Myeloproliferative disorders Clonal haematopoeitic disorders Proliferation of one of myeloid lineages –Granulocytic –Erythroid –Megakaryocytic Relatively normal maturation

Myeloproliferative disorders WHO Classification Chronic Myeloid leukemia ( CML ) Polycythemia Vera ( PV ) Essential Thrombocythemia ( ET ) Myelofibrosis ( agnogenic myeloid metaplasia )

Bone marrow stem cell Clonal abnormality Granulocyte precursors Red cell precursors MegakaryocytesReactive fibrosis Essential thrombocytosis (ET) Polycythaemia rubra vera (PRV) Myelofibrosis AML Chronic myeloid leukemia 70% 10% 30%

Polycythemia vera

Causes of secondary polycythemia ERYTHROPOIETIN (EPO)-MEDIATED –Hypoxia-Driven Chronic lung disease Right-to-left cardiopulmonary vascular shunts High-altitude habitat Chronic carbon monoxide exposure (e.g., smoking) Hypoventilation syndromes including sleep apnea Renal artery stenosis or an equivalent renal pathology –Hypoxia-Independent (Pathologic EPO Production) Malignant tumors –Hepatocellular carcinoma –Renal cell cancer –Cerebellar hemangioblastoma Nonmalignant conditions –Uterine leiomyomas –Renal cysts –Postrenal transplantation –Adrenal tumors EPO RECEPTOR–MEDIATED –Activating mutation of the erythropoietin receptor DRUG-ASSOCIATED –EPO Doping –Treatment with Androgen Preparations

POLYCYTHEMIA VERA Chronic, clonal myeloproliferative disorder characterized by an absolute increase in number of RBCs 2-3 / Median age at presentation: M/F: 0.8: % of pateints associated with concurrent leucocytosis and / thrombocytosis.

POLYCYTHEMIA VERA JAK2 Mutation JAK/STAT: cellular proliferation and cell survival deficiency in mice at embryonic stage is lethal due to the absence of definitive erythropoiesis Abnormal signaling in PV through JAK2 was first proposed in 2004 a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) in the majority of PV patients

Clinical features Plethora Persistent leukocytosis Persistent thrombocytosis Splenomegaly Generalized pruritus (after bathing) Unusual thrombosis (e.g., Budd-Chiari syndrome) Erythromelalgia (acral dysesthesia and erythema)

Clinical features Hypertention Gout Leukaemic transformation Myelofibrosis

Increased Hb female > 16.5 g / dL male > 18 g /dL

Diagnostic Criteria A1Raised red cell mass A2Normal O2 sats and EPO A3Palpable spleen A4No BCR-ABL fusion B1Thrombocytosis >400 x 109/L B2Neutrophilia >10 x 109/L B3Radiological splenomegaly B4Endogenous erythroid colonies A1+A2+either another A or two B establishes PV

Treatment

The mainstay of therapy in PV remains phlebotomy to keep the hematocrit below 45 percent in men and 42 percent in women Additional hydroxyurea in high-risk pts for thrombosis (age over 70, prior thrombosis, platelet count >1,500,000/microL, presence of cardiovascular risk factors) Aspirin ( mg/d) if no CI IFNa (3mu three times per week) in patients with refractory pruritus, pregnancy Anagrelide (0.5 mg qds/d) is used mainly to manage thrombocytosis in patients refractory to other treatments. Allopurinol

Essential Thrombocythaemia (ET) Clonal MPD Persistent elevation of Plt >600 x109/l Poorly understood Lack of positive diagnostic criteria 2.5 cases/ M:F 2:1 Median age at diagnosis: 60, however 20% cases<40yrs

Clinical Features Vasomotor –Headache –Lightheadedness –Syncope –Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) –Transient visual disturbances (eg, amaurosis fujax, ocular migraine) Thrombosis and Haemorrhage Transformation

Investigations ET is a diagnosis of exclusion Rule out other causes of elevated platelet count

Diagnostic criteria for ET Platelet count >600 x 109/L for at least 2 months Megakaryocytic hyperplasia on bone marrow aspiration and biopsy No cause for reactive thrombocytosis Absence of the Philadelphia chromosome Normal red blood cell (RBC) mass or a HCT <0.48 Presence of stainable iron in a bone marrow aspiration No evidence of myelofibrosis

Treatment A symptomatic --- no therapy just aspirin. Interferon-alpha,anagrelide can also reduce the platelets count. Hydroxyurea --- only if these agents are not effective or tolerable. Aminocaproic acid ---- if bleeding associated with thrombocytosis.