MYELOPROLIFERATIVE DISORDERS The myeloproliferative disorders are a group of chronic conditions characterized by clonal proliferation of precursor marrow cells and include : 1-Polycythemia rubra vera :proliferation of erythroid precursors. 2-Primary thrombocythemia; prliferation of megakaryocyte. 3-chronic idiopathic myelofibrosis; replasment of B.M. by fiberous tissue. 4-Chronic myeloid leukemia : proliferation of myeloid cells.

POLYCYTHEMIA RUBRA VERA (PRV );- PRV is proliferation of erythroid precarser, In polycythemia, erythroid precursors do not divide more rapidly than their normal counterparts, but they accumulate because they do not die normally. Etiology is unknown.

Clinical features;- -Mainly affects patients above 40 but no adult age group is spared. -It is most often first discovered by incidental finding of a high Hb or hematocrit. -It may first present with massive splenomegaly (however, splenomegaly may be absent ) , or symptoms of hyperviscosity. -such as lassitude, headache ,dizziness, blackouts, pruritus, visual disturbances.-

-Systolic hypertension may be present due to increased red cell mass. -There may be easy bruising, epistaxis or git bleeding. Patients are frequently plethoric. -Venous or arterial thrombosis may be the presenting manifestation e.g CVA, Budd-Chiari syndrome and digital ischemia. Splenic infarction may occur.-

-There may be hyperuricemia ,gout and uric acid stones. -Peptic ulcer disease is more common in PRV. -With the exception of aquagenic pruritus, no symptom distinguish PRV from other causes of erythrocytosis. -There may be leucocytosis and thrombocytosis

Diagnosis ;- 1- High Hb. 2-High p.c.v. 3-Hyper uresemia. 4-JAK 2 (+ve) in 97%. 5-Splenomegaly. 6-Exclude secondary causes of erythrocytosis e.g. lung diseases , Renal diseases, uterine , Hepatoma. 7-Erythropoiten level normal . 8- Red cell mass can be reliably determined by isotope dilution using the patient's 51 Cr-tagged red cell

Treatment ;- -Maintenance of Hb level ≤ 140g/l in men and ≤ 120g/l in women is mandatory to avoid the thrombotic complications. -Venesection (phlebotomy ) gives prompt relief of hyperviscosity symptoms. Between 400-500ml of blood are removed and the venesection is repeated every 5-7 days until the hematocrit is reduced to below 45% . Periodic venesections thereafter (usually every 3 months ) serve to maintain the red cell mass within the normal range and to induce a state of iron deficiency, which prevents an accelerated expansion of red cell mass. In PRV, thrombosis is correlated with erythrocytosis and not with thrombocytosis.

-Asymptomatic hyperuricemia requires no therapy, but allopurinol must be administered to avoid further elevation of uric acid when chemotherapy is employed to reduce splenomegaly or pruritus, and for treatment of gout and uric acid stones. -Generalized pruritus may be ameliorated with hydroxyurea (may be leukemogenic ) or interferon alpha. -Symptomatic splenomegaly can be treated with hydroxyurea or IFN-α .If these fail ,splenectomy may be undertaken. Allogeneic BMT may be curative in young patients

Prognosis ;- Patients with PRV can be expected to live long and useful lives when their red cell mass is effectively managed with phlebotomy. Chemotherapy is never indicated to control the red cell mass.

CHRONIC IDIOPATHIC MYELOFIBROSIS Also called agnogenic myeloid metaplasia. It is characterized by marrow fibrosis ,myeloid metaplasia with extramedullary hematopoiesis, a leucoerythroblastic blood picture and splenomegaly. The marrow is initially hypercellular with an excess of abnormal megakaryocytes ,which release transforming growth factor β (resulting in proliferation of fibroblasts ) and thrombopoietin. As the disease progresses , the marrow becomes fibrosed. Fibroblasts are not part of the neoplastic clone.

Clinical features;_ It affects patients usually in their sixth decade or later. Most patients are asymptomatic at presentation and usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination. Splenic enlargement could be rapid and cause splenic infarction with fever and pleuretic chest pain.

A blood smear reveals the characteristic features of extramedullary hematopoiesis : teardrop red cells, nucleated red cells ,myelocytes and promyelocytes; myeloblasts may also be present but have no prognostic significance. Giant platelets my be seen. Anemia, usually mild initially ,is the rule. leukocyte and platelet counts are normal ,increased or decreased.

There may be hyperuricemia and gout (increased cell breakdown ) There may be hyperuricemia and gout (increased cell breakdown ) .Folate deficiency may be present. Lassitude ,loss of weight and night sweets may be present. _About 10% of cases evolve into acute leukemia. _Median survival is 4 years ( range 1-20 years ).

Diagnosis;_ The marrow is often difficult to aspirate due to fibrosis and a trephine biopsy shows an excess of megakaryocytes ,increased reticulin and fibrous tissue. The presence of JAK-2 molecule due to mutation in gene in chromosome 9 support the diagnosis which are (+ve ) in 50% of cases. Polycythemia rubra vera ,chronic myeloid leukemia and other conditions can mimic myelofibrosis , therefore the diagnosis of myelofibrosis is one of exclusion which requires ruling out of the following conditions which also cause myelofibrosis :

*Chronic idiopathic myelofibrosis * Polycythemia rubra vera * Chronic myeloid leukemia * Carcinoma metastasis to the bone marrow * Multiple myeloma * SLE * Infection e,g Tb *Lymphoma

Treatment;_ Red cell transfusion for anemia. Folic acid supplement. Allopurinol for hyperuricemia Hydroxyurea for controlling splenomegaly. Splenectomy may be required for a grossly enlarged spleen or symptomatic cytopenia secondary to splenic pooling of cells and hypersplenism. Roxolitinibe new drug use to decrease size of spleen. BMT may be considered for younger patients.