Gangguan Myeloproliferatif Kronik

Gangguan Myeloproliferatif KronikDefinisiGangguan myeloproliferatif kronik : gangguan akibat abnormalitas clonal hematopoetic stem cell yg didapat (akuisita), mengakibatkan peningkatan selularitas sum2 tulang yg diikuti peningkatan jumlah sel darah perifergangguan ini berpotensi menjadi lekemia akut_______________________________________Hematopoetic stem cell : sel primitif sum2 tulang, asal dari seluruh jenis sel darahClonal/Monoclonal : propagasi sel yang berasal dari sel progenitor tunggal

Gangguan Myeloproliferatif KronikPolisitemia Vera (PV) : eritrosit Trombositosis Esensial (TE) : trombosit Myelofibrosis Idiopatik Kronik : fibrosis sum2 tulang Chronic Myelocytic Leukemia (CML) : lekosit seri myeloid CML memiliki abnormalitas kromosom unik (kromosom Philadelphia) yg tidak didapat pd kelainan lain, perjalanan klinis & implikasi terapi berbeda CML dibicarakan dlm keganasan hematologiPerbandingan Gangguan MyeloproliferatifMorfologiSDMPlateletHCTLekositNN atau NCMLAbNTdk khasN atau Tdk khasMyelofibrosisNN atau N atau PVNNN atau TEPolisitemia VeraKenaikan HCT > 54 () dan 51(). Evaluasi awal : massa eritrosit (ml/kg) DD dgn hemokonsentrasi (polisitemia spuria)Klinis PV :, massa eritrosit tanpa sebab sekunder Saturasi oksigen arteri normalKadar eritropoetin (EPO) normal/rendah splenomegali

Polisitemia Vera Essentials of Diagnosis Increased red blood cell mass. Splenomegaly. Normal arterial oxygen saturation. Usually elevated white blood count and platelet count.

DD Polisitemia VeraPolisitemia spuria : cairan tubuh pemakaian diuretik, sebab lainPolisitemia sekunder : Hipoksia : penyakit jantung, paru, ketinggianHbCO2 : merokokLesi ginjalTumor dgn sekresi EPOHb abnormalCauses of polycythemia.Spurious polycythemiaPrimary polycythemia : PV Secondary polycythemiaHypoxia: cardiac disease, pulmonary disease, high altitudeCarboxyhemoglobin: smokingRenal lesions4. Erythropoietin-secreting tumors (rare)

Sign and simptomSymptoms related to expanded blood volume and increased blood viscosity. Common complaints: headache, dizziness, tinnitus, blurred vision, and fatigue. Generalized pruritus,and epistaxis. 60% are men, and the median age at presentation is 60 years. Polycythemia rarely occurs in persons under age 40 years.Physical examination: reveals plethora and engorged retinal veins. Spleenomegaly in 75% of cases but is nearly always enlarged when imagedThrombosis is the most common complication of polycythemia vera and the major cause of morbidity and death.There is a high incidence of peptic ulcer disease. Laboratory FindingHematocrit above normal, at times greater than 60%. Red blood cell morphology is normal. The red blood cell mass is elevated. The white blood count is elevated to 10,000-20,000/uL The platelet count is variably increased, sometimes to counts exceeding 1,000,000/uL. Platelet morphology is usually normal.The bone marrow is hypercellular, with panhyperplasia Iron stores are usually absent from the bone marrowOverproduction of uric acid may lead to hyperuricemia. Microcytosis, hypochromia, and poikilocytosis may result from iron deficiencyProgressive hypersplenism may also lead to elliptocytosis.Differensial DiagnosisLaboratory features of myeloproliferative disorders. WhiteCount Hematocrit Platelet Count Red cellMorphologyChronic myeloid leukemia I N N or I NMyelofibrosis N or D or I N or I D or N or I Abn Polycythemia vera N or I I N or I NEssential thrombocytosis N or I N I NTerapi Polisitemia VeraTerapi pilihan : flebotomi sd HCT < 45Obat myelosupresan : hydoxyurea, indikasi keperluan flebotomi terlalu sering trombositosis terapi suportif: antitrombotik

