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Dr . Yenny Dian Andayani SpPD -KHOM Divition Hematologic Oncologi Medic Dept Internal Medicine Moh HoesinGeneral Hospital Palembang Faculty of Medicine Sriwijaya University Palembang
Morphological classification of anemias
• microcytic, hypochromic anemia
– (decreased MCV)
• normocytic, normochromic anemia
– (normal MCV)
• macrocytic, normochromic anemia
– (increased MCV)
Normochrome normocyter anemia
• MCH normal • MCHC normal • MCV normal
MICROCYTIC HYPOCHROME anemia
• MCV MCH MCHC • microcytic, hypochromic RBC in the peripheral blood • MCV < 80fl • MCH < 27pg
MACROCYTIC anemia • MCV • MCH • MCHC .
Fe dalam terapi ? Periksa ACTH Infiltrasi Keganasan Hipoplasia SSTL Cincin sideroblastik ? BMP Kehilangan/Penghancuran Berlebihan Periksa: Bilirubin indirek. C3/C4 Anti dsDNA Hemolisis Ekstravaskular Defect Extra corpuscular Mekanik. Infeksi Positif Hb/ hemosiderin Positif AIHA Primer or Secunder Negatif Defect Intra corpuscular Hemolisis Intravaskular . Toksin. LDH Normal Perdarahan ? Tidak Ya Tinggi Anemia Hemolitik Periksa urin Negatif Tes coombs.FLOW CHART ANEMIA NORMOSITIK NORMOKROM Anemia MCV 80-100 fL and MCHC 30 g/dL or MCH > 27 pg/dL Indeks retikulosit <10‰ Indeks retikulosit 10-15‰ Indeks retikulosit >15‰ Abnormal Hambatan Produksi/Pematangan Normal Anemia hemolitik/def.
Feritin Elektroforesis hemoglobin Normal/Tinggi Defisiensi Fe Normal Dalam terapi Fe ? Abnormal Hemoglobinopati Thalasemia BMP Pasokan.FLOW CHART ANEMIA MIKROSITIK HIPOKROM Anemia MCV<80fl & MCHC<30g/dL or MCH ≤ 27 pg/dL Indeks retikulosit <10‰ Indeks retikulosit 10-15‰ Indeks retikulosit >15‰ SI/IBC. Transferin. Absorpsi ? Hemolitik ? Gangguan metabolisme Fe Mielodisplasia (MDS) Anemia of Chronic Diseases (ACD) .
Internal Medicine Moh Hoesin General Hospital Faculty of Medicine /Sriwijaya University Palembang .HEMOLYTIC ANEMIAS Yenny Dian Andayani Hematology Oncology Medic Division Dept.
HEMOLYTIC ANEMIA • Anemia of increased destruction – Normochromic.Response to increased RBC destruction – Increased indirect bilirubin – Increased LDH . normochromic anemia – Shortened RBC survival – Reticulocytosis .
Classification of Hemolytic Anemia • Intracorpuscular factor • Extracorpuscular factor .
Acquired 1. Membrane defect (spherocytosis.1. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency. sickle cell anemia ) B. elliptocytosis) 2. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH) . Pyruvate kinase (PK) deficiency) 3. Intracorpuscular factor Red cell abnormality A. Hemoglobinopathies (unstable hemoglobins. thalassemias. Hereditary 1.
thrombotic thrombocytopenic purpura (TTP) .uremic syndrome (HUS) . Transfusion of incompatible blood B. venons 3.hemolytic .caused by cold-reactive antibodies 2. Chemicals 2. Extracorpuscular factors A.prosthetic heart valves 4. Autoimmune hemolytic anemia . Nonimmune hemolytic anemias 1. parasitic infections (malaria). Hemolysis due to physical trauma . Hypersplenism .II. Bacterial infections.caused by warm-reactive antibodies . Immune hemolytic anemias 1.
Hemolysis .RBC destruction Extravascular Hemolysis Ingested by RE cell (spleen & liver) Heme Globin Intravascular Hemolysis Hgb liberated in blood vessel Hgb + haptoglobin Serum haptoglobin + hemalbumin & plasma Hgb + hemoglobinuria & hemosidenuria Iron Reutilized Protoporphyrin Hgb + albumin Hgb excreted in urine Reutilized bilirubin .
