Essential thrombocytosis in Myeloproliferative Disorders.pptx

A presentation in hematology and blood transfusion from College of Medicine, Gombe State University, Nigeria

1. Essential Thrombocytaemia DR AI GIREI

2. ET: Outline Introduction Pathophysiology Clinical features Laboratory features Diagnostic criteria Treatment Course/prognosis

3. ET-Introduction A clonal, myeloproliferative neoplasm characterized by marked proliferation of megakaryocytes in bone marrow and thrombocytosis in peripheral blood First described by Epstein and Goedel in 1934 and called hemorrhagic thrombocythemia Dameshek classified it as one of the myeloproliferative disorders in 1951

4. ET pathophysiology ET is a clonal stem cell disorder involving granulocytes, platelets and red cells Molecular basis for the clonality can be found in 80–90% of patients 60%- JAK 2 mutation 25% CALR 5% MPL mutations 10% Triple negative ET is heterogenous: clinical and pathological features varying significantly between patients

5. ET pathophysiology- contd JAK 2 V617F mutation Constitutive activation of JAK-STAT pathway leading to cytokine-independent proliferation Calreticulin gene frame-shift mutation Abnormal reticulin that binds and activate thrombopoietin receptor leading to megakaryocyte proliferation MPL W515L/K mutations Activating mutations in the TPO receptor Triple negative mutations: may have other rare mutations

6. ET pathophysiology- contd Dysregulated JAK-STAT, MAPK, PI13K-AKT pathways Survival and proliferation of megakaryocytes TPO levels-normal or low Mutations make megakaryocytes hypersensitive to TPO

7. ET pathophysiology- contd Two distinct biologic forms are recognized: JAK 2-mutated type and non-JAK 2 mutated type JAK 2 mutated type: shares some similarities with PV increased Hb levels, neutrophil counts and bone marrow erythropoiesis more venous thromboses and a higher incidence of polycythaemic transformation Non-JAK 2 mutated type: 75% have mutations in the CALR gene

8. ET: pathophysiology- contd Characteristics of patients with CALR mutation Younger age group Higher platelet count Lower Hb and WBC count Lower thrombosis risk Better survival rate

9. ET: Clinical features Epidemiology Incidence: about 2/100,000 annually The median age at onset: 50–55 years, with a small second peak in women of reproductive age May occur at any age but very rare in children

10. ET: Clinical features Asymptomatic patients in 50% of cases Constitutional symptoms Vasomotor symptoms in about 40% of patients: visual disturbances light-headedness headaches palpitations chest pain erythromelalgia acral paraesthesia

11. ET: Clinical features Thrombotic complications: Arterial and venous thrombosis DVT and PE Portal vein thrombosis Cerebrovascular ischaemia Coronary ischaemia Digital ischaemia Bleeding complications Splenomegaly in 50% of cases Splenic atrophy

12. ET: Laboratory features/diagnosis

13. ET morphology: PBF

14. ET morphology: Bone marrow

15. ET morphology: megakaryocyte

16. ET: Laboratory features

17. ET: WHO diagnostic criteria (2022) Major Criteria Persistent platelet count 450 × 10^9/L Bone marrow biopsy P redominant proliferation of the megakaryocyte lineage, characterized by increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei There is no notable increase or left shift in neutrophil granulopoiesis or erythropoiesis O nly occasional minor (grade 1) reticulin fiber elevation Exclusion of other myeloid malignancies, including polycythemia vera, primary myelofibrosis, BCR::ABL1-positive chronic myeloid leukemia, or myelodysplastic syndromes Detection of an acquired pathogenic mutation in JAK2, CALR, or MPL genes  

18. ET: WHO diagnostic criteria (2022)

19. ET: Treatment The decision to treat is based on risk-based management as life expectancy in this disease is nearly normal High Risk: >60yrs age; history of thrombosis; platelet 1,500X10 9 /L; treatment necessary Low Risk: <40yrs age; no history of thrombosis; low dose aspirin usually given Medium risk: 40-60yrs age; it is not clear if treatment is beneficial  

20. ET: Treatment

21. ET course and prognosis