PNH PNH is a rare acquired clonal disorder of marrow stem cells in which there is deficient synthesis of the glycosylphosphatidylinositol GPI anchor a structure that attaches ID: 933605
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Slide1
Paroxysmal nocturnal haemoglobinuria(PNH)
Slide2PNH
is
a rare, acquired,
clonal
disorder of marrow stem cells
in which
there
is
deficient synthesis of
the
glycosyl-phosphatidyl-inositol
(GPI
) anchor, a structure that attaches
several
surface
proteins to the cell membrane.
There
is a clinical triad
of chronic intravascular
haemolysis
,
venous
thrombosis and
bone marrow failure
Slide3It results
from acquired mutations in the
X chromosome
gene coding for
phosphatidylinositol
glycan
protein
class A (PIG‐A), which is essential for the
formation of
the GPI anchor
.
The net result is that GPI‐linked proteins
(such as CD55 and CD59) are absent from the cell surface
of all
the cells derived from the abnormal stem cell
Slide4Slide5CD55 and CD59 are also normally present on white
cells and
platelets.
The
lack of the surface molecules
decay‐activating factor
(DAF, CD55) and membrane inhibitor of
reactive
lysis
(MIRL, CD59) render red cells sensitive to
lysis
by complement
and the result is chronic intravascular
haemolysis
.
Slide6Haemosiderinuria
is a constant feature and can give rise
to iron
deficiency which may exacerbate the
anaemia
.
Haptoglobins
are
absent; free
haemoglobin
may damage the kidney
and it
removes nitric oxide from smooth muscle causing
dysphagia
and
pulmonary hypertension.
Slide7The other main clinical problem
in PNH is of venous thrombosis. Patients may develop recurrent thromboses of large vessels, including the portal, hepatic and mesenteric veins. Arterial thrombosis, such as strokes or myocardial infarction, can also occur. Intermittent abdominal pain due to mesenteric vein thrombosis is a common feature
Slide8PNH is almost invariably associated with some
form of
bone marrow
hypoplasia
and there may even be
complete
aplastic
anaemia
.
It appears that the PNH clone may expand as a
result of a selective pressure, possibly immunologically mediated,
against cells that have normal GPI‐linked membrane proteins
Slide9PNH is diagnosed by flow cytometry
which shows loss
of expression
of the GPI‐linked proteins CD55 and CD59.
This has
replaced the demonstration of red cell
lysis
in serum at
low pH
– the Ham test.
Slide10Eculizumab
, a humanized antibody against complement C5,
inhibits the activation of terminal components of complement
and reduces
haemolysis
, transfusion requirements and the incidence
of thrombosis. Iron therapy is used for iron deficiency and
long‐term anticoagulation with
warfarin
may be needed.
Immunosuppression
can be useful and
allogeneic
stem cell transplantation
is a definitive treatment. The disease occasionally remits
spontaneously. The median survival is over 10 years. As for
aplastic
anaemia
, transformation to MDS or AML may occur.
Slide11Red cell aplasia
Slide12Chronic form
This
is a rare syndrome characterized by
anaemia
with
normal leucocytes
and platelets and grossly reduced or absent erythroblasts
in the marrow
The
congenital form is
known as
Diamond–
Blackfan
syndrome
Slide13inherited as a recessive condition. It is associated with a varying
number of somatic abnormalities (e.g. of the face or heart).
Mutation of a gene on chromosome 19 or other genes
that encode
ribosomal proteins underlies most cases
Slide14Corticosteroids are the first line of treatment and SCT may be
curative. Androgens may also produce improvement but
sideeffects
on growth can be severe. Iron
chelation
is needed after
multiple transfusions
Slide15The acquired chronic
can occur without any obvious
associated disease or precipitating factor (idiopathic), or
may be
seen with autoimmune diseases (especially systemic lupus
erythematosus
), with a
thymoma
, lymphoma or chronic
lymphocytic
leukaemia
.
Slide16In some cases,
immunosuppression
with corticosteroids,
rituximab
,
ciclosporin
,
azathioprine
or ATG
is helpful
.
Monoclonal antibodies, such as
rituximab
(anti‐CD20), are being used increasingly in treatment of
refractory acquired red cell
aplasia
and other
autoimmune
cytopenias
.