Intravascular .Extravascular .Mechanisms of hemolysis / pathogenesis: .
Clinical states associated with Intravascular hemolysis: Acute hemolytic transfusion reactions Severe and extensive burns Paroxysmal nocturnal hemoglobinuria (PNH) Severe microangiopathic hemolysis Physical trauma Bacterial infections and parasitic infections (sepsis) .Inravascular hemolysis : .Red cells destruction occurs in vascular space .
.Laboratory signs of intravascular hemolysis: Indirect hyperbilirubinemia Erythroid hyperplasia Hemoglobinemia Methemoalbuminemia Hemoglobinuria Absence or reduced of free serum haptoglobin Hemosiderynuria .
Red cells destruction occurs in reticuloendothelial system (RES) .Extravascular hemolysis : .Clinical states associated with extravascular hemolysis : Autoimmune hemolysis Delayed hemolytic transfusion reactions Hemoglobinopathies Hereditary spherocytosis Hypersplenism Hemolysis with liver disease .Laboratory signs of extravascular hemolysis: Indirect hyperbilirubinemia Increased excretion of bilirubin by bile Erythroid hyperplasia Hemosiderosis .
Anamnesa • • • • • • • • Fatigue Pallor Shortness of Breath Bleeding/petechiae Joint symptoms Rash-eg malar Family History Medications .
Physical Exam Findings • • • • • Tachycardia Tachypnea Jaundice Splenomegaly Signs of congestive heart failure in rapidly progressive anemia .
Blood smear .Anisopoikilocytosis.Erythroblasts . Laboratory features .Schistocytes 3. spherocytes .Laboratory features: Hematology test 1.Erythroid hyperplasia .Antiglobulin Coombs’ test is positive 2. Bone marrow smear .Normocytic/macrocytic. hyperchromic anemia .Increased serum iron .Reticulocytosis .
systemic lupus erythematosus . Primary II. Quinidine) 2. Quinine.drugs ( -Methyldopa.rheumatoid arthritis. WaldenstrÖm’s macroglobulinemia) . Secondary 1.Extra corpuscular Factor Autoimmune Hemolytic Anemia (AIHA) * warm-reactive antibodies: I.lymphoproliferative disorders (chronic lymphocytic leukemia. Chronic . lymphomas. Penicillin.viral infections . malignancy ) .Acute .miscellaneous (thyroid disease.
Primary cold agglutinin disease II. Secondary hemolysis: . Paroxysmal cold hemoglobinuria .Viral infections .* cold-reactive antibodies: I.Lymphoproliferative disorders III.Mycoplasma infections .
Diagnosis .splenectomy .positive Coombs’ test (DAT) Treatment: .steroids .transfusion .immunosupressive agents .
inositol (GPI) anchor abnormality .intravascular hemolysis 2.deficiency of the GPI anchored membrane proteins (decay-accelerating factor =CD55 and a membrane inhibitor of reactive lysis =CD59) . Symptoms .an acquired clonal disease. arising from a somatic mutation in a single abnormal stem cell .Intracorpuscular FACTOR: Accquired : Paroxysmal Nocturnal Hemoglobinuria (PNH) 1.passage of dark brown urine in the morning .red cells are more sensitive to the lytic effect of complement .glycosyl-phosphatidyl. Pathogenesis .
CD55) 4.3.positive Ham’s test (acid hemolysis test) .hemoglobinuria .positive sugar-water test .specific immunophenotype of erytrocytes (CD59.pancytopenia . PNH –laboratory features: .washed RBC transfusion .allogenic bone marrow transplantation . Treatment : .hemosiderinuria .iron therapy .chronic urinary iron loss .serum iron concentration decreased .
Hemoglobin SC – Thallasemias • Unstable RBC Membrane – Hereditary spherocytosis • Metabolic Machinery – G6PD deficiency – Pyruvate kinase deficiency .Intracorpuscular Factor Herediter ( defect) • Hemoglobinopathies – Sickle Cell Disease. Sickle cell trait.
