Essential thrombocytosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]Parth Vikram Singh, MBBS[3]
Overview
Essential thrombocytosis (ET) or primary thrombocytosis is a clonal myeloproliferative neoplasm characterized by thrombocytosis and risks of thrombosis and bleeding. It is a rare hematologic disorder which arises from hematopoietic stem cells that give rise to megakaryocytes which in turn produce platelets (thrombocytes), that are normally involved in blood clotting. Essential thrombocytosis is characterized by overproduction of platelets in the absence of an underlying disease. ET is defined by a persistent platelet count >=450 x 10^9/L.[1] Essential thrombocytosis was first defined by Emil Epstein and Alfred Goedel, two Austrian pathologists, in the year 1934 and was initially called hemorrhagic thrombocythemia.[2] Subsequently, essential thrombocytosis was classified as a myeloproliferative disorder along with chronic myelogenous leukemia (CML), polycythemia vera (PV), and chronic idiopathic myelofibrosis (CIMF).[3] Approximately 90% of patients have JAK-STAT pathway driver variants (JAK2 64%, CALR 23%, MPL 4%); about 10% are triple-negative. The incidence of essential thrombocytosis is approximately 0.6-2.5 cases per 100,000 individuals worldwide annually.[4] The annual incidence rate in the US is 1.5 per 100,000 persons. A Swedish population-based study with an age-standardized incidence 1.6 per 100,000, similar to US adults. The prevalence of essential thrombocytosis is about 30 for every 100,000 people worldwide.[5] Females are more commonly affected with essential thrombocytosis than males.[6] The female to male ratio is approximately 2 to 1.[4] The median age at diagnosis is 59 years, and the median overall survival exceeds 35 years among those diagnosed at age 40 years or younger. Symptoms of essential thrombocytosis include vision disturbances, transient loss of consciousness, chest pain, intense burning pain in hands or feet (erythromelalgia), numbness and tingling of hands and feet, persistent and painful erection of the penis (priapism).[7] Bone marrow biopsy may be helpful in the diagnosis of essential thrombocytosis, in addition to ruling out other secondary causes of thrombocytosis.[8] The majority of cases of essential thrombocytosis only require supportive care. ET is associated with increased risks of arterial thrombosis (11%), venous thrombosis (7%), and hemorrhagic complications (8%). Pharmacologic medical therapies for essential thrombocytosis include aspirin therapy for low risk patients and platelet lowering drugs such as (hydroxyurea, interferon-α, and anagrelide) for high risk patients.
Historical Perspective
Essential thrombocytosis was first defined by Emil Epstein and Alfred Goedel, two Austrian pathologists, in the year 1934 and was initially called hemorrhagic thrombocythemia.[2]
Classification
There is no classification system established for essential thrombocytosis. However, essential thrombocytosis may be broadly classified into sporadic and familial forms.[9]
Pathophysiology
Essential thrombocytosis arises from hematopoietic stem cells which give rise to megakaryocytes which give rise to platelets (thrombocytes), that are normally involved in blood clotting. Approximately 90% of patients have JAK-STAT pathway driver variants: JAK2 (64%), CALR (23%), and MPL (4%). About 10% are triple-negative (no JAK2/CALR/MPL variant). Development of essential thrombocytosis is the result of a genetic mutation in the janus kinase 2 (JAK2) gene in 50% of the patients. Other genes that may be involved in the pathogenesis of essential thrombocytosis are CALR, MPL, and THPO genes.[10] On microscopic histopathological analysis, thrombocytosis and bone marrow hyperplasia with hyperlobated megakaryotic nuclei evident of thrombopoiesis are characteristic findings of essential thrombocytosis.
