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Primary Myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. The abnormality stems from genetic mutations Genetic Mutations Carcinogenesis of the hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis (typically, JAK2 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations). Primary symptoms are anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types and extramedullary hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis, which include severe fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, and hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus. Laboratory findings include anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (and other cytopenias Cytopenias IPEX Syndrome), and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma reveals extensive fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. Management is with hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation and symptom-directed interventions.

Last updated: Apr 21, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by proliferation of myeloid cells Myeloid Cells The classes of bone marrow-derived blood cells in the monocytic series (monocytes and their precursors) and granulocytic series (granulocytes and their precursors). White Myeloid Cells: Histology, with nonclonal fibroblast proliferation and hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder, resulting in an obliterative marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. Other names include chronic idiopathic Idiopathic Dermatomyositis myelofibrosis and agnogenic myeloid metaplasia Metaplasia A condition in which there is a change of one adult cell type to another similar adult cell type. Cellular Adaptation.

Epidemiology

  • 0.5–1.5 cases per 100,000 individuals in the United States
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 4–6 per 100,000 population
  • Increased prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in Ashkenazi Jews
  • Male > females
  • Generally occurs at > 50 years of age, with a median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion age of 65 years

Etiology

  • Generally unknown
  • Linked to the following risk factors/exposures:
    • Thorium dioxide (thorium-based radiographic contrast material)
    • Petroleum-manufacturing plants Plants Cell Types: Eukaryotic versus Prokaryotic (toluene and benzene)
    • Ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
    • Atomic bomb at Hiroshima
  • About 90% of cases have mutations involving JAK2, CALR, or MPL.
    • Janus kinase 2 (JAK2) mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: 60%–65% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • MPL mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: 5% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • CALR mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: 20%–25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • No JAK2, CALR, or MPL mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (triple-negative): 8%–10% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship

Pathophysiology

Hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis

Hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis starts with the hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors)

  • Lymphoid stem cell: gives rise to lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology
  • Myeloid stem cell: eventually differentiates into platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology, erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation, basophils Basophils Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. Innate Immunity: Phagocytes and Antigen Presentation, eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation) and monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation:
    • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis into myeloid progenitor cells Myeloid progenitor cells Stem cells derived from hematopoietic stem cells. Derived from these myeloid progenitor cells are the megakaryocytes; erythroid cells; myeloid cells; and some dendritic cells. Acute Myeloid Leukemia
    • Granulocyte macrophage colony-stimulating factor Granulocyte macrophage colony-stimulating factor An acidic glycoprotein of mw 23 kda with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. White Myeloid Cells: Histology ( GM-CSF GM-CSF An acidic glycoprotein of mw 23 kda with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. White Myeloid Cells: Histology) → differentiation from myeloid progenitors to granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation) and monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation 
    • IL-5 → differentiation to eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation
    • Thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology (TPO) → differentiation to thrombocytes ( platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology)
    • Erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology ( EPO EPO Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology) → differentiation to erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology ( RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology)
Bone marrow hematopoiesis

Bone-marrow hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis: proliferation and differentiation of the formed elements of blood.
CFU-GEMM CFU-GEMM Platelets: Histology: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte Megakaryocyte Very large bone marrow cells which release mature blood platelets. Platelets: Histology
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF GM-CSF An acidic glycoprotein of mw 23 kda with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. White Myeloid Cells: Histology: granulocyte-macrophage colony-stimulating factor
M-CSF M-CSF A mononuclear phagocyte colony-stimulating factor (M-CSF) synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a mw of 70 kda. It binds to a specific high affinity receptor. White Myeloid Cells: Histology: macrophage colony-stimulating factor Macrophage colony-stimulating factor A mononuclear phagocyte colony-stimulating factor (M-CSF) synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a mw of 70 kda. It binds to a specific high affinity receptor. White Myeloid Cells: Histology
G-CSF: granulocyte colony-stimulating factor Granulocyte colony-stimulating factor A glycoprotein of mw 25 kda containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. White Myeloid Cells: Histology
NK: natural killer
TPO: thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology

Image by Lecturio. License: CC BY-NC-SA 4.0

Mutations

Mutations in genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure associated with hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis are noted in a significant proportion of cases of PMF.

