Management of

Essential Thrombocytosis
What can we do?
Dimmy Prasetya
Divisi HOM FKUP/RSHS
PKB 2019

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 outline

Thrombocytosis

Diagnosis approach

Essential Thrombocytosis/ET

Etiology and Diagnosis ET

Risk stratification

Treatment and Prognosis

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 Thrombocytosis

Definition : Thrombocyte count ≥ 4,5 x 109 / L (150 to 450 x 109 /L)

Commonly : accidental finding

Patients doctor

Why ? etiology?
How does it happend ? Pathogenesis?
Is it danger ? Complication?
Bisa diobati ? Treatment-prognosis ?

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THE CURRENT TREATMENT PARADIGM. ASH 2017
Etiology/Classification

Infeksi/Inflamasi, keganasan, def Fe,

Reactive hemolisis,recovery, post splenectomi,
tissue injury

Myeloproliferative neoplasm
Thrombocytosis Primary Essential Thrombocytosis
PV,CML,PMF

Mutation
Inherited MPL

Rodgers MG., Thrombocytosis and Essential Thrombocytemia. Wintrobe’s Clinical Hematology. 2014: 1122-27.
Pathophisiology

total platelet
mass

Thrombocyte Thrombopoietin
production (TPO)

MPL
(TPO-R)

1. Thrombocytosis and Essential Thrombocytemia. Wintrobe’s Clinical Hematology. 2014: 1122-27.

2. The thrombopoietin receptor.Frontier in endocrinol. 2017
 Diagnosis approach to thrombocytosis
Thrombocyte ≥ 4.5 x10 9 /L

Life long and/or family history of thrombocytosis

yes No

Inherited/familial Ax/PD, ADT, LED/CRP/panel IDA

Mutation test
cMPL Reactive ?

80% yes No 20%

Reactive Clonal BCR-ABL

trombositosis evaluation JAK2/MPL
BMP
Not return to cytogenetic
normal

Thrombocytosis and Essential Thrombocytemia. Wintrobe’s Clinical Hematology. 2014: 1122-27.

Essential Thrombocytosis : Definition

• Clonal stem cell disorder that share phenotype and pathologic similarities with other
myeloproliferative neoplasms (MPNs)

• Philadelphia negative classical MPN

• The term myeloproliferative neoplasms (MPN) typically refers to essential
thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF)

• No firm definition and diagnosis with just single criteria

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Blood. 2016;128 :2403-2414
Essential Thrombocytosis : Epidemiology

• 15% of MPNs
• 1/3 of philadelphia negative MPNs
• 9-24 new cases/ 100.000 population
• Female: male = 2:1
• Median age at diagnosis 60 years
• 20% maybe younger than 40 years

8 Blood. 2016;128 :2403-2414

Essential Thrombocytosis : Etiology and Pathogenesis

• JAK2 mutation – 60 to 65 percent

• CALR mutation – 20 to 25 percent
• MPL mutation – 5 percent
• No JAK2, CALR, or MPL mutation
("triple negative") – 10 to 15
percent

The increased platelet counts are a result of

excessive platelet production and not
prolonged platelet survival in the peripheral
blood.

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Blood. 2014;123(24):3714-19
 Diagnosis : Clinical Findings

Clonal Thrombocytosis Reactive Thrombocytosis

Findings

Systemic disease No Often clinically apparent

Vasomotor symptom common No
(erythromelalgia, flushing)
Digital thrombosis or CVD Chracteristic No
Splenomegaly Yes in about 40% of patients No
Blood smear Thrombocyte anisocytosis and giant Normal thrombocyte
thrombocyte Increase
Bone Marrow Giant MK, dysplastic form with Normal morphology
increase ploidy, Large masses of
thrombocyte

NEJM. 2004;350:1211-9
Blood Smear

CML All stage of granulocyte maturation

PMF LEB + tear drop cell + normoblast

• marked thrombocytosis in the

peripheral blood
ET
• The platelets vary in size
(platelet anisocytosis), ranging
from very small to giant
platelets.

• The red blood cells are usually

normochromic and
normocytic.

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NEJM. 2004;350:1211-9
Diagnosis : 4 major or 3 major + 1 minor

Major criteria
 Platelet count ≥450 x 109/L (≥450,000/microL)
 Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with
increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No
significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very
rarely minor (grade 1) increase in reticulin fibers.
 WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, polycythemia vera, primary
myelofibrosis, myelodysplastic syndrome, or other myeloid neoplasm not met
 Demonstration of a JAK2, CALR, or MPL mutation

Minor criteria
• Demonstration of another clonal marker (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or
SR3B1 mutation) or no identifiable cause of thrombocytosis (eg, infection, inflammation,ron
deficiency anemia)
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Blood. 2016;127(20):2391-2405.
Treatment planning : Risk Stratification

CVD Thrombosis
usia
Risk history
1

ET 2

3
Jak2
CALR MPL 4
VF617F

Very Low Risk

Low Risk

Intermediete Risk
1. Blood. 2016;128 :2403-2414
2. Blood cancer J. 2018;8:2 High Risk
 Cytoreductive agent : 10-40 x 109/L
First line : Hydroxyurea 15 mg/kg
2nd Line : peg-interferon α
Busulfan

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1. Blood. 2016;128 :2403-2414
2. Blood cancer J. 2018;8:2
IFN alfa

• The choice of cytoreductive therapy differs from that of the general population due to concerns
about potential teratogenicity of HU and anagrelide, interferon is DOC in patients ET with
pregnancy.

• Pegylated IFN alfa-2a is generally administered with an initial dose of 45 mcg/week

subcutaneously for the first two weeks, and increased as tolerated to a maximal dose of 180
mcg/week.

• IFN alfa for PV is 3 million units subcutaneously three times per week.

1. Blood. 2016;128 :2403-2414

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2. Blood cancer J. 2018;8:2
2nd line : Anagrelide

tablet 0.5 mg dan 1 mg

ANAGRELIDE
Dose : 0.5 mg q6hr or 1 mg q12hr Second line
increase not more 0.5 mg/day/week Not affect white cell
not exceed 10 mg/day 0r 2.5 mg/dose count
platelet response 7-14 day Non cytotoxic
Unlikely to be
time to complete response 4-12 weeks leukemogenic
HYDROXYUREA
Polycythemia Vera StudyGroup criteria First line
809 patients with ET :
Increased risk of
- Equivalent long-term control of the leukemic
platelet count was achieved in both transformation
groups Increased risk of
- Anagrelide was associated with an skin neoplasia
increase in bone marrow reticulin
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Hong and Erusalimsky, Leukemia 2002
Prognosis and treatment thrombocytemia. www uptodate.com 2019
Resistance or intolerance to HU as defined by the ELN :

• Platelet count >600,000/microL after three months of ≥2 g/day of HU (≥2.5 g/day in

patients with a body weight >80 kg)
• Platelet count >400,000/microL combined with white blood cell (WBC) count <2500/microL or
hemoglobin <10 g/dL at any dose of HU
• Leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU
• HU-related fever

Plateletpheresis :
• Severe or life-threatening organ dysfunction (eg, stroke, pulmonary embolism, ischemic
digital necrosis)
• Acute bleeding due to acquired von Willebrand disease

1. Blood. 2016;128 :2403-2414

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2. Blood cancer J. 2018;8:2
Prognosis

International Prognostic Score for Essential Thrombocythemia (IPSET) study (N 891) :

Patients were assigned a total score based on the following three features:
1. Age ≥60 years(2 points)
2. White blood cell (WBC) count ≥11,000/microL (1 point)
3. History of thrombosis (1 point)

Median survivals were as follows:

• Low risk (total score 0; 48 percent of patients) – Not reached
• Intermediate risk (total score 1 or 2; 47 percent of patients) – 24.5 years
• High risk (total score 3 or 4; 5 percent of patients) – 13.8 years

Median survival 2-7 bulan : transformation to AML, MDS, MF

18 Prognosis and treatment thrombocytemia. www uptodate.com 2019

 Summary

 Reactive thrombocytosis still the main cause of thrombocytosis cases

 ET diagnosis raised from exclusion of a reactive thrombocytosis and other MPNs
 The Goal treatment in ET is prevent arterial and venous thrombosis
 Risk Stratification according to age, CVD risk, history of thrombosis and Jak2 mutation
are factors in choosing drug of choice
 For patients (of any age) with high-risk ET and a history of venous thrombosis,
treatment should with a cytoreductive agent in combination with systemic
anticoagulation
 For patients (of any age) with high-risk ET and a history of arterial thrombosis, treatment
should with a cytoreductive agent in combination with low-dose aspirin

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 THANK YOU

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