Epidemiology and Demographics
The incidence of essential thrombocytosis is approximately 0.6-2.5 cases per 100,000 individuals worldwide annually.[4] The annual incidence rate of ET in the US is 1.5 per 100,000 persons (age-standardized incidence 1.6 per 100,000 in a Swedish population-based study). The median age at diagnosis is 59 years.[11] The prevalence of essential thrombocytosis is approximately 30 per 100,000 individuals worldwide.[5] The incidence of essential thrombocytosis increases with age; the median age at diagnosis is 65-70 years. Patients of all age groups may develop essential thrombocytosis. However, essential thrombocytosis commonly affects individuals older than 60 years of age.[6] Females are more commonly affected with essential thrombocytosis than males.[6] The female to male ratio is approximately 2 to 1.[4]
Risk Factors
Common risk factor in the development of essential thrombocytosis is female sex.[12] Common risk factors in the development of thrombotic complications in patients with essential thrombocytosis are previous history of thrombotic events and age greater than 60 years.[12]
Screening
Screening for essential thrombocytosis by cell-based quantitative assays for JAK2V617F mutation is recommended among individuals with a positive family history for the disease (autosomal dominant inheritance) and in patients who present with thrombocytosis, erythrocytosis, and monocytosis.[13][14]
Causes
Essential thrombocytosis may be caused by a mutation in the janus kinase 2 (JAK2) gene (in 64% of the patients), CALR (23%), MPL (4%), or THPO genes. About 10% are triple-negative (no JAK2/CALR/MPL variant).
Differential Diagnosis
Essential thrombocytosis must be differentiated from other causes of thrombocytosis, such as chronic myelogenous leukemia (CML), myelodysplastic syndrome, polycythemia vera, primary myelofibrosis, secondary thrombocytosis.[15] Secondary causes account for >85% of thrombocytosis; exclude secondary thrombocytosis before diagnosing ET.
Table: ET vs secondary thrombocytosis[16]
| Feature | Suggests ET | Suggests secondary thrombocytosis |
| Clinical clues | Microcirculatory symptoms like s include erythromelalgia, acral paresthesias, burning toes and fingers, blurred vision, or headaches (~29%);
thrombosis history (~22%); splenomegaly (~12%); splanchnic vein thrombosis (~5%); Superficial thrombophlebitis (<5%); cerebral vein thrombosis (<2%) |
Symptoms/signs of infection/inflammation/malignancy;
recent trauma/surgery; prior splenectomy; iron deficiency |
| Exam | Palpable splenomegaly | Absence of splenomegaly |
| Labs | Sustained thrombocytosis; JAK2/CALR/MPL variant detected | New-onset thrombocytosis;
positive blood culture; neutrophilia/left shift; elevated CRP/ESR; iron deficiency; functional asplenia markers (Howell-Jolly bodies, nucleated RBCs) |
| Treatment note | - | No evidence supports routine aspirin/anticoagulation/cytoreduction/plateletpheresis for reactive thrombocytosis regardless of platelet count |
Table: Common causes of secondary thrombocytosis.[17]
| Cause (percent representation) | Mechanism | Typical management |
| Infections (17%-43%) | Inflammatory cytokines; nonspecific stimulation; platelet release | Resolves with treatment; may persist with chronic infection |
| Inflammatory diseases (4%-12%) | Increased thrombopoietic factors | Treat underlying condition |
| Malignancy (10%) (eg, lung/GI/lymphomas) | Increased thrombopoietic factors | Treat underlying malignancy |
| Iron deficiency (7%-11%) | Increased progenitor proliferation | Replete iron; typically resolves in 1-2 months |
| Splenectomy (1%-2%) | Decreased sequestration/turnover; peak 1-3 weeks | May be lifelong; may resolve in 1-5 years |
| Surgery/trauma (22%-32%) | Increased thrombopoietic factors from tissue damage | Resolves in days to weeks |
| Rebound thrombocytosis (7%) | Recovery from chemotherapy; cessation of excess alcohol; vitamin deficiency/ITP treatment | Resolves in 2-4 weeks |
| Drugs (1%-3%) | Medication-related | Dose modify/stop (variable) |
Natural History, Complications and Prognosis
If left untreated, patients with essential thrombocytosis may progress to develop symptoms like headache, dizziness, vision disturbances, chest pain, intense burning pain in hands and/or feet (erythromelalgia), numbness and tingling of hands and feet, priapism (persistent and painful erection of the penis) and so on depending on the vessel occluded with the thrombus.
