Essential Thrombocytosis 

Updated: Aug 22, 2019
Author: Asheesh Lal, MBBS, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Essential thrombocytosis (primary thrombocythemia) is a nonreactive, chronic myeloproliferative disorder in which sustained megakaryocyte proliferation leads to an increase in the number of circulating platelets [1] (see the images below). Mutations in JAK2, CALR, or MPL are found in approximately 90% of patients with essential thrombocytosis.

Peripheral blood smear in essential thrombocytosis Peripheral blood smear in essential thrombocytosis showing increased platelet numbers. Courtesy Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
Bone marrow biopsy in essential thrombocytosis sho Bone marrow biopsy in essential thrombocytosis showing increased megakaryocytes. Courtesy Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.

Essential thrombocytosis was first described by Epstein and Goedel in 1934[2] and was traditionally considered a clonal disorder that involved pluripotent stem cells. However, studies have indicated that some patients may have polyclonal hematopoiesis.[3]

Essential thrombocytosis is characterized by the following[4, 5, 6, 7, 8, 9, 10] :

  • A persistently elevated platelet count greater than 450,000/µL

  • Megakaryocytic hyperplasia

  • Splenomegaly

  • A clinical course complicated by thrombotic or hemorrhagic episodes or both

Pathophysiology

Platelet survival is normal in essential thrombocytosis. Instead, the elevated counts result from increased production of platelets by megakaryocytes. The cause of this increase in platelet production remains unclear, but possibilities include the following:

  • Autonomous production
  • Increased sensitivities to cytokines (eg, interleukin-3 [IL-3])
  • Decreased effect of platelet-inhibiting factors (eg, transforming growth factor [TGF] beta)
  • Defects in the accessory cell microenvironment

Bone marrow megakaryocytic precursors (colony-forming unit–megakaryocyte [CFU-Meg]) from patients with essential thrombocytosis form colonies in the absence of exogenous thrombopoietin (Tpo). There is no evidence for mutations in the genes for Tpo, and patients with essential thrombocytosis have normal or even decreased plasma Tpo levels, possibly reflecting increased Tpo clearance due to the elevated circulating platelet mass.

The majority of patients with essential thrombocytosis have mutations in one of three genes: Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Rare cases involve mutations in the thrombopoietin gene (THPO), which are associated with autosomal dominant hereditary thrombocytosis, and somatic mutations in tet methylcytosine dioxygenase 2 (TET2).[11]

MPL mutations have been associated with only about 3-5% of essential thrombocytosis cases. MPL codes for the thrombopoietin receptor protein, which promotes the growth and proliferation of megakaryocytes. The mutations consist of amino acid substitutions at position 505 in familial cases or 515 in sporadic cases These result in constitutive activation of the thrombopoietin receptor protein.[11]

JAK2 mutations possibly turn the thrombopoietin receptor on permanently, leading to overproduction of megakaryocytes. JAK2 mutation is seen in approximately 50-60% of patients.

Somatic mutations in CALR are detected in peripheral blood in the approximately 25% of essential thrombocythemia cases. CALR mutations are mutually exclusive with JAK2 or MPL mutations.

One study found that patients with JAK2 mutations tend to be older than patients with CALR mutations and to have a higher hemoglobin level and white blood cell count, as well as a lower platelet count and serum erythropoietin level. Risk of thrombosis was twice as high in patients with JAK2 mutations than in those with CALR mutations. Transformation to polycythemia was not observed in patients with CALR mutations, whereas the cumulative risk of polycythemic transformation was 29% at 15 years in those with JAK2 mutations.[12]

The mechanism by which thrombocythemia produces hemorrhage or thrombosis is not well defined. Several defects have been described, including a decrease in aggregation, hyperaggregation, and intracellular concentration of various chemicals. In addition, reports show a decrease in von Willebrand ristocetin cofactor activity and high molecular weight von Willebrand factor multimers.[13, 14] Some reports show patients with an acquired deficiency of antithrombin III, protein C, and protein S.[7]

Epidemiology

Frequency

United States

Clinicians diagnose approximately 6000 cases of essential thrombocytosis (primary thrombocythemia) each year. Some researchers speculate that the incidence rate may be several times higher. A study from southeastern Minnesota reported an incidence of 2.38 cases per 100,000 population per year.[15]

Mortality/Morbidity

Patients with essential thrombocytosis (primary thrombocythemia) have a 10-year survival rate of 64-80%, which may not be significantly different from that of the age-matched general population. Death occurs from thrombotic complications.

