primary myelofibrosis
TRANSCRIPT
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PRIMARY MYELOFIBROSIS
BY
DR. EMMANUEL E. EKANEM
DEPARTMENT OF HAEMATOLOGYUUTH, UYO.
November 17,2014
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OUTLINE
Introduction
Epidemiology
Classification
Aetiology & Pathogenesis
Pathology
Clinical and Laboratory Features
Diagnosis and Prognostic Features
Advances in Management Conclusion
References
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Introduction
Primary Myelofibrosis is a clonal myeloiddisorder characterized by anaemia,splenomegaly, immature granulocytes,
marrow fibrosis and osteosclerosis. Tear drop Poikilocytes and
leukoerythroblastosis with increased CD34+cells in the peripheral blood film.
A rare haematologic malignancy classified asone of the Ph negative MPNs (PRV, ET)
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Epidemiology
Annual incidence is put at 0.41 to 1.46 per100,000 population
2.7% (2010, Benin)
None recorded in UUTH After the age of 50 years
Median age at diagnosis is approx. 65 to 70 years
Can occur from Neonatal period to the ninth
decade of life When it occurs in children, it is in the first 3 years
of life
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Contd
F:M of 2:1
In adults F:M is 1:1
Can cluster in families ()
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Contd
Classification
The IWG-MRT subdivided MF into 2 main
groups:
Primary: de novo disease accounting for 90%
of cases
Secondary: transformed from PRV, ET, orCML
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Aetiology
The exact aetiology of primary MF isunknown, however, it has been linked withseveral agents such as
Ionizing radiation Benzene
Toluene
thorium dioxide: high incidence associatedwith thorium-based radiographic contrastmaterials
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Contd
Atomic bomb exposure
Genetic abnormalities: current understanding
suggests that evolution of primary MF is
secondary to acquired genetic abnormalities
that target the haemopoietic stem cell in 40%-
60% of patients at the time of diagnosis.
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Contd
Genetic abnormalities include:
i. Interstitial deletions of ch. 13q and 20q
ii. Trisomy 8 iii. Abnormalities of ch. 1, 7, and 9
iv. Mutations involving the gene encoding
Janus Kinase-2 (JAK2 V617F) Involvement of chromosomes 5,6,7,9,13,20,21
is frequent
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Contd
(JK2), at position V617F found in 5065% of
patients with primary MF, 96% of PRV, and
55% of ET
iv. Myeloproliferative Leukaemia virus
oncogene/thrombopoietin receptor (MPL),
and
v. Loss of function mutation (LNK)
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Pathogenesis
Mutations in JAK2, LNK result:
a) Activation of JAK/STAT (signal transducer and
activator of transcription) pathway which
promotes transcription of
i. Proliferative and anti-apoptotic genes
ii. Inflammation which results in disturbed
cytokine production which causes the release
of growth factors
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Contd
that:
-stimulate fibroblasts proliferation,
-local fibrosis, and later -osteosclerosis, and eventually
-BM failure
b) Cytokines released can also stimulate theJAK/STAT
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Contd
b)Fibrosis: the secondary BM fibrosis results
from non-clonal fibroblastic proliferation and
hyperactivity induced by growth factors
abnormally shed from clonally expandedmegakaryocytes
c) Others: there is increased number of
stroma cells, the level of extracellular matrixproteins, increased
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Contd
resulting in the propagation of the cycle
including
Platelet-derived growth factor (PDGF)
Basic fibroblast growth factor (bFGF)
Transforming growth factor beta (TGF-)
Vascular endothelial growth factor (VEGF) Tumour necrosis factor alpha (TNF-)
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Contd
angiogenesis and osteosclerosis.
