Trombocytos - reaktiv eller essentiell? · Aspleni/post-splenektomi Malignitet Nylig kirurgi, trauma eller blodförlust Nefrit/nefros Pankreatit Hemolytisk anemi Läkemedel - Adrenalin

Trombocytos

- reaktiv eller essentiell?

Ulf Tedgård

VPH Utbildningsdag 2017

Thrombocytosis – “adult definitions”

• Sustained Thrombocytosis – platelet count >450 x109/l

• 450-700 x109/l Mild thrombocytosis

• 700-900 x109/l Moderate thrombocytosis

• >900 x109/l Severe thrombocytosis

• >1000 x109/l Extreme thrombocytosis

Case 1 - nine year old boy with fever

• Previously healthy. Active in ice hockey and football

• Headache mainly in the afternoon for 5 months

• High fever and intense headache for 8 days (Jan 2011)

• Influenza like symptoms. Sore throat.

• Light sensitive. No nuchal rigidity. Lp normal.

• CRP 10-0.3, Hb 135 g/l, Lkc 19.1-12, Neutr 16.6-7,6, Monoc 0.9

• Trc 1390 x109/l rose to 1970 after 4 days

• Influenza B test pos

• MRI & MRI angiography of the brain normal

• mild splenomegaly (10,6 cm)

What is NOT correct ?

1. Thrombocytosis is common in hospitalized children

2. Thrombocytosis is often secondary to an infection

3. Thrombocytosis is often seen in patients with iron deficiency anemia (IDA)

4. The risk of thrombosis is high in children with extreme thrombocytosis

What is NOT correct ?

1. Thrombocytosis is common in hospitalized children

Thrombocytosis in 6-15% of hospitalized children

2. Thrombocytosis is often secondary to an infection

Thrombocytosis in children is most often secondary toinfection or inflammation and many other causes

3. Thrombocytosis is often seen in patients with iron deficiency anemia (IDA)

Thrombocytosis in children is common in patients with IDA

4. The risk of thrombosis is high in children with extreme thrombocytosis

Thrombosis is uncommon among children (as compared to adults with extreme thrombocytosis)

What is NOT recommended in this

situation?

1. Start treatment with low-dose Aspirin (ASA)

2. Look for less obvious reasons for reactive thrombocytosis as coeliac disease, rheumatic disease, allergy, kidney disease, malignancy…..

3. Wait and see – follow blood counts

What is NOT recommended in this

situation?

1. Start treatment with low-dose Aspirin (ASA)

ASA is NOT recommended in patients with thrombocytes >1500 due to increased risk of bleeding and should be used with caution in children less than 12 years of age due to the risk of Reye syndrome

2. Look for less obvious reasons for reactive thrombocytosis as coeliac disease, rheumatic disease, allergy, kidney disease, malignancy…..

3. Wait and see – follow blood counts

Case 1 – BM after 2 months, Trc 2300- 1347

• BM: Increased numbers of megakaryocytes,rather large with hypersegmentednuclei

• Both parents normal blood counts

• Genetic tests:

– Normal karyotype – no Philadelphia chromosome

– No JAK2 mutation (found in about 55% of adult ET)

• Test for prothrombotic risk factors negative

• Doing fine - no symptoms. No signs of inflammation

0

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110128 110201 110202 110203 110204 110209 110210 110215 110221 110301 110310 110321

Platelet count - first 2 months

ASA 2 mg/kg/d

Case 1 – after one year

• Platelet levels going down

• Repeated BM:same findings -ET

• No MPL mutation(TPO receptor)

• No signs of inflammation

– CRP normal, ANA negative, coeliac disease negative

• Doing fine - no symptoms

• ASA 2 mg/kg continued

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Platelet count - first year

Case 1 – five years later

• Below 450 for one year – now normal platelet count – 265 !

• ASA stopped one year ago

• Spleen still at the upper limit for age

• Ferritin down to 21 (27-365), dec 2013 and 16, nov 2015. Iron treatment

• May ´16: Hb 137 g/l, Hkr 41%, Lkc 6.3, Neutr 3.5, Lymph 2.1, Monoc 0.5

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Platelet count

ASA 2 mg/kg/d

Iron

treatment

Is this an example of

reactive or essential thrombocytosis?

1. Reactive Thrombocythosis

2. Essential Thrombocythemia




I believe this is a case of reactive thrombocytosis although no underlyingcondition could be identified.

Spontaneous remisson of ET is not described

Sparse clinical checkups and blood counts are planned


Trombocytos

• Trombocytos är vanligt fynd när man tar fullständigt blodstatus

• Är oftast övergående

• Vanligare hos yngre barn

• Förekommer sekundärt till bakomliggande medicinsk sjukdom(reaktiv trombocytos)

baserad på Hofmann, J Hematopathol, 2015

Infektion

Inflammation

- allergi

- transplantat-mot-värd-reaktion (GVHD)

- IBD eller celiaki

- reumatiska sjukdomar

- brännskador

Brist av vitaminer och spårämnen

- järn

- kobalamin

- vitamin E

Aspleni/post-splenektomi

Malignitet

Nylig kirurgi, trauma eller blodförlust

Nefrit/nefros

Pankreatit

Hemolytisk anemi

Läkemedel

- Adrenalin

- β-laktamantibiotika

- Kortikosteoider

- Lågmolekylärt heparin (LMWH)

Reactive Thrombocythosis

(RT)

Essential Thrombocythemia

(ET) – in childhood

Common – RT in 6-15% of hospitalized children

Mostly <2 years

Platelet count mostly <800 x109/l

Duration: wks, months, temporary

(Hepato)splenomegaly rare

Few symptoms

Thrombosis and bleeding disorders extremely rare

Increased megakaryocyte number, normal morphology

No mutations

0,1-1 per million children/year2,5 per 100 000 adults/year

Median age in children 11 years

Platelet mostly >1000 x109/l

Months, years, or permanently

(Hepato)splenomegaly (20%)

Some have symptoms- headache

Thrombosis and bleeding disorders common among adults, less in children and rare in familiar thrombocytemia

Increased megakaryocyte number with large and mature morphology with hyperlobated nuclei

Adults often mutation – children?

Classic MPNs according to the 2008 WHO classification

Myeloproliferative Neoplasms (MPNs)

Philadelphia chromosome

negative (Ph-)


positive (Ph+)

Chronic

myelogenous

Leukemia (CML)

Primary

Myelofibrosis

(PMF)

Essential

Thrombocythemia

(ET)

Other

JMML

et al

Polycythemia

Vera

(PV)

MPNs are characterized by an uncontrolled cell growth and splenomegaly

risk (in adults) of thrombotic events (10-25%) and bleeding (4%)

potential to transform to acute myeloid leukemia (AML) or myelofibrosis

Classic MPNs according to the 2008 WHO classification

Myeloproliferative Neoplasms (MPNs)

Mutations identified

in most adult cases


negative (Ph-)


positive (Ph+)

Chronic

myelogenous

Leukemia (CML)

Primary

Myelofibrosis

(PMF)

Essential

Thrombocythemia

(ET)

Other

JMML

et al

Polycythemia

Vera

(PV)

Mutationer vid Ph- MPNs

Klampfl et al, NEJM, dec 2013

Primary

Myelofibrosis

(PMF)

Essential

Thrombocythemia

(ET)

Polycythemia

Vera

(PV)

ET – de vanligaste mutationerna

Adult

55% JAK2 Increased

signaling

25% CALR

Calreticulin

5-10% MPLTPO receptor

Pediatric

25-50% JAK2

CALR?

MPL?

Figure from ”Congenital Erythrocytosis and Hereditary Thrombocytosis”, MPN&MPNr-EuroNet

Kriterier för Essentiell trombocytemi

Samtliga 4 kriterier ska vara uppfyllda för diagnos:

1. Kvarstående TPK >450 × 109/L. 2. Benmärgsbiopsi som visar proliferation i megakaryopoesen med ökat antal

förstorade mogna megakaryocyter; ingen vänsterförskjutning av neutrofil granulopoes eller erytropoes.

3. Uppfyller ej kriterier för PVA, PMFB, CMLC, MDSD eller annan myeloid neoplasi 4. Påvisad mutation i JAK2 eller annan klonal markör, eller i avsaknad av klonal

markör inga bevis för reaktiv trombocytos.

Kommentarer:

A. Om ferritin är lågt ska inte järnsubstituion öka Hb till onormalt hög nivå. B. Frånvaro av retikulinfibros, kollagenfibros, perifer leukoerytroblastos,

hypercellulär benmärg för åldern med megakaryocytmorfologi som vid PMF. C. Frånvaro av BCR-ABL. D. Frånvaro av dyserytropoes och -granulopoes.

VPH Vårdprogram Trombocytos och polycytemi/erytrocytos

Essential Thrombocytemia - diagnosis

• WHO definition:

– Sustained platelet count >450x109/l

– Bone marrow biopsy showing increased megakaryocyte numbers displaying large and mature morphology with hyperlobated nuclei and no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis

– Exclusion of PV, primary myelofibrosis, chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS) or other myeloid neoplasms

– Demonstration of JAK2 or other clonal marker, or, in the absence no evidence for reactive thrombocytosis.

Case 2 – nine years old boy with headache

• Asthma – pos for mite, fur, grass. Treated with inhalation steroids and bronchodilation

• Food allergy? – genotype for adult lactose intolerance

• Heredity for ulcerative colitis, migraine and coeliac disease (risk genotype for CD but anti-tTG negative at several times. Normal growth)

• April 2012 – intense headache for 3 days. On the 3rd day nausea & vomiting, light and sound sensitive.

• No signs of infection. CRP<0.6, SR 3, Hb 132, Lkc 10,9 Neutr 8.5

• Trc 976-760 (normal platelet count when 3 years old, 187)

• Lp and CT brain normal

• Migraine?

Case 2 – the following 2 ½ years

• Platelet count successively lower. No treatment. Parents normal Plt count

• Some asthma problems

• Problem with headache, tiredness, concentration. Diagnosed with ADHD

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Platelet count

JAK2-mutation neg

BCR-ABL neg

Regular

controls

closed

Case 2- what has happened until now

• Spring 2015

– Weight loss. Side effect of Methylphenidate? Other reasons?

– Pain in legs and ankles – plays football

– CRP <0.6, protein profile, f-calprotectin, ANA neg. No iron deficiency

• Platelets up till 1500

– intensified asthma treatment

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Platelet count

BM: ET but ref Path says RT

JAK2, CALR, MPL neg

BM: ET x2

Infection +

excerciseSpring 2015

Weight loss

+ fatigue

ASA 1,5 mg/kg/d








2. Essential Thrombocythemia ??

Utredning

Trombocytos

Trombocytos- se VårdprogramTrc-värdesgränsåldersberoende

Basal provtagning Järnbrist

Nya prover efter järntillskott

CRP/SR

KvarståendeTrombocytos

Normalt

Förhöjt

= reaktiv trombocytos

Nya prover om 4 v

Uteslut sekundära

orsaker

Benmärgs-undersökning

aspirat & biopsi

Genetik

BCR-ABL, JAK2, MLP och CALR

Familjeutredning

blodstatus med differentialräkni

ng

ET eller ärftlig trombocytos

se Appendix 1för kriterier

Ingen diagnos

följ patienten regelbundet

MPN-utredni

ng

Primär/sekundär vårdnivå

Tertiärvårdnivå

Omarbetning efter Kucine et al,

Haematologica 2014

VPH Vårdprogram

Behanding och uppföljning

anpassad från Kucine et al, Haematologica 2014

Högrisk(komplikationer trots aspirin,

blödningar, tromboser,

bestående extrem

trombocytos)

Lågrisk/asymptomatisk Lågrisk/symptom(organförstoring, huvudvärk,

erytrmelalgi, riskfaktorer för

hjärtproblem eller trombos)

Ingen behandling

Läkarbesök 1-2 x/år

Provtagning 2-4 x/år.

BM-us 1 x / 1-2 år

Lågdos ASA (1mg/kg;

max dos 75 mg/dag)

Läkarbesök 2-4 x/år


BM-us 1x/år

ASA + Cytoreduktiv

behandling

Hydroxyurea

Interferon α

Anagrelide

Trombaferes

Läkarbesök 4 x/år


BM-us 1x/år

Take home message

1. Reaktiv trombocytos är vanligt hos barn

2. Om reaktiv trombocytos är “utesluten” och barnet har fortsatt svår eller extrem trombocytos remiss till tertiär nivå för utredning för att utesluta MPN/ET

3. Vid MPN/ET utredning motiverat med genetisk utredning avseende mutationer associerade med MPN/ET hos vuxna

Frågor?

Documents

Trombocytos - reaktiv eller essentiell? · Aspleni/post-splenektomi Malignitet Nylig kirurgi, trauma eller blodförlust Nefrit/nefros Pankreatit Hemolytisk anemi Läkemedel - Adrenalin