Transformation to acute myelogenous leukemia (AML) occurs in 0.6-5% of patients during the first decade and increases significantly in subsequent decades.[16] Risk factors include advanced age, anemia (hemoglobin less than 12 g/dL in females and less than 13.5 g/dL in males), leukocytosis, platelet count of >1,000,000/μL, and sequence variants/mutations involving TP53 and EZH2.[17]  Treatment with alkylating agents or radiophosphorus may be associated with higher risk of leukemic transformation.

Morbidity in patients with essential thrombocytosis may involve large-vessel or microvascular thrombosis and bleeding.

Sex

In older patients with essential thrombocytosis, the frequency is similar in both sexes. In younger patients, however, essential thrombocytosis occurs more often in women than in men.

Age

Essential thrombocytosis (primary thrombocythemia) is more frequent in older patients, although younger patients may develop the disease. The median age at diagnosis is 60 years, and perhaps up to 20% of patients are younger than 40 years. The disease is rare in children.

 

Presentation

History

Approximately 25-33% of patients with essential thrombocytosis (primary thrombocythemia) are asymptomatic at diagnosis. The remainder report vasomotor symptoms or complications from thrombosis or bleeding. Most symptomatic patients present with symptoms that relate to small- or large-vessel thrombosis.

  • Microvascular occlusion of the toes and fingers causes digital pain; gangrene; or erythromelalgia, which is is characterized by burning pain and dusky extremity congestion
  • The pain increases with exposure to heat and improves with cold; a single dose of aspirin may provide relief for several days

Headache is the most common neurologic symptom. Patients also report paresthesias and episodic transient ischemic attacks; transient neurologic symptoms include the following:

  • Unsteadiness
  • Dysarthria
  • Dysphoria
  • Vertigo
  • Dizziness
  • Migraine
  • Syncope
  • Scotoma
  • Seizures

Thrombosis of large veins and arteries is common and may result in occlusion of the leg, coronary, and renal arteries. Other arteries may be involved, including retinal arteries.[18] Venous thrombosis of the splenic, hepatic, or leg and pelvic veins may develop. Priapism is a rare complication. Pulmonary hypertension may result from pulmonary vasculature occlusion.

Bleeding complications are as follows:

  • The gastrointestinal tract is the primary site of bleeding complications; approximately 40% of these patients have duodenal arcade thrombosis, resulting in sloughing of the duodenal mucosa, simulating a duodenal ulcer

  • Other sites of bleeding include the skin, eyes, gums, urinary tract, joints, and brain

  • Bleeding is usually not severe and only rarely requires transfusion

  • The bleeding is generally associated with a platelet count greater than 1 million/µL

Constitutional symptoms occur in 20-30% of patients. Weight loss is unusual. Other symptoms include sweating, low-grade fever, and pruritus.

Pregnancy complications are as follows[19] :

  • Spontaneous abortions increase

  • Placental infarctions may occur, resulting in intrauterine growth retardation and fetal death.

  • In most cases, fetal loss occurs during the first trimester

  • A patient history of spontaneous abortion is the greatest risk factor for subsequent spontaneous abortions

  • Excessive bleeding during delivery is rare

  • Patients with successful pregnancies show a decrease in platelet count

Physical

In most patients with essential thrombocytosis, physical examination findings are unremarkable. Approximately 40-50% of patients present with splenomegaly; 20% present with hepatomegaly.