Common complications of essential thrombocytosis include thrombotic events (DVT, cerebrovascular accidents,etc), bleeding (bruises, gum bleeds, epistaxis, etc), acute leukemia and myelofibrosis.[18][19] ET is associated with increased risks of arterial thrombosis (11%), venous thrombosis (7%), and hemorrhagic complications (8%).[20] In one study of 170 patients with ET, 20% had laboratory findings consistent with acquired von Willebrand syndrome (AvWS); mean platelet count was 701 x 10^9/L with AvWS vs 472 x 10^9/L without AvWS (P < .01). Screening for clinically relevant AvWS is generally advised when platelet count is >1000 x 10^9/L (reported in 16%–26%) because this is associated with increased bleeding susceptibility. Aspirin is generally avoided if von Willebrand factor activity is <20%-30% until corrected with cytoreductive therapy.
Prognosis is generally good, and the survival rate of patients is usually normal with regular medical supervision. However, the disease may rarely undergo a leukemic conversion or develop myelofibrosis. At a median of 8.5 years from diagnosis, approximately 10% of patients develop myelofibrosis and about 3% develop acute myeloid leukemia.
Median overall survival varies by age and sex:
- <50 years: 39 years (women) and 31 years (men);
- 50-70 years: 21 years (women) and 20 years (men);
- >70 years: 11.2 years (women) and 8.4 years (men).
Diagnosis
The diagnosis of ET should not be made until secondary causes of thrombocytosis are excluded, because secondary causes account for more than 85% of thrombocytosis cases. Patients with thrombocytosis should be evaluated for infections, solid tumor malignancy (eg, breast or lung carcinomas; lymphomas) or lymphoma, postsplenectomy state/functional asplenia (eg, Howell-Jolly bodies), iron deficiency, and rebound thrombocytosis (eg, recovery from excess alcohol use or chemotherapy). If no secondary cause is suggested clinically, peripheral blood testing for JAK2, CALR, and MPL variants is recommended.
Diagnostic Criteria
The diagnosis of essential thrombocytosis is made when all four of the following diagnostic criteria are met:[8]
- Sustained elevation of platelet counts > 450,000,000 × 10³/L, AND
- Bone marrow biopsy specimen showing proliferation, mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes and no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis, AND
- Not meeting WHO criteria for polycythemia vera (PV), PMF, CML, MDS, or other myeloid neoplasm, AND
- Demonstration of JAK2 617VF or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis. Presence of the first 3 criteria plus no evidence for secondary thrombocytosis is also sufficient for diagnosis.
History and Symptoms
People with essential thrombocytosis are usually asymptomatic. Symptoms[7] of essential thrombocytosis include vision disturbances, transient loss of consciousness, chest pain, intense burning pain in hands or feet (erythromelalgia), numbness and tingling of hands and feet, persistent and painful erection of the penis (priapism). Neurologic symptoms like headache may occur but the pathophysiology is not completely understood.[7] A positive family history of may be present in those with familial essential thrombocytosis.
Laboratory Findings
Laboratory findings consistent with the diagnosis of essential thrombocytosis include abnormal complete blood count (CBC), elevated platelet count, peripheral blood smear showing large platelets, megakaryocyte fragments and platelet aggregates, presence of JAK2 mutation and absence of BCR-ABL or Philadelphia chromosome.[21] Leukocytosis, erythrocytosis, and mild anemia may be present. Bone marrow biopsy is an important test and needed to make a diagnosis of essential thrombocytosis as per WHO definition.[8]
Electrocardiogram
There are no EKG findings associated with essential thrombocytosis. However, EKG should always be ordered in essential thrombocytosis patients who present with chest pain to rule out other dangerous causes of chest pain like myocardial infarction (MI).
Chest X Ray
A chest x-ray is not diagnostic of essential thrombocytosis. However, a chest x-ray may be a helpful test in the management of complications that develop due to essential thrombocytosis, such as pulmonary thromboembolism.[22]
CT Scan
CT scan is not diagnostic of essential thrombocytosis. Findings on abdominal CT suggestive of essential thrombocytosis include splenomegaly. A spiral chest CT may be helpful in the diagnosis of complications from essential thrombocytosis like pulmonary thromboembolism in patients with suggestive symptoms.[22]
MRI
There are no MRI findings associated with essential thrombocytosis.
