Assist Professor DrMaysem Mouayad Alwash LEC2 Objectives 1Define myeloproliferative disorders MPD and Classify MPD 2Enumerate causes of polycythemia 3Define Essential ID: 916438
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Slide1
Myeloproliferative Disorders(MPD)
Assist. Professor :
Dr.Maysem
Mouayad
Alwash
LEC.2
Slide2Objectives: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.
Slide3Myeloproliferative 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.
Slide4The three major subtypes are:1.Polycythaemia vera (PV);
2.Essential
thrombocythaemia
(ET); 3.Primary myelofibrosis
Slide5These 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.
Slide6Relationship between the three myeloproliferative diseases
Slide7Polycythaemia Polycythaemia is defined as an increase in the haemoglobin
concentration above the upper limit of normal for the patient’s age and sex.
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.
Slide92. Relative or pseudopolycythaemia, or apparent
polycythaemia
, in which the red cell volume is normal but the plasma volume is reduced. .
Slide10It 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.
Slide11.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
Slide12B.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
Slide13Polycythaemia 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
Slide14Clinical featuresPV is usually a disease of older people and has an equal sex incidence. Clinical features result from
hyperviscosity
,
hypervolaemia, hypermetabolism or thrombosis
Slide151 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.
Slide16Slide173 Splenomegaly .4
Haemorrhage
or thrombosis, either arterial or venous.
5 Gout (as a result of raised uric acid production)
Slide18Slide19Laboratory 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.
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
.
Slide21-Transition from PV to myelofibrosis can occur in some of patients -Few progress to acute myeloid leukaemia
(AML).
Slide22Can 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 -------------------------
Slide23Essential thrombocythaemia (ET):
In
this condition there is a sustained increase in the platelet count due to megakaryocyte proliferation and overproduction of platelets.
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
Slide25-50% to 60% of patients show the JAK2 (V617F) mutation. Mutations in the CALR
gene, mutation in
MPL
gene can be seen in ET patients
Slide26Causes of a raised platelet count (thrombocytosis):1.Reactive
-
Haemorrhage
. - Trauma. - Postoperative -Chronic iron deficiency
-Malignancy
-Chronic infections
-Connective tissue diseases
-
Post‐
splenectomy
Slide272.Endogenous--Essential thrombocythaemia.
--Some cases of
polycythaemia
vera, primary myelofibrosis.
Slide28Clinical 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
Slide29Slide30----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.
-
Slide31Slide32Bone marrow biopsy in ET MEGAKARYOCYTE HYPERPLASIA
Slide33Course The disease may transform after a number of years to myelofibrosis or less frequently to AML .
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).
Slide35Clinically 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.
Slide36Fibroblasts 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.
Slide37Clinical 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
3 .Hypermetabolic symptoms such as loss of weight, anorexia, fever and night sweats are common.
Slide40Laboratory 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
.
Slide41Leukoerythroblastic blood picture and tear drop RBCs in myelofibrosis.
Slide42Primary myelofibrosis
Slide434 .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.
Slide445 .JAK2 is mutated in approximately half of cases and CALR mutations can occur .
6.
Transformation to AML occurs in some of patients.
Slide45Marrow section. Low power. Hypercellular marrow withincreased number of hypolobular megakaryocytes.
Slide46Marrow section. Collagen fibrosis with extensive replacement of marrow with swirls of collagen fibers
Slide47Case 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?
Slide48