Causes

The etiology and predisposing factors for the development of essential thrombocytosis (primary thrombocythemia) remain unclear. Genetic transmission of this disorder is rare, although reports show several families with multiple members affected by essential thrombocytosis (primary thrombocythemia). Research suggests that a thrombopoietin production or receptor abnormality can cause familial essential thrombocytosis (primary thrombocythemia).[20]

 

DDx

Diagnostic Considerations

Elevation in the platelet count can result from physiologic or pathologic mechanisms. Essential thrombocytosis must be differentiated from secondary thrombocytosis, which may be due to an inflammatory state, iron deficiency, or recent surgery or to an underlying solid tumor or hematologic neoplasm.[21]

British guidelines propose the following five criteria for diagnosis of essential thrombocytosis[22] :

  1. Sustained platelet count ≥450 × 109/L
  2. Presence of an acquired pathogenetic mutation (eg, in the JAK2, CALR or MPL genes)
  3. No other myeloid malignancy, especially polycythemia vera, primary myelofibrosis, chronic myeloid leukemia, or myelodysplastic syndrome
  4. No reactive cause for thrombocytosis and normal iron stores
  5. Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm; reticulin is generally not increased (grades 0–2/4 or grade 0/3)

Diagnosis requires the presence of criteria 1–3 or criterion 1 plus criteria 3–5.[22]

Differential Diagnoses

 

Workup

Approach Considerations

The principal diagnostic criteria for essential thrombocytosis are an elevated platelet count, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation.[23]  Accordingly, the tests and procedures used in the workup for essential thrombocytosis include the following:

  • Complete blood cell count (CBC)
  • Genetic studies – For JAK2 V617F, CALR, and MPL mutations
  • Bone marrow aspirate and biopsy
  • Coagulation studies
  • Platelet aggregation studies
  • Serum chemistry

Cytogenetic study results are usually normal. Molecular studies (eg, polymerase chain reaction [PCR], Southern [genomic] blotting) may be used as sensitive means of excluding chronic myelogenous leukemia.

Computed tomography (CT) scanning or ultrasonography of the spleen may reveal splenomegaly in patients with essential thrombocytosis even when this condition is not physically detectable.

Histologic Findings

Approximately 90% of patients with essential thrombocytosis show an increase in bone marrow cellularity. Megakaryocytic hyperplasia is present. Giant megakaryocytes are frequently observed, and clusters of megakaryocytes may be present. Significant dysplasia of the megakaryocytes is unusual. Hyperplasia of granulocyte and reticulocyte precursors is common. Bone marrow reticulin is usually increased, but collagen fibrosis is uncommon.

In essential thrombocytosis, as in other myeloproliferative disorders, bone marrow iron stain results may be negative when other studies do not support the presence of iron deficiency. For practical purposes, a ferritin level that is within the reference range or increased, along with an RBC mean corpuscular volume (MCV) that is within the reference range, is sufficient to exclude reactive thrombocytosis secondary to iron deficiency and the possibility of polycythemia vera masked by iron deficiency.

Blood Studies

A complete blood cell count (CBC) is essential for the diagnosis of essential thrombocytosis. CBC findings are as follows:

  • The hallmark of essential thrombocytosis (primary thrombocythemia) is a sustained, unexplained elevation in the platelet count

  • Leukocytosis, erythrocytosis, and mild anemia may also be found

  • The peripheral blood may show occasional immature precursor cells (eg, myelocytes, metamyelocytes); large platelets (thrombocytes) are typically identifiable on routine peripheral blood smear

  • Mild basophilia and eosinophilia may be found

The results of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) studies are usually within reference ranges. The bleeding time may or may not be prolonged.

Platelet aggregation study findings are abnormal and show impaired platelet aggregation to epinephrine, adenosine diphosphate, and collagen but not to ristocetin and arachidonic acid. Some patients may present with spontaneous platelet aggregation.

