Myeloproliferative Disorders Flashcards
Myeloproliferative disorders
These are clonal neoplastic disorders of _____________ characterized by excessive proliferation of one or more of the ______ cell lineages ( granulocytic, erythroid ,megakaryocytic , and ____ cells)
pluripotent haematopoietic stem cell (HSC)
myeloid
masst
Myeloproliferative disorders characteristics are:
- Originates from ________
- Usually _______ predominates in a given disorder.
- Enlargements of _____ and ____ occur commonly.
- Usually in (children or adults?) with a peak in the ___ to ____ decade
a single stem cell
one cell line
spleen and liver
adults; 5th to 7th
INTRODUCTION to myeloproliferative disorders
Maturation of blood cells is relatively (normal or abnormal?) , so that (mature or immature ?) cells increase in number in the absence of ___________
Normal
mature
physiologic stimulus.
INTRODUCTION to myeloproliferative disorders
There is a close relationship between different disorders with ________, overlapping ___________, and progression to __________ and ___________.
interconversions
manifestations
myelofibrosis and acute leukaemia
INTRODUCTION to myeloproliferative disorders
Extramedullary hematopoiesis: blood cell production can also occur outside the bone marrow leading to ________________
enlargement of the liver and spleen.
CLASSIFICATION is Based on nature of predominant proliferating cell line:
____________ (erythroid)
___________(megakaryocytic)
________________(granulocytes)
__________________ (fibrous tissue)
Primary polycythemia
Essential thrombocythemia
Chronic myeloid leukemia
Primary myelofibrosis
CLASSIFICATION is Based on nature of predominant proliferating cell line:
_____________ leukaemia
_____________ leukaemia
Mastocytosis
_________________ (unclassifiable)
Chronic neutrophilic
Chronic eosinophilic
Myeloproliferative neoplasm
PATHOGENESIS of Myeloproloferative diseases
The presence of mutated, constitutively activated _______ protein: ______.
Which results in the ______- (dependent or independent?) proliferation and survival of marrow progenitors
Proliferation of HSCs leads to a _______ marrow.
Proliferating cells undergo ( normal or abnormal?) differentiation, which results in increased blood counts of one or more mature blood elements.
tyrosine kinases ; JAK2
growth factor
independent; hypercellular
normal
Tyrosine kinases activation normally occurs by the binding of __________ to ________ on the marrow progenitor cells.
hematopoietic growth factors
surface receptors
POLYCYTHAEMIA
Polycythemia (Erythrocytosis) is defined as an increase in the ____________, usually with a corresponding increase in _________ level.
total red cell mass (RCM)
haemoglobin
POLYCYTHAEMIA
The increase in RCM can be ______ or _______.
absolute or relative
POLYCYTHAEMIA
can be classified into:
________ polycythemia (red cell mass is __________)
__________ or __________ polycythemia (red cell mass is _______________).
Absolute
raised
Relative or pseudo
normal but the plasma volume is reduced
POLYCYTHAEMIA
Absolute polycythemia : which is subdivided into ____ and _______ polycythemia.
primary and secondary
POLYCYTHAEMIA
In men, Hb > ____ g/dL or HCT >____
In women, Hb >____ g/dL or HCT >___
18.5; 0.52
16.5; 0.48
Relative polycythemia
Characterized by ______ plasma volume with a _____ red cell mass.
reduced
normal
Relative polycythemia
May result from ________: following ———-,———- , excessive use of _______
dehydration
vomiting, diarrhea,
diurectics
Relative polycythemia
It can occur in ______ syndrome(______ spurious )
______ age
_____weight
Hypertensive
_____
Gaisbock
Middle
Over
anxiety
POLYCYTHAEMIA
Secondary
Caused by physiologically appropriate increase in __________ in :
(Low or high?) altitudes
Pulmonary disease and alveolar hypoventilation (______)
Cardiovascular disease , especially ___________
Increased _____ of haemoglobin
Familial (congenital) polycythemia
Heavy cigarette smoking
erythropoietin
High; sleep apnea
cyanotic heart disease
affinity
Causes of relative polycythemia
______________.
_________ syndrome
Haemoconcentration
Gaisbock
POLYCYTHEMIA VERA(PCV)
Clonal, acquire disorder of the pluripotent haematopoietic stem cells causing excessive proliferation of the __________________________________ lineage
erythroids, myeloids, and megakaryocyte
POLYCYTHEMIA VERA(PCV)
However, the major manifestation is seen in _______.
