Myeloproliferative Disorders (MPD) PDF

Bone marrow MYELOPROLIFERATIVE DISORDERS (MPD) O Polycythemia Vera ② EssentialThrombocythemia ③ Primary Myelofibrosis ① Chronic Myeloid Leukemia NUR NA JMI MOHAMAD ANUAR ...

Bone marrow MYELOPROLIFERATIVE DISORDERS (MPD) O Polycythemia Vera ② EssentialThrombocythemia ③ Primary Myelofibrosis ① Chronic Myeloid Leukemia NUR NA JMI MOHAMAD ANUAR  MPD/MPN? uncontrol proliferation ~ Also known as myeloproliferative neoplasm (MPN) - proliferation of one/more hematologic cell lines Clonal hematopoietic stem cell diseases with excessive production of: Erythrocytes Granulocytes Platelets More common in 50+ age group Common findings & overlap between the various diseases Increased risk of transforming to acute leukaemia  FOUR DISORDERS! JAKI VG17F mutation NON-LEUKAEMIC ↑ XRBC F POLYCYTHAEMIA RUBRA VERA (PRV) Hb - ↑ , ↑Act N/L EPO , VGI7F CALR/mPL mulation -JAK2 , ESSENTIAL THROMBOCYTHAEMIA (ET) Thrombocytes - N/1 WBC (PIGelet) - MYELOFIBROSIS (MF) JAK2 VG17F CALR/mpL mutation - , ↳Froia hematopoiesis cells, nucleated RBC extramedullary immature WBC LEUKAEMIC , CHRONIC MYELOID LEUKAEMIA - BCLR-ABL-1 fusion gene L Philadelphia chromosomes - granulocytes F I basophilia basoph (BCLR-ABL-1 fusion gene) neutrophil  DIAGNOSIS Peripheral Blood Smear – Morphology FBC Bone Marrow Biopsy – Morphology Cytogenetics Chronic Myeloid Leukaemia - BCR/ABL Polycythaemia Rubra Vera - JAK2 V617F, JAK2 exon 12 Myelofibrosis and Essential thrombocythaemia - JAK2 V617F, MPL W151L/K  POLYCYTHAEMIA ~ packed cel ▪Hb, RCC B & PCV volume ▪ERYTHROCYTOSIS CLASSIFICATION: 1)Absolute polycythaemia : Primary or Secondary ▪Raised in RBC volume 2) Relative / pseudo polycythaemia RBC volume is normal, but the plasma volume is reduced POLYCYTHAEMIA RUBRA VERA (PRV/PV) (Symptoms : headache PRIMARY POLYCYTHAEMIA increase in RBC volume a clonal malignancy of a marrow stem cell for erythrocyte precursor can be manifested together with granulocytosis and thrombocytosis 97% is positive for JAK-2 mutation tyrosine kinase (TK) mutation TK is activated regardless of EPO level (EPO is not required) → Thus, hematopoietic cells continue to grow and proliferate.  PV - CLINICAL FEATURE (Major complications : cerebrovascular and cardiovascular events) Hyperviscosity Syndrome ❑Reduce cerebral flow – confusion, headache ❑High BP ❑Bleeding episodes – due to reduce platelet function ❑Pruritis – due to high histamine level ❑Splenomegaly ❑Affect systemic blood circulation ❑Respiratory symptoms : Dyspnea PV – LAB FINDINGS  FBE:  Hb, RCC & PCV, MCV & MCH usually normal × May have associated  neutrophils (>50%) & PLT (~50%)   NAP (neutrophil alkaline phosphatase)   LDH  [EPO] may be N or   Bone marrow × Hypercellular with prominent megakaryocytes and erythrocyte precursors.  iron stores PV – LAB FINDINGS Molecular analysis 100% patients → JAK2 mutation (Janus- associated kinase 2) mutation (V617F) change of valine to phenylalanine at the 617 position hematopoietic cells more sensitive to growth factors such as EPO and thrombopoietin × Cytogenetics -- trisomy 8 or 9 & del(20q) Morphology - PRV Rodak's Hematology: Clinical Principles and Applications JAK2 MUTATION Janus kinase (JAK) family - enzymes associated with cytokine receptors on the surface of cells. part of the Signal Transducer and Activation of Transcription (STAT) pathway → involved in inflammatory and immune responses. An abnormality in the pathway → abnormal proliferation of cells. Possible outcomes : polycythaemia vera, leukaemia and lymphoma. JAK MUTATION  WHO Guidelines in Dx PRV Diagnosis of PV made by: ❖A1 and A2 and any other A ❖A1 and A2 with any 2 parameters in B Rodak's Hematology: Clinical Principles and Applications Polycythaemia vera (PV) PV – DIFFERENTIAL DIAGNOSIS Secondary ❖EPO secreting tumor ❖Reactive polycythaemia/erythrocytosis ( EPO) Smoking, renal disease/tumour, cyanotic congenital heart disease hypoxia altitude, oxygen affinity Hb ❖Apparent polycythaemia plasma volume Alcohol consumption, diuretics, dehydration & vomiting PV – TREATMENT Myelosuppresive Drug - interferon, Hydroxyurea Anti-histamine – manage symptom Aspirin – reduce risk of thrombosis Phlebotomy/venesection – reduce symptom of hyperviscoscity Morphology -PV FBE Bone Marrow ESSENTIAL THROMBOCYTEMIA (ET) Sustained increase in platelet count ( > 600 x 109/l ) due to megakaryocytes proliferation and overproduction of platelets. Usually 50–70-year-olds & both