Polycythemia Veraand other

Myeloproliferative Neoplasms

A.Mousavi

Chronic MPNs

Multipotent hematopoietic progenitor cell is origin.

Overproduction of one or more formed element of blood cells without significant dysplasia

Predilection to

extramedullary hematopoiesis

mylofibrosis

transformation at rarying rates to acute leukemia

PV,PMF and ET

Classified in chronic MPNs

Substantial overlap in clinical and

genetic features

Distinct different clinical courses

PV

Clonal disorder of multipotent hematopoiticprogenitor cell

Accumulation of phenotypicolly normal red cells, granulocytes and PLTs without physiologic stimulus

Most common cMPNs

Incidence rate 2.5/100000

10/100000 in older population

Female>male

Etiology

Unknown etiology

Deletion of 20q,trisomy 8 & 9 in up to 30%

JAK2 V617F mutation have central role in the pathogenesis of PV.

JAK2 serves as tyrosine kinase function for receptors of EPO and TPO.

JAK2 functions as an obligate chaperone for EPO and TPO receptors in the Golgi apparatus and responsible for their cell-surface expression.

Cont…

JAK2 on short arm of 9th chromosome

More than 95% is mutated in PV and 50% in ET and PMF

Mutation may be homozygote in 30% of PV , 60% of PMF and rare patients with ET.

Most PV patients without JAK2V617F mutation, express a mutation in exon 12 of the kinase.

Clinicaly , no difference between hetro and homozygotes and patients with mutation in exon 12

Clinical features

Incidental finding of high Hgb or Hct in CBC

Aquagenic pruritus , distinguishing symptom of PV from other causes of erythrocytosis

Hyperviscosity vertigo , tinnitus , headache , visual distrubances and TIA

Cont …

Systolic HTN

Venous or arterial thrombosis

cerebral , cardiac , mesentric

Budd_Chiari syndrome

Digital ischemia , easy bruising , epistaxis, acid-peptic disease and GI bleeding , erythromelalgia

Hyperurecemia ,gout

Hypermetabolism symptoms

Diagnosis

Easy with erythrocytosis in combination with leukocytosis and thrombocytosis and or splenomegaly

Difficult in high Hgb or Hct alone

High red cell mass and plasma volume

JAK2 V617F mutation with normal O2 saturation

Low or normal EPO level

Complications Splenic infarction

Myelofibrosis

Stem cell failure in about 15% with extramedullaryhematopoiesis , hepatosplenomegaly , anemia and myelofibrosis

Erythromelalgia

Ocular migraine

Portal HTN , cachexia

Thrombosis in vital organs (liver,heart,brain,lungs)

in uncontrolled erythrocytosis

Treatment

Phelebotomy

goal : Hgb=<14g/dl , Hct <45% in men

Hgb =<12g/dl , Hct <42% in women

and iron deficiency state

ASA

Hydroxyurea for splenomegaly , leukocytosis or pruritus

Allopurinol

Anagrelide

Inf –a , pegylated Inf-a

Ruxolitinib for splenomegaly

Primary myelofibrosis

Clonal disorder of multipotent hematopoietic progenitor cell

Marrow fibrosis

Extramedullary hematopoiesis

Splenomegaly

Least common chronic MPNs

Male and older age are prone to disease

Etiology Unknown

Nonrandom chromosome abnormalities such as 9p,20q-,13q-, trisomy 8,9,partial trisomy 1q are common .

JAK2 V617F mutation, 50%

MPL mutation 5%

Most of the rest of patients have calreticulin gene (CALR) mutations

Overproduction of TGF-B and tissue inhbitors of metalloproteinases are associated with fibrosis

Angiogenesis due to high VEGF

Clinical features

No specific symptoms or signs

Splenomegaly and or abnormal CBC

At presentation night sweats , fatigue , weight loss are common.

Leukoerythroblastic picture in PBS

Anemia

WBC , PLTs usually high

LDH & ALP

Cont… Bone marrow , inaspirable

Exuberant extramedullary hematopoiesis can cause portal , pulmonary or intracranial HTN, ascites ,…

Splenic infarction

Hyperurecemia and secondary gout

Diagnosis

Leukoerythroblastic picture in PBS

Tear drop RBCs in PBS

Inaspirable bone marrow

Hypercellular , trilineage hyperplasia in BM

Autoimmune abnormalities

Cytogenetic analysis

Increased number of circulating CD34+ cells

JAK2 V617F mutation , MPL and CALR mutation

Complications

Marrow failure

transfusion dependent anemia , increased

organomegaly and extramedullary

hematopoiesis

Acute leukemia in about 10% of patients

Treatment

Prednisolone

for anemia

Low dose thlidomide and prednisolone for anemia and thrombocytopenia

Splenic irradiation

Allopurinol

INF-a

Ruxolitinib , JAK2 inhbitor

Allo-HSCT is only curative treatment

Essential thrombocytosis

Clonal disorder

Overproduction of PLTs

Female > male

1-2/100000 incidence rate

JAK2V617F mutation in about 50% of patient

Etiology

Unknown

IL-3 and stem cell factor for early erythroid , myeloid and megakaryocytic progenitors proliferation

Stromal cell –drived factor 1 (SDF-1)

Thrombopoietin

JAK2V617F mutation and CALR mutation

Inherited forms

Clinical features

Most often identified incidentally in CBC .

No specific symptoms or signs

Hemorrhage

easy bruising

Thrombosis

erythromelalgia , ocular migraine , TIA

Mild splenomegaly

Mild neutrophilia

Diagnosis

JAK2V617F mutation in about 50% of patient

Cytogenetic study in JAK2 negative patients CML or MDS

FISH for bcr-abl in ph chromosome negative

CALR mutation assay

In presence of splenomegaly red cell mass determination is required.

PBS and BM findings

Complications

More thrombosis in older than 60 year patients

Tobacco use is most important risk factor for thrombosis in ET patients .

Acquired vWD and bleeding

Evolution to PMF

Treatment

Survival of patients with ET is not different than for the general populations.

No need for treatment of asymptomatic patients without CVD risk factors

ASA

Aminocaproic acid

Plateletpheresis

Hydroxyurea and ASA in TIA

Anagrelide

Pegylated INF-a