Hereditary Spherocytosis

and
Hereditary Elliptocytosis
 Hereditary spherocytosis and hereditary
elliptocytosis
• congenital RBC membrane disorders.
• Symptoms, generally milder in hereditary
elliptocytosis, include variable degrees of
anemia, jaundice, and splenomegaly.
• Diagnosis requires demonstration of increased
RBC osmotic fragility and a negative direct
antiglobulin test. Rarely, patients < 45 yr with
symptomatic disease require splenectomy.
HEREDITARY SPHEROCYTOSIS
 HEREDITARY SPHEROCYTOSIS
• characterized by spherical RBC due to a
molecular defect in one of the proteins in the
cytoskeleton of the RBC membrane; this leads
to a loss of membrane and hence decreased
ratio of surface area to volume and
consequently spherocytosis.
 HEREDITARY SPHEROCYTOSIS
• Usually an autosomal dominant trait, this
disorder has an incidence of 1:1000 to 1:4500.
In ~20% of patients, the absence of
hematologic abnormalities in family members
suggests either autosomal recessive
inheritance or a spontaneous mutation.
• The disorder is sometimes clinically apparent
in early infancy but often escapes detection
until adult life.
 HEREDITARY SPHEROCYTOSIS
• The molecular abnormality in hereditary
spherocytosis primarily involves the proteins
responsible for tethering(fastening) the lipid
bilayer to the underlying cytoskeletal network.
• About 50% of patients have a defect in
ankyrin, the protein that forms a bridge
between protein 3 and spectrin.
 HEREDITARY SPHEROCYTOSIS
• About 25% of patients have a mutation of protein 3,
resulting in a deficiency of that protein and mild
anemia with dominant inheritance.
• Most of the remaining 25% have mutations of
spectrin, leading to impaired synthesis or self-
association. β-spectrin mutants are generally mild,
with dominant inheritance, while α-spectrin deficiency
is severe, with a recessive inheritance pattern.
• Less often, deficiency of palladin (protein 4.2) is a
cause of hereditary spherocytosis.
HEREDITARY SPHEROCYTOSIS
 HEREDITARY SPHEROCYTOSIS
• Because the lipid bilayer is not well anchored when
these proteins are defective, part of it is lost by
vesiculation, resulting in a more spherical and less
deformable cell.
• Because of their shape and rigidity, spherocytes are
trapped in the spleen where their increased
metabolic rate cannot be sustained, causing a
further loss of surface membrane. This
“conditioning” produces a subpopulation of
hyperspheroidal RBC in the peripheral blood.
 HEREDITARY SPHEROCYTOSIS
• As the spleen normally targets abnormally
shaped red cells (which are typically older), it
also destroys spherocytes. In the spleen, the
passage from the cords of Billroth into the
sinusoids may be seen as a bottleneck, where
erythrocytes need to be flexible in order to
pass through. In hereditary spherocytosis,
erythrocytes fail to pass through and get
phagocytosed, causing extravascular hemolysis.
HEREDITARY SPHEROCYTOSIS
 HEREDITARY SPHEROCYTOSIS
• The major clinical features:
– Splenomegaly is very common. The hemolytic rate may
increase transiently during systemic infections, which
induce further splenic enlargement.
– Compensation may be temporarily interrupted by
episodes of relative erythroid hypoplasia precipitated
by infections, particularly parvovirus.
– Bone marrow's capacity to increase erythropoiesis=the
rate of hemolysis anemia is usually mild or moderate
or may be absent in an otherwise healthy individual.
 HEREDITARY SPHEROCYTOSIS
– Jaundice - intermittent and tends to be less
pronounced in early childhood.
– Pigmented gallstones are common, even in
childhood, because of the increased bile pigment
– Compensatory erythroid hyperplasia of the bone
marrow occurs, with the extension of red marrow
into the midshafts of long bones and occasionally
with extramedullary erythropoiesis, at times
leading to the formation of paravertebral masses
visible on chest x-ray.