i. Fibroblast proliferation: PDGF and
Calmodulin
ii. Collagen synthesis: TGF-
iii. Angiogenesis: VEGF and bFGF
iv. Osteogenesis: TGF- and bFGF
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Clinicopathological features
BM fibrosis: this is the hallmark and
contribute to the impaired haematopoiesis
that leads to the severe anaemia
Marked splenomegaly
Extramedullary haemopoiesis
Severe constitutional symptoms
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Clinical features
Generally, clinical features of MF is classifiedeither as spleen-related or non-spleen related
a) Spleen-related: reported in 60% to 80% of
cases -abdominal discomfort due to massive
splenomegaly
-abdominal pain due to ischaemia or infarction(Spleen)
-early satiety
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Contd
-pain under the ribs
-portal hypertension and variceal bleeding
-ascites b) Non-spleen related: reported in about 60%
of cases
-fever, night sweat, weight loss, -pruritus
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Contd
-fatigue, bone and muscle pain
These constitutional symptoms are mediated
by the released cytokines
c) cytopenia: about 30% of patients may
present with anaemia at diagnosis and it
varies from mild to transfusion-dependent
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Contd
Miscellaneous:
-hepatomegaly, ascites, pleural effusion
-lymphadenopathy, nerve/cord compression -osteosclerosis
-thrombohaemorrhagic complications
secondary to leukocytosis and/orthrombocytosis
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Laboratory features
FBC+Peripheral Blood Film:
RED CELLS
Normocytic-Normochromic anaemia present in most cases
Anisocytosis & poikilocytosis are constant findings.
Tear drop-shaped red cells (dacrocytes) in every oilimmersion field.
nRBC in blood film of most patient. Average of 2% (Range 0-30%).
Mild reticulocytosis
Hb conc. In a series of patients is approx. 9.0 to 12.0g/dl
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Contd
Anaemia may be worsened by plasma volume
expansion and higher MCV in patients with
enlarged spleen.
In some Patients haemolysis may be present
Polychromatophilia and very elevated
reticulocyte count.
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PBF
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Contd
WBC
Mildly elevated TWBC count due to
granulocytosis
Mean TWBC count maybe 10 to 14x109/L
Small proportions of myelocytes &
promyelocytes in PBF
0.5% to 2% blast may be found in blood film
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Contd
At diagnosis blast can range b/w 0-20%
Hypersegmentation and Hyposegmentation maybe present.
Abnormal granulation of neutrophils MAP scores may be elevated in 25% of patients
or deceased in 25% of cases
Basophils is slightly increased
Neutropenia is present approx. 20% of cases attime of diagnosis
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Contd
PLATELETS
Mean platelet count at diagnosis is 175 x109/L to580 x 10/L. But may be up to 3125 x109/L.
Elevated in 40% of cases Mild to moderate thrombocytopaenia is present
in 1/3 of patients
Characteristically there is presence of giant
platelet and abnormal platelet granulation Presence of megakaryocytes in systemic venous
blood
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Contd
10% present with pancytopaenia because of
severe impairment of haemopoiesis affecting
all cell lines, coupled with sequestration in
massively enlarged spleen.
Pancytopaenia is usually associated with
intense marrow fibrosis
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Contt
An increase in blood CD34+ cells which is very
characteristic of primary MF.
The conc. Of CD34+ cells correlates with the
extent of disease and disease progression.
> 15 x 109/L CD34+ cells is Diagnostic
>300 x 109/L CD34+ cells have rapid
progression.
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Contd
Endothelial progenitor cells are significantly
higher in Primary MF than in normal subjects
(CD+CD133+ & VEGFR2 Positive cells)
Decreased CD3+,CD4+,CD8+&CD3-/CD56+ T-
cells due to mild lymphopoiesis is the rule.
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Bone Marrow Findings
In Fibrotic Phase; BMA may be difficult, and
often yielding no aspirate (dry tap) due to
fibrosis.
Trephine Biopsy:
- Fibrotic Hypercellular marrow
- Decreased, normal or increased erythoid cells
- There is granulocytic and megakaryocytic
hyperplasia
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Contd
Granulocytes may show hyperlobulation &
hypolobulation of nucleus
Nuclear blebs
Nuclear-cytoplasmic maturation asynchrony
Clusters of blasts & CD34+ cells are present
Increase micro vessel density in 75% patients
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Contd
Silver Stain: shows increased reticulin fibers.