sexes affected equally  ET – CLINICAL MANIFESTATION ▪Arterial or venous thrombosis ▪haemorrhage due to abnormal platelet function ▪40% patient with splenomegaly or splenic atrophy ▪Erythromelalgia – sensation hand or feet, relief by aspirin  ET – LAB DIAGNOSIS  Platelet count persistently >450 x 109/L but can be  up to 600-1000. × Megakaryocyte nuclei & cytoplasmic fragments × normal Hb, RBC, Hct ×  or N ESR, CRP & fibrinogen  Bone marrow ×  megakaryocytes  Molecular analysis × ~50% JAK2 mutation (Janus-associated kinase 2) × Ph chromosome negative –exclude CML  Morphology -ET Rodak's Hematology: Clinical Principles and Applications  ET – DIFF DIAGNOSIS  Reactive thrombocytosis × Inflammation, post surgery, infections, blood loss, hemolytic anemia  Polycythaemia vera, Myelofibrosis  Chronic myeloid leukaemia Morphology - ET Peripheral blood smears - mild to marked thrombocytosis with giant platelets (arrow). Morphology - ET Megakaryocyte nucleus  ET - TREATMENT ❑Aspirin – antithrombotic agent ❑Chemotherapy drug : Hydroxycarbamide an antineoplastic drug ❑Anagrelide : drug to inhibit megakaryocyte maturation and thus reduce platelet counts ❑cytotoxic drugs, e.g. Hydroxyurea (HU) TO TAKE NOTE… -The disease is stationary for 10-20 years - may transform to myelofibrosis due to PDGF over secretion which can stimulate fibroblast growth.  PRIMARY MYELOFIBROSIS (PMF) unknown Idiopathic MF Progressive fibrosis of the bone marrow (myeloid metaplasia) marrow is replaced by scar tissue and is not able to make healthy blood cells extramedullary hematopoiesis association with the development of hematopoiesis in the spleen and liver hypotheses : stimulation of fibroblast by platelet derived growth factor (PDGF) and other proteins secreted by platelets and megakaryocytes some patients may have previous history of PRV or ET.  PRIMARY MYELOFIBROSIS Fibroblasts are normal but responding to increased growth factors released from abnormal megakaryocytes. Clonal abnormality in haemopoietic stem cell →  megakaryocyte activity →  fibroblast proliferation and progressive reactive fibrosis of bone marrow Growth factors including Platelet Derived Growth Factor (PDGF), Transforming Growth Factor-β,IL1 Fibroblast Growth Factor stimulate fibroblasts  bone marrow fibrosis Pathogenesis MF 27  WHY HEMATOPOIESIS? How hematopoiesis is affected? Bone marrow fibrosis will lead to bone marrow failure. Affect hematopoiesis Release early precursor cells to blood – produce Leukoerythroblastic film (LEF). Will cause migration of precursors to other side than bone marrow Produce extramedullary hematopoiesis MYELOFIBROSIS – CLINICAL FEATURE -ithey MYELOFIBROSIS – LAB FINDINGS 1. Full blood Counts Anemia, variable level of WBC and platelet, pancytopenia normal MCV/MCH, Hb 2. Blood film Leukoerytroblastic film RBC with tear drop poikilocytes Giant platelet Nucleated RBC 3. Bone marrow biopsy Fibrosis initially myeloid hypercellularity but then  fibrosis & deposition of reticulin  Megakaryocyte clustering 4. Screen for JAK-2 mutation  Morphology -PMF Rodak's Hematology: Clinical Principles and Applications  MYELOFIBROSIS - TREATMENT ✓anemia - blood transfusion and folic acid therapy, EPO administration ✓splenectomy ✓JAK-2 inhibitor ✓Chemotherapy drug - Hydroxyurea (HU) ✓Allogeneic bone marrow transplant ✓B12/folate supplements ( demand/cell turnover) Prognosis 4-5 years survival Can progress to AML  Morphology - PMF O D Peripheral smear from a patient with myeloid metaplasia. This image shows the presence of teardrop red blood cells (RBCs) and a leucoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells. Normal bone maror myofibrosis 35 36 Key Points ✓Proliferation of Myeloid Lineage-Cells ✓ Erythrocyte Precursor, Megakaryocyte, Myeloid Precursors ✓ They can shift / change in between pathology. Eg : Polycytemia Rubra Vera can transform to Essential Thrombocytopenia M m ✓Involve specific kind of mutation at Chromosome 9 (Jak-2 gene) – which lead to increase response to erythropoietin and thrombopoietin - stimulate proliferation. Key Points ✓Proliferation of Myeloid Lineage-Cells ✓ Erythrocyte Precursor, Megakaryocyte, Myeloid Precursors ✓ They can shift / change in between pathology. Eg : Polycytemia Rubra Vera can transform to Essential Thrombocytopenia ✓Involve specific kind of mutation at Chromosome 9 (Jak-2 gene) – which lead to increase response to erythropoietin and thrombopoietin - stimulate proliferation.