Myeloproliferative Disorders(MPD) - PowerPoint Presentation

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Myeloproliferative Disorders(MPD)

Assist. Professor :

Dr.Maysem

Mouayad

Alwash

LEC.2

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Objectives:1-Define myeloproliferative disorders(MPD) and Classify MPD2-Enumerate causes of polycythemia.3-Define Essential

thrombocythaemia

(ET)

.4- Enumerate causes of thrombocytosis.5- Enumerate clinical features and laboratory findings in ET.6- Define myelofibrosis(MF).7-Enumerate clinical features and laboratory findings in MF.

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Myeloproliferative neoplasms

(MPN)

Myeloproliferative

neoplasms are a group of conditions arising from marrow stem cells and characterized by clonal proliferation of one or more haemopoietic components in the bone marrow.

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The three major subtypes are:1.Polycythaemia vera (PV);

2.Essential

thrombocythaemia

(ET); 3.Primary myelofibrosis

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These subtypes are closely related to each other and mutation of the JAK2 gene is detected in nearly all patients with PV and approximately half of those with ET and primary myelofibrosis

.

Mutations in CALR or MPL are present in most cases without a JAK2 mutation.

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Relationship between the three myeloproliferative diseases

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Polycythaemia Polycythaemia is defined as an increase in the haemoglobin

concentration above the upper limit of normal for the patient’s age and sex.

 

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Classification of polycythaemiaThe major subdivision is into :

1.Absolute

polycythaemia

or erythrocytosis, in which the red cell mass (volume) is raised to greater than 125% of that expected for body mass and gender.

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2. Relative or pseudopolycythaemia, or apparent

polycythaemia

, in which the red cell volume is normal but the plasma volume is reduced. .

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It occurs particularly in young or middle‐aged men and may be associated with cardiovascular problems such as hypertension or cerebral transient ischaemic attacks. Diuretic therapy, heavy smoking, obesity and alcohol consumption are frequent associations.

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.Causes of absolute polycythaemia (erythrocytosis)

primary

polycythaemia

(in which there is an intrinsic overactivity in the bone marrow)It is either :-

Congenital

:

Erythropoietin receptor mutations

or

Acquired

:

Polycythaemia

vera

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B.secondary polycythaemia

in

which the bone marrow is driven by increase in erythropoietin

:as in -Chronic lung disease-Smoking-High altitude-Renal

disaese

e.g.Renal

cysts (polycystic kidney disease)

-

Pathological erythropoietin production

e.g.

cerebellar

tumours

, ,

hepatocellular

carcinoma, renal cell cancer

-

Drug‐associated

e.g. Erythropoietin administration ,Androgen administration

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Polycythaemia vera (PV)

In

PV the increase in red cell volume is caused by a clonal malignancy of a marrow stem cell. The disease results from

somatic mutation of a single haemopoietic stem cell which gives its progeny a proliferative advantage. The JAK2

mutation is present in

haemopoietic

cells in about 97% of patients

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Clinical featuresPV is usually a disease of older people and has an equal sex incidence. Clinical features result from

hyperviscosity

,

hypervolaemia, hypermetabolism or thrombosis

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1 Headaches, dyspnoea, blurred vision and night sweats. Pruritus, characteristically after a hot bath, can be a severe problem.

2

.

Plethoric appearance: ruddy cyanosis ,conjunctival suffusion and retinal venous engorgement.

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3 Splenomegaly .4

Haemorrhage

or thrombosis, either arterial or venous.

5 Gout (as a result of raised uric acid production)

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Laboratory findings1

.The

haemoglobin

, haematocrit and red cell count are increased.

The total red cell volume is increased.

2 .

A neutrophil

leucocytosis

, some have increased

basophils

.

3

.

A

raised platelet count is present in about half of

]

patients

.

4 .

The

JAK2

mutation is present in

haemopoeitic

cells ..

5

.

The

bone marrow is

hypercellular

with

trilineage

growth.

 

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Course :-Thrombosis and

haemorrhage

are the major clinical problems

. Increased viscosity, vascular stasis and high platelet levels and altered platelet function may all contribute to thrombosis, whereas defective platelet function may promote

haemorrhage

.

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-Transition from PV to myelofibrosis can occur in some of patients -Few progress to acute myeloid leukaemia

(AML).