H&E: Stain: Shows mild collagen fibrosis.
Occasionally fibrosis is extreme. Maybe more
evident using Gomori Trichrome stain that
stains collagen green.
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Marrow section
Silver impregnation stain:marked increase in
argentophilic fibers
representing collagen type III
(reticulin)
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Marrow section
Collagen fibrosis withextensive replacement of
marrow with swirls of
collagen fibers.
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Contd
In pre-fibrotic phase: The marrow has no or
slight reticular fibrosis
Hypercellular marrow
Erythropoiesis may be slightly increased
Increased late neutrophil precursor
(myelocyte, metamyelocytes & bands)
Myelocytes and CD34+ cells are inconspicuous
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Contd
The hallmark of this phase is increased and
abnormal megakaryocytopoiesis
Clusters of megakaryocytes
Large megakaryocytes admixed with small
megakaryocytes
Bare megakaryocyte nucleus
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Bone marrow Slide
Bone marrow slideat low power:
Shows
hypercellular
marrow with
increased number
of hypolobular
megakaryocytes.
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MRI
Hypodensity of T1-weighted & T2 weighted
images due to increase cellularity & fibrosis.
Patchy or diffuse osteosclerosis is a common as
are sandwiched vertebrae so called because ofthe marked radio density of superior and inferior
margins of the vertebral body.
MRI can also show the periosteal reactions thatusually occur in the distal femur, proximal tibia
and ankle.
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Contd
Sodium fluoride positron emmission
tomography can be virtually specific for
osteosclerosis of primary MF.
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chemistry
Increased Uric acid, LDH,bilirubin, alkalinephosphatase & HDL are frequently seen.
Reduced albumin, and cholesterol also
frequent Calcium levels or
thrombopoietin and IL-6
IL-2 receptor Vascular Endothelium Growth Factor
Urinary calmodulin is up to 3 times of normal
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Diagnosis
Differential diagnosis of MF should include BM
fibrosis associated with both neoplastic and
non-neoplastic conditions, including CML,
CMML, MDS, Lymphomas, AML,carcinomatosis
However, the presence of specific cytogenetic
abnormalities JAK2 or MPL mutations rule outreactive BM fibrosis, while
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c) The presence of trisomy 9 or 13q- deletion
suggests MF
d) WHO Criteria: for accurate diagnosis, there
are major and minor criteria that must be met
by patient
Major Criteria: all these must be present
1. Megakaryocyte proliferation and atypia:
responsible for reticulin or collagen fibrosis
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Contd
2. Does not meet the criteria for other
myeloid disorders (PRV, CML, MDS, ET)
3. Presence of clonal markers such as
JAK2V617F, MPL: there should be no evidence
of secondary BM fibrosis
Minor criteria: at least 2 of these are
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Minor criteria: at least 2 of these are
required
1. Increased serum LDH levels
2. Palpable splenomegaly
3. Leukoerythroblastosis
4. Anaemia
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Prognosis
MF is a progressive disease, with its prognosis
depending on several factors.
The IPSS estimates survival from the time of
diagnosis, using the following risk factors:
Age 65 yrs or older
Anaemia, with Hb level
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CONTD
Presence of constitutional symptoms
5. Leukocytosis, with WBC of > 25,000/cmm
6. Circulating blasts of at least 1%
The IWG-MRT proposed a scoring system
based on number of these factors present and
categorized patients into 4
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Contd
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Prognosis contd
IPSS has now been updated to dynamic IPSS
(DIPSS) using the same prognostic factors and
can be used to estimate survival at any point
during the course of the disease
The DIPSS has been upgraded to DIPSS-plus by
incorporating 3 additional factors including:
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Contd
Blood transfusion dependency
Thrombocytopenia of < 100,000/cmm, and
Presence of unfavourable karyotype (Trisomy
8, monosomy 7 or 7q-, inv 3, 11q23, 12p-
Based on this additional factor, patients canbe group into 4 prognostic categories:
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Contd
Other factors that may contribute to survival
include:
Monocytosis of > 1 x 109/L
JAK2 mutation
Male sex
Hepatomegaly
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Treatment
Allogeneic Stem Cell Transplantation
Signal Transduction Inhibitors
JAK inhibitors
Symptomatic/Supportive treatment
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Treatment
1. Allogeneic Stem Cell Transplantation
Any treatment that excludes ASCT is not
curative This will, however, be used in selected high-
risk eligible patients
This is currently the only potential cure forpatients with DIPSS-plus intermediate 2 andhigh-risk disease if
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Contd
is younger than 40 to 50 years
Patients with DIPSS-plus low or intermediate-1
risk disease may not be considered for ASCT
because the risk of conditioning regimen may
outweigh the benefit that is derivable.
