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• PV is a clonal disorder involving a multipotent hematopoietic progenitor cell in which phenotypically normal
red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus.
• Most common of all chronic MPNs
• Incidence : 2.5 per 100,000 persons, increases with age to rates over 10/100,000.
• Age :
• All ages, including early adulthood and occasionally in children and adolescents
• The median age at diagnosis is approximately 60 years
• Approximately one-quarter of cases present before age 50 years and one-tenth before age 40 years.
• Familial transmission : Infrequent
• Sex : F>M (Sporadic)
• Mutation in the autoinhibitory pseudo kinase domain of the tyrosine kinase JAK2—that replaces
valine with phenylalanine (V617F) causing constitutive kinase activation.
• JAK2 serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin receptors.
• JAK2 gene is located on the short arm of chromosome 9, and Loss of heterozygosity on
chromosome 9p due to mitotic recombination is the most common cytogenetic abnormality in
• More than 95% of PV patients express this mutation, as do approx. 50% of PMF and ET patients.
• Most PV pts who do not express JAK2 V617F express a mutation in exon 12 of the kinase.
• Incidental discovery of a high hemoglobin or hematocrit.
• Isolated thrombocytosis or leukocytosis
• Splenomegaly : Early satiety , Lt. upper quadrant dragging sensation or mass.
• Aquagenic pruritus : distinguish PV from other causes of erythrocytosis.
• Uncontrolled erythrocytosis hyper viscosity neurologic symptoms such as vertigo,
tinnitus, headache, visual disturbances, and TIAs
• Systolic HTN.
• Venous or arterial thrombosis : may be the presenting manifestation
• Any vessel can be affected; but cerebral, cardiac, or mesenteric vessels are most commonly
• M/C cause of hepatic vein thrombosis.
• Digital ischemia, easy bruising, epistaxis, PUD, or GI bleed may occur due to vascular stasis or
• Erythema, burning, and pain in the extremities : Erythromelalgia, due to increased platelet
• Hyperuricemia with secondary gout, uric acid stones
• Erythrocytosis in combination with leukocytosis, thrombocytosis, or splenomegaly.
• Red cell mass and plasma volume necessary
• To establish the presence of an absolute erythrocytosis and
• To distinguish from relative erythrocytosis due to a reduction in plasma volume alone
(also known as stress or spurious erythrocytosis or Gaisböck’s syndrome).
• Assay for JAK2 mutations in the presence of a normal SaO2
• A normal serum erythropoietin level does not exclude the presence of PV, but an
elevated EPO level is more consistent with a secondary cause for the erythrocytosis.
• Increased LAP.
• Only three situations cause microcytic erythrocytosis: β thalassemia trait, hypoxic erythrocytosis,
• A bone marrow aspirate and biopsy provide no specific diagnostic information : may be normal or
indistinguishable from ET or PMF.
• No specific cytogenetic abnormality is associated.
• The absence of a cytogenetic marker does not exclude the diagnosis.
• Hyper-viscosity syndrome
• Pruritus : mast cell activation by JAK2 V617F.
• Sudden increase in spleen size painful splenic infarction.
• Arterial and venous thrombosis.
• PUD and GI bleed.
• Increased incidence of non-lymphocytic leukemia.
• Secondary Uric acid stones and urate nephropathy.
# Erythrocytosis Thrombosis
# Thrombocytosis Bleeding.
• Indolent disorder.
• Thrombosis due to erythrocytosis is the most significant complication and often the presenting
• Maintenance of the Hb level at ≤ 14 g/dL; (hematocrit <45%) in men and ≤ 12 g/dL; (hematocrit
<42%) in women is mandatory to avoid thrombotic complications.
• Once an iron-deficient state is achieved, phlebotomy is usually only required at 3-month
• Anticoagulants are only indicated when a thrombosis has occurred.
• Asymptomatic hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol s/b
administered when chemotherapy is used.
• Generalized pruritus intractable to antihistamines or antidepressants such as doxepin :
IFN-α, PUVA therapy, and hydroxyurea
• Asymptomatic thrombocytosis requires no therapy unless the platelet count is
sufficiently high to cause bleeding due an acquired form of VWD.
• Symptomatic splenomegaly can be treated with Pegylated IFN-α can also produce
complete hematologic and molecular remissions.
• Phosphodiesterase inhibitor
• Can reduce the platelet count
• Preferable to hydroxyurea because it lacks marrow toxicity and is protective against
• Alkylating agents and radioactive sodium phosphate (32P) are leukemogenic in PV, and
their use should be avoided.
• If a cytotoxic agent must be used, hydroxyurea is preferred, but this drug does not
prevent either thrombosis or myelofibrosis in PV, is itself leukemogenic, and should be
used for as short a time as possible.
• Non-specific JAK2 inhibitor RUXOLITINIB
• Currently undergoing clinical trials in PV patients intolerant of hydroxyurea.
• A role for allogeneic BMT in PV has not been defined.
• Idiopathic myelofibrosis
• Agnogenic myeloid metaplasia
• Myelofibrosis with myeloid metaplasia
• Clonal disorder of a multipotent hematopoietic progenitor cell of unknown etiology
characterized by marrow fibrosis, extramedullary hematopoiesis, and splenomegaly.
• Least common chronic MPN.
• PMF primarily afflicts men in their sixth decade or later.
• No cytogenetic abnormality specific to the disease.
• JAK2 V617F is present in approx. 50% of PMF pts.
• Mutations in the thrombopoietin receptor Mpl occur in about 5%.
