Overview

Definition

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by excessive platelet production and increased thrombotic and hemorrhagic tendency. Other names are essential thrombocytosis and primary thrombocytosis.

Epidemiology

• Incidence: 1–2.5 cases per 100,000 in the United States
• Incidence increases with age (median age at diagnosis: 60 years)
• Female:male ratio of 2:1

Etiology

• Proliferation of bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow megakaryocytes due to presence of 1 of 3 driver mutations involving:
  • Janus kinase 2 (JAK2): 50%–60% of patients
  • Calreticulin (CALR): 25% of patients
  • Myeloproliferative leukemia virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview oncogene (MPL): 5%–10% of patients
• Predisposing conditions in patients with above mutations:
  • Age
  • Chronic 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

Clinical Presentation

Signs and symptoms

• Asymptomatic (60%): diagnosis made incidentally
• Weight loss, 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
• 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
• Pruritus (not commonly seen, unlike in 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)
• Vasomotor:
  • Headache, dizziness, syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
  • Erythromelalgia: red warm congestion and burning sensation of digits and toes due to microvascular thrombosis
  • Livedo reticularis: mottled reticulated purplish discoloration of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Transient visual problems: scintillating scotoma, amaurosis fugax, ophthalmic migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache
• 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

Complications

• Thrombosis:
  • Deep venous thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis) often involving unusual anatomic sites:
    • Portal vein 
    • Hepatic venous system ( Budd-Chiari syndrome Budd-Chiari syndrome Budd-Chiari syndrome is a condition resulting from the interruption of the normal outflow of blood from the liver. The primary type arises from a venous process (affecting the hepatic veins or inferior vena cava) such as thrombosis, but can also be from a lesion compressing or invading the veins (secondary type). The patient typically presents with hepatomegaly, ascites, and abdominal discomfort. Budd-Chiari Syndrome)
    • Splenic vein
    • Mesenteric vein
    • Retinal artery or vein
  • Cerebrovascular events, transient ischemic attacks
  • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism
  • MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Peripheral vascular disease (leading to gangrene)
  • Superficial thrombophlebitis
• Bleeding:
  • GI or genitourinary bleeding
  • Bruises, ecchymosis
  • Gingival bleeding
  • Excessive bleeding after trauma/surgery
• Recurrent first-trimester pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care loss

Diagnosis

Medical history

• Prior thrombotic events
• Chronic inflammatory diseases
• Autoimmune diseases
• Family history of thrombosis or other hematologic disorders
• History of splenectomy

WHO criteria (2016)

Diagnosis requires all 4 major criteria or first 3 major criteria and 1 minor criterion.

• Major criteria:
  • Platelet count ≥ 450 × 10⁹/L
  • 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. Structure of Bones marrow biopsy: megakaryocyte proliferation with large and mature morphologic features, without significant erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes or granulopoiesis
  • Does not fit the criteria for other myeloproliferative disorders (i.e., 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, 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)
  • Presence of JAK2, CALR, or MPL mutation
• Minor criterion: presence of other clonal marker or reactive thrombocytosis ruled out

Laboratory findings

• CBC:
  • ↑↑ Platelets (≥ 450 × 10⁹/L)
  • ↑ Bleeding time
  • Normal Hb
  • Normal WBC
• Biochemistry (all due to increased cell turnover):
  • ↑ Potassium
  • ↑ Uric acid
  • ↑ Phosphate
• Peripheral blood smear:
  • Increased 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
  • Platelet anisocytosis
• 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. Structure of Bones marrow biopsy:
  • Megakaryocytic hyperplasia
  • Giant megakaryocytes
  • Lobulated and/or hyperlobulated nuclei
• Genetic testing:
  • Screen for genetic mutations: JAK2 (most common), CALR, MPL
  • Strengthens diagnosis and also gives information regarding complications (CALR mutation has lower risk of thrombosis than JAK2 mutation)

Comparison with other myeloproliferative neoplasms

Myeloproliferative neoplasms can be compared with the following WHO classification:

