)- signature of
oxidative damage to red cells (they are also
seen with unstable hemoglobins
35. • LDH is high
• Unconjugated bilirubin
• development of acute renal failure.
• very small minority of subjects with G6PD
deficiency have chronic nonspherocytic
hemolytic anemia.
36.
37. Management
• only a quantitative test can give a definitive
result.
• DNA testing
• Avoid exposure to triggering factors of
previously screened subjects.(fava beans,
drugs)
• if the anemia is severe, it may be a medical
emergency : blood transfusion.
38. • If there is acute renal failure, hemodialysis
may be necessary.
• if the anemia is not severe, regular folic acid
supplements and regular hematologic
surveillance will suffice.
• splenectomy has proven beneficial in severe
cases
39. • deficiency of glutathione peroxidase (GSHPX)
due to transient nutritional deficiency of
selenium, an element essential for the activity
of GSHPX. called infantile poikilocytosis,
present in first month of life.
• Pyrimidine 5’ nucleotidase deficiency: (P5N) :
basophilic stippling.
40. FAMILIAL (ATYPICAL )HEMOLYTIC
UREMIC SYNDROME
• mostly affecting children
• characterized by microangiopathic HA with
presence of fragmented erythrocytes in the
peripheral blood smear, thrombocytopenia
(usually mild), and acute renal failure.
• mutations in any one of several genes encoding
complement regulatory proteins: complement
factor H (CFH), CD46 or membrane cofactor
protein (MCP), complement factor I (CFI),
complement component C3, complement factor B
(CFB), and thrombomodulin
41. • The anti-C5 complement inhibitor eculizumab
was found to greatly ameliorate the
microangiopathic picture, with improvement
in platelet counts and in renal function.
43. • INFECTION
– Shiga toxin–producing E. coli O157:H7
• intravascular hemolysis, due to a toxin with
lecithinase activity, occurs with Clostridium
perfringens sepsis.
46. TREATMENT
• Transfusion of RBCS
• Prednisone 1mg/kg/day
• Rituximab anti CD20 antibody
• Relapse or refractory : splenectomy
• azathioprine, cyclophosphamide,cyclosporine,
and intravenous immunoglobulin
47.
48. Paroxysmal cold hemoglobinuria (PCH)
• mostly in children, usually triggered by a viral
infection, usually self-limited.
• Donath-Landsteiner antibody. In vitro, this
antibody has unique serologic features; it has
anti-P specificity and binds to red cells only at a
low temperature (optimally at 4°C), but when the
temperature is shifted to 37°C, lysis of red cells
takes place in the presence of complement.
• Consequently, in vivo there is intravascular
hemolysis, resulting in hemoglobinuria
49. COLD AGGLUTININ DISEASE
• autoantibody involved reacts with red cells poorly or not at
all at 37°C, whereas it reacts strongly at lower
temperatures.
• As a result, hemolysis is more prominent the more the
body is exposed to the cold.
• The antibody is usually IgM; usually it has an anti-I
specificity (the I antigen is present on the red cells of
almost everybody), and it may have a very high titer
(1:100,000 or more has been observed).
• Second, the antibody is produced by an expanded clone of
B lymphocytes, i.e., as a monoclonal gammopathy.
• Third, because the antibody is IgM, CAD is related to
Waldenstrom’s macroglobulinemia (WM)
50. • Immunosuppressive/cytotoxic treatment with
azathioprine or cyclophosphamide can reduce
the antibody titer, but clinical efficacy is
limited.
• Unlike in AIHA, prednisone and splenectomy
are ineffective.
• Plasma exchange
• Rituximab
51. TOXIC AGENTS AND DRUGS
• hyperbaric oxygenV(or 100% oxygen), nitrates,
chlorates, methylene blue, dapsone, cisplatin,
and numerous aromatic (cyclic) compounds.
• arsine, stibine, copper, and lead.
• The HA caused by lead poisoning is
characterized by basophilic stippling;
52. • Severe intravascular hemolysis can be caused
by the venom of certain snakes (cobras and
vipers), and HA can also follow spider bites.
53. PNH
• PNH is an acquired
• chronic HA characterized by persistent
intravascular hemolysis subject to recurrent
exacerbations. In addition to hemolysis, there is
often pancytopenia and a distinct tendency to
venous thrombosis.
• This triad makes PNH a truly unique clinical
condition; however, when not all of these three
features are manifest on presentation, the
diagnosis is often delayed, although it can always
be made by appropriate laboratory investigations
54. • median survival is estimated to be about 8–10
years;
• in the past, the most common cause of death
has been venous thrombosis, followed by
infection secondary to severe neutropenia and
hemorrhage secondary to severe
thrombocytopenia.
• Rarely (estimated 1–2% of all cases), PNH may
terminate in acute myeloid leukemia
55.
56. • Anemia- USUALLY NORMOMACROCYTIC
• Reticulocytosis
• anemia may become microcytic
57. • definitive diagnosis of PNH must be based on the
demonstration that
• increased susceptibility to complement (C), due
to the deficiency on their surface of proteins
(particularly CD59 and CD55) that normally
protect the red cells from activated C.
• The sucrose hemolysis test is unreliable; in
contrast, the acidified serum (Ham) test
• Flow cytometry gold standard
58. • Hemolysis in PNH is mainly intravascular and is due to
an intrinsic abnormality of the red cell, which makes it
exquisitely sensitive to activated C, whether it is
activated through the alternative pathway or through
an antigen-antibody reaction.
• The former mechanism is mainly responsible for
chronic hemolysis in PNH; the latter explains why the
hemolysis can be dramatically exacerbated in the
course of a viral or bacterial infection.
Hypersusceptibility to C due to membrane protective
protein deficiency esp CD59, shortage of GPI (mutation
of PIGA).
59. Treatment PNH
• most patients receive supportive treatment only, including
transfusion of filtered red cells whenever necessary.
• Folic acid supplements (at least 3 mg/d) are mandatory; the serum
iron should be checked periodically, and iron supplements should
be administered as appropriate.
• Long-term glucocorticoids are contraindicated.
• eculizumab, which binds to the complement component C5. iv
route once in 14 days.
• The only form of treatment that currently can provide a definitive
cure for PNH is allogeneic Bone marrow transplantation
• For patients with the PNH-AA syndrome, immunosuppressive
treatment with antithymocyte globulin and cyclosporine
