Hospital Medicine

Essential thrombocythemia

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Essential Thrombocythemia

I. What every physician needs to know.

Essential Thrombocythemia is also known as Essential Thrombocytosis or ET. ET is considered one of the myeloproliferative disorders and is characterized by persistently elevated platelet counts, usually >600.

II. Diagnostic Confirmation: Are you sure your patient has Essential Thrombocythemia?

World Health Organization Diagnostic Criteria:

Platelets >450K (was >600K in original Polycythemia Vera Study Group criteria). Proliferation of mature megakaryocytes on bone marrow. Must exclude: iron deficiency, polycythemia vera, chronic myelogenous leukemia, myelofibrosis, splenectomy, and reactive causes such as inflammation, malignancy. Revised criteria: JAK2 clonal marker present (or if not present, the above reactive causes excluded). JAK 2 is present in about 50% of cases of ET.

Polycythemia Vera Study Group includes absence of the Philadelphia Chromosome, using molecular studies for BCR-ABL.

A. History Part I: Pattern Recognition.

Persistently high platelet count which is usually detected on routine CBC.

Most patients are asymptomatic and diagnosed after further work up for an incidentally found high platelet count.

Patients may have complaints of dizziness, light-headed, paresthesia, visual changes, or headaches. Patients may also have findings of bleeding, or alternately thrombosis.

B. History Part 2: Prevalence.

2 Females: 1 Males.

The prevalence in the United States is about 24 cases/100,000: A 2003 study reviewing commercial health insurance as well as Medicare and Medicaid claims data in Connecticut estimated the age standardized prevalence to be 24/100,000. Applying these numbers to the United States results in an estimate of 71,078 cases within the population.

Median age is 60-years old.

C. History Part 3: Competing diagnoses that can mimic Essential Thrombocythemia.

Post splenectomy.

Reactive thrombocytosis (inflammation, infection, post-surgical).

Iron deficiency.

Other myeloproliferative disorders (polycythemia, CML, myelofibrosis).

D. Physical Examination Findings.

Most patients will have a normal physical exam.

Splenomegaly may be present.

Erythromelalgia is characterized by erythema and warmth of the distal extremities. It may also be present in polycythemia vera.

E. What diagnostic tests should be performed?

CBC with differential.

Iron studies (iron, ferritin, TIBC).

BCR-ABL gene rearrangement to evaluate for CML.

JAK2.

C-reactive protein, ESR.

Bone marrow biopsy (optional, helpful if other studies unclear).

Physical exam to assess for splenomegaly: Splenomegaly may be found in myeloproliferative disorders but is unlikely in reactive causes of thrombocytosis. Exam may also reveal a focus of infection or inflammation which may be causing reactive increase in platelets.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Iron studies to exclude iron deficiency.

BCR-ABL to exclude chronic myelogenous leukemia.

CRP, ESR to exclude reactive causes.

JAK2 mutation: positive in about 50% of patients, but not specific for ET and may be present in other myeloproliferative disorders.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

None are necessary.

Ultrasound of the abdomen may be helpful in evaluating if splenomegaly is present.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Serum thrombopoeitin (TPO) levels: not specific for ET versus reactive causes.

III. Default Management.

The first step in the work up of a high platelet count is to determine if thrombocytosis is new or old (> 6 months). Then consider whether the thrombocytosis is reactive to an acute issue such as recent surgery or infection. Review the CBC to see if the patient has elevations in other cell lines; increased WBC or hemoglobin which would suggest polycythemia or CML instead of ET.

If ET is suspected, get JAK2 mutation which helps exclude reactive causes if it is positive.

If ET is your diagnosis, the next step is to risk stratify the patient into low risk versus high risk:

Low-risk < age 60, no prior thrombotic events, platelets <1 million/µl (or 1,000 x 109/L)

High-risk= age 60 or more, history of thrombotic events.

High-risk requires treatment to lower the platelets.

Low-risk patients may be observed.

The preferred treatment of high-risk patients is hydroxyurea + low dose aspirin.

An alternative is anagrelide (agylin), however this was shown to be inferior to hydroxyurea in clinical trials.

Low-dose ASA (75 to 325 mg/day) is helpful for vasomotor symptoms.

If a low-risk patient has platelets >1 million/µl, check a ristocetin cofactor (need value >30%) to screen for an acquired von Willebrands disease before starting ASA as patients who have an associated acquired von Willebrands may have increased bleeding.

A. Immediate management.

Not usually an emergency. If an ET patient presents with an acute severe thrombotic event such as a stroke with platelets >1 million/µl, consult hematology for platelet pheresis, which will quickly lower the platelet count. Platelet-lowering therapy such as hydroxyurea is simultaneously started for long term control.

B. Physical Examination Tips to Guide Management.

Monitor clinically for signs of bleeding, bleeding gums, DVT, erthromelalgia.

