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DEFINITION

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  • Primary myelofibrosis is a chronic myeloid neoplasm that originates in mutations in a multipotential hematopoietic cell, possibly the lymphohematopoietic stem cell. The disease is characterized by (1) anemia; (2) splenomegaly; (3) increased CD34+ cells, immature granulocytes, erythroid precursors, and teardrop-shaped red cells in the blood; (4) increased dysmorphic megakaryocytes, the cytokines from which induce marrow fibrosis; and (5) osteosclerosis.

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EPIDEMIOLOGY

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  • Onset is characteristically after age 50 years.

  • Median age at diagnosis is approximately 70 years.

  • Adult males and females are affected equally.

  • Incidence is approximately 1.0 case per 100,000 in persons of European descent.

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PATHOGENESIS

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  • Origin is in the neoplastic transformation of a multipotential primitive hematopoietic cell.

  • In approximately 50% of patients, a mutation, JAK2 V617F, in approximately 35% of patients a mutation, CALR, and in approximately 5% of patients a mutation, MPL, can be found in the blood cells. Approximately 10% of patients’ blood cells do not have one of these mutations.

  • Frequently other mutations may be found in patients’ blood cells, including, for example, those involving TET2, ASXL1, DNMT3A, EZH2, IDH1, TP53, and CBL.

  • Constitutive mobilization and circulation of CD34+ cells occurs as a result of epigenetic methylation of the CXCR4 promoter, leading to decreased expression of CXCR4 on CD34+ cells and their enhanced migration from marrow to blood.

  • CD34+ cells in this disorder generate about 24-fold the megakaryocytes in culture than do CD34+ cells from normal persons.

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Fibroplasia

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  • Reticulin fibers (type III collagen), as detected by silver staining, are increased in the marrow in most patients. Fibrosis may progress to thick collagen bands (type I collagen) identified with the trichrome stain.

  • Increased plasma concentrations of procollagen III amino-terminal peptide, prolylhydroxylase, and fibronectin are present.

  • The extent of fibrosis is correlated with the prevalence of dysmorphic megakaryocytes and release of fibroblast growth factors from the megakaryocyte α granules (eg, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-β, and others).

  • The fibroblastic proliferation in the marrow is a reaction to the cytokines released by an increased density of dysmorphic megakaryocytes, not an intrinsic part of the clonal expansion of hematopoietic cells.

  • Thicker bands of collagen fibrosis (type I collagen) may develop as the marrow fibrosis advances.

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CLINICAL FEATURES

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  • The median age at diagnosis is approximately 70 years, but the disorder may occur at any age.

  • The sex incidence is equal in adults, but the disorder occurs in twice as many females as males in young children.

  • Rarely, myelofibrosis is preceded by extended high-dose ionizing radiation.

  • Approximately 25% of patients are asymptomatic at time of diagnosis.

  • Fatigue, weakness, shortness of breath, palpitations, weight loss, night sweats, and bone pain are common presenting symptoms.

  • Wasting, peripheral edema, or bone tenderness may occur.

  • Left upper quadrant fullness, pain or dragging sensation, left shoulder pain, and early satiety may ...

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