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 such as headaches, erythromelalgia, and transient visual disturbances. The clinical course can be complicated by thrombohemorrhagic events as well as progression to myelofibrosis and AML. The diagnosis is based on a laboratory finding of thrombocytosis, bone marrow biopsy, and genetic studies. Treatment aims to reduce platelet count by cytoreductive agents (hydroxyurea) and to decrease thrombosis with aspirin and systemic anticoagulation based on thrombosis risk stratification.

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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 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 oncogene (MPL): 5%–10% of patients
  • Predisposing conditions in patients with above mutations:
    • Age
    • Chronic inflammation

Pathophysiology

Hematopoiesis

Hematopoiesis starts with the hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors).

  • Lymphoid stem cells: give rise to lymphocytes
  • Myeloid stem cell: eventually differentiate into platelets, erythrocytes, granulocytes (neutrophils, basophils, eosinophils) and monocytes
    • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells.
    • Granulocyte macrophage colony-stimulating factor (GM-CSF) → differentiation from myeloid progenitors to granulocytes (neutrophils) and monocytes 
    • IL-5 → differentiation to eosinophils
    • Thrombopoietin (TPO) → differentiation to thrombocytes (platelets)
    • Erythropoietin (EPO) → differentiation to erythrocytes (RBCs)

Production of platelets:

  • Liver and kidneys produce thrombopoietin, which regulates production of platelets.
  • Thrombopoietin binds to the thrombopoietin cell receptor (TPO-R) (encoded by MPL gene) in stem cells → JAK2 activated for signal transduction
  • Results in hematopoietic cell division and maturation of megakaryocytes → platelets
Bone marrow hematopoiesis

Bone-marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

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

Driver mutations

  • Mutation of JAK2 gene:
    • Affects JAK2:
      • A nonreceptor tyrosine kinase (encoded by the JAK2 gene) in the cytoplasm involved in signal transduction (JAK–signal transducer of activators of transcription (STAT) pathway) 
      • Mediates the cellular response to growth factors and cytokines
      • Allows extracellular signals to activate genes 
      • Most common mutation: valine to phenylalanine at codon 617: JAK2 V617F 
    • Effect:
      • Gain of function mutation → constitutive activation of JAK–STAT resulting in cytokine-independent cell proliferation
      • Leads to activation of TPO-R → ↑ receptivity to thrombopoietin → overproduction of megakaryocytes
  • Mutation of CALR gene:
    • Affects calreticulin, a Ca2+-binding protein involved in cellular proliferation, differentiation, and apoptosis
    • Effect:
      • Mutant CALR interacts directly with the TPO-R, causing its constitutive activation
      • ↑ Platelets, even without thrombopoietin
  • Mutation of MPL gene:
    • The TPO-R is encoded by MPL.
    • Gain of function point mutation
    • Effect: constitutive activation of thrombopoietin receptor

Thrombosis in essential thrombocythemia

Increased incidence due to:

  • ↑ Platelet chemotaxis in response to procoagulation signals
  • Thrombus formation from misshapen, abnormally large platelets 
  • ↑ Levels of soluble markers of platelet activation (i.e., P-selectin)
  • Concurrent activation of leukocytes and endothelial cells → platelet aggregation

Hemorrhagic diathesis in essential thrombocythemia

Increased hemorrhagic diathesis in ET is due to:

  • Severe thrombocythemia (i.e., platelet counts > 1000 × 10⁹/L) → ↑ platelet metalloproteinases → ↑ proteases causing proteolysis
  • Proteolysis of large von Willebrand Factor (VWF) multimers leads to functional VWF deficiency → acquired type 2 von Willebrand syndrome

Clinical Presentation

Signs and symptoms

  • Asymptomatic (60%): diagnosis made incidentally
  • Weight loss, fever
  • Gout
  • Pruritus (not commonly seen, unlike in polycythemia vera)
  • Vasomotor:
    • Headache, dizziness, syncope, 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
    • Transient visual problems: scintillating scotoma, amaurosis fugax, ophthalmic migraine
  • Splenomegaly
Physical findings of essential thrombocythemia

Physical findings of essential thrombocythemia:
Livedo reticularis and areas of mottled bluish ischemia of fingers (A) and toe gangrene (B)

Image: “Thromboembolic complication in essential thrombocythemia” by Mozaheb, Z. License: CC BY 2.0

Complications

  • Thrombosis:
    • Deep venous thrombosis (DVT) often involving unusual anatomic sites:
      • Portal vein 
      • Hepatic venous system (Budd-Chiari syndrome)
      • Splenic vein
      • Mesenteric vein
      • Retinal artery or vein
    • Cerebrovascular events, transient ischemic attacks
    • Pulmonary embolism
    • MI
    • 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 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 marrow biopsy: megakaryocyte proliferation with large and mature morphologic features, without significant erythropoiesis or granulopoiesis
    • Does not fit the criteria for other myeloproliferative disorders (i.e., polycythemia vera, CML)
    • 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
    • Platelet anisocytosis
  • Bone 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)
Bone marrow biopsy in essential thrombocythemia

Bone marrow biopsy in essential thrombocythemia:
Increased megakaryocytes can be seen.

