Paroxysmal nocturnal haemoglobinuria - PowerPoint Presentation

Slide1

Paroxysmal nocturnal haemoglobinuria(PNH)

Slide2

PNH

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

Slide3

It 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

Slide4

Slide5

CD55 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

.

Slide6

Haemosiderinuria

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.

Slide7

The 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

Slide8

PNH 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

Slide9

PNH 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.

Slide10

Eculizumab

, 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.

Slide11

Red cell aplasia

Slide12

Chronic 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

Slide13

inherited 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

Slide14

Corticosteroids 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

Slide15

The 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

.

Slide16

In 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

Slide17

Transient 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

Slide18

Slide19

Congenital 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

Slide20

In 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.

Slide21

Slide22

CDA 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

.

Slide23

Slide24

CDA 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

Slide25

At 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

Slide26

Slide27

CDA 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

.

Slide28

Slide29

Osteopetrosis

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.