  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of Janus kinase 2 (JAK2) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
    • Affects JAK2:
      • A non-receptor tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase (encoded by JAK2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics) in the cytoplasm involved in signal transduction Transduction The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique. Bacteriology (JAK–signal transducer Transducer A device placed on the patient’s body to visualize a target Ultrasound (Sonography) of activators of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription (STAT) pathway) 
      • Mediates the cellular response to growth factors and cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response
    • Effect:
      • Rapid hematopoietic cell division Cell Division A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle and maturation, with a large number becoming megakaryocytes
      • Stimulation of megakaryocytes to secrete fibroblast growth factors
  • Mutations of the MPL gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
    • MPL codes for the thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors protein.
    • Effect: constitutive activation of thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 
  • Mutations of CALR gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
    • CALR codes for calreticulin.
    • Calreticulin is a Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+-binding protein in the JAK–STAT pathway and is essential in cellular proliferation and apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage.
    • Effect: induces thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors activation
Mutations underlying the pathophysiology of myelofibrosis

Mutations underlying the pathophysiology of myelofibrosis:
Commonly affects the JAK–STAT pathway
JAK2 (JAK2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics involved): non-receptor tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase facilitating extracellular signals to reach the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles and activate genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
MPL or thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (MPL gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics involved): activation of the thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
Calreticulin (CALR gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics involved) is a regulator of STAT, and mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations causes activation of thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.

Image: “Overcoming treatment challenges in myelofibrosis and polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera: the role of ruxolitinib Ruxolitinib Targeted and Other Nontraditional Antineoplastic Therapy” by Bryan JC, Verstovsek S. License: CC BY 4.0

Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans

  • With atypical megakaryocytic hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation, there is inappropriate output of fibrogenic factors, including:
    • Transforming growth factor β (TGF-β): 
      • Major cytokine derived from megakaryocytes
      • Collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology deposition and angiogenesis Angiogenesis Bartonella
      • Interacts with thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology
    • Platelet-derived growth factor Platelet-derived growth factor Mitogenic peptide growth hormone carried in the alpha-granules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. Hypertrophic and Keloid Scars (PDGF)
    • Epidermal growth factor (EGF)
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (fibroblastic and stromal deposition) progresses, leaving no room for hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis → extramedullary hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy

Clinical Presentation

  • Approximately 15%–30% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic.
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types:
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia (most common symptom)
    • Shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Palpitations Palpitations Ebstein’s Anomaly
  • Hypermetabolic state Hypermetabolic State Neurological Examination:
    • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
    • Night sweats Night sweats Tuberculosis
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Extramedullary hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis
    • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly:
      • LUQ abdominal tenderness
      • Abdominal fullness with early satiety Early Satiety Bariatric Surgery
      • Left shoulder pain Shoulder Pain Acute shoulder injuries are a common reason for visits to primary care physicians and EDs. Common acute shoulder injuries include acromioclavicular joint injuries, clavicle fractures, glenohumeral dislocations, proximal humerus fractures, and rotator cuff tears. Acute Shoulder Pain: due to inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of tissues around spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
    • Hepatomegaly (with complications such as portal hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites)
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types and joint involvement:
    • Can cause severe bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types and joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, especially in the lower extremities
    • Osteosclerosis Osteosclerosis An abnormal hardening or increased density of bone tissue. Paget’s Disease of Bone:
      • Diffuse or patchy increase in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types density
      • Prominent/thick bony trabeculae
      • Mottled bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types on X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests in up to 66% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or “gout flare,” followed later by chronic deforming arthritis. Gout, from increased uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis production 

Diagnosis

Initial evaluation

  • Historical details and symptoms
  • Examination:
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy enlargement (hallmark physical finding of PMF)
    • Hepatomegaly
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types tenderness
    • Increased warmth over the tibias and knees due to increased cortical blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests

  • CBC:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will have hemoglobin < 10 g/dL) 
    • Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology:
      • Early stage: either thrombocytosis or thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
      • Late stage: predominantly thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia 
    • WBC count:
      • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables: leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus or leukopenia
      • Reflects variation in neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation
  • Biochemistry:
    • LDH LDH Osteosarcoma: ineffective hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis
    • Uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis: from increased cell turnover
    • ↑ Leukocyte alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types involvement
    • ↑ Vitamin B12: increased neutrophil mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
  • Peripheral blood smear Blood smear Myeloperoxidase Deficiency:
    • Teardrop cells (dacrocytes): misshapen RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology due to damage from marrow production
    • Leukoerythroblastosis: release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of nucleated myeloid (“leuko”) and erythroid (“erythro”) cells that are immature (“blast”)
    • Anisocytosis and poikilocytosis
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow aspirate: dry tap Dry Tap Hairy Cell Leukemia (no blood cells)
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
    • Fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans: hallmark of PMF, seen in almost all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Megakaryocytic hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation (with abnormal morphology)
    • Osteosclerosis Osteosclerosis An abnormal hardening or increased density of bone tissue. Paget’s Disease of Bone 
  • Cytogenetic analysis Cytogenetic analysis Examination of chromosomes to diagnose, classify, screen for, or manage genetic diseases and abnormalities. Following preparation of the sample, karyotyping is performed and/or the specific chromosomes are analyzed. Non-Hodgkin Lymphomas:
    • JAK2 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (majority of cases)
    • CALR mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
    • MPL mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 
    • Triple-negative in up to 10%