TreatmentPhlebotomy. One unit of blood (approximately 500 mL) weekly target: less than 45%. Myelosuppressive therapy : a high phlebotomy requirement, thrombocytosis, and intractable pruritus. Hydroxyurea >> Alkylating because of less leukemogenic potential. The usual dose is 500-1500 mg/d orally Target: platelets < 500,000/uL and neutrophil count < 2000/uL. Anagrelide is a new drug for trombositosisLow-dose aspirin (81-325 mg daily) has been shown to reduce the risk of thrombosis.PrognosisPolycythemia is an indolent disease with median survival of 11-15 years. The major cause of morbidity and mortality is arterial thrombosis. Polycythemia vera may convert to myelofibrosis or to chronic myelogenous leukemia. In approximately 5% of cases, the disorder progresses to acute myelogenous leukemia, which is usually refractory to therapy.

Trombositosis EsensialPeningkatan trombosit tanpa sebab lainMassa eritrosit NKromosom Philadelphia (-) DD dgn CMLKlinis berisiko trombosis, atau justru terjadi perdarahan krn defek platelet kualitatifDD :* Polisitemia Vera * Trombositosis reaktif (pada infeksi, anemia def besi, perdarahan) Jumlah trombosit pd trombositosis reaktif jarang > 1 juta/mmk

Essential TrombositosisEssentials of Diagnosis Elevated platelet count in absence of other causes. Normal red blood cell mass. Absence of Philadelphia chromosome.

Symptoms and SignsMedian age: 50-60 years, slightly increased incidence in women. Finding of an elevated platelet count. First sign is thrombosis. Venous thromboses may occur in unusual sites such as the mesenteric, hepatic, or portal vein. Some patients experience erythromelalgia(painful burning and erythema) BleedingSplenomegaly is present in at least 25% of patients.

Laboratory Findings Elevated platelet count is the hallmark of this disorder, and may be over 2,000,000/uL. WBC mildly elevated (not above 30,000/uL), but with some immature myeloid forms. The hematocrit is normal.The peripheral blood smear reveals large platelets, but giant degranulated forms seen in myelofibrosis are not observed. Red blood cell morphology is normal. The bleeding time is prolonged in 20% of patients. The bone marrow : increased megakaryocytes but no other morphologic abnormalities. The Philadelphia chromosome is absent to differentiate from chronic myeloid leukemia.

Differensial DiagnosisLaboratory features of myeloproliferative disorders. WhiteCount Hematocrit Platelet Count Red cellMorphologyChronic myeloid leukemia I N N or I NMyelofibrosis N or D or I N or I D or N or I Abn Polycythemia vera N or I I N or I NEssential thrombocytosis N or I N I NTerapi Trombositosis EsensialTerapi myelosupresan utk mencegah trombosis : hydroxyurea target terapi AT < 500.000/mmkLow dose aspirin, untuk mencegah trombosis belum disepakatiTreatmentStandard therapy has consisted of hydroxyurea in a dose of 0.5-2 g/d. Anagrelide is highly effective in a dose of 2-4 mg/d but may cause headache, mild anemia, and peripheral edema, and in high doses congestive heart failure. Vasomotor symptoms such as erythromelalgia and paresthesias respond rapidly to aspirin and eventually to control of the platelet count.Plateletpheresis.

PrognosisEssential thrombocytosis is an indolent disorderAverage survival is longer than 15 years from diagnosisThe major source of morbidity thrombosis can be reduced by appropriate platelet control.The bone marrow may become fibrotic, and massive splenomegaly may occur, sometimes with splenic infarction. There is a 10-15% risk of progression to myelofibrosis after 15 years, and a 1-5% risk of transformation to acute leukemia over 20 yearIDIOPATHIC (AUTOIMMUNE) THROMBOCYTOPENIC PURPURAEssentials of Diagnosis Isolated thrombocytopenia. Other hematopoietic cell lines normal. No systemic illness. Spleen not palpable. Normal bone marrow with normal or increased megakaryocytes.

