Trombocytos - reaktiv eller essentiell? Ulf Tedgård

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1 Trombocytos - reaktiv eller essentiell? Ulf Tedgård VPH Utbildningsdag 2017

2 Thrombocytosis adult definitions Sustained Thrombocytosis platelet count >450 x10 9 /l x10 9 /l Mild thrombocytosis x10 9 /l Moderate thrombocytosis >900 x10 9 /l Severe thrombocytosis >1000 x10 9 /l Extreme thrombocytosis

3 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 , Hb 135 g/l, Lkc , Neutr ,6, Monoc 0.9 Trc 1390 x10 9 /l rose to 1970 after 4 days Influenza B test pos MRI & MRI angiography of the brain normal mild splenomegaly (10,6 cm)

4 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

5 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 to infection 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)

6 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

7 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

8 Case 1 BM after 2 months, Trc BM: Increased numbers of megakaryocytes, rather large with hypersegmented nuclei Both parents normal blood counts Genetic tests: Platelet count - first 2 months 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 ASA 2 mg/kg/d

9 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 Platelet count - first year

10 Case 1 five years later Platelet count Iron treatment ASA 2 mg/kg/d 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 Iron treatment May 16: Hb 137 g/l, Hkr 41%, Lkc 6.3, Neutr 3.5, Lymph 2.1, Monoc 0.5

11 Is this an example of reactive or essential thrombocytosis? 1. Reactive Thrombocythosis 2. Essential Thrombocythemia

12 Is this an example of reactive or essential thrombocytosis? 1. Reactive Thrombocythosis I believe this is a case of reactive thrombocytosis although no underlying condition could be identified. Spontaneous remisson of ET is not described Sparse clinical checkups and blood counts are planned 2. Essential Thrombocythemia

13 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) 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) baserad på Hofmann, J Hematopathol, 2015

14 Reactive Thrombocythosis (RT) Essential Thrombocythemia (ET) in childhood Common RT in 6-15% of hospitalized children Mostly <2 years Platelet count mostly <800 x10 9 /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/year 2,5 per adults/year Median age in children 11 years Platelet mostly >1000 x10 9 /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?

15 Classic MPNs according to the 2008 WHO classification Myeloproliferative Neoplasms (MPNs) Philadelphia chromosome negative (Ph-) Philadelphia chromosome positive (Ph+) Polycythemia Vera (PV) Essential Thrombocythemia (ET) Primary Myelofibrosis (PMF) Other JMML et al Chronic myelogenous Leukemia (CML) 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

16 Classic MPNs according to the 2008 WHO classification Myeloproliferative Neoplasms (MPNs) Philadelphia chromosome negative (Ph-) Philadelphia chromosome positive (Ph+) Polycythemia Vera (PV) Essential Thrombocythemia (ET) Primary Myelofibrosis (PMF) Other JMML et al Chronic myelogenous Leukemia (CML) Mutations identified in most adult cases

17 Mutationer vid Ph- MPNs Polycythemia Vera (PV) Essential Thrombocythemia (ET) Primary Myelofibrosis (PMF) Klampfl et al, NEJM, dec 2013

18 ET de vanligaste mutationerna Adult 55% JAK2 Increased signaling Pediatric 25-50% JAK2 CALR? MPL? 25% CALR Calreticulin 5-10% MPL TPO receptor Figure from Congenital Erythrocytosis and Hereditary Thrombocytosis, MPN&MPNr-EuroNet

19 Kriterier för Essentiell trombocytemi Samtliga 4 kriterier ska vara uppfyllda för diagnos: 1. Kvarstående TPK > /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 PV A, PMF B, CML C, MDS D 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

20 Essential Thrombocytemia - diagnosis WHO definition: Sustained platelet count >450x10 9 /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.

21 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 3 rd 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 (normal platelet count when 3 years old, 187) Lp and CT brain normal Migraine?

22 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 Platelet count JAK2-mutation neg BCR-ABL neg Regular controls closed

23 Case 2- what has happened until now Platelet count BM: ET but ref Path says RT JAK2, CALR, MPL neg BM: ET x Spring 2015 Weight loss + fatigue Infection + excercise ASA 1,5 mg/kg/d 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

24 Is this an example of reactive or essential thrombocytosis? 1. Reactive Thrombocythosis 2. Essential Thrombocythemia

25 Is this an example of reactive or essential thrombocytosis? 1. Reactive Thrombocythosis 2. Essential Thrombocythemia??

26 Utredning Trombocytos Trombocytos - se Vårdprogram Trc-värdesgräns åldersberoende CRP/SR Basal provtagning Järnbrist Förhöjt = reaktiv trombocytos Normalt Kvarstående Trombocytos Nya prover efter järntillskott Nya prover om 4 v Uteslut sekundära orsaker Primär/sekundär vårdnivå MPNutredni ng Familjeutredning blodstatus med differentialräkni ng Genetik BCR-ABL, JAK2, MLP och CALR Benmärgsundersökning aspirat & biopsi Tertiär vårdnivå Omarbetning efter Kucine et al, Haematologica 2014 VPH Vårdprogram Ingen diagnos följ patienten regelbundet ET eller ärftlig trombocytos se Appendix 1 för kriterier

27 anpassad från Kucine et al, Haematologica 2014 Behanding och uppföljning Lågrisk/asymptomatisk Lågrisk/symptom (organförstoring, huvudvärk, erytrmelalgi, riskfaktorer för hjärtproblem eller trombos) Högrisk (komplikationer trots aspirin, blödningar, tromboser, bestående extrem trombocytos) 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 Provtagning 4-8 x/år. BM-us 1x/år ASA + Cytoreduktiv behandling Hydroxyurea Interferon α Anagrelide Trombaferes Läkarbesök 4 x/år Provtagning 4-8 x/år. BM-us 1x/år

28 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

29 Frågor?