Polycythemia vera

Polycythemia vera: It is a primary myeloproliferative disorder characterized by increased number of RBCs or erythrocytosis along with increased WBC and platelet counts (not attributed by other causes like hypoxia or renal disease). It is an acquired condition caused by somatic mutations in JAK2 and TET2 genes. Some cases may be inherited in an AD manner. It presents typically in men>age of 60 years with headaches, dizziness, tinnitus, stroke, pruritus, erythema, visual defects, IHD, PE and splenomegaly. Most symptoms are due to increased blood viscosity. It may progress to leukemia. Erythropoietin levels are low as a compensatory response. Major WHO criteria for the diagnosis of polycythemia vera include hemoglobin >16.5 g/dL in men or >16.0 g/dL in women or hematocrit >49% in men or >48% in women or increased red cell mass ; BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes and the presence of JAK mutations. Low dose aspirin, phlebotomy, hydroxyurea and bone marrow transplantation are used as therapy. SSRIs and interferon alpha can be used to control associated pruritus.

Primary myelofibrosis: It is a disorder characterized by excessive fibrosis within the bone marrow and defective hematopoiesis resulting in extramedullary hematopoiesis with hepatosplenomegaly. Exposure to petrochemicals like benzene and toluene and ionizing radiation carries increased risk of developing myelofibrosis. It is associated with mutations in JAK2, MPL, CALR (calreticulin) and TET2 genes. JAK2 and MPL are part of the JAK-STAT pathway that is involved in signal transduction and cell growth and differentiation. There is overproduction of megakaryocytes which release cytokines like TGF beta that increase collagen deposition and fibrosis. Other bone marrow changes include osteosclerosis (hardening) and angiogenesis. Patients present with symptoms resulting from reduced production of bone marrow cells like RBCs, platelets and WBCs that result in anemia, fatigue, dyspnea, easy bruising, bleeding tendencies, infections etc. Peripheral smear will show “tear drop” cells and bone marrow biopsy yields a “dry tap”. Bone marrow shows increased reticulin fibres and increased collagen with focal areas of hypercellularity. Supportive therapy with blood transfusions, androgens and corticosteroids can be done to increase RBC counts. Hydroxyurea, ruxolitinib (anti JAK 1 and 2) and lenalidomide can be used. Stem cell transplantation is used as a last resort. Some cases need splenectomy.

Myelodysplastic syndrome (MDS): The MDS are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. They are more common in men and whites. Exposure to radiation, benzene, tobacco smoke, previous chemotherapy, environmental toxins like herbicides, fertilizers and pesticides can all predispose to MDS. It may progress to AML. Megaloblastoid erythroid hyperplasia with macrocytic anemia, associated with normal vitamin B12 and folate levels, is frequently observed. Other bone marrow changes include micromegakaryocytes, giant or hypogranular platelets and abnormal myeloid progenitors. Peripheral blood granulocytes are hyper or hypogranular and may show Pelger-Huet abnormality. Clinical features include fatigue, easy bruising, hepatosplenomegaly, fever etc. Trisomy 8 and deletion of chromosome 5 or 7 is seen. Mutations lead to increased apoptosis of bone marrow cells. Laboratory findings include pancytopenia and characteristic bone marrow findings (above). Ringed sideroblasts and basophilic stippling may be seen. Supportive therapy with blood transfusions, darbepoetin, G-CSF is used. Lenalidomide, immunosuppressive therapy with anti-thymocyte globulin, DNA methyltransferase inhibitors like decitabine and 5-azacitidine and allogeneic bone marrow transplantation are effective therapies.