 HEREDITARY SPHEROCYTOSIS
• The characteristic erythrocyte abnormality is the spherocyte .
• The mean corpuscular volume (MCV) is usually normal or
slightly decreased
• Mean corpuscular hemoglobin concentration (MCHC) is
increased to 350 to 400 g/L.
• Spheroidicity may be quantitatively assessed by
measurement of the osmotic fragility of the RBC on exposure
to hyposmotic solutions causing a net influx of water.
• On microscopic examination, spherocytes are usually
detected as small cells without central pallor.
 HEREDITARY SPHEROCYTOSIS
DIAGNOSIS
• Hereditary spherocytosis must be distinguished
primarily from the spherocytic hemolytic anemias
associated with RBC antibodies.
• The family history of anemia and/or splenectomy is
helpful, when present.
• The diagnosis of immune spherocytosis is usually
readily established by a positive direct Coombs test .
 HEREDITARY SPHEROCYTOSIS
• Spherocytes are also seen in association with
hemolysis induced by splenomegaly in patients
with cirrhosis, in clostridial infections, and in
certain snake envenomations (due to the
action of phospholipases on the membrane).
• A few spherocytes are seen in the course of a
wide variety of hemolytic disorders, particularly
glucose-6-phosphate dehydrogenase (G6PD)
deficiency.
 HEREDITARY SPHEROCYTOSIS
TREATMENT
Splenectomy is recommended in patients with
moderate or severe hemolysis. Although the
RBC defect and its consequent morphology
persist, anemia is ameliorated. The operative
risk is low, particularly if performed by
laparoscopy. RBC survival after splenectomy is
normal or nearly so; if it is not, an accessory
spleen or another diagnosis should be sought.
 HEREDITARY SPHEROCYTOSIS
Splenectomy in children should be postponed
until age 4, if possible, to minimize the risk of
severe infections with gram-positive
encapsulated organisms. Pneumococcal,
meningococcal, and Haemophilus influenzae
vaccines should be administered at least 2
weeks before splenectomy.
In patients with severe hemolysis, folic acid (1
mg/d) should be administered prophylactically.
HEREDITARY ELLIPTOCYTOSIS
 HEREDITARY ELLIPTOCYTOSIS
• Hereditary elliptocytosis is an autosomal
dominant trait and affects 1 per 4000 to 5000
people, a frequency similar to that of
hereditary spherocytosis.
• In most affected individuals, a structural
abnormality of erythrocyte spectrin leads to
impaired assembly of the cytoskeleton.
 HEREDITARY ELLIPTOCYTOSIS
• In some families, affected individuals have a
deficiency of erythrocyte membrane protein
4.1, which stabilizes the interaction of spectrin
and actin in the cytoskeleton.
• In Southeast Asia, the incidence of hereditary
ovalocytosis is high
• a small internal deletion of protein 3 makes the
membrane rigid and confers resistance against
malaria.
HEREDITARY ELLIPTOCYTOSIS
HEREDITARY ELLIPTOCYTOSIS
 HEREDITARY ELLIPTOCYTOSIS
• The great majority of patients manifest only mild
hemolysis, with little or no anemia. RBC destruction
occurs predominantly in an enlarged spleen.
• The blood smear reveals elongated or oval red cells
(elliptocytes). Patients with marked hemolysis have
microovalocytes, bizarre-shaped RBC, and RBC
fragments, all of which increase in number after
splenectomy.
• Hemolysis is corrected by splenectomy.
 HEREDITARY
PYROPOIKILOCYTOSIS
 HEREDITARY PYROPOIKILOCYTOSIS
• Hereditary pyropoikilocytosis is a rare disorder
related to hereditary elliptocytosis and is
characterized by bizarre-shaped, microcytic RBC that
undergo disruption at temperatures of 44 to 45°C (in
contrast, normal RBC are stable up to 49°C).
• This condition results from a deficiency of spectrin
and an abnormality of spectrin self-assembly.
Hemolysis is usually severe, is recognized in
childhood, and is partially responsive to splenectomy.