A red blood cell (RBC) mass study helps to exclude polycythemia vera. The RBC mass is elevated in polycythemia vera, but is normal in essential thrombocytosis.

Other blood work results are as follows:

  • Uric acid (UA) levels are elevated in 25% of patients at diagnosis

  • Pseudohyperkalemia may occur, and falsely elevated phosphorus (P) and acid phosphatase levels may be noted

  • Pseudohypoxemia may develop from extreme thrombocytosis

  • Vitamin B-12 levels are increased in 25% of patients

  • Elevation of C-reactive protein (CRP), fibrinogen, and interleukin 6 levels suggests secondary thrombocytosis, because those are acute-phase reactants

On in vitro studies using peripheral blood mononuclear cells, an increase in the formation of endogenous erythroid cells and/or megakaryocytic colonies with increased sensitivity to interleukin-3 indicates the presence of abnormal hematopoietic progenitor cells. This finding is a diagnostic criterion for essential thrombocytosis; however, the test is primarily a research tool.

Genetic Studies

The principal mutations found in patients with essential thrombocytosis are in the JAK2 and CALR genes. Mutations in the MPL gene have been found in up to 4% of patients with essential thrombocytosis, but the prognostic significance of its presence is unclear.

JAK2

The JAK2 V617F mutation is present in 50% of patients with essential thrombocytosis.[24] V617F -positive patients displayed multiple features resembling polycythemia vera, with significantly higher hemoglobin levels, neutrophil counts, bone marrow erythropoiesis and granulopoiesis, more venous thromboses and a higher incidence of polycythemic transformation.

Teofili et al noted that specific JAK2 mutations activate the JAK-STAT pathway in polycythemia vera and essential thrombocytosis, with the presence of biologic markers such as endogenous erythroid colony (EECs) growth or over expression of polycythemia rubra vera 1 gene (PRV-1), RNA.[25] Because these findings are also seen in patients with wild-type JAK2, the authors hypothesized that a deregulation of the suppressor of cytokine signaling (SOCS) protein system in these cases could produce the activation of the JAK-STAT pathway.

Teofili et al evaluated 81 patients with polycythemia vera and essential thrombocytosis (53 adults and 28 children) for the methylation status of the SOCS-1, SOCS-2 and SOCS-3 CpG islands and for several myeloproliferative markers (including JAK2 and MPL mutations and clonality of hematopoiesis). The authors identified SOCS-1 or SOCS-3 hypermethylation in 23 patients, which was associated with a significant decrease of SOCS-1 or SOCS-3 RNA and protein levels, and demonstrated that the gene expression was restored by exposing cells to the demethylating agent 2-deoxyazacytidin.[25] The investigators concluded that "SOCS-1 or SOCS-3 hypermethylation can activate the JAK-STAT signaling pathway in alternative or together with JAK2 mutations," which may "represent a potential therapeutic target."[25]

Ohyashiki et al studied JAK2 mutational status with cytogenetic analysis in 54 patients with essential thrombocythemia to obtain evaluate the correlation between clinicohematologic features and genetic abnormalities.[26, 27] These investigators found that recurrent der(9;18) in essential thrombocythemia with JAK2 V617F is highly linked to myelofibrosis development.

Ohyashiki et al reported that of six patients with essential thrombocytosis who developed myelofibrosis, four had JAK2 V617F mutation. In addition, three of four patients with JAK2 V617F had add(18)(p11). However, the remaining two patients with essential thrombocytosis who developed myelofibrosis did not have JAK2 V617F or add(18)(p11), and none of the patients with essential thrombocytosis and JAK2 V617F and chromosome changes other than add(18)(p11) developed myelofibrosis. The authors concluded that "add(18)(p11), possibly due to der(9;18), may contribute a link to myelofibrosis in" JAK2 V617F -positivity in patients with essential thrombosis, whereas "those with wild-type JAK2 may use another pathway toward myelofibrosis."[26]

CALR

Mutations in the calreticulin (CALR) gene have been reported in 15-25% of patients with essential thrombocytosis. CALR mutations have been found to be exclusive of JAK-2 and MPL mutations. Initial studies have indicated that patients with CALR mutations are younger; more frequently male; and have higher platelet counts, lower hemoglobin and leukocyte counts, and a lower risk of thrombosis than those with the JAK2 mutation. There has been no difference in the rate of transformation to myelofibrosis.