Ultrasound
Abdominal ultrasound may be helpful in the diagnosis of Essential thrombocytosis. Findings on abdominal ultrasound suggestive of essential thrombocytosis include Splenomegaly.[23] There are no electrocardiogram findings associated with essential thrombocytosis.
Other Imaging Findings
There are no other imaging studies associated with essential thrombocytosis.
Bone Marrow Biopsy Findings
Bone marrow biopsy is an important test and needed to make a diagnosis of essential thrombocytosis[8] as per WHO definition. The bone marrow biopsy shows hypercellularity with clusters of megakaryocytes that stain positive for iron. There may be increased reticulin but no collagen fibrosis.
Treatment
Medical Therapy
The majority of cases of essential thrombocytosis only require supportive care. Pharmacologic medical therapies for essential thrombocytosis include aspirin therapy for patients at low risk and platelet lowering drugs (Hydroxyurea, interferon-α and anagrelide) for patients at high risk for thrombosis.
Treatment Algorithm and Evidence[24]
1) Assess JAK2 status and prior major thrombosis (excluding superficial thrombophlebitis).
2) Very low risk (age <60, JAK2 wild type, no prior thrombosis): observation alone or once-daily aspirin; if cardiovascular risk factors (eg. hypertension, diabetes mellitus, hyperlipidemia, tobacco use) are present, use once-daily aspirin.
3) Low risk (age <60, JAK2 variant, no prior thrombosis): twice-daily aspirin (consider once-daily in selected cases per clinician judgment).
4) Intermediate risk (age >=60, JAK2 wild type, no prior thrombosis): twice-daily aspirin; in selected patients if cardiovascular risk factors are present, consider hydroxyurea and once-daily aspirin.
5) High risk (prior thrombosis OR age >=60 with JAK2 variant): hydroxyurea plus aspirin (often twice-daily); if venous thrombosis, add systemic anticoagulation.
6) Second-line cytoreductive options for hydroxyurea intolerance/refractory disease: pegylated interferon alfa or busulfan.
Aspirin safety note: In extreme thrombocytosis, aspirin requires monitoring for bleeding and acquired von Willebrand syndrome; aspirin is generally avoided if von Willebrand factor activity is <20%-30%. Screening is advised for platelet count >1000 x 10^9/L or excessive mucocutaneous bleeding.
Venous thrombosis: For splanchnic or cerebral venous thrombosis, treatment often includes LMWH for 1-3 months followed by long-term anticoagulation with vitamin K antagonists or DOACs indefinitely unless risk-benefit changes.
Surgery
Surgical intervention is not recommended for the management of essential thrombocytosis.
Perioperative management should have a multidisciplinary approach involving hematology and the surgical team. Some experts target preprocedure platelet counts <450 x 10^9/L in high-risk and <600 x 10^9/L in low-risk patients. Achieving the low-risk target may require a short course of hydroxyurea.[25]
Evidence is lacking for perioperative aspirin/anticoagulation decisions specific to ET, so experts recommend following general perioperative guidelines for people without ET.
Primary Prevention
There is no established method for primary prevention of Essential thrombocytosis.
Secondary Prevention
Secondary prevention strategy following essential thrombocytosis include low dose aspirin therapy.
References
- ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help). - ↑ 2.0 2.1 Steven Sanchez & April Ewton (2006). "Essential thrombocythemia: a review of diagnostic and pathologic features". Archives of pathology & laboratory medicine. 130 (8): 1144–1150. PMID 16879015. Unknown parameter
|month=ignored (help) - ↑ Levine, R. L.; Gilliland, D. G. (2008). "Myeloproliferative disorders". Blood. 112 (6): 2190–2198. doi:10.1182/blood-2008-03-077966. ISSN 0006-4971.