PatophysiologyITP: autoimmune disorder in which an IgG autoantibody is formed that binds to platelets.Platelets are not destroyed by direct lysis.Destruction takes place in the spleen, where splenic macrophages with Fc receptors bind to antibody-coated platelets. Splenectomy is highly effective therapy.

Symptoms and SignsITP commonly in childhoodPrecipitated by viral infection and usually self-limited.Adult form is usually a chronic disease and only infrequently follows a viral infection. Incidence between ages 20 and 50 years, and there is a 2:1 female predominance. Presenting complaint is mucosal or skin bleeding (epistaxis, oral bleeding, menorrhagia, purpura, and petechiae). An enlarged spleen should lead one to doubt the diagnosis.Laboratory Findings The hallmark of the disease is thrombocytopenia, with platelet counts that may be less than 10,000/uL. Other counts are usually normal except for occasional mild anemia, which can be explained by bleeding or associated hemolysis (Evans's syndrome).Peripheral blood cell morphology is normal except that platelets are slightly enlarged (megathrombocytes). The bone marrow will appear normal, with a normal or increased number of megakaryocytes. Coagulation studies will be entirely normal.Differensial DiagnosisCauses of thrombocytopenia.Bone marrow disordersAplastic anemiaHematologic malignanciesMyelodysplasiaMegaloblastic anemiaChronic alcoholismNonmarrow disordersImmune disordersIdiopathic thrombocytopenic purpuraDrug-inducedSecondary (CLL, SLE)1Posttransfusion purpuraHypersplenismDisseminated intravascular coagulationThrombotic thrombocytopenic purpuraHemolytic-uremic syndromeSepsisHemangiomasViral infections, AIDSLiver failureCLL = chronic lymphocytic leukemia; SLE = systemic lupus erythematosus.

TreatmentInitial treatment is with prednisone, 1-2 mg/kg/d. Prednisone works primarily by decreasing the affinity of splenic macrophages, reduces the binding of antibody to the platelet surface, decrease antibody production, enhanced vascular stability.the risk of bleeding is small with platelet counts above 50,000/uL. An alternative steroid regimen is the use of high-dose dexamethasone, 40 mg/d for 4 days. Splenectomy is the most definitive treatment for idiopathic thrombocytopenic purpura, Splenectomy is indicated if patients do not respond to prednisone. Splenectomy can be performed safely even with platelet counts less than 10,000/uL. CR 80%TreatmentHigh-dose intravenous immunoglobulin, 1 g/kg for 1 or 2 days, is highly effective in rapidly raising the platelet count. Use for bleeding emergencies or situations.Danazol, vincristine, azathioprine, cyclosporine, and cyclophosphamide. Rituximab can produce good responses in some patients with refractory disease. Platelet transfusions are rarely used in the treatment of idiopathic thrombocytopenic purpura, PrognosisThe prognosis for remission is good. The major concern during the initial phases is cerebral hemorrhage, which becomes a risk when the platelet count is less than 5000/uL.Very low platelet counts caused fatal bleeding is rare. THROMBOTIC THROMBOCYTOPENIC PURPURA

Essentials of Diagnosis Thrombocytopenia. Microangiopathic hemolytic anemia. Neurologic and renal abnormalities, fever. Reduced level of ADAMTS13. Normal coagulation tests. Elevated serum LDH.

IntroducingTTP is an uncommon syndrome with microangiopathic hemolytic anemia, thrombocytopenia, and a markedly elevated serum LDH.Deficiency of a von Willebrand factor-cleaving protease, ADAMTS13, to platelet agglutination and adhesion to endothelium. TTP is seen primarily in young adults between ages 20 and 50 years, female predominance. The syndrome is occasionally precipitated by estrogen use, pregnancy, drugs, or infections. The most common drugs implicated are quinine and ticlopidine.