Bone Marrow Aspirate and Biopsy

A bone marrow aspirate and biopsy are useful. Use specialized needles to obtain the aspirate and biopsy material over the posterior iliac crest. Obtaining an aspirate over the sternum may also be helpful, although most physicians prefer the posterior iliac crest. Do not attempt to obtain a biopsy from the sternum.

Bone marrow findings in essential thrombocytosis are as follows:

  • Approximately 90% of patients with show an increase in bone marrow cellularity

  • Megakaryocytic hyperplasia is common

  • Giant megakaryocytes are often observed; clusters of megakaryocytes may be present; significant dysplasia of the megakaryocytes is unusual

  • Hyperplasia of granulocyte and reticulocyte precursors is common

  • Bone marrow reticulin is usually increased,[28] but collagen fibrosis is uncommon

  • Iron stores may be absent in the bone marrow; this may be due to gastrointestinal tract bleeding or menorrhagia. However, in essential thrombocytosis, as in other myeloproliferative disorders, bone marrow iron stain results may be negative even when other studies do not support the presence of iron deficiency

 

Treatment

Medical Care

Treatment in patients with essential thrombocytosis (primary thrombocythemia) should be individualized on the basis of risk factors for thrombosis or bleeding. Risk factors include the following:

  • Age 60 years or older
  • History of thrombosis
  • Platelet count greater than 1500 x 10 9/L (1.5 million/µL), which is paradoxically associated with an increased risk of gastrointestinal tract bleeding in young women
  • Obesity
  • Cardiovascular risk factors such as smoking, hypertension, and hypercholesterolemia
  • Markers of hypercoagulability such as factor V Leiden and antiphospholipid antibodies [5]
  • JAK2 or MPL mutation

Observation may be appropriate for very-low-risk patients (ie, those lacking any of the above risk factors), although once-daily aspirin may be used in those with cardiovascular risk factors.[29] Generally, surgery or pregnancy is not associated with significantly increased thrombohemorrhagic risk in low-risk patients.

Low-risk patients (ie, those whose only risk factor is JAK2 or MPL mutation) can be treated with daily low-dose (100 mg) aspirin therapy; low-dose aspirin can be given twice daily, especially in patients with both of those risk factors.[29]  In addition, low-dose aspirin may be useful in treating patients with symptoms of microvascular occlusion (eg, erythromelalgia).

In emergencies, plateletpheresis may be useful to achieve a rapid decrease in platelet counts in the setting of acute thrombosis and/or marked thrombocytosis. In emergencies, plateletpheresis may be useful to achieve a rapid decrease in platelet counts. Plateletpheresis may be indicated in the setting of acute thrombosis and/or marked thrombocytosis.

Cytoreductive therapy should be used to decrease the platelet count in high-risk patients (eg, those over 60 years of age, those with a history of thrombosis, or platelet counts greater than 1.5 million/µL). Low-dose aspirin with cytoreductive therapy or observation may help treat intermediate-risk patients (ie, those who do not fit into either high-risk or low-risk groups).

Lifestyle modifications should be recommended for all patients with reversible risk factors. These include diet and exercise to promote weight loss for obese patients and smoking cessation for smokers.

Cytoreductive therapy

Cytoreductive therapy is used to reduce the risk of hemorrhage for patients with platelet counts above 1 million/μL. Extreme thrombocytosis may promote the abnormal adsorption of large von Willebrand factor (VWF) multimers. These patients should be screened for the presence of acquired von Willebrand disease (VWD). Low-dose aspirin therapy (eg, ≤100 mg/day) is acceptable if the ristocetin cofactor level is at least 30% in absence of other high risk factors; if it is less than 30%, all aspirin should be avoided.