G6PD deficiency • Most frequently encountered abnormality of red cell metabolism • Over 200 million people worldwide • ? Survival advantage with malaria infection • X chromosome • Extensive polymorphism .
Internal Medicine Moh.Macrocytic Anemia Yenny Dian Andayani Hematology Oncology Medic Division Dept.Hoesin General Hospital /Faculty of Medicine Sriwijaya University Palembang .
.Megaloblastic anemia/Macrocytic anemia • fault in DNA synthesis • 95% of cases of megaloblastic anemia are – deficiency of vitamin B12 – deficiency of folic acid • macrocytic blood picture • megaloblastic erythropoesis.
Vitamin B12 deficiency • • • • • • inadequate diet (no animal products!) malabsorption pernicious anemia (PA) partial or total gastrectomy blind loop syndrome fish tapeworm .
oral contraceptive). alcoholism. hepatoma . • Reduced hepatic stores alcohosm. malignancy. hyperthytoidsm) • Defective utilisation : drugs (anticonvulsant.Folate deficiency • Reduced intake ( nutritional & malabsorpsi) • increased utilisation (pregnancy.
• Disorder of the central nervous system : paresthesias of the hands & feet. neuropathy • Other symptom : sore mouth.Clinical Feature Sympton and sign Vit B12 Def : • Severe : anemia. . atropy mucosa of the tongue. memory loss etc.loss of taste. unsteadiness of gait.
especially alcoholic who have a very poor diet and maintain blood alcohol levels above 100 mg/dl→ enteropatic cycle of folate supply to the intestine and tissues impared. . • Diagnosis is made difficult → clinician must be suspicious of the possibility of folate def. in the alcoholic.Syptom & sign folic acid def • Often go undiagnosed.
The peripheral blood smear in Macrocytic Anemia • • • • • • • • • oval macrocytes anisocytosis poikilocytosis. hypersegmental neutrophils (>5% with more than five nuclear lobes) platelets bizarre in shape and size (giant platelets) neutropenia thrombocytopenia (not as severe as in AA) low reticulocytosis The bone marrow shows a megaloblastic erythropoesis .
giant metamyeolcytes giant bands many Howell-Jolly’es bodies Cabot’s rings .Bone marrow smear in MA • • • • • • megaloblastic erythropoesis bone marrow rich in cells.
Biochemical findings in MA • serum indirect (unconjugated) bilirubin • serum LDH (principally LDH-1) • serum iron – (unless the anemia is complicated with iron deficiency) • vitamin B12 concentration ↓ • folic acid concentration ↓ .
The diagnosis of megaloblastic anemia
• serum vitamin B12 concentration • serum folic acid concentration • if vitamin B12 and folate assays are within normal limits, then the bone marrow examination is performed (before blood transfusion or vitaminB12, folate administration). • Schilling test
• Establised based on laboratory test. • DD : Macrocytosis in patients : dysplastic anemias, liver disease, hemolysis, exposure to the chemotherapeutic agents.
• Folic Acid and Vit B12 ( etiology must known well) • Severe with anemias : PRC transfusion
APLASTIC /HYPOPLASTIC ANEMIA Yenny Dian Andayani Hematologic Oncology Medic Division Dept Internal Medicine Moh.Hoesin General Hospital Faculty of medicine Sriwijaya University Palembang .
life threatening syndrome in which production of erythrocytes. WBCs. • Aplastic anemia may occur in all age groups and both genders.Aplastic anemia • Aplastic anemia is a severe. and platelets has failed. . • The disease is characterized by peripheral pancytopenia and accompanied by a hypocellular bone marrow.
Hypocellular bone marrow in aplastic anemia .
