Myleoproliferative Neoplasms

what are myeloproliferative neoplasms characterized by

excessive proliferation of hematopoietic precursors in the bone marrow an of mature cells

where do heterogenous diseases originate from

clonal expansion of the hematopoietic pluripotent stem cell

the 4 clinical entities of MPNs

chronic myelogenous leukemia (CML)

polycythemia vera (PV)

essential thrombocythemia (ET)

primary myelofibrosis (PMF)

what do the MPNs share and differ in

share molecular and cellular characteristics

differ in phenotype and clinical presentation

the most prominent feature of CML is what

Philadelphia chromosome-positive [Ph(+)] with a 9;22 translocation and BCR-ABL1 fusion gene present.

PV, ET, and PMF MPN characterization

[Ph(-)]

characterized by increased clonal proliferation of myeloid cells due to JAK2 mutations

what is there an overproduction of in CML

granulocytes

what is there an overproduction of in PV

erythrocytes

what is there an overproduction of in ET

platelets

PMF is characterized by a prominence of what

marrow fibrosis and extramedually hematopoiesis in the liver and spleen

hallmark finding of MPNs

splenomegaly

40-99% of patients

if anemia is present, what is it?

myelophthisic anemia

bone marrow of MPNs

hypercellular with degrees of fibrosis

the three lesser known classifications of CMPNs

‒ Chronic neutrophilic leukemia (CNL)

‒ Chronic eosinophilic leukemia (CEL)

‒ Unclassifiable myeloproliferative diseases

WHO classification of myelodysplastic/myeloproliferative diseases

‒ Juvenile myelomonocytic leukemia

‒ Atypical chronic myeloid leukemia (lacking the 9;22 translocation; [Ph(+)])

‒ Chronic myelomonocytic leukemia

how do you identify MPNs

molecular genetic alteration

PV, ET, and PMF involve what mutations

JAK2/CALR/MPL

CML has what mutation

BCR-ABL1

what can MPNs transform into

AML or ALL

definition of PV

chronic abnormality of the hematopoietic stem cell characterized by uncontrolled proliferation of erythroid, granulocytic, and

megakaryocytic cells, with normal erythropoietin

level

what should PV be differentiated from

secondary polycythemia and relative erythrocytosis

what is increased in secondary PV

only erythrocytes

what is increased in relative erythrocytosis

the increase in hematocrit is secondary to a disease in plasma volume

what does true polycythemia mean

increase in the total RBC mass in the body

hematocrit and hemoglobin of true polycythemia

high and high

what causes an increase in secondary polycythemia

increased EPO

hypoxia

tumors

high altitude

COPD

what is apparent polycythemia

the hematocrit is only high because plasma volume is low

the rbc count of apparent polycythemia

rbc count normal

causes of apparent polycythemia

dehydration

vomiting or diarrhea

burns

stress polycythemia

incidence of MPNs

less than 6 per 100,000

median age of PV

65

PV is most common in what group of people

Jewish individuals of eastern europe descent

what does JAK activate

JAK-STAT pathway

what does JAK-STAT do

intracellular signaling in transduction of extracellular signals to the nucleus to control gene expression

well-regulated JAK signaling is essential for what

cell production

cell proliferation

immune function

MPNs are likely the result of what

combined genetic dysregulation

what can PV patients present with

thrombosis

bleeding secondary to erythroid expansion

hyper viscosity

elevated platelets

symptoms of PV

headache

epistaxis

ischemic or hemorrhagic stroke

angina

MI

claudication

most common complication of PV and occurs in how many patients

thrombosis

1/3

most common physical finding of PV and in how many patients

splenomegaly

50-80%

hypertension occurs in how many patients

50%

the most significant peripheral blood finding in PV

absolute erythrocytosis

hemoglobin concentrations of PV

>18.5 g/dL in males

>16.5 g/dL in females

rbcs for PV

6-10 × 10^12/L

Hematocrit of PV

>52% in men

>48% in women

what should also be taken into account when looking at lab results for PV and why