Hydroxyurea is generally considered the first-line drug for cytoreductive therapy in essential thrombocytosis.[1, 30, 31, 32] Second-line agents include the following[32, 1] :

  • Busulfan
  • Anagrelide [31, 33]
  • Interferon alfa
  • Ruxolitinib

 A combination of cytoreductive agents may be needed in cases difficult to manage by single-agent therapy.

A European study in 382 patients concluded that cytoreductive therapy should not be used in patients with essential thrombocytosis who are age 40 to 59 years and lack high-risk factors. After a median follow-up of 73 months, vascular events, myelofibrotic transformation, or leukemic transformation were not significantly different in patients who received hydroxyurea plus aspirin than in those receiving aspirin only.[34]

Interferon alfa produces high rates of clinical and molecular responses in patients with JAK2 or CALR mutations.[35, 36] Italian guidelines recommend interferon alfa as a first-line platelet-lowering therapy for patients younger than 40 years, male or female, who have no childbearing potential.[37] Interferon alfa may also be used as second-line therapy in older patients.[38]

Ruxolitinib is a JAK1/JAK2 inhibitor that is approved for use in myelofibrosis and polycythemia vera, and some benefit has been reported in patients with essential thrombocytosis.[39] However, results of a randomized phase II trial of ruxolitinib versus best available therapy in patients with essential thrombocytosis or polycythemia vera who were resistant or intolerant to hydroxyurea suggest that ruxolitinib is not superior to current second-line treatments.[40]

In that trial, Harrison et al reported no evidence of improvement in complete response within 1 year in 27 of 58 patients treated with ruxolitinib versus 23 of 52 treated with best available therapy (46.6% versus 44.2%, respectively; P= 0.40). At 2 years, some disease-related symptoms had improved in patients receiving ruxolitinib relative to best available treatment, but rates of thrombosis, hemorrhage, and transformation were not significantly different, and molecular responses were uncommon.[40]

Another JAK inhibitor, fedratinib, is indicated for adults with intermediate-2 or high-risk post–essential thrombocythemia myelofibrosis. Fedratinib is a selective JAK2 inhibitor.[44]

The investigational drug imetelstat, a telomerase inhibitor, has shown promise in the treatment of essential thrombocytosis. In a phase II trial that included18 patients in whom prior treatments had been ineffective or had caused unacceptable side effects from, all 18 had hematologic responses, and 16 patients had a complete hematologic response; most patients also demonstrated a molecular response.[41]

Surgical Care

Patients with essential thrombocytosis (primary thrombocythemia) undergoing surgery are at increased risk for bleeding and thrombosis. Administer cytoreductive therapy to decrease the platelet count to the reference range before surgery. Avoid splenectomy because it can markedly increase the platelet count and the risk of both hemorrhagic and thrombotic events.

Consultations

A hematologist can help manage patients with essential thrombocytosis as well as monitor the cytoreductive therapy.

 

Medication

Medication Summary

Treatment for essential thrombocytosis (primary thrombocythemia) commonly includes the use of hydroxyurea, which is an antimetabolite similar in structure to naturally occurring compounds required for normal cell function. This structural similarity allows many of the antimetabolites to serve as substrates for important cellular enzymes. These substrates inhibit cell replication by direct inhibition of the enzymes needed for DNA replication or DNA repair or by incorporating directly into DNA.

Tumors and healthy cells with high growth fractions (eg, bone marrow) are sensitive to inhibition by the antimetabolites. Anagrelide is a phosphodiesterase-3 enzyme (PDE-3) inhibitor that inhibits platelet aggregation. Anagrelide appears to decrease platelet counts by decreasing platelet production.

Ruxolitinib is a Janus associated kinase (JAK1/JAK2) inhibitor. Busulfan is an alkylating agent that affects myeloid cells more than lymphoid cells. Each of these drugs decrease serum platelets.