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

Management approach

• Factors considered in treating patients with ET:
  • Presence and severity of symptoms
  • Presence of thrombotic events
  • Comorbidities (diabetes and other factors increase cardiovascular risk)
  • The risk for developing post-ET myelofibrosis and acute myeloid leukemia Acute Myeloid Leukemia 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 is lower than for developing thrombosis.
• Goals:
  • ↓ Risk of thrombosis and bleeding
  • ↓ Associated symptoms
• Therapeutic options:
  • Aspirin:
    • 40–100 mg once or twice daily
    • Screen for acquired VWF in patients with 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 > 1 million/µL (cannot give aspirin if VWF present owing to ↑ bleeding risk).
  • Hydroxyurea:
    • Cytoreductive agent of choice
    • Goal is to maintain platelet count at 100,000–400,000/µL.
    • Teratogenic
  • Anagrelide:
    • ↓ Platelet count and aggregation
    • Possible cardiac toxicity
  • Pegylated interferon-ɑ:
    • Immunomodulatory antiproliferative agent
    • Can be given to pregnant women

Risk stratification

• The choice of treatment is based on thrombosis risk stratification.
• Use of aspirin or cytoreductive therapy does not cure ET but can decrease risk of complications.

Differential Diagnosis

Other chronic myeloproliferative neoplasms

• Primary myelofibrosis Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis (PMF): chronic myeloproliferative neoplasm characterized by fibrosis of the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow and extramedullary 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 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. Primary myelofibrosis Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis is linked to the same somatic mutations as ET. Clinical findings are severe fatigue, splenomegaly, hepatomegaly, and 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. The peripheral blood smear shows leukoerythroblastosis and contains precursors of WBCs and RBCs, nucleated RBCs, and teardrop cells. Diagnosis is made by bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow examination and molecular testing. In contrast to ET, PMF is associated with obliterative bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow fibrosis. Management includes allogeneic hematopoietic stem cell transplantation and the medications ruxolitinib and fedratinib.
• PV: chronic myeloproliferative neoplasm characterized by overproduction of RBCs, distinguishing it from ET. In addition, WBCs and 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 are also increased, which differentiates PV from the erythrocytosis seen with chronic hypoxia and other conditions. Similar to ET, this disease has a genetic basis due to mutation in the JAK2 gene. Management includes phlebotomy, low-dose aspirin, and myelosuppressive therapies.
• 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, which contains the BCR-ABL1 fusion gene. The effect is constitutive tyrosine kinase activation leading to uncontrolled granulocyte production. Patients can have constitutional symptoms, sternal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and splenomegaly. Studies show elevated WBCs, increased immature cells on peripheral blood smear, and Philadelphia chromosomes demonstrated by cytogenetic techniques. Management includes tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation, and palliative agents.

Other disorders that resemble essential thrombocythemia

• Secondary thrombocythemia: reactive thrombocythemia is by far the most frequent cause of thrombocytosis encountered in routine clinical practice. This disorder can be due to chronic infection, malignancy, iron deficiency, having undergone splenectomy (or in cases of functional asplenia Asplenia Asplenia is the absence of splenic tissue or function and can stem from several factors ranging from congenital to iatrogenic. There is a distinction between anatomic asplenia, which is due to the surgical removal of the spleen, and functional asplenia, which is due to a condition that leads to splenic atrophy, infarct, congestion, or infiltrative disease. Asplenia, after blood loss), and autoimmune and chronic inflammatory conditions. Medical history, absence of specific mutations associated with ET and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy without hypercellularity and megakaryocyte cluster formation help differentiate this condition from ET.
• Myelodysplastic syndrome: group of malignant stem cell disorders characterized by hypercellularity of the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow yet with maturation defects. Notable findings are blast cells (< 20%), peripheral blood cytopenias, and dysplasia. There is a 30% risk of transformation into 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. Patients are older adults (> 60 years of age) and present with fatigue and symptoms of 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, neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (predisposing to infections), 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 (bleeding).