M
erythropoiesis
POLYCYTHEMIA VERA(PCV)
Many cases of PCV also has an increase number of granulocytes or platelets
T/F
T
POLYCYTHEMIA VERA
Two phases of PV can be recognized:
A _________ or _________ phase
A _____ or ___________ phase
proliferative or polycythemic
“spent”, or post-polycythemic
POLYCYTHEMIA VERA
A proliferative or polycythemic phase: a ________ phase characterized by ________ leading to ____________
A “spent”, or post-polycythemic phase: this is characterized by _______ and ______
initial; proliferation of erythoid cells
increased red cell mass
cytopaenia and myelofibrosis
_______ is the most common myeloproliferative disorder.
PCV
Epidemiology of PCV
The incidence is approximately ___ cases per _____ per year.
Median age at diagnosis is ____ years
3; 100000
60
PCV occurs at all ages
PCV is very common below 30 years
T
F(but it is very rare below 30 years)
Pathophysiology of PCV
An ____eased number of cases have been reported in survivors of the ___________
Cytogenetic abnormalities are found in only _____% of patients at diagnosis.
incr ; Hiroshima atomic bomb.
10-20
Pathophysiology of PCV
____________ mutation associated
Growth factor- independent proliferation and progenitor survival
JAK2 V617F
A genetic predisposition has been reported in some families of patients that have PCV
T/F
T
Pathophysiology of PCV
Increased _______in PV results in an increased _______ and increased blood ______ which can lead to vascular _______ and/or _______.
red cell production
red cell mass ; viscosity; thrombosis; bleeding
Pathophysiology of PCV
The ______ is directly proportional to the number of thrombotic events.
hematocrit
Pathophysiology of PCV
Studies have demonstrated a reduction in cerebral blood flow in patients with hematocrits above ____%.
___________ can also contribute to bleeding and thrombosis.
53
Thrombocytosis
Clinical features of PCV
Patients are frequently (symptomatic or asymptomatic?) at diagnosis and are discovered ______ when an elevated hematocrit is noted on a FBC.
Most patients will develop symptoms as the __________ and _______ ————
asymptomatic; incidentally
hematocrit and/or platelet count increase.
PCV Clinical features
Major symptoms can be listed as follows:
•Symptoms of _______ associated with an elevated hematocrit include headache, _______, _______, weakness, ______ and _______
hyperviscosity
blurred vision; dizziness
priapism and paresthesias.
PCV Clinical features
_________ typically following a (cold or hot?) shower may be the main complaint. The etiology is unclear but may be associated with cutaneous _________
Pruritus
Hot
mast cell degranulation.
PCV Clinical Features
Venous or arterial _______, involving ________ vessels is common.
Complications include _______, TIA, CVA, myocardial infarction, and ________
thrombosis
small and large
cyanosis
deep vein thrombosis.
PCV Clinical Features
________ sites of thromboses are seen more frequently in PCV: splenic, hepatic, portal, and mesenteric veins
Ten percent of patients with _________ syndrome (_______________) have coexisting PV.
Unusual
Budd-Chiari
hepatic/IVC thrombosis
PCV Clinical Features
Abnormalities in __________ can lead to epistaxis, bruising, gastrointestinal and gingival bleeding.
Hyper metabolism caused by __________ can lead to ________ and _______
platelet function
increased blood cell turnover
hyperuricemia and gout.
PCV Clinical Features
Gastrointestinal complaints are (common or rare?) including __________ and ________.
Physical findings include _____,________, and _________
Common
epigastric discomfort and peptic ulcer disease
splenomegaly, hepatomegaly and facial plethora.
Laboratory findings of PCV
Full blood count:
1. The haemoglobin , haematocrit and red cell count are increased (In men, Hb >_____ g/dL or HCT >0.52 and in women, Hb >_____ g/dL or HCT >0.48).
- A ______ leukocytosis, raised ______ and raised _______ count is present in about half of the patients.
18.5
16.5
neutrophil; platelets; basophil
Laboratory findings of PCV
JAK2 mutation analysis: JAK2 mutation is present in the _______ and peripheral blood _______ in 95% of patients.
____________________ (NAP) score is usually
increased.
bone marrow; granulocytes
Neutrophil alkaline phosphatase
Laboratory findings of PCV
Bone marrow examination: The bone marrow is _______ with prominent _______ , best assessed by a ______ biopsy.
Serum erythropoietin assay: Serum erythropoietin usually low in __________ but high in _______________
hypercellular; megakaryocytes; trephine
polycythemia vera
secondary polycythemia.
Laboratory findings of PCV
Arterial oxygen saturation
T/F
T
Criteria for diagnosis of polycythaemia (rubra) vera
Major: ________ or __________
Minor: _____,______, or ________
Elevated red cell mass
JAK2-V617F mutation
Hypercellular bone marrow
Low erythropoietin (EPO)
EEC growth in vitro
PCV treatment
Treatment focuses on decreasing the _________ to reduce ________ and its attendant complications.
hematocrit
plasma viscosity
PCV treatment
The goal of therapy is a hematocrit <___% and a platelet count <______.
45
400,000
PCV treatment
_________
___________ agents
A small daily dose of ______ is recommended for its anti-platelet effect.
___________ to prevent urate nephropathy
Phlebotomy
Myelosuppressive
aspirin
Allopurinol
Prognosis of PCV
Without therapy, median survival of patients with PV is only __________, but is more than ______ with treatment.
Major causes of death are _______ and _______
Up to 20% of patients develop __________ or __________ which are fatal.
6-18 months; 10 years
thrombosis and hemorrhage.
acute myelogeneous leukemia or myelodysplastic syndrome
Prognosis of PCV
PCV patients can develop a “spent phase” late in their courses that resembles chronic idiopathic _______ with _____ and marrow _____ and ____ – referred to as post polycythemic myelofibrosis or _________
Post polycythemic myelofibrosis frequently transforms to _________
myelofibrosis; cytopenia
hypoplasia and fibrosis; secondary myelofibrosis.
acute leukemia
ESSENTIAL THROMBOCYTHEMIA
Clonal myeloproliferative disorder that involves primarily the _____ cell line.
It leads to the dysregulated production of large numbers of _________ in the marrow resulting in marked rise in platelet counts.
________ mutation are found in approximately 50% of patients with ET.
megakaryocyte
mature megakaryocytes
JAK2
ET Epidemiology
The incidence of the disease is ______/100,000 individuals annually.
Usually occurs at the age of _______ years.
A second peak occurs at approximately ____ years of age, typically in (men or women?) .
2-3
50-60
30
Women
ET Clinical features
Many patients are (symptomatic or asymptomatic?) and discovered when a routine blood count is performed.
______ manifestation and a predisposition to _______ events are the main clinical findings
asymptomatic
Bleeding
thrombotic
ET Clinical features
_________ is classic of ET and is believed to be due to microvascular thrombosis of the digital vessel of fingers and toes.
Spontaneous ______ due to placental thrombosis.
Erythromelalgia
abortion
ET Clinical features
Bleeding occurs most commonly from mucosal surfaces especially the __________
There may be mild ________ and less often _______________.
gastrointestinal tract.
splenomegaly
hepatomegaly
ET clinical features
Transformation of ET to ________ or a _________ occurs in fewer than ___% of patients.
There can also be delayed disease transformation into a fibrotic state called ______________ or _________
acute myeloid leukemia; myelodysplastic syndrome
5
post thrombocythemia myeloid metaplasia or myelofibrosis
ET Lab features
Peripheral blood film shows marked ________.
The platelets often display _______ (range from tiny forms to Giant platelets)
thrombocytosis
anisocytosis
ET Lab features
The bone marrow biopsy is usually ______. The most striking abnormality is marked proliferation of ___________________, usually occurring in loose clusters
hypercellular
large and giant megakaryocytes
ET Lab features
The white blood cell count and differential are usually (normal or abnormal?) .
The red blood cells are ____cytic and _____chromic. _______________________.
Normal
normo
normo
Leukoerythroblastosis
Diagnostic Criteria for ET
- Persistent elevation of the _____ count ≥ _____ x 109/L.
- Megakaryocyte proliferation with _______ and ———- morphology: _______ or _______ granulocyte or erythroid proliferation.
Platelet; 450
large and mature
little or no
Diagnostic Criteria for ET
- Not meeting ______ criteria for CML, PV, PMF, MDS, or other myeloid neoplasm.
- Demonstration of ________ or other clonal marker or in the absence of a clonal marker, no evidence of reactive thrombocytosis.
WHO
JAK2-V617F
ET Treatment and Prognosis
ET is (an indolent or aggressive?) disorder, characterised by long symptom free intervals, interrupted by occasional life- threatening _________ or _______ episodes.
Most patients enjoy a normal life expectancy.
indolent
thromboembolic or hemorrhagic
ET Treatment and Prognosis
Risk stratification in ET is primarily based upon factors that influence the occurrence of _______ complications.
Patients are considered to be at high risk if they are >____ years of age and/or have a __________
thrombotic
60
prior history of thrombosis.
PRIMARY MYELOFIBROSIS (PMF)
Clonal disorder of pluripotent stem cell characterised by the proliferation of mainly _________ and _______ elements in the bone marrow associated with reactive _______________________
megakaryocytic and granulocytic
deposition of bone marrow connective tissue.
PRIMARY MYELOFIBROSIS (PMF)
As the bone marrow becomes ____ and normal hematopoiesis can no longer occur, ______________ (EMH) occurs in the _________ - which worsens throughout the disease course.