Interferon alfa is a biologic response modifier. Interferon alfa is not known to be teratogenic and does not cross the placenta, perhaps making it safe for use during pregnancy. Platelet counts rebound in most patients after stopping interferon. Platelet counts are reduced to less than 600,000/μ L in 90% of cases after 3 months. Adjust drug dosing to achieve a platelet count within the reference range (target range, < 450,000/μ L).

Low-dose aspirin may be used to control microvascular symptoms.

Consider the patient's age, status, and adverse effect profile, in addition to the drug's cost, when choosing the treatment agent.[42]

Antimetabolites

Class Summary

Antimetabolites are similar in structure to the naturally occurring compounds required for the normal function of a cell. This structural similarity allows many of the antimetabolites to serve as substrates for important cellular enzymes, and they inhibit cell replication by direct inhibition of the enzymes needed for DNA replication or repair or by incorporating directly into DNA. Tumors and normal cells with high growth fractions (eg, bone marrow) are sensitive to inhibition by the antimetabolites.

Hydroxyurea (Hydrea)

Inhibitor of deoxynucleotide synthesis and one of the drugs of choice for inducing hematologic remission in chronic myelogenous leukemia.It is used off-label in the U.S. for essential thrombocytosis to decrease serum platelets. Hydroxyurea is less leukemogenic than alkylating agents (eg, busulfan, melphalan, chlorambucil). Myelosuppressive effects last a few days to a week and are easier to control than those of alkylating agents; busulfan has prolonged bone marrow suppression and can cause pulmonary fibrosis. The dose can be administered as a single daily dose or divided into 2-3 doses at higher dose ranges. Changes in blood cell counts may take 3-4 d to be apparent after a change in the drug dose.

PDE-3 Inhibitors

Class Summary

Phosphodiesterase-3 enzyme (PDE-3) inhibitors suppress megakaryocyte maturation, and thereby decrease platelet counts without affecting other hematopoietic cell lines.

Anagrelide (Agrylin)

Mechanism by which anagrelide reduces blood platelet count remains under investigation. It inhibits cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. Effective in polycythemia vera with elevated platelet counts as it elicits a dose-related decrease in platelet production. It is approved in the U.S. for thrombocythemia. Studies in patients support a hypothesis of dose-related reduction in platelet production, resulting from a decrease in megakaryocyte hypermaturation.

Kinase Inhibitors

Class Summary

Janus associated kinase (JAK) inhibitors (eg, ruxolitinib) mobilize signals to cytokine receptors that are disrupted by myelofibrosis.

Ruxolitinib (Jakafi)

Selectively inhibitors Janus associated kinase (JAK) inhibitors JAK1 and JAK2. These kinase inhibitors mediate signals if cytokines and growth factors responsible for hematopoiesis and immune function. It is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Biological Response Modifiers

Class Summary

The exact mechanism of action of biologic response modifiers is undetermined. These agents may be beneficial because of myelosuppressive and antiproliferative effects.

Interferon alfa 2b (Intron A)

Myelosuppressive protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Helps control thrombocytosis associated with myeloproliferative disorders.

Antineoplastics, Alkylating

Busulfan (Busulfex, Myleran)

Has prolonged bone marrow suppression and can cause pulmonary fibrosis. Consider use if other agent ineffective.

 

Follow-up

Complications

Thrombosis may be serious and life threatening in patients with essential thrombocytosis (primary thrombocythemia). Bleeding is usually from the gastrointestinal tract and is, in most cases, mild.

Transformation to acute myelogenous leukemia (AML) occurs in 0.6-5% of patients with essential thrombocytosis; the risk may be comparable to that of the healthy population. In an Italian series of 2316 retrospectively collected cases, the rate of transformation to AML or myelodysplastic syndrome was 1% in patients left untreated.[43] Use of interferon or hydroxyurea elicited a similar rate of AML or myelodysplastic syndrome, whereas transformation occurred in 4% of patients treated with alkylators.[43]

Hydroxyurea does not appear to increase the risk of transformation to AML in older patients when used as the sole agent for treatment of essential thrombocytosis (primary thrombocythemia). Whether prolonged use, as needed in younger patients, may be associated with an increased risk of transformation to AML is unclear.

