Polycythemia vera

Polycythemia vera: Polycythemia vera is a primary myeloproliferative disorder characterized by an increased number of RBCs (erythrocytosis), usually along with increased WBC and platelet counts. These findings are not due to secondary causes such as hypoxia or renal disease. It is an acquired condition caused by somatic mutations in the JAK2 and TET2 genes, although some cases may be inherited in an AD manner.

It typically presents in men >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: Primary myelofibrosis is characterized by excessive fibrosis within the bone marrow and defective hematopoiesis, leading to extramedullary hematopoiesis with hepatosplenomegaly. Exposure to petrochemicals such as benzene and toluene, and to ionizing radiation, increases the 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, which is involved in signal transduction and cell growth and differentiation. There is overproduction of megakaryocytes, which release cytokines such as TGF beta that increase collagen deposition and fibrosis. Other bone marrow changes include osteosclerosis (hardening) and angiogenesis.

Patients present with symptoms due to reduced production of bone marrow cells (RBCs, platelets, and WBCs), leading to anemia, fatigue, dyspnea, easy bruising, bleeding tendencies, infections, etc. Peripheral smear shows “tear drop” cells, and bone marrow biopsy may yield 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 used 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): MDS is a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. It is more common in men and whites. Predisposing exposures include radiation, benzene, tobacco smoke, previous chemotherapy, and environmental toxins such as herbicides, fertilizers, and pesticides. It may progress to AML.

Megaloblastoid erythroid hyperplasia with macrocytic anemia (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 may be hypergranular or hypogranular and can 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, and G-CSF is used. Lenalidomide, immunosuppressive therapy with anti-thymocyte globulin, DNA methyltransferase inhibitors such as decitabine and 5-azacitidine, and allogeneic bone marrow transplantation are effective therapies.