ESSENTIALS OF DIAGNOSIS
Teardrop poikilocytosis on peripheral smear.
Leukoerythroblastic blood picture; giant abnormal platelets.
Initially hypercellular, then hypocellular bone marrow with reticulin or collagen fibrosis.
Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR, or MPL mutations; bone marrow fibrosis; anemia; splenomegaly; and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis. Myelofibrosis can also occur as a secondary process following the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis). It is believed that fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines. In response to bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes. In these sites, mesenchymal cells responsible for fetal hematopoiesis can be reactivated. According to the 2016 WHO classification, “prefibrotic” primary myelofibrosis is distinguished from “overtly fibrotic” primary myelofibrosis; the former might mimic essential thrombocytosis in its presentation and it is prognostically relevant to distinguish the two.
Primary myelofibrosis develops in adults over age 50 years and is usually insidious in onset. Patients most commonly present with fatigue due to anemia or abdominal fullness related to splenomegaly. Uncommon presentations include bleeding and bone pain. On examination, splenomegaly is almost invariably present and is commonly massive. The liver is enlarged in more than 50% of cases.
Later in the course of the disease, progressive bone marrow failure takes place as it becomes increasingly more fibrotic. Progressive thrombocytopenia leads to bleeding. The spleen continues to enlarge, which leads to early satiety. Painful episodes of splenic infarction may occur. The 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.
Patients are almost invariably anemic at presentation. The white blood count is variable—either low, normal, or elevated—and may be increased to 50,000/mcL (50 × 109/L). The platelet count is variable. The peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line (eFigure 13–21). 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.
Primary myelofibrosis, peripheral blood smears. A: In classical idiopathic myelofibrosis, tear drop–shaped red cells (dacrocytes) and nucleated red cells are characteristically present throughout, along with a few other poikilocytes (abnormally shaped red blood cells). B: Again, note ...