• Fibrosis in this disorder is a/w overproduction of TGF-β and tissue inhibitors of
metalloproteinases, whereas osteosclerosis is associated with overproduction of osteoprotegerin,
an osteoclast inhibitor.
• Marrow angiogenesis occurs due to increased production of VEGF.
• Many patients - asymptomatic at presentation.
• Usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a
• Night sweats, fatigue, and weight loss : common.
• Anemia, usually mild initially, is the rule, whereas the leukocyte and platelet counts are either normal
or increased, but either can be depressed.
• Mild hepatomegaly may accompany the splenomegaly but is unusual in the absence of splenic
• Isolated lymphadenopathy suggest another diagnosis.
• Exuberant extramedullary hematopoiesis can cause ascites; portal, pulmonary, or intracranial
• Causes for anemia : multifactorial
• Ineffective erythropoiesis
• Hemodilution due to splenomegaly
• Splenic sequestration
• Blood loss secondary to thrombocytopenia or portal HTN
• Folic acid deficiency
• Systemic inflammation
• Autoimmune hemolysis
• Diagnosis of PMF is one of exclusion.
• PBS : characteristic features of extramedullary hematopoiesis: teardrop-shaped RBCs,
nucleated RBCs, myelocytes, and promyelocytes.
• The presence of leukocytosis, thrombocytosis with large and bizarre platelets, and
circulating myelocytes suggests the presence of an MPN as opposed to a secondary form
• Marrow aspiration results dry tap but marrow biopsy will reveal a hypercellular marrow
with trilineage hyperplasia.
• Splenomegaly due to extramedullary hematopoiesis may be sufficiently massive to cause portal
HTN and variceal formation.
• An intriguing feature of PMF is the occurrence of autoimmune abnormalities such as immune
complexes, ANA ,RF, or a positive Coombs’ test.
• Cytogenetic analysis of blood
• Useful to exclude CML
• Prognostic purpose : complex karyotype abnormalities poor prognosis in PMF.
• The number of circulating CD34+ cells is markedly increased in PMF (>15,000/μL) compared to
the other chronic MPNs, unless they too develop myeloid metaplasia.
• Serum LDH and ALP : can be elevated.
• LAP score : can be low, normal, or high.
• Bone x-rays may reveal osteosclerosis.
• Approx. 50% of PMF pts. express JAK2 V617F mutation.
• PMF pts expressing an MPL mutation tend to be more anemic and have lower leukocyte counts.
• Somatic mutations in exon 9 of the calreticulin gene (CALR) have been found in a majority of
patients with PMF and ET who lack mutations in either JAK2 or MPL.
• Marrow failure
• Huge organomegaly : Portal HTN and/or variceal bleed.
• Transformation into aggressive form of acute leukemia.
• No specific therapy exists for PMF.
• Management of anemia and thrombocytopenia
• Neither recombinant erythropoietin nor androgens such as danazol have proven to be
• Erythropoietin may worsen splenomegaly and will be ineffective if the serum erythropoietin
level is >125 mU/L.
• Low dose thalidomide with prednisolone effective
• Splenomegaly is by far the most distressing and intractable problem
• Surgical removal of a massive spleen is a/w significant postoperative complications including
mesenteric venous thrombosis, hemorrhage, rebound leukocytosis and thrombocytosis.
• For unexplained reasons, also increases the risk of blastic transformation.
• Allopurinol can control significant hyperuricemia
• Bone pain can be alleviated by local irradiation.
• JAK2 inhibitor, RUXOLITINIB : effective in reducing splenomegaly and alleviating constitutional
symptoms while also prolonging survival.
• Allogeneic bone marrow transplantation is the only curative treatment for PMF and should be
considered in younger patients.
• Essential thrombocythemia
• Idiopathic thrombocytosis
• Primary thrombocytosis
• Hemorrhagic thrombocythemia
• Clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell manifested
clinically by overproduction of platelets without a definable cause.
• Incidence : 1–2/100,000
• Sex : distinct female predominance
• Age : can occur at any age.
• Approx. 50% of ET patients carry the JAK2 V617F mutation, but its absence does not exclude the disorder.
• Uncontrolled thrombopoiesis.
• In addition to its role in thrombopoiesis, thrombopoietin also enhances the survival of
multipotent hematopoietic stem cells and their bone marrow residence.
• No symptoms or signs are specific for ET.
• Hemorrhagic tendencies : Easy bruising
• Microvascular occlusive events : Erythromelalgia, ocular migraine, or TIA.
• Splenomegaly is indicative of another MPN, in particular PV, PMF, or CML.
• About 50% of ET pts. express the JAK2 V617F mutation.
• CALR mutations are present in most pts. who do not have JAK2 mutations.
• Splenomegaly should suggest the presence of another MPN.
• Marrow biopsy :
• Megakaryocyte hypertrophy and hyperplasia, as well as an overall increase in marrow
• If marrow reticulin is increased consider another diagnosis.
• Absence of stainable iron demands an explanation because iron deficiency alone can cause
thrombocytosis, and absent marrow iron in the presence of marrow hypercellularity is a
feature of PV.
• An elevated platelet count in an asymptomatic patient without cardiovascular risk factors
requires no therapy.
• Bleeding usually responds to EACA.
• Pegylated IFN-α, anagrelide, or hydroxyurea can be used to reduce the platelet count.
• Hydroxyurea and aspirin are more effective than anagrelide and aspirin for prevention of
TIA but not more effective for the prevention of other types of arterial thrombosis and
are actually less effective for venous thrombosis.