Myeloproliferative Disorders 2007

Myeloproliferative DisordersTika Adilistya

Myeloproliferative Disorders (MPD)Definisi: Sekelompok kondisi yg timbul dari sel stem sumsum, yg ditandai adanya proliferasi klonal dari satu atau lebih komponen hematopoietik di sumsum tulang, dan di beberapa kasus: hepar & lien.Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.KlasifikasiPolisitemia rubra vera (PRV)Trombositemia esensial (ET)MielofibrosisHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Hubungan antara ketiga MPD

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006.p.231.JAK2Suatu protein tirosin kinase yg berperan dlm transduksi signal sel hematopoietik melalui reseptor sitokin & growth factor, di antaranya:IL-3GM-CSFTrombopoetin

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Patofisiologi MPD: Mutasi JAK2 JAK2 V617FMutasi pada nukleotida 1849Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Guanin Timin (pada kodon 617)Valin FenilalaninPatofisiologi MPD: Mutasi JAK2Mutasi terjadi pada:Hampir semua pasien PRV50% pasien ET & mielofibrosisAkibat mutasi:Aktivasi JAK-2 terus menerus disregulasi pada JAK-STAT signaling pathwayTerkait dgn perkembangan & progresivitas MPDHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.JAK-STAT Signaling PathwaySteensma DP. JAK2 V617F in myeloid disorders: molecular diagnostic techniques and their clinical utility. J Mol Diagn 2006;8:397-411

Peran mutasi JAK2 pada MPDHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

Tiga jalur utama aktivasi JAK2Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation.Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006;355:2452-66

Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation.Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006;355:2452-66

POLISITEMIA (RUBRA) VERAPatogenesisProliferasi klonal > 1 komponen hematopoietik di sumsum tulang, hati & limpa. Ditandai oleh peningkatan massa eritrosit total akibat mutasi pada:JAK2 V617F, atauExon 12 pada kromosom 9p24Klasifikasi polisitemia berdasarkan etiologiPolisitemia absolut (massa eritrosit total )Polisitemia primerPolisitemia kongenital familial e/c mutasi reseptor EPOPolisitemia vera e/c mutasi JAK2Polisitemia sekunder e/c hipoksiaPolisitemia relatif (vol plasma )Perokok, stres, dehidrasi, kehilangan plasma (luka bakar, enteropati)

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Volume eritrosit & plasma pada keadaan normal dan polisitemiaHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

Penyebab PolisitemiaHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

Perjalanan PenyakitDilaporkan adanya fibrosis akibat substansi yg dihasilkan sel stroma & fibroblas.Dapat mengalami transformasi menjadi leukemia akut : PRV yg gambarannya mirip ET post PV-MF fase akselerasi / MDS AML.Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran KlinisHiperviskositas (massa eritrosit ) sakit kepala, gangguan penglihatan, phletoraHipermetabolismeCepat lelah, penurunan BB, goutTrombosisPerdarahan gusi, menoragia, hemoptisis, perdarahan GIT gangguan kualitas & kuantitas tromb.

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran Klinis (lanjutan) Organomegali e/c hematopoeisis ekstramedulerHipertensi e/c hiperviskositas, penurunan aliran darah & peningkatan resistensi pembuluh darah periferHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran LaboratoriumKelainan hematologiHB, HCT, jumlah eritrosit Leukositosis dgn neutrofilia (kadang basofilia). Trombositosis (50% kasus)Skor NAP BM: hiperseluler dgn megakariosit prominenKadar vit B12 serum & kapasitas daya ikat vit B12 Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006..p235

Gambaran LaboratoriumEPO serum Viskositas darah Hiperurisemia, LDH serum normalMutasi JAK2 (100% kasus)Circulating erythroid progenitors meningkatCFUEBFUE

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

Algoritme diagnostik untuk tersangka PRVTefferi A. JAK2 mutations in polycythemia vera: molecular mechanism and clinical applications. N Engl J Med 2007;356:444-5

Kriteria diagnosis PRV menurut WHOKriteria mayorHb > 18,5 g/dl (). 16,5 g/dl () ATAU terdapat pe massa eritrositTerdapat JAK2 V617F atau mutasi JAK2 exon 12Kriteria minorBiopsi sutul: hiperseluler, pan-mielosis dgn dominasi proliferasi seri eritroid, granulosit, megakariositKadar EPO Endogenous erythroid colony formation in vitroKriteria diagnostik PRV menurut PVSGHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

A1A2A3A4Diagnosis PV bila:A1+A2+A3 atauA1+A2+A4 atauA1+A2+ 2 krite-ria B

Trombositemia EsensialE TDefinisi : Suatu gangguan klonal pada sel stem pluripoten yg ditandai adanya proliferasi berlebihan sel turunan megakario-sit disertai pembentukan trombosit dalam jumlah sangat besar.Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Penyebab trombositosis

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.PatofisiologiProliferasi megakariositOverproduksi trombositHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Perjalanan PenyakitStasioner selama 10-20 tahun.Paling jinak dibandingkan MPD lainKemungkinan terkecil berakhir menjadi leukemia akut (400x109/LGDT: platelet besar abnormal, fragmen megakariositBMP: =PRV namun megakariosit abnormal lebih menonjolSitogenetik: gen BCR-ACL (-), kromosom Philadelphia (-)Tes fungsi trombosit: abnormalAgregasi trombosit: rendahHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran Darah Tepi pada ET

Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Megakariosit abnormal

MIELOFIBROSISMyelofibrosis ~ SinonimMielosklerosisAgnogenic myeloid metaplasiaMielofibrosis idiopatikMyelofibrosis with myeloid metaplasia (MMM)Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.PatofisiologiPembentukan jaringan ikat (fibrosis) di sumsum tulangHematopoiesis ekstrameduler

Fibrosis Sumsum TulangHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran KlinisGejala anemiaGejala splenomegali masifGejala hipermetabolik: BB turun, anoreksia, demam, keringat malamGangguan perdarahan, nyeri tulang, gout jarangHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran LaboratoriumAnemia tidak selaluLeukositosis & trombositosis (awal penyakit) leukopenia & trombositopenia GDT: gambaran leukoeritroblastik dgn sel tear-drop & eritroblas (khas).BM: dry tap. Jika ada: fibrotik, hiperseluler, megakariosit Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Gambaran Darah Tepi pada MielofibrosisHoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.

Tefferi A. N Engl J Med 2000;342:1255-1265Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia44Figure 3. Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia.

Panel A shows myelophthisis of the blood. Immature granulocyte precursors, a nucleated red cell, and teardrop-shaped red cells are visible (Wright-Giemsa, x200). Biopsy specimens of the bone marrow core show stromal stranding and atypical megakaryocytes (Panel B; hematoxylin and eosin, x128), collagen fibrosis on silver-impregnation staining of reticulin (Panel C, x128), and thickening of the bone trabeculae (osteosclerosis) and intramedullary sinusoidal hematopoiesis (Panel D; hematoxylin and eosin, x128).Gambaran Laboratorium (lanjutan)Mutasi JAK2 (50% kasus)Skor NAP Kimia: asam urat , LDH Hoffbrand AV, Moss PAH, Pettit JE. Essential Haematology. 5th ed. Massachusetts: Blackwell Publishing; 2006. p. 230-9.Thank You Very Much

Kriteria Diagnosis Mielofibrosis (WHO)

MinorMayorSkor NAP