Patients with reactive thrombocytosis, even with platelets >1000 x109/L, will not usually experience vasomotor symptoms or significant bleeding or thrombosis.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

CBC with differential if on treatment with hydroxyurea: every 1-2 weeks at initiation and every 1-2 months if on a stable dose.

Hydroxyurea may cause myelosuppresion such as neutropenia, thrombocytopenia. Hold hydroxyurea if WBC < 2.5 x 109/L or neutrophils counts < 1000/mm3.

Monitor liver function studies in the unusual event of liver toxicity due to hydroxyurea. Monitor renal function as chronic kidney disease may warrant lower doses of hydroxyurea.

D. Long-term Management.

Hydroxyurea + low dose ASA.

Observation for low risk patients (CBC every 4-6 months).

Smoking cessation (may increase risk of thrombosis).

Avoid NSAIDS as they may increase the risk of bleeding.

E. Common Pitfalls and Side-Effects of Management.

If the patient had normal platelet counts on admission, and is now post-operative with a rising platelet count, it is most likely due to surgery or blood loss.

Hydroxyurea can cause severe prolonged myelosuppression, thus monitor closely during initiation and dose adjustments.

Be especially cautious in the elderly when using hydroxyurea.

Macrocytosis is a normal consequence of hydroxyurea.

Recommended dose of Hydroxyurea is 15 mg/kg a day. However, it is usually supplied in 500 mg tabs and dose is usually rounded to the nearest tablet size.

Hydroxyurea 500 -1000 mg PO daily, start with 500 mg in the elderly or those with increased creatinine. Increase as needed to keep goal platelet < 450 x 109/L.

Low-dose ASA daily. Avoid high doses of aspirin due to bleeding risk.

Some patients may not achieve goal platelets < 450 x 109/L (or if they do it is at the expense of severe anemia or neutropenia). In this situation, try to get as close as possible to goal levels.

About 8.3 percent of patients on hyroxyurea may develop mucocutaneous toxicity with skin ulcers or oral apthous ulcers, which may require discontinuation.

IV. Management with Co-Morbidities.

Pregnancy

If ET is diagnosed during pregnancy or in a woman who may become pregnant, AVOID Hydroxyurea, as it may cause birth defects.

Low-risk patients do not need treatment.

Platelets may decrease as a result of typical changes in pregnancy.

For high-risk patients requiring treatment, interferon alpha may be considered.

Elderly

Elderly patients need to be followed more closely and are at risk of toxicity, particularly myelosuppresion with hydroxyurea.

A. Renal Insufficiency.

Patients on hydroxyurea may require lower doses.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

If Anagrelide (Agrylin) is used as platelet-lowering therapy, use caution in patients with cardiac disease as common side effects include palpations and edema, and heart failure has rarely been reported.

D. Coronary Artery Disease or Peripheral Vascular Disease.

If Anagrelide (Agrylin) is used as platelet-lowering therapy, use caution in patients with cardiac disease as common side effects include palpations and edema.

E. Diabetes or Other Endocrine Issues.

No change in standard management.

F. Malignancy.

Malignancy may be a cause of reactive thrombocytosis.

Concurrent chemotherapy with hydroxyurea may increase myelosuppression.

Patients with malignancy on chemotherapy will likely have lower counts since chemotherapy is myelosuppressive.

G. Immunosuppression (HIV, chronic steroids, etc.).

Hydroxyurea may cause macrocytosis.

HIV medications can cause increased toxicity if used with hydroxyurea.

H. Primary Lung Disease (COPD, Asthma, ILD).

Monitor clinically for rare pulmonary fibrosis with hydroxyurea.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

Concurrent antiplatelet therapy may increase risk of bleeding.

Concurrent chemotherapy will increase myelosuppression.

K. Dementia or Psychiatric Illness/Treatment.

None

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Be aware that the hospitalized patient may be more at risk for both bleeding and thromboembolic events.

B. Anticipated Length of Stay.

Usually an outpatient course.

C. When is the Patient Ready for Discharge?

No need for hospitalization, ET can usually be managed as an outpatient.

D. Arranging for Clinic Follow-up.

If newly diagnosed and on medications such as hydroxyurea, CBC with differential in 1-2 weeks.

1. When should clinic follow up be arranged and with whom?

Hematology / Oncology within 4 weeks if you suspect the diagnosis, usually a non-urgent evaluation. If just started on hydroxyurea, appointment in 1-2 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Usually an outpatient evaluation. If ET is not diagnosed but suspected, order ESR, CRP, iron, ferritin, TIBC, peripheral blood for JAK 2.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

CBC with differential.

Comprehensive metabolic panel with liver function studies and creatinine.

E. Placement Considerations.

None; although the facility needs to know if the patient is on medication and how often to monitor CBC.

F. Prognosis and Patient Counseling.

Most patients have a normal life span.