•
fibrotic
extramedullary hematopoiesis
liver and spleen
PRIMARY MYELOFIBROSIS (PMF)
The EMH seems to be (effective or ineffective?) and the patients become _________.
A leukoerythroblastic blood smear with ________ shaped red cells ( _______ ) is a characteristic finding in the fibrotic stage.
ineffective; pancytopenic
tear drop; dacrocytes
PRIMARY MYELOFIBROSIS (PMF)
Bone marrow fibrosis results from stimulation of _______ proliferation and ________ synthesis by _____________ and transforming growth factor
fibroblastic; collagen
platelet derived growth factor
PMF Epidemiology
Is a (common or rare?) disease
The incidence MF is ___ per 100,000 populations per year.
. Occurs predominantly in in persons over the age of ____ year.
Rare; 1.5
60
PMF Epidemiology
Exposure to ______ and ______ has been documented in some cases.
Up to 50% of patients have clonal ______ abnormalities at diagnosis.
benzene and ionizing radiation
karyotypic
PMF Clinical Features
About _____ of patients are asymptomatic at the time of diagnosis n.
The symptoms of this disease are often non-specific. The majority are due to the ________ and ______.
one third
anemia and splenomegaly
PMF Clinical Features
The anemia can lead to weakness, fatigue and dyspnea.
The enlarged spleen and liver can lead to abdominal discomfort and early _____.
Progressive ______ is common because of early satiety
_________ is present in at least 50% of the patients.
satiety
weight loss
Hepatomegaly
PMF Clinical Features
Other constitutional symptoms include fever, anorexia, night sweats and bone pain.
As the disease progresses, _______ occurs due to both ____________ and decreased ______________
pancytopenia
splenic sequestration
effective hematopoiesis.
PMF Clinical Features
Rarely, extramedullary hematopoiesis can occur at other sites such as the skin, lung, bladder, lymph nodes, genitourinary tract, gastrointestinal tract and the central nervous system.
T/F
T
PMF Clinical Features
Bleeding is typically due to _______ or related to ______ from portal vein thrombosis.
The proliferation of cells leads to chronic overproduction of _____ which can cause attacks of gouty arthritis.
thrombocytopenia; varices
uric acid
PMF Diagnosis
gold standard” for the diagnosis of PMF is ???
There is no “gold standard” for the diagnosis of PMF.
PMF Diagnosis
Full blood count; RBC
Haemoglobin usually ____(because of _________ and _______)
_____chromic ____cytic indices
low
ineffective erythropoiesis and hypersplenism
Normo; normo
PMF Diagnosis
Full blood count; WBC
____________ but it can be markedly _____.
Platelet; usuall ____________,but ____eases as diseases progress
normal or reduced
normal or elevated
decr
PMF Diagnosis
Blood film:
•________ shaped red cell
•____________
•Bone marrow aspirate: usually _____(____)
•Bone marrow biopsy: shows _____,increase in the number of __________. It is essential for the diagnosis
Tear drops
Leucoerythroblastosis
unsucessfull (dry tap)
fibrosis; abnormal megakaryocytes
Leucoerythroblastosis (________ red cells and ________ white blood cell)
nucleated
immature
PMF stages
_________ (_______) stage:
_______ stage:
Prefibrotic(cellular)
Fibrotic
PMF stages
Prefibrotic(cellular) stage:
_________ marrow due to _______ proliferation
Minimal or absent reticulin fibrosis Increased and abnormal ________
Hypercellular; granolocytes
megakaryocytes
PMF stages
Fibrotic stage:
Presence of _______ fibrosis
_____________ features
marrow
Leucoerythroblastic
PMF Treatment and Prognosis
____________ treatments to reverse the process of idiopathic myelofibrosis.
Treatment is mainly ________
Most care is directed toward ___________
There are no available
supportive
symptomatic management
PMF Treatment and Prognosis
The anemia usually requires _____________ but may also respond to __________, ( low or high?) dose steroid or erythropoietin.
Patients younger than ______ years old should be considered for allogeneic bone marrow transplantation.
red blood cell transfusions
androgens ; Low
55
PMF Treatment and Prognosis
The most common causes of death include infection, hemorrhage, thrombosis, cardiovascular disease, cerebrovascular disease and transformation to acute leukemia which occurs in 10-20% of patients in the first 10 years.
T
PMF Treatment and Prognosis
_______ splenomegaly can be treated with chemotherapy (Hydroxyurea), splenectomy, splenic radiation or alpha Interferon.
Painful
PMF Treatment and Prognosis
Average life expectancy is the worst among the CMPDs at ______years, but may approach _____ years in young patients with good prognostic factors.
5-7
15