MCV

occasionally present with iron deficiency secondary do occult GI blood loss

what can cause iron deficiency in PV

repeated therapeutic phlebotomy

a peripheral blood picture with PV can be very similar to what diseases (W/ iron deficiency)

thalassemia with significant microcytosis

lab characteristics of PV patients with iron-deficient erythropoiesis secondary to GI blood loss

normal hematocrit with profound microcytosis

with PV, where is there a increase in RBC production

Intramedullary sites

RBCs of PV

normochromic

normocytic

regular RBC life span

As PV progresses, extramedullary ineffective hematopoiesis leads to what

increasing ansiocytosis and poikilocytosis

shortened RBC life span secondary to splenic sequestration

relative and absolute granulocytosis occurs in approx. how many patients with PV

2/3

WBC count of PV

elevated

12-25 10^9/L

what can occasionally be seen on peripheral smears of PV

basophilia

eosinophilia

few metamyleocytes and myelocytes + other immature cells

in PV, is there a shift to the left or to the right

shift to the left

LAP score of PV

>100

thrombocytosis appears in how many patients with PV

50%

platelet count of PV

moderately elevated

450-800

PV; PT, aPTT, TT, and fibrinogen

all normal

ESR of PV

low to normal

can giant platelets be found in PV

yes

what does the BM of PV show

panmyelopathy- with erythroid, myeloid, and megakaryocytic hyperplasia

megakaryocytes in PV

increased in number, atypical, deeply lobulated nuclei

bone marrow stores with PV

reduced or absent

what mutation has high frequency with PV

JAK2

what is recommended as the first step in the initial evaluation of a patient suspected with PV

blood screening for JAK2

what % of patients with PV have the JAK2 mutation

95%

what must PV be differentiated from

benign causes of secondary erythrocytosis and relative polycythemia so that the effective therapy can be initiated

arterial oxygen saturation of a PV patient

>92%

patients with an arterial oxygen saturation of <92% should be suspected for what

having secondary polycythemia related to hypoxia

Unlike secondary polycythemia, what is PV associated with

a panmyelopathy associated with thrombocytosis and leukocytosis

what does PV treatment provide

relief of symptoms, minimize long-term complication, thrombosis and hemorrhage, and to avoid increasing the risk of leukemic transformation

the most common treatment of PV

therapeutic phlebotomy

how often can therapeutic therapy be performed

weekly or twice weekly

what is a target hematocrit of PV

45%

what can reduce the thrombosis rate, normalize platelet count and spleen size, and ameliorate hypercatabolic symptoms of PV

Hydroxyurea

what type of therapy is reserved for high risk patients of PV

Cytoreductive

What is Essential Thrombocythemia characterized by

marked thrombocytosis with bone marrow megakaryocytic hyperplasia and a tendency to develop thrombotic and hemorrhagic complication

platelet count of Essential Thrombocythemia Major

>450

what does BM biopsy show with Essential Thrombocythemia

proliferation of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei

is there a significant shift to the left in neutrophil granulopoiesis

no

is there erythropoiesis present in essential thrombocythemia major

no

incidence of ET

0.38-1.7 per 100,000 persons per year

what is the most frequent of the MPNs

Essential thrombocythemia

median age of ET, and who is it the most common in

68

more common in women

what pathway plays a role with ET (mutation)

JAK

JAK2 mutation occurs in what % of ET patients

55%

thrombopoietin receptor gene MPL mutations occurs in what % of ET patients

4%

how many ET patients are asymptomatic at diagnosis

2/3

what are symptoms of ET

hemorrhagic symptoms

vaso-occlusive symptoms

the most common clinical complications in ET

thrombosis (11-25%)

hemorrhage (3.6-37%)

what is thrombosis caused by (ET)

intravascular clumping of platelets

ET symptoms: compromised cerebral blood flow

headache, dizziness, weakness or numbness on one side of the body, and slurred speach

what MPN is associated with recurrent abortions, fetal growth retardation, pruritus, gout, and priapism

ET

peripheral blood smear of ET

marked thrombocytosis

platelet ansiocytosis

platelet aggregates

abnormally granulated platelets

megakaryocytic cytoplasmic fragments

why are peripheral smear reviews for platelet aggregates important

to avoid errors in platelet counting

can anemia be present in ET?

yes- mild normocytic normochromic anemia

what % of patients can present with mild normochromic normocytic anemia with ET, also what is the hemoglobin volume

50%

hemoglobin not usually <10 g/dL