Image: “Sequential occurrence of thrombotic thrombocytopenic purpura, essential thrombocythemia, and idiopathic thrombocytopenic purpura in a 42-year-old African-American woman: a case report and review of the literature” by Farhat MH, Kuriakose P, Jawad M, Hanbali A. License: CC BY 2.0

Comparison with other myeloproliferative neoplasms

Myeloproliferative neoplasms can be compared with the following WHO classification:

Table: Classic types of myeloproliferative neoplasms
DiseaseMutationsKey points
CMLBCR-ABL1 (Philadelphia chromosome)Proliferation of mature and maturing granulocytes
ETJAK2, CALR, or MPLExcessive clonal platelet production
Polycythemia vera (PV)JAK2Elevated RBC mass
Primary myelofibrosis (PMF)JAK2, CALR, or MPLObliterative bone marrow fibrosis

Other types:

  • Chronic neutrophilic leukemia (CNL)
  • Chronic eosinophilic leukemia (CEL), 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 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 > 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.
Table: Thrombosis risk stratification
Risk for thrombosisFeaturesTreatment
Very low risk
  • No history of thrombosis
  • Age ≤ 60 years
  • No JAK2 V617F mutation
  • Observation alone
  • Vasomotor symptoms: aspirin daily
  • Cardiovascular risk factors: aspirin daily
Low risk
  • No history of thrombosis
  • Age ≤ 60 years
  • JAK2 V617F mutation
  • Aspirin once daily
  • JAK2 mutation and cardiovascular risk factors: aspirin twice daily
Intermediate risk
  • No history of thrombosis
  • Age > 60 years
  • No JAK2 V617F mutation
  • Aspirin once or twice daily (especially if with cardiovascular risk factors)
  • Hydroxyurea (may be given but with less clear benefit)
High risk
  • History of thrombosis
  • Age > 60 years, especially with JAK2 V617F mutation
  • Options:
    • Hydroxyurea
    • Anagrelide
    • Interferon-α
  • Aspirin once or twice daily
  • Anticoagulation if with history of DVT

Differential Diagnosis

Other chronic myeloproliferative neoplasms

  • Primary myelofibrosis (PMF): chronic myeloproliferative neoplasm characterized by fibrosis of the bone marrow and extramedullary hematopoiesis in the spleen and liver. Primary myelofibrosis is linked to the same somatic mutations as ET. Clinical findings are severe fatigue, splenomegaly, hepatomegaly, and anemia. The peripheral blood smear shows leukoerythroblastosis and contains precursors of WBCs and RBCs, nucleated RBCs, and teardrop cells. Diagnosis is made by bone marrow examination and molecular testing. In contrast to ET, PMF is associated with obliterative 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 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: malignant proliferation of the granulocytic cell line, with a fairly normal differentiation. 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, 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, after blood loss), and autoimmune and chronic inflammatory conditions. Medical history, absence of specific mutations associated with ET and 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 yet with maturation defects. Notable findings are blast cells (< 20%), peripheral blood cytopenias, and dysplasia. There is a 30% risk of transformation into AML. Patients are older adults (> 60 years of age) and present with fatigue and symptoms of anemia, neutropenia (predisposing to infections), or thrombocytopenia (bleeding).

References

  1. Michiels, J.J., et al. (2006). The paradox of platelet activation and impaired function: platelet–von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera. Semin Thromb Hemost 32:589–604. https://doi.org/10.1055/s-2006-949664
  2. Rick, M. (2021). Acquired von Willebrand syndrome. UpToDate. Retrieved April 23, 2021, from https://www.uptodate.com/contents/acquired-von-willebrand-syndrome
  3. Tefferi, A. (2021). Diagnosis and clinical manifestations of essential thrombocythemia. UpToDate. Retrieved April 20, 2021, from https://www.uptodate.com/contents/diagnosis-and-clinical-manifestations-of-essential-thrombocythemia
  4. Tefferi A. (2021). Prognosis and treatment of essential thrombocythemia. UpToDate. Retrieved April 20, 2021, from https://www.uptodate.com/contents/prognosis-and-treatment-of-essential-thrombocythemia
  5. Tefferi, A., Barbui, T. (2015). Essential thrombocythemia and polycythemia vera: focus on clinical practice. Mayo Clin Proc 90:1283–1293. https://doi.org/10.1016/j.mayocp.2015.05.014

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