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Key Features

Essentials of Diagnosis

  • Striking splenomegaly

  • Teardrop poikilocytosis on peripheral smear

  • Leukoerythroblastic blood picture; giant abnormal platelets

  • Hypercellular bone marrow with reticulin or collagen fibrosis

General Considerations

  • Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR or MPL mutation, bone marrow fibrosis, anemia, splenomegaly, and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis

  • A myeloproliferative disorder, also known as myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, and idiopathic myelofibrosis

  • Can also occur as a secondary process following other myeloproliferative disorders (see Polycythemia Vera and Essential Thrombocytosis)

  • It is believed that bone marrow fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines

  • In response to the bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes

  • Abnormalities of JAK2 and MPL are involved in the pathogenesis

Clinical Findings

Symptoms and Signs

  • Onset is usually insidious

  • Develops in adults over age 50 years

  • Most common presentations

    • Fatigue due to anemia

    • Abdominal fullness related to splenomegaly

  • Uncommon presentations

    • Bleeding

    • Bone pain

  • Splenomegaly

    • Almost invariably present

    • Commonly massive

  • Liver is enlarged in > 50% of cases

  • Later in the course of the disease

    • Splenomegaly may result in early satiety

    • Splenic infarction may occur

    • Progressive bone marrow failure takes place as it becomes increasingly more fibrotic

    • Progressive thrombocytopenia leads to bleeding

    • Patient becomes cachectic and may experience severe bone pain, especially in the upper legs

    • Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space

Differential Diagnosis

  • Severe infection, inflammation, or infiltrative bone marrow processes

  • Metastatic carcinoma, Hodgkin lymphoma, and hairy cell leukemia

  • Chronic myeloid leukemia (CML)

  • Polycythemia vera

  • Essential thrombocytosis

Diagnosis

Laboratory Findings

  • Anemia

  • White blood count

    • Variable—either low, normal, or elevated

    • May be increased to 50,000/mcL

  • Platelet count is variable

  • Peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line

  • Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts

  • Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen

  • The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis

  • Bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease it is hypercellular, with a marked increase in megakaryocytes

  • Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers; later, marrow biopsy reveals more severe fibrosis, with eventual replacement of hematopoietic precursors by collagen

  • There is no characteristic chromosomal abnormality

  • JAK2 is mutated in ~65% of cases, and MPL and ...

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