Symptoms and Signs

Anemia, bleeding, or neurologic abnormalities.Neurologic symptoms include headache, confusion, aphasia, and alterations in consciousness from lethargy to coma. With more advanced disease, hemiparesis and seizures may occur. On examination, the patient appears acutely ill and is usually febrile. Pallor, purpura, petechiae, Patients may have abdominal pain and tenderness due to pancreatitis.

Differential Diagnosis

The normal values of coagulation tests differentiate TTP from DIC. Other conditions causing microangiopathic should be excluded Evans's syndrome is the combination of autoimmune thrombocytopenia and autoimmune hemolytic Laboratory FindingsAnemia Reticulocytosis and circulating nucleated red blood cells. The hallmark is a microangiopathic blood picture with fragmented red blood cells Thrombocytopenia is invariably present and may be severe. Increasing indirect bilirubinLDH is markedly elevated in proportion to the severity of hemolysis; Coombs test is negative.

Coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen) are normal unless ischemic tissue damage causes secondary disseminated intravascular coagulation (DIC) present elevated fibrin degradation products may be seen.ADAMTS13 is usually absent during active disease. Pathologically, there may be thrombi in capillaries and small arteries, with no evidence of inflammation.

Differensial DiagnosisEvans's syndrome is the combination of autoimmune thrombocytopenia and autoimmune hemolytic anemia, but the peripheral smear will show spherocytes and not red blood cell fragments. TTP and hemolytic-uremic syndrome are not distinct disease entities, TTP characterized by more neurologic and severe thrombocytopenia and hemolytic-uremic syndrome with more renal failure.

TreatmentPlasmapheresis. 60 to 80 mL/kg of plasma should be removed and replaced with fresh-frozen plasma. Treatment should be continued daily until the patient is in complete remission. Prednisone and antiplatelet agents (aspirin [325 mg three times daily] and dipyridamole [75 mg three times daily])The combination of splenectomy, corticosteroids, and dextran has been used with success. Splenectomy performed in remission may prevent subsequent relapses. Immunosuppression with drugs such as cyclophosphamide has also been effective.

PrognosisWith plasmapheresis, 80 to 90 percent of patients now recover completely.Neurologic abnormalities are almost always completely reversed.Most complete responses are durable, but in 20% of cases the disease will be chronic and relapsing.

Myelofibrosis Idiopatik KronikAdanya proses fibrosis pd sum2 tulang, yg diduga dipicu pelepasan platelet-derived growth factor (PDGF) dan sitokin lainFibrosis sum2 tulang hematopoesis ekstra meduler (hepar, splen, dan lnn) gagal sum2 tulang (bone marrow failure) pd tahap akhirKlinis : splenomegali masif dgn anemiagambaran drh tepi leukoeritroblastik (AL, eritrosit berinti , skistosit) hapusan sum2 tulang : hiperselular sum2 tulang dgn fibrosis retikuler/kolagenPrognosis terburuk di antara gangguan myeloproliferatifTerapi Idiopatik MyelofibrosisSuportif : mengatasi anemiaThalidomideTransplantasi sum2 tulang allogenik (berasal dari orang lain)Sindrom Myelodisplasia(MDS)DefinisiKelainan clonal stem cell akuisita dgn ciriSitopenia Sum2 tulang hiperselularAdanya abnormalitas sitogenetik dan morfologi selKausa : idiopatik, sebagian kasus terjadi pasca kemoterapi sitotoksikPreleukemic state menjadi AML pd 10-50% kasusTidak terdapat abnormalitas kromosom spesifikSindrom Myelodisplasia (Pembagian WHO)Refractory anemia (RA)RA with ringed sideroblast (RARS)RA with excess blast-1 (RAEB-1)RA with excess blast-2 (RAEB-2)MDS, unclassifiedMDS with isolated del(5q)

Terapi MDSSuportif dan allotransplanALHAMDULILLAH