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2. Signal Transduction Inhibitors
i. Imatinib mesylate
Its use is based on its inhibition of PDGF-
mediated signalling
It also ameliorate BM fibrosis and microvessel
density
It is effective in restoring megakaryocyticdifferentiation
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Contd
and thus, effective in the treatment of
thrombocytopenia
ii. Farnesyl transferase inhibitor
Can cause significant reduction in
splenomegaly
Has negligible effect on anaemia
Myelosuppression is the main side effect
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Contd
3. JAK Inhibitor
The discovery of the role of JAK/STAT pathway
in the pathogenesis of MF has made targeting
JAK2 a therapeutic goal
Ruxolitinib is the only JAK inhibitor approved
US FDA for use
It is an oral formulation
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Contd
JAK1 and JAK2 inhibitor for intermediate and
high-risk MF
It has been found to cause significant
reduction in splenic size in 35% of patients
The most common side effects are
thrombocytopenia and anaemia
Dose to be given is limited by platelet count:
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Contd
Platelet of
>200,000/cmm give up to 20mg bid
100,000200,000/cmm give 15mg bid
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Contd
4. Symptomatic/Supportive
a) Splenectomy
Has no clear effect on patients survival,
disease course or intramedullary
manifestation of the disease
However, significant decrease in symptoms
was observed in 30% to 50% of patients
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Contd
Complications rates are high, hence, candidate
for splenectomy should be carefully chosen
Indication for splenectomy include:
1. Substantial and refractory symptomatic
splenomegaly
2. Refractory cytopenia, particularly, anaemia
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Contd
3.Evidence of portal hypertension
4.Hypermetabolic symptoms
i. Conditions: patients should be surgically
stable
ii. Must have failed at least one medical
therapy (including JAK inhibitor)
iii. Good performance status
iv. Have life expectancy of more than 1 year
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Contd
b) Radiotherapy
Patients with extramedullary haemopoiesis
are sensitive to radiation
It is palliative in patients not eligible for
splenectomy, or
Have short expected survival
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Contd
c) Immunomodulating agents
Thalidomide, Lenalidomide, andPomalidomide used alone or in combination
with Corticosteroids are good at amelioratingcytopenias
i. Thalidomide:
significant response in anaemia (62%),thrombocytopenia (75%), and splenomegaly(19%) have
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Contd
been reported with low-dose combined with
prednisolone
Neuropathy, DVT, constipation are the main
side-effects
ii. Lenalidomide:
response rate of 22% for anaemia, 33% for
splenomegaly, and 50% for thrombocytopenia.