Aplastic anemia • Etiology – Acquired » Most cases of aplastic anemia are idiopathic and there is no history of exposure to substances known to be causative agents of the disease » Exposure to ionizing radiation – hematopoietic cells are especially susceptible to ionizing radiation. With sublethal doses. Whole body radiation of 300-500 rads can completely wipe out the bone marrow. and certain insecticides. » Chemical agents – include chemical agents with a benzene ring. . chemotherapeutic agents. the bone marrow eventually recovers. » Idiosyncratic reactions to some commonly used drugs such as chloramphenicol or quinacrine.
cytomegalovirus infections. WBCs and platlets have an abnormality making them susceptible to complement mediated lysis. infectious hepatitis.Aplastic anemia » Infections – viral and bacterial infections such as infectious mononucleosis. and miliary tuberculosis occasionally lead to aplastic anemia » Pregnancy (rare) » Paroxysmal nocturnal hemoglobinuria – this is a stem cell disease in which the membranes of RBCs. » Other diseases – preleukemia and carcinoma .
Congenital defects such as skin hyperpigmentation and small stature are also seen in affected individuals. » Familial aplastic anemia – a subset of Fanconi’s anemia in which the congenital defects are absent. .Aplastic anemia – Congenital disorders » Fanconi’s anemia – the disorder usually becomes symptomatic ~ 5 years of age and is associated with progressive bone marrow hypoplasia.
Clinical features • • • • • • Fatique Heart palpitation Palor Infections Ptchiae Mucosal bleeding/gum bleeding .
• In rare instances it is the result of abnormal hormonal stimulation of stem cell proliferation • or the result of a defective bone marrow microenvironment • or from cellular or humoral immunosuppression of hematopoiesis.Aplastic anemia • Pathophysiology: – The primary defect is a reduction in or depletion of hematopoietic precursor stem cells with decreased production of all cell lines. • This may be due to quantitative or qualitative damage to the pluripotential stem cell. . This is what leads to the peripheral pancytopenia.
Aplastic anemia – Lab findings » Severe pancytopenia with relative lymphocytosis (lymphocytes live a long time) » Normochromic. normocytic RBCs (may be slightly macrocytic) » Mild to moderate anisocytosis and poikilocytosis » Decreased reticulocyte count » Hypocellular bone marrow with > 70% yellow marrow .
PNH 4.Differential Diagnosis of pancytopenia and hypoplastic marrow • • • • • • • • • • 1. Idiopathic myelofibrosis 7.Hypoplastic antecedent of hairy cell leukemia 6. Hypoplastic antecedent phase of acute lymphocytic leukemia 5. Aplastic anemia 2. Pure red cell aplasia 8. Agranulocytosis. . Hypoplastic myelodysplastic syndrome or hypoplastis AML 3.
Bone Marrow cellularity < 50 % with fewer the 30 % the neutrophil cell .Diagnosis Criteria for Severe AA • At least two of following .Absolute neutrophil count < 0.Bone marrow cellularity <25 % . • One of the following .Anemia with corrected reticulocyte count < 1 %.5 x 10 9 /L .Platelet count < 20 x 10 9/L .
Treatment • Marrow tranplantation isI curative for < 40 years. • Immunosuppressive therapy : not curative -ATG -Cyclosporin -Androgen .Corticosteroids . • Only one –third of patients have suitable donor.
Internal Medicine RSMH/Faculty of medicine Sriwijaya University Palembang .Anemia of chronic disease =Anemia of chronic disorders (ACD) Yenny Dian Andayani Division Hematology Oncology Medic Dept.
It does not include anemias caused by marrow replacement. blood loss. even when these disorders are chronic. inflammatory. renal insufficiency. hepatic disease. or neoplastic diseases that persist for more than 1 or 2 months. . hemolysis. or endocrinopathy.Definition ACD is a common type of anemia that occurs in patients with infectious.
or known hematologic malignancy were excluded. 52% of anemic patients met laboratory criteria for the anemia of chronic disorders • ACD is observed in 27% of outpatients with rheumatoid arthritis . hemolysis. .Epidemiology • ACD is more common that any anemia syndrome other than blood loss with consequent iron deficiency • ACD is the most common cause of anemia in hospitalized patients • After patients with bleeding.
Pelvic inflammatory disease . emphysema. tuberculosis.Rheumatoid arthritis . thermal injury.Pulmonary infections: abscesses.Sever trauma.LES (Systemic lupus erythematosus) . Osteomyelitis • Chronic. Chronic fungal disease .Subacute bacterial endocarditis . pneumonia .Disorders Associated with the Anemia of Chronic Disease • Chronic infections . Vasculitis .Chronic urinary tract infections.HIVinfections. noninfectious inflammations .