Adverse predictors of survival are age >60 years & WBC > 15 x 109/L.

Rarely ET may progress to an acute leukemia (rates vary from 0.6-5% transformation) or myelofibrosis. M4 or M7 phenotype is the most common type of AML if blastic transformation occurs. Karyotypic abnormalities may also predispose to the progression of AML.

Older age, anemia, and platelets >1000K are associated with an increased risk of progression to leukemia.

Smoking may increase the risk of thromboembolic events, thus cessation is advised.

Avoid NSAIDS if on ASA as there is an increased risk of major bleeding.

Small case series have shown a higher rate of miscarriages, particularly in the first trimester in pregnant women with essential thrombocythemia.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

None

VII. What's the Evidence?

Tefferi, A, Thiele, J, Orazi, A, Kvasnikcka, HM, Barbui, T, Hanson, CA. "Proposals and rationale for revision of the World Health Organization diagnositc criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel,". Blood. vol. 110. 2007. pp. 1092.

Damaj, G, Delabesse, E, Le Bihan, C, Asnafi, V, Rachid, M, Lefrère, F, Radford-Weiss, I, Macintyre, E, Hermine, O, Varet, B. "Typical essential thrombocythaemia does not express bcr-abelson fusion transcript". Br J Haematol. vol. 116. 2002. pp. 812.

Schafer, AI. "Bleeding and thrombosis in the myeloproliferative disorders". 1. vol. 64. 1984.

Ma, X, VAnasse, G, Cartmel, B, Wang, Y, Selinger, HA. "Prevalence of polycythemia vera nad essential thrombocythemia". Am J Hematol. vol. 83. 2008. pp. 359.

Van genderen, PJ, Michiels, JJ. "Erythromelalgia: a pathognomonic microvascular thrombotic complication is essential thrombocythemia and polycythemia vera". Semin Thromb Hemost. vol. 23. 1997. pp. 357.

Murphy, S, Peterson, P, Iland, H, Laszlo, J. "Experience of the Polycythemia Vera Study Group with Essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment". Semin Hematol. vol. 34. 1997. pp. 29.

Budde, U, van Genderen, PJ. "Acquired Willebrand in patients with high platelet counts". Semin Thromb Hemost. vol. 23. 1997. pp. 425.

Ruggeri, M, Finazzi, G, Tosetto, A, Riva, S, Rodeghiero, F, Barbui, T. "No treatment for low-risk thrombocythemia: results from a prospective study". Br J Haematol. vol. 103. 1998. pp. 772.

Gangat, N, Wolanskyj, AP, McClure, RF, Li, CY, Schwager, S, Wu, W, Tefferi, A. "Risk stratification for survival and leukemic transformation is essential thrombocythemia: a single institutional study of 605 patients". Leukemia. vol. 21. 2007. pp. 270.

Tefferi, A, Fonseca, R, Pereira, DL, Hoagland, HC. "A long term retrospective study of young women with essential thrombocythemia". Mayo Clin Proc. vol. 76. 2001. pp. 22.

Shibata, K, Shimamoto, Y, Suga, K, Sano, M, Matsuzaki, M, Yamaguchi, M. "Essential thrombocythemia terminating in acute leukemia with minimal myeloid differentiation--a brief review of recent literature". Acta Haematol. vol. 91. 1994. pp. 84.

Antonioli, E, Guglielmelli, P, Pieri, L, Finazzi, M, Rumi, E, Martinelli, V, Vianelli, N, Luigia Randi, M, Bertozzi, I, De Stefano, V, Za, T, Rossi, E, Ruggeri, M, Elli, E, Cacciola, R, Cacciola, E, Pogliani, E, Rodeghiero, F, Baccarani, M, Passamonti, F, Finazzi, G, Rambaldi, A, Bosi, A, Cazzola, M, Barbui, T, Vannucchi, AM. "AGIMM Investigators Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN". Am J Hematol. vol. 87. 2012. pp. 552-4.

Latagliata, R, Spadea, A, Cedrone, M, Di Giandomenico, J, De Muro, M, Villivà, N, Breccia, M, Anaclerico, B, Porrini, R, Spirito, F, Rago, A, Avvisati, G, Alimena, G, Montanaro, M, Andriani, A, Gruppo, Laziale. "Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: The Mister Hyde face of a safe drug". Cancer. vol. 118. 2012. pp. 404.

Buss, DH, Cashell, AW, O'Connor, ML, Richards, F. "Occurrence, etiology, and clinical significance of extreme thrombocytosis: a study of 280 cases". Am J Med. vol. 96. 1994. pp. 247.

Beressi, AH, Tefferi, A, Silverstein, MN, Petitt, RM, Hoagland, HC. "Outcome analysis of 34 pregnancies in women with essential thrombocythemia". Arch Intern Med. vol. 155. 1995. pp. 1217.

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