Prednisolone did not improve the outcome
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Contd
Reduce fibrosis in patients with concurrent 5q-
deletion
Milder myelosuppression
iii. Pomalidomide:
Improve anaemia in 20% to 30% of patients in
low dose
No substantial BM suppression or neuropathy
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Contd
d) Cytoreductive agents
i.Hydroxyurea: useful in the control of
splenomegaly (50%), leukocytosis, and
thrombocytosis
ii.Melphalan: reduces spleen size in 66% of
cases. However, acute leukaemia is the main
side effect
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Contd
iii. Interferon-:
Has cytoreductive effect similar toHydroxyurea
It inhibits Megakaryocyte and Fibroblastproliferation, and controls Collagenproduction
It also inhibits fibrogenic cytokines such asTGF-1 and PDGF in patients withhyperproliferative features
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Contd
However, not well tolerated due to toxicity,particularly cytopenia
iv. Cladribine gives 50% response in splenomegaly,
thrombocytosis, leukocytosis, and anaemia,
respectively Myelosuppression and GIT upset are its limiting
toxicity
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Contd
v. Azacytidine
Gives 21% response rate for splenomegaly
Requires frequent visits for administration
Myelosuppression is the main side effect
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Contd
Management of anaemia
Common; and tend to progress over the
course of the disease
Aetiology is multifactorial including
hypersplenism, BM fibrosis, ineffective
haemopoiesis, and haemolysis
Androgens, Corticosteroids, and Erythropoietin
are used
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Contd
in treatment
Androgens
Preparations containing different compounds
such as Fluoxymesterone, Nandrolone,
Oxymethalone, Testosterone, Enanthate, and
Danazol have shown improvement in 30% to
40% of cases
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Contd
Danazol is particularly useful in correcting
thrombocytopenia
2. Erythropoietin
In the absence of splenomegaly,
erythropoietin stimulating agents (ESAs =
Epoetin alpha, Darbepoetin alpha) are useful
in patients with Hb < 10mg/dL
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Contd
Transfusion-dependent patients or those with
Epo levels higher than 125U/L are unlikely to
benefit from ESAs
Thrombocytosis and Thrombosis
1. Anagrelide hydrochloride
An oral preparation approved by the US FDA
as a first-line
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Contd
agent for the control of thrombocytosis
associated with MF
Chronic exposure to Anagrelide results in a left
shift in megakaryocyte maturation andinhibition of endoduplication
This causes a decrease in ploidy and cell size,
and an increase in the number ofpromegakaryoblasts
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Contd
Its effects on megakaryocyte is important as itprevent the secretion of cytokines that
promote fibrosis and osteosclerosis However, the drug has no impact on BM
fibrosis or on the production of profibroticcytokines, TGF- and PDGF
2. Aspirin and HU are also useful in preventingthrombosis
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Differential Diagnosis
CML
MDS
Primary Thrombocythaemia
Hairy Cell Leukaemia Hepatic Disease
Primary Immune Myelofibrosis
Sporadic Idiopathic or Familial PulmonaryHypertension
Metastatic carcinoma of breast or prostate
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Contd
Or disseminated mycobacterial infection Others include:
Mastocytosis
Angioimmunoblastic Lymphadenopathy
Angiosarcoma
Lymphoma Multiple Myeloma
Renal osteodystrophy
Hyperthrophic osteoarthropathy
Gray Platelet Syndrome
SLE
Polyarteritis nodosa
Hypereosinophilic syndrome
d
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Contd
Kala azar PrimarThrombocytopaenic Purpura
TTP
Neuroblastoma
Giant Lymph node hyperplasia
Vit. D def. rickets
Acute Promyelocytic Leukaemia
Langerhans cells histiocytosis Malignant histiocytosis
/ l
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Summary/Conclusion
Primary Myelofibrosis is one of the several
disorders in the spectrum of clonal myeloid
diseases, malignant diseases that originate in
the clonal expansion of a single neoplastichaematopoietic mutipotential cell. About 50%
of cases have a mutation in the Janus Kinase 2
gene. Characterized mainly by anaemia,thrombocytosis, and splenomegaly with an
overall median survival of 5 years.
f
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References
Lichtman MA; Beutler E; Kipps T; Seligschn V;Kaushnsky K; Prchal J; Chapner B; Wilson Wand Supko J Williams Haematology, 8thedition. The Mcgraw-Hill Companies.
Shirish M. Kawthalkar. Essential ofHaematology. Jaypee Books.
A.V. Hoffbrand et al. Blackwell publishing:
Essential Haematology, 6thed.
www.accessmedicine.com
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