Alcoholic liver disease .Leukemias .Cancer .• Malignant diseases .Hodgkin’s disease and Non-Hodgkin’s Lympmhomas .Multiple myeloma • Miscellanous .Ischemic heart disease • Idiopathic ACD .Thrombophlebitis .
IFN-) affects erythropoiesis by inhibiting the growth of erythroid progenitors .Serum erythropoietin levels in patiens with ACD are normal when compared to healthy subjects but much lower than levels in non-ACD anemic patients .Pathogenesis • Shortened red cell life span.Cytokines released from inflammatory cells (TNF-. moderately 20-30% (from 120 to 60-90 days) • Relative bone marrow (erythropoiesis) failure . IL-1.
increase sequestration in the spleen and in the foci of inflammation. increase loss ) .Pathogenesis ABNORMAL IRON METABOLISM • Activation of the reticuloendothelial system with increased iron retention and storage within it • impaired release of iron from macrophages to circulating transferrin (impaired reutilization of iron) • Reduced concentration of transferrin (decreased production.
ACD Infection and inflammation Interleukin-1 (IL-1) Other Cytokines Stored iron in reticuloendothelial system [Leukocytes (granulocytes)] Lactoferrin Plasma iron Lactoferrin iron Decreased circulating plasma iron .
Increased stored iron Increased membrane receptors .Increased avidity for RBCs and iron-binding proteins IL-1 Granulocytes Acute-phase reactants Lactoferrin Circulating plasma iron (Lactoferrin-iron complex) Decreased plasma iron (hypoferremia) .ACD infection Inflammation Immune response Macrophage activity Increased phagocytosis .Decreased RBC survival Reticulo endothelial system Increased ferritin synthesis .
myalgias and artralgia.Symptoms and Sign • Symptoms of the underlying disease ( malignancy or chronic inflammatory disease) : weight loss. fever. • Symptoms of the anemia .chills. anorexia.
most often normal or slightly decreased number.lower values are observed in 20-30% of patients • The anemia is most often normochromic and normocytic (MCHC and MCV are normal) .Laboratory features • The anemia is usually mild or moderate ( Hb 7-11g/dl) .usually rapid • Retikulocytes .MCV 70-80 fl in 5-40% of patients with ACD .MCHC 26-32 g/dl in 40-70% • Erythrocyte sedimentation rate (ESR) . increased count is rarely .
Serum Ferritin-increased or normal 5. Saturation index is decreased and is often < 15 %. Serum Transferrin Receptor (sTR)-Normal 6. 4.decreased (it is necessary for the diagnosis of ACD) 2.Laboratory features • Iron metabolism 1. Sideroblasts in the bone marrow-reduced (5-20%) .reduced or low-normal (N) 3. TIBC . Serum Iron .
N <10% . . N >200g/L.Differential diagnosis Laboratory features sFe TS TIBC sFerritin Sideroblasts sTR Iron deficiency without iron deficiency <10% <10g/L <10% >10% . <30g/L. N 10-20% N ACD with iron deficiency <10% N.
IS benefit patients with ACD associated with auto-immune or rheumatic disorders.when ACD is complicated by iron deficiency (about 27% patients).for patients with ACD with chronic infection or malignancy IS should be strictly avoided .Therapy 1. Iron supplementation (IS) . Treatment of the underlying disorder 2. . .
Sequential administration of erythropoietin and iron (48h later) 5.v. in the absence of response 20000j. Iron chelation with deferoxamine . or s. Recombinant erythropoietin 10.c. 2-3tg. the treatment should be discontinued. Transfusion demand (about 30% ) patients who have low Hb and are symptomatic 4.000 units 3 times a week i. If there is still no respose.3. (in 40% of patients it reduces number of transfusions) 5. In future anti-TNF-antibodies .in some patients therapy was associated with a rise in hemoglobin level 6.
.POYCYTHEMIA Yenny Dian Andayