Essential thrombocytosis medical therapy

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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

The majority of cases of essential thrombocytosis only require supportive care. Anti-thrombotic therapy is individualized based on patients' risk of developing thrombosis, which include aspirin therapy for low-risk patients and platelet lowering drugs (hydroxyurea, interferon-α and anagrelide) for high-risk patients.

Risk Stratification

• Individuals with essential thrombocytosis are grouped into high-risk and low-risk groups, based on the presence or absence of risk factors for the development of complications.
• Risk factors guide therapeutic decisions.
• The risk factors for complications include:
  • Very low risk (age <60, JAK2 wild type, no prior thrombosis)
  • Low risk (age <60, JAK2 variant, no prior thrombosis)
  • Intermediate risk (age >=60, JAK2 wild type, no prior thrombosis)
  • High risk (prior thrombosis OR age >=60 with JAK2 variant)
• In a study of 1019 patients, annual thrombosis risk was
  • 1.05%/year in the very-low-risk category and 0.44%/year among very-low-risk patients without cardiovascular risk factors;
  • 1.59%/year in low risk with JAK2 variant alone and 2.57%/year in low risk with JAK2 variant plus cardiovascular risk factors;
  • 1.44%-1.64%/year in intermediate risk; and
  • 2.36%-4.17%/year in high risk.

Medical Therapy

• Majority of the patients with essential thrombocytosis are asymptomatic and do not require treatment. Patients are usually diagnosed with essential thrombocytosis on routine testing for other conditions.
• Patients at low risk for complications are placed on low dose aspirin therapy to lower the risk of thrombosis. However, there may be an increased risk of bleeding, if aspirin is initiated whilst the platelet count is very high or, if the patient is predisposed to gastrointestinal bleeds. In the latter cases, aspirin is withheld.
• In those who are at high risk for complications, platelet reduction can be achieved by hydroxyurea (hydroxycarbamide), interferon-α or anagrelide.
• The PT1 study compared hydroxyurea in combination with aspirin to anagrelide in combination with aspirin as initial therapy for essential thrombocytosis. Hydroxyurea was superior, with lower risk of arterial thrombosis, lower risk of severe bleeding and lower risk of transformation to myelofibrosis (although the rate of venous thrombosis was higher with hydroxycarbamide than with anagrelide).
• In life threatening cases, emergent plateletpheresis may be performed where the blood of a patient is passed through an apparatus which separates out platelets and returns the remainder to the circulation.

Treatment Algorithm and Evidence

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.

Latest Evidence:

1.     In a randomized trial of 114 high-risk patients, hydroxyurea reduced thrombotic events compared with no cytoreductive therapy (3.6% vs 24%; P < .01).

2.     In a randomized trial of 382 patients aged 40–59 years without thrombosis history or extreme thrombocytosis, hydroxyurea plus aspirin vs aspirin alone showed no difference in a composite vascular/bleeding/death endpoint (11 events in each group).

3.     Extreme thrombocytosis (platelets >1000 x 10^9/L) in otherwise low-risk ET is not associated with increased thrombosis risk and does not by itself require cytoreductive therapy.

Management Guidelines for Essential Thrombocythemia based on IPSET-T (International Prognostic Score of Thrombosis in World Health Organization–Essential Thrombocytopenia), NCCN (National Comprehensive Cancer Network) and ELN (European Leukemia Net)

Special Care Related to Pregnancy

• Pregnancy in patients with essential thrombocytosis is associated with a two to three fold increase in risk for spontaneous micarriage.
• Hydroxyurea and anagrelide are contraindicated during pregnancy and nursing.
• Essential thrombocytosis can be linked with increased risk of spontaneous abortion or miscarriage in the first trimester of pregnancy. Throughout pregnancy, close monitoring of the mother for thrombosis as well as placenta is recommended to ensure blood clots are diagnosed in time for interventions.
• Post partum, often daily injections of low dose low molecular weight heparin (e.g. enoxaparin) and low dose aspirin are prescribed as prophylaxis for several weeks as this is a period where the mother is at higher risk of developing a blood clot.
• Across 4 observational studies (n=598), live birth rates ranged from 68% to 75%, fetal loss from 25% to 32%, first-trimester fetal loss from 16% to 26%, and maternal complications (including hemorrhage/preeclampsia) from 8% to 13%. In a cohort of 200 pregnancies, fetal loss was lower among patients who took aspirin before conception and continued during pregnancy (16% vs 45%; P < .01). Hydroxyurea (pregnancy category D) and anagrelide (category C) are not recommended during pregnancy or lactation.
• Hormone therapy: In a retrospective study of 305 women, thrombosis rates were similar in those taking vs not taking oral estrogen-based therapy at diagnosis (19% vs 25%) and in those who continued vs discontinued therapy after diagnosis (31% vs 29%).

References

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