If regular blood transfusions are needed, iron
chelation
therapy will also be necessary. SCT has been carried out
in some
severe cases
Slide17Transient form
Parvovirus
B19 infects red cell precursors via the P antigen and
causes a transient (5–10 days) red cell
aplasia
.
This
can
result in
rapid onset of severe
anaemia
in patients with
pre‐existing shortened
red cell survival, such as those with sickle cell disease
or hereditary
spherocytosis
(Fig.
22.7
Transient red cell
aplasia
with
anaemia
may also
occur
in association with drug
therapy
and in normal infants or children, often with a
history of a viral infection in the preceding 3 months
Slide18Slide19Congenital dyserythropoietic anaemia
are a group of hereditary refractory
anaemias
characterized by ineffective
erythropoiesis
and erythroblast
multinuclearity
.
The patient may
be jaundiced with bone marrow expansion.
The white cell
and platelet counts are normal.
The
reticulocyte
count
is low
for the degree of
anaemia
, despite increased marrow
cellularity
.
The
anaemia
is of variable severity and is usually first
noted
in infancy or
childhood
Iron overload may develop
and
splenomegaly
is common
Slide20In 1968Wendt and Heimpel
classified CDA into
three types (I, II and III) (Table 10.9).Over the
yearsmany
additional
subtypes (IV, V, VI and VII) have been added to the list,
often based on case reports.
Slide21Slide22CDA type I
The majority of patients present with
splenomegaly
and
mild to
moderate
anaemia
(∼66–116 g/L); approximately 70%
have
macrocytosis
.
In
some cases non-
haematological
features (
e.g. skeletal
abnormalities, abnormal skin pigmentation) have
been observed
. Ineffective
erythropoiesis
is evidenced
by morphological abnormalities
in the peripheral blood (
anisocytosis
) and in
the marrow (
megaloblastic
erythroid
precursors,
internuclear
chromatin bridging,
binuclearity
affecting 3–7% of
erythroblasts; as
well as by
increased markers
of
haemolysis
(elevated lactate
dehydrogenase
and
bilirubin
).
The defining
ultrastructural
feature is a spongy (‘Swiss cheese’) appearance of
the
heterochromatin in
themajority
of erythroblasts on
electron
microscopy .
Recognized
to be AR, the first gene responsible for CDA type
I (
CDAN1, called
codanin
) was identified in 2002. Recently a
second gene,
C15ORF41, was found to be responsible for some
cases of CDA type I
.
Slide23Slide24CDA type II
This
is the most common subtype of CDA and was initially
described as hereditary
erythroblastic
multinuclearity
with
a positive acidified serum
lysis
test (HEMPAS) in 1969. It
is inherited as an AR trait. The
anaemia
is variable (
Hb
80–110 g/L). Approximately 10% of cases require regular
transfusions and some cases present with
anaemia
at birth.
The clinical presentations include a variable degree of
jaundice,
hepatomegaly
,
splenomegaly
and cirrhosis. Mental
retardation has
been reported in some cases.
Peripheral blood morphology shows moderate to marked red
cell
anisocytosis
. BM features include
normoblastic
erythroid
hyperplasiawith
usuallymore
than 10%binucleate erythroblasts
Slide25At the electron microscope level, the
erythroid
cells have a characteristic peripheral arrangement of the endoplasmic
reticulumgiving
the appearance of a ‘
doublemembrane
’
Red cells from patients with CDA type II are
haemolysed
by some acidified sera, but not by the patient’s own
serum. In 2009 the gene encoding the
secretory
COPII
component SEC23B
was shown to be responsible for CDAII
Slide26Slide27CDA type III
This
subtype is rare. In one of the largest (Swedish) families
investigated, the disease was characterized by giant
multinucleated erythroblasts
in the marrow
.
There
appears
to be
an increased prevalence of
lymphoproliferative
disorders
in CDA
type III
.
CDA
III exhibits AD transmission and is caused
by mutations in
KIF23. KIF23 encodes mitotic
kinesin
-like
protein 1, which plays a critical role in
cytokinesis
during
cell division
.
Slide28Slide29Osteopetrosis
This
is a rare heterogeneous group of disorders due to
failure of
bone
resorption
by
osteoclasts
.
Inheritance
may be
recessive or
dominant. The bones are dense but brittle and fractures
are common
.
The
marrow space is reduced and a
leucoerythroblastic
anaemia
occurs. The liver and spleen are enlarged. Early
death from the consequences of bone marrow failure is usual.
SCT offers a chance of cure.