- ↑ 4.0 4.1 4.2 4.3 Fabris F, Randi ML (2009). "Essential thrombocythemia: past and present". Intern Emerg Med. 4 (5): 381–8. doi:10.1007/s11739-009-0284-x. PMID 19636672.
- ↑ 5.0 5.1 Essential Thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia. Accessed on October 29, 2015
- ↑ 6.0 6.1 6.2 Essential Thrombocythemia (ET). MPN Research foundation. http://www.mpnresearchfoundation.org/Essential-Thrombocythemia Accessed on November 15, 2015.
- ↑ 7.0 7.1 7.2 Brière JB (2007). "Essential thrombocythemia". Orphanet J Rare Dis. 2: 3. doi:10.1186/1750-1172-2-3. PMC 1781427. PMID 17210076.
- ↑ 8.0 8.1 8.2 8.3 Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1182/blood-2007-04-083501 Check
|pmid=value (help). - ↑ Trifa, Adrian P.; Cucuianu, Andrei; Popp, Radu A. (2014). "Familial Essential Thrombocythemia Associated withMPLW515L Mutation in Father andJAK2V617F Mutation in Daughter". Case Reports in Hematology. 2014: 1–3. doi:10.1155/2014/841787. ISSN 2090-6560.
- ↑ Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
- ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help). - ↑ 12.0 12.1 Beer PA, Erber WN, Campbell PJ, Green AR (2011). "How I treat essential thrombocythemia". Blood. 117 (5): 1472–82. doi:10.1182/blood-2010-08-270033. PMC 3145107. PMID 21106990.
- ↑ The Asco Post. JAK2 and MPL Mutation Screening: What Are the Indications and How to Interpret the Results. http://www.ascopost.com/issues/february-15-2012/jak2-and-mpl-mutation-screening-what-are-the-indications-and-how-to-interpret-the-results.aspx
- ↑ Tefferi A, Noel P, Hanson CA (2011). "Uses and abuses of JAK2 and MPL mutation tests in myeloproliferative neoplasms a paper from the 2010 William Beaumont hospital symposium on molecular pathology". J Mol Diagn. 13 (5): 461–6. doi:10.1016/j.jmoldx.2011.05.007. PMC 3157620. PMID 21723416.
- ↑ Essential Thrombocytosis Differential Diagnoses. Medscape. http://emedicine.medscape.com/article/206697-differential Accessed on November 12, 2015.
- ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help). - ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help). - ↑ Frewin, R (October 2012). "Headache in essential thrombocythaemia" (PDF). International Journal of Clinical Practice. 66 (10): 976–83. doi:10.1111/j.1742-1241.2012.02986.x. PMC 3469735. PMID 22889110. Unknown parameter
|coauthors=ignored (help) - ↑ Tefferi, A (March 2011). "Annual Clinical Updates in Hematological Malignancies: a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management". American Journal of Hematology. 86 (3): 292–301. doi:10.1002/ajh.21946. PMID 21351120.
- ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help). - ↑ Essential Thrombocythemia. Merck manual. http://www.merckmanuals.com/professional/hematology-and-oncology/myeloproliferative-disorders/essential-thrombocythemia. Accessed on November 11,2015.
- ↑ 22.0 22.1 Arampatzis, Spyridon; Stefanidis, Ioannis; Lakiopoulos, Vassilios; Raio, Luigi; Surbek, Daniel; Mohaupt, Markus G (2010). "Postpartal recurrent non-ST elevation myocardial infarction in essential thrombocythaemia: case report and review of the literature". Thrombosis Journal. 8 (1): 12. doi:10.1186/1477-9560-8-12. ISSN 1477-9560.
- ↑ How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood journal. http://www.bloodjournal.org/content/113/22/5394?sso-checked=true Accessed on November 17, 2015.
- ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help). - ↑ Tefferi A, Gangat N, Loscocco GG, Guglielmelli P, Szuber N, Pardanani A, Orazi A, Barbui T, Vannucchi AM (February 2025). "Essential Thrombocythemia: A Review". JAMA. 333 (8): 701–714. doi:10.1001/jama.2024.25349. PMID 39869325 Check
|pmid=value (help).