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Can you answer ????1- Apparent polycythaemia is seen in---------2-The major clinical problem in PV are------3-97 % of PV cases have a mutation in -------------gene4-Causes of secondary polycythemia

are-------------------

5-

Clinical features in PV result from----------------------6- In PV causes of thrombosis may be due to--------------7- In PV causes of bleeding may be due to--------------8-Mutation in the following genes are found in cases of Myeloproliferative diseases -------------------------

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Essential thrombocythaemia (ET):

In

this condition there is a sustained increase in the platelet count due to megakaryocyte proliferation and overproduction of platelets.

 

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Persisting platelet count of greater than 450 × 109

/L is the central diagnostic feature, but other causes of a raised platelet count need to be fully excluded before the diagnosis can be made

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-50% to 60% of patients show the JAK2 (V617F) mutation. Mutations in the CALR

gene, mutation in

MPL

gene can be seen in ET patients

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Causes of a raised platelet count (thrombocytosis):1.Reactive

-

Haemorrhage

. - Trauma. - Postoperative -Chronic iron deficiency

-Malignancy

-Chronic infections

-Connective tissue diseases

-

Post‐

splenectomy

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2.Endogenous--Essential thrombocythaemia.

--Some cases of

polycythaemia

vera, primary myelofibrosis.

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Clinical and laboratory findings-Most cases are asymptomatic and diagnosed on a routine blood count.

-

The dominant clinical features are thrombosis and

haemorrhage.-A characteristic symptom is erythromelalgia, a burning sensation felt in the hands or feet and promptly relieved by aspirin.

Some patients will have palpable

splenomegaly,whereas

in others there may be

splenic

atrophy because of infarction

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----Abnormal large platelets and

megakaryocyte

fragments may be seen on the blood film.-The bone marrow is hypercellular with an excess of abnormal megakaryocytes

.

-

Platelet function

tests are rarely needed, but are

consistently abnormal.

-

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Bone marrow biopsy in ET MEGAKARYOCYTE HYPERPLASIA

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Course The disease may transform after a number of years to myelofibrosis or less frequently to AML .

 

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Primary myelofibrosisThe predominant feature of primary myelofibrosis

is a progressive generalized reactive fibrosis of the bone marrow in association with the development of

haemopoiesis

in the spleen and liver (known as myeloid metaplasia).

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Clinically this leads to anaemia and massive splenomegaly . In some patients there is osteosclerosis.

The fibrosis of the bone marrow is secondary to hyperplasia of abnormal megakaryocytes.

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Fibroblasts are stimulated by platelet‐derived growth factor and other cytokines secreted by megakaryocytes and platelets.The JAK2, CALR and MPL

genes are mutated in most cases.

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Clinical features1.

An insidious onset in older people is

usual with symptoms of

anaemia.2 .Symptoms resulting from massive splenomegaly are frequent and include abdominal discomfort, pain or indigestion.

Splenomegaly is the main physical finding

 

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3 .Hypermetabolic symptoms such as loss of weight, anorexia, fever and night sweats are common. 

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Laboratory findings1

.

Anaemia

is usual.2 .The white cell and platelet counts are frequently high

at the time of presentation. Later in the disease leucopenia and thrombocytopenia are common.

3 .

A

leucoerythroblastic

blood film

is found. The red cells show characteristic ‘

tear‐drop’

poikilocytes

.

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Leukoerythroblastic blood picture and tear drop RBCs in myelofibrosis.

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Primary myelofibrosis

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4 .Bone marrow is usually unobtainable by aspiration. Trephine biopsy shows a fibrotic, hypercellular marrow. Increased

megakaryocytes are frequently seen

.

In some cases there is increased bone formation with increased bone density on X‐ray.

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5 .JAK2 is mutated in approximately half of cases and CALR mutations can occur .

6.

Transformation to AML occurs in some of patients.

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Marrow section. Low power. Hypercellular marrow withincreased number of hypolobular megakaryocytes.

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Marrow section. Collagen fibrosis with extensive replacement of marrow with swirls of collagen fibers

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Case A 67 year-old man presents with abdominal pain and enlargement .He is found to be pale with enlargement of the spleen . FBC shows WBC s 3.8 x 10 9 /l, Hb

9

g /dl ,platelets 82 X 10 9 Blood film shows leukoerythroblastic with many tear drop RBCs are seen.Q1/What is the diagnosis?Q2/Explain the findings seen on bone marrow aspirate and biopsy?

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