Patients with essential thrombocytosis in whom hydroxyurea therapy fails and who are then treated with alkylating agents or phosphorus-32 have a higher risk of developing AML. Anagrelide or interferon alfa may be good therapeutic options in patients for whom hydroxyurea therapy fails.

Transformation to polycythemia vera and agnogenic myeloid metaplasia may occur in patients with essential thrombocytosis. Spontaneous abortion, intrauterine death, or intrauterine growth retardation may complicate pregnancy.

Prognosis

The life expectancy of patients with essential thrombocytosis (primary thrombocythemia) is nearly that of the healthy population. Median survival is approximately 20 years. For patients younger than age 60 years, median survival is 33 years.[9]

 

Questions & Answers

Overview

What is essential thrombocytosis (primary thrombocythemia)?

What is the pathophysiology of essential thrombocytosis (primary thrombocythemia)?

What is the prevalence of essential thrombocytosis (primary thrombocythemia) in the US?

What is the mortality and morbidity associated with essential thrombocytosis (primary thrombocythemia)?

What are the sexual predilections of essential thrombocytosis (primary thrombocythemia)?

Which age group has the highest prevalence of essential thrombocytosis (primary thrombocythemia)?

Presentation

Which clinical history findings are characteristic of essential thrombocytosis (primary thrombocythemia)?

What are the bleeding complications of essential thrombocytosis (primary thrombocythemia)?

What are the constitutional signs and symptoms of essential thrombocytosis (primary thrombocythemia)?

How does essential thrombocytosis (primary thrombocythemia) affect pregnancy outcomes?

Which physical findings are characteristic of essential thrombocytosis (primary thrombocythemia)?

What causes essential thrombocytosis (primary thrombocythemia)?

DDX

What are the diagnostic criteria for essential thrombocytosis (primary thrombocythemia)?

What are the differential diagnoses for Essential Thrombocytosis?

Workup

How is essential thrombocytosis (primary thrombocythemia) diagnosed?

Which histologic findings are characteristic of essential thrombocytosis (primary thrombocythemia)?

What is the role of blood testing in the workup of essential thrombocytosis (primary thrombocythemia)?

What is the role of genetic testing in the workup of essential thrombocytosis (primary thrombocythemia)?

What is the prevalence of CALR gene mutation in essential thrombocytosis (primary thrombocythemia)?

What is the role of bone marrow biopsy in the workup of essential thrombocytosis (primary thrombocythemia)?

Treatment

How is treatment selected for essential thrombocytosis (primary thrombocythemia)?

How is essential thrombocytosis (primary thrombocythemia) treated?

What is the role of cytoreductive therapy in the treatment of essential thrombocytosis (primary thrombocythemia)?

What precautions are taken for patients with essential thrombocytosis (primary thrombocythemia) undergoing surgery?

Which specialist consultations are beneficial to patients with essential thrombocytosis (primary thrombocythemia)?

Medications

What is the role of medications in the treatment of essential thrombocytosis (primary thrombocythemia)?

Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Essential Thrombocytosis?

Which medications in the drug class Biological Response Modifiers are used in the treatment of Essential Thrombocytosis?

Which medications in the drug class Kinase Inhibitors are used in the treatment of Essential Thrombocytosis?

Which medications in the drug class PDE-3 Inhibitors are used in the treatment of Essential Thrombocytosis?

Which medications in the drug class Antimetabolites are used in the treatment of Essential Thrombocytosis?

Follow-up

What are the possible complications of essential thrombocytosis (primary thrombocythemia)?

What is the prognosis of essential thrombocytosis (primary thrombocythemia)?