Mnemonic

To remember PMF in summary: Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow is crying (teardrop cells) because it is fibrosed and is a dry tap Dry Tap Hairy Cell Leukemia.

WHO diagnostic criteria

  • Major criteria (all 3 required):
    • Megakaryocytic proliferation and atypia Atypia Fibrocystic Change, with reticulin and/or collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans 
    • The following are ruled out the basis of WHO criteria:
      • Polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera ( PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera)
      • Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. Essential Thrombocythemia (ET)
      • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
      • Myelodysplastic syndrome
      • Other myeloid neoplasm 
    • Demonstration of a JAK2, CALR, or MPL mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations or another clonal marker or reactive fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans ruled out
  • Minor criteria (confirmed in 2 consecutive measurements):
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types not attributable to a comorbid condition
    • Leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus (≥ 11 × 10⁹/L)
    • Palpable splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • LDH LDH Osteosarcoma above the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal
    • Leukoerythroblastosis

Comparison with other myeloproliferative neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors

Myeloproliferative neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors can be compared with the following WHO classification:

Table: Classic types of myeloproliferative neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors
Disease Mutations Key points
CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia BCR-ABL1 (Philadelphia chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics) Proliferation of mature and maturing granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology
ET JAK2, CALR, or MPL Excessive clonal platelet production
Polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera ( PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera) JAK2 Elevated RBC mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
PMF JAK2, CALR, or MPL Obliterative bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans

Other types:

  • Chronic neutrophilic leukemia (CNL)
  • Chronic eosinophilic leukemia Chronic eosinophilic leukemia Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia ( CEL CEL Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia), not otherwise specified
  • Myeloproliferative neoplasm, unclassifiable

Management

Approach

Assessment of risk is important in making treatment decisions.

  • Risk stratification:
    • Reduced survival noted:
      • Old age
      • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
      • Leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus, + blasts Blasts Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. Blunt Chest Trauma
      • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
      • Requires transfusion
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, night sweats Night sweats Tuberculosis
    • Driver mutations:
      • CALR mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: best outcome
      • Triple-negative: worst outcome
    • Other high-risk gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations are associated with poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas (i.e., ASXL1).
  • More risk factors as listed above = higher risk of PMF
  • Transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology to acute leukemia:
    • Seen in minority of cases
    • Predictive factors:
      • Circulating blasts Blasts Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. Blunt Chest Trauma: ≥ 3%
      • Platelet count: < 100,000/µL

Options

  • High-risk PMF:
    • Hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation if eligible
    • Clinical trial enrollment if not eligible for transplantation
    • Agents:
  • Low-risk PMF: 
    • Asymptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: observation and monitoring 
    • Symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: Janus-associated kinase inhibitors, hydroxyurea Hydroxyurea An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. Antimetabolite Chemotherapy 
  • Splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen if symptomatic from massive splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Transfusion as needed

Differential Diagnosis

Other chronic myeloproliferative neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors

  • Chronic myeloid leukemia Chronic myeloid leukemia Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia ( CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia): malignant proliferation of the granulocytic cell line, with a fairly normal differentiation. Chronic myeloid leukemia Chronic myeloid leukemia Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia has the Philadelphia chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics, which contains the BCR-ABL1 fusion gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (which PMF does not have). The effect of constitutive tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase activation leads to uncontrolled granulocytic production. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can have constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis, sternal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly. Studies show elevated WBCs, increased immature cells in the peripheral blood smear Blood smear Myeloperoxidase Deficiency, and Philadelphia chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics demonstrated by cytogenetic techniques. Management includes tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitors, allogeneic HCT and palliative agents.
  • Polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera ( PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera): condition also associated with mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the JAK2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. However, PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera is from unregulated overproduction of mainly RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology despite low levels of erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology. The majority of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with hyperviscosity Hyperviscosity Hypercoagulable States symptoms. Management includes phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis, low-dose aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs), and myelosuppressive therapies.
  • Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. Essential Thrombocythemia (ET): proliferation of megakaryocytes associated with genetic mutations Genetic Mutations Carcinogenesis (in JAK2, CALR, or MPL). The megakaryocytes are large and mature-appearing. Clinical manifestations include headaches, visual disturbances, and erythromelalgia Erythromelalgia A peripheral arterial disease that is characterized by the triad of erythema, burning pain, and increased skin temperature of the extremities (or red, painful extremities). Erythromelalgia may be classified as primary or idiopathic, familial or non-familial. Secondary erythromelalgia is associated with other diseases, the most common being myeloproliferative disorders. Polycythemia Vera. Excessive counts of platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology result in both thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus and bleeding. Management aims to reduce platelet count (with medications such as hydroxyurea Hydroxyurea An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. Antimetabolite Chemotherapy) and decrease the risk of thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus (by systemic anticoagulation Anticoagulation Pulmonary Hypertension Drugs and/or antiplatelet agents Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Drugs). While ET and PMF share similar mutations, PMF has significant bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans and leukoerythroblastosis in the peripheral blood smear Blood smear Myeloperoxidase Deficiency
  • Chronic neutrophilic leukemia (CNL): rare disorder with proliferation of mature granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology in the blood and marrow. Organ infiltration can occur, leading to hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus. Increased leukocyte alkaline phosphatase score Leukocyte Alkaline Phosphatase Score Chronic Myeloid Leukemia is noted in this disorder. Chronic neutrophilic leukemia does not usually progress to AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia. Management is less clear, but ruxolitinib Ruxolitinib Targeted and Other Nontraditional Antineoplastic Therapy is an option.
  • Chronic eosinophilic leukemia Chronic eosinophilic leukemia Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia ( CEL CEL Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia): rare clonal chronic myeloproliferative disorder characterized by excessive production of eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation in the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow that leads to eosinophilic proliferation in the blood and organ infiltration (hepatomegaly/ splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly). Management is supportive and imatinib Imatinib A tyrosine kinase inhibitor and antineoplastic agent that inhibits the bcr-abl kinase created by chromosome rearrangements in chronic myeloid leukemia and acute lymphoblastic leukemia, as well as pdg-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors. Targeted and Other Nontraditional Antineoplastic Therapy therapy.

Other disorders resembling primary myelofibrosis

  • Acute myelofibrosis: very rare form of AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia in which there is rapid onset of severe bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. Other findings include teardrop RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia, and a leukoerythroblastic blood smear Blood smear Myeloperoxidase Deficiency. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy is usually not palpable. Management is induction chemotherapy Chemotherapy Osteosarcoma with or without hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation.
  • Secondary myelofibrosis (post-ET or post-PV): Fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow can develop in both PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera and ET. Secondary myelofibrosis requires a previous diagnosis of either ET or PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera. Clinical features and management are generally similar to those for PMF.

References

  1. Tefferi, A. (2021). Clinical manifestations and diagnosis of primary myelofibrosis, In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-primary-myelofibrosis
  2. Tefferi, A. (2021). Management of primary myelofibrosis. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/management-of-primary-myelofibrosis
  3. Tefferi, A. (2021). Pathogenic mechanisms in primary myelofibrosis. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/pathogenetic-mechanisms-in-primary-myelofibrosis?search=primary+myelofibrosis
  4. Visani, G., Finelli, C., Castelli, U., et al. (1990). Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol 75:4–9. https://pubmed.ncbi.nlm.nih.gov/2375922/
  5. DeLario, M.R., Sheehan, A.M., Ataya, R., et al. (2012). Clinical, histopathologic, and genetic features of pediatric primary myelofibrosis—an entity different from adults. Am J Hematol 87:461–464. https://pubmed.ncbi.nlm.nih.gov/22389089/
  6. Emanuel, R.M., Dueck, A.C., Geyer, H.L., et al. (2012). Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol 30:4098–4103. https://pubmed.ncbi.nlm.nih.gov/23071245/
  7. Deeg, H.J., Bredeson, C., Farnia, S., et al. (2015). Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups. Biol Blood Marrow Transplant. 21(11),1883–1887. https://pubmed.ncbi.nlm.nih.gov/26371371/
  8. Van Etten, R. (2021). Clinical manifestations and diagnosis of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-chronic-myeloid-leukemia
  9. Schiffer, C., Atallah, E. (2021). Overview of the treatment of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-chronic-myeloid-leukemia

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