Pathophysiology
Summary
The myeloid cell line encompasses a variety of cells, including red blood cells (RBCs), various types of granulocytes (basophils, eosinophils, neutrophils), monocytes that can differentiate into macrophages and dendritic cells, mast cells, and megakaryocytes, which give rise to platelets. Disorders of the myeloid cell line manifest in different forms of leukemias and myeloproliferative neoplasms.
Acute myeloid leukemia (AML) is characterized by the proliferation of immature granulocyte and monocyte precursors, known as myeloblasts, in the bone marrow. This rapid and uncontrolled growth impedes the development of mature and functional cells.
In contrast, myeloproliferative neoplasms involve the overproduction of mature myeloid cell types and include diseases such as chronic myelogenous leukemia (CML), polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Chronic myelogenous leukemia (CML) is caused by the proliferation of more mature granulocyte progenitor cells in the bone marrow. CML always arises from a stem cell with a BCR-ABL fusion gene, housed in the Philadelphia chromosome. This gene codes for the BCR-ABL fusion protein, which is a constitutively activated receptor tyrosine kinase that drives cell proliferation.
Polycythemia vera, essential thrombocythemia, & primary myelofibrosis are associated with a constitutively active JAK2 mutation. Specifically, polycythemia vera is associated with increases in hemoglobin, hematocrit, and RBC count.
Essential thrombocythemia is characterized by an elevated number of platelets, which are often of variable size, as well as an increased number of hyperlobulated megakaryocytes in the bone marrow. It presents with an increased risk for thrombotic events such as myocardial infarction (MI), deep vein thrombosis (DVT), and pulmonary embolism (PE), as well as a propensity for bleeding manifestations like ecchymosis, epistaxis, menorrhagia, and gingival bleeding. In essential thrombocythemia, von Willebrand factor may be depleted due to its consumption by the elevated platelet count. Aspirin is commonly used to reduce the risk of thrombotic events in this condition.
Primary myelofibrosis is a myeloproliferative neoplasm distinguished by fibrosis in the bone marrow. It initiates with a hyperproliferative phase, characterized by a hypercellular bone marrow that shows an increase in granulocytes and megakaryocytes. Early in the disease course, megakaryocyte atypia manifests with irregular nuclei and coarse chromatin. These abnormal megakaryocytes stimulate fibroblast growth, leading to collagen deposition and bone marrow fibrosis. A hallmark of primary myelofibrosis is the ‘dry tap’ encountered during bone marrow aspiration.
Clinically, primary myelofibrosis manifests as hepatosplenomegaly due to extramedullary hematopoiesis. Severe splenomegaly can lead to early satiety and splenic infarcts. The condition is marked by anemia, fluctuating leukocyte and platelet counts, and unique blood smear characteristics like nucleated RBCs with anisocytosis and poikilocytosis. Teardrop-shaped RBCs and granulocyte precursors such as myelocytes and metamyelocytes may also be visible in peripheral blood. Constitutional symptoms like fever and fatigue are common.
For treatment, hydroxyurea is often utilized to lower platelet levels, whereas ruxolitinib, a JAK2 inhibitor, is particularly effective for treating myeloproliferative disorders such as polycythemia vera and myelofibrosis.
Myelodysplastic syndromes are more prevalent among the elderly and are characterized by dysplastic and ineffective production of myeloid cells. The hypercellularity in the bone marrow obstruction of normal cell development, resulting in pancytopenia. This typically manifests as weakness, bleeding, and increased susceptibility to infections. The presence of ringed sideroblasts in the bone marrow is a notable feature.
Both myeloproliferative neoplasms and myelodysplastic syndromes carry the risk of transformation into acute myeloid leukemia (AML), known as blast phase transformation. Additionally, both can lead to myelofibrosis in their fibrotic phase.
Lesson Outline
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FAQs
Myeloproliferative neoplasms result from the overproduction of myeloid cells and include chronic myelogenous leukemia (CML), polycythemia vera, essential thrombocythemia, and primary myelofibrosis. CML is distinct as it results from a stem cell possessing the BCR-ABL fusion gene, resulting in an uptick in granulocyte progenitor cell maturation. Conversely, polycythemia vera, essential thrombocythemia, and primary myelofibrosis are primarily linked to an active JAK2 mutation.
Essential thrombocythemia is characterized by a surge in platelet counts and an abundance of enlarged, hyperlobulated megakaryocytes in the bone marrow. This condition heightens the risk of thrombotic events, such as myocardial infarction and pulmonary embolism, and also amplifies bleeding tendencies, leading to symptoms like ecchymosis and epistaxis. Aspirin is frequently prescribed to reduce thrombotic complications.
Primary myelofibrosis is marked by fibrosis in the bone marrow instigated by abnormal megakaryocytes that promote fibroblast growth and consequent deposition of collagen. In the early stages, there's an increase in atypical megakaryocytes in the bone marrow. As the condition advances, bone marrow aspirations often yield a ‘dry tap.’ Patients may experience symptoms such as hepatosplenomegaly, anemia, and variable blood cell counts, accompanied by systemic symptoms like fatigue and weight loss.
JAK2 mutations, particularly the constitutively active JAK2 mutations, are prevalent in myeloproliferative neoplasms like polycythemia vera, essential thrombocythemia, and primary myelofibrosis. This mutation triggers the persistent activation of the JAK2 tyrosine kinase, propelling the overproduction of certain myeloid cells. To counteract this pathway, JAK2 inhibitors such as ruxolitinib are employed, offering effective treatment for these conditions.
Myelodysplastic syndromes are characterized by the dysplastic and inefficient production of myeloid cells, and predominantly affects older individuals. The hypercellular bone marrow can obstruct the development and release of other ‘normal’ hematopoietic cells, resulting in pancytopenia. Symptoms include weakness, bleeding, and a heightened risk of infections. The presence of ringed sideroblasts in the bone marrow is a notable feature. Over time, these syndromes can evolve into acute myeloid leukemia or result in myelofibrosis.
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