HEREDITARY PYROPOIKILOCYTOSIS
Paroxysmal Nocturnal
Hemoglobinuria (PNH)
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• This hemolytic disorder is distinctive because
it is an intracorpuscular defect acquired at the
stem cell level.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• PNH is an acquired clonal disease, arising from an
inactivating somatic mutation in a single
hematopoietic stem cell of a gene on the X-
chromosome (pig-A) necessary for the biosynthesis
of the glycosylphosphatidylinositol (GPI) anchor.
• This anchor attaches a number of proteins to the
external membrane surface, and its partial or
complete absence results in the absence of those
proteins.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• Two of these are the complement defense proteins
CD55 [PNH decay accelerating factor (DAF)] and
CD59, which block complement activation on the
cell surface.
• Their absence accounts for the sensitivity of RBC to
complement lysis and for the tendency of platelets
to abnormally initiate clotting. The normal clones of
stem cells do not completely disappear, and the
proportion of cells that are abnormal varies among
patients and over time in a single patient.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• The three common manifestations are:
(1) Hemolytic anemia. Anemia is highly
variable, with hematocrit values ranging from
≤20% to normal. RBC are normochromic and
normocytic unless iron deficiency has
occurred from chronic iron loss in the urine.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• Clinical hemoglobinuria is intermittent in
most patients and never occurs in some, but
hemosiderinuria is usually present. Since
hemolysis is due to abnormalities of the RBC
leading to sensitivity to the hemolytic action
of complement, it is manifest when
complement is activated, for example, by
infection.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
(2) Deficient hematopoiesis. Granulocytopenia
and thrombocytopenia are common and
reflect impaired hematopoiesis. The life span
of the platelet is normal. However, the
activation of complement indirectly stimulates
platelet aggregation and hypercoagulability;
this probably accounts for the tendency
toward thrombosis seen in PNH.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
(3) Venous thrombosis. A common complication
of patients of European origin, affecting ~40%
at one time or another; it is less common in
Asian patients. It occurs primarily in intra-
abdominal veins (hepatic, portal, mesenteric)
and results in Budd-Chiari syndrome,
congestive splenomegaly, and abdominal pain.
It may occur in cerebral venous sinuses and is a
common cause of death in patients with PNH.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• The bone marrow may appear normocellular,
but in vitro marrow progenitor assays are
abnormal. In about 15 to 30% of long-term
survivors of aplastic anemia, PNH cells appear
in the circulation; in some patients, the
manifestations of PNH become dominant.
Patients with PNH may have aplastic periods
lasting from weeks to years.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
TREATMENT
• Transfusion therapy is useful in PNH not only for raising
the hemoglobin level but also for suppressing the
marrow production of RBC during episodes of sustained
hemoglobinuria.
• Washed RBC are the preferred source to prevent
exacerbation of hemolysis. Therapy with androgens
sometimes results in a rise in hemoglobin level.
Glucocorticoids reduce the rate of hemolysis in moderate
doses (15 to 30 mg prednisone) on alternate days. 
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• Iron deficiency is common. Iron replacement
may exacerbate hemolysis because of the
formation of many new RBC, which may be
sensitive to complement. This occurrence may
be minimized by giving prednisone (60 mg/d)
or by suppressing the bone marrow with
transfusions.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• Acute thrombosis in PNH, particularly Budd-
Chiari syndrome and cerebral thrombosis -
should be treated with thrombolytic agents.
Heparin therapy should be instituted rapidly
and maintained using low-molecular-weight
heparin, at least for several weeks to months
and perhaps indefinitely in severe cases.
 Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• Antithymocyte globulin (total dose, 150 mg/kg
over 4 to 10 days) is often of use in treating
marrow hypoplasia; prednisone counteracts
the immune-complex disease that results from
the administration of this foreign protein. 
• In patients with either hypoplasia or
thrombosis who have an appropriate sibling
donor, marrow transplantation should be
considered early in the course of the disease.