The three major myeloproliferative syndromes are polycythemia vera, idiopathic myelofibrosis, and essential thrombocytosis. All are clonal disorders of hematopoietic stem cells and all are associated with a mutation in the JAK2 kinase (V617F) that results in activation of the kinase. The mutation is seen in 90% of pts with polycythemia vera and ∼45% of pts with idiopathic myelofibrosis and essential thrombocytosis.
The most common myeloproliferative syndrome, this is characterized by an increase in red blood cell (RBC) mass, massive splenomegaly, and clinical manifestations related to increased blood viscosity, including neurologic symptoms (vertigo, tinnitus, headache, visual disturbances) and thromboses (myocardial infarction, stroke, peripheral vascular disease; uncommonly, mesenteric and hepatic). It must be distinguished from other causes of increased RBC mass (Chap. 47 Anemia and Polycythemia). This is most readily done by assaying serum erythropoietin levels. Polycythemia vera is associated with very low erythropoietin levels; in other causes of erythrocytosis, erythropoietin levels are high. Assays for the JAK2(V617F) mutation are now widely available. Pts are effectively managed with phlebotomy. A daily aspirin and keeping the hematocrit <43% in women and <45% in men reduces the risk of thrombosis. Some pts require splenectomy to control symptoms, and those with severe pruritus may benefit from psoralens and UV light. Twenty percent develop myelofibrosis, <5% acute leukemia. An inhibitor of JAK1 and JAK2, ruxolitinib, is being tested.
This rare entity is characterized by marrow fibrosis, myeloid metaplasia with extramedullary hematopoiesis, and splenomegaly. Evaluation of a blood smear reveals teardrop-shaped RBC, nucleated RBC, and some early granulocytic forms, including promyelocytes. However, many entities may lead to marrow fibrosis and extramedullary hematopoiesis, and the diagnosis of primary idiopathic myelofibrosis is made only when the many other potential causes are ruled out. The following diseases are in the differential diagnosis: CML, polycythemia vera, Hodgkin's disease, cancer metastatic to the marrow (especially from breast and prostate), infection (particularly granulomatous infections), and hairy cell leukemia. Supportive therapy is generally used; novel inhibitors of JAK2 and telomerase have shown activity in reducing splenomegaly and marrow fibrosis in some cases; however, no study has yet shown a particular drug therapy to improve survival. Cases that do not have JAK2 mutations often have mutations in CALR.
This is usually noted incidentally upon routine platelet count done in an asymptomatic person. Like myelofibrosis, many conditions can produce elevated platelet counts; thus, the diagnosis is one of exclusion. Platelet count must be >500,000/μL, and known causes of thrombocytosis must be ruled out including CML, iron deficiency, splenectomy, malignancy, infection, hemorrhage, polycythemia vera, myelodysplasia, and recovery from vitamin B12 deficiency. Although usually asymptomatic, pts should be treated if they develop migraine headache, transient ischemic attack, or other bleeding or thrombotic disease manifestations. Interferon α is effective therapy, as are anagrelide and hydroxyurea. Treatment should not be given just because the absolute platelet count is high in the absence of other symptoms. Usually platelet counts up to 1.5 million/μL are not associated with bleeding or thrombosis, the two major risks. Bleeding can occur from platelet absorption of von Willebrand factor. JAK2 and CALR mutations account for about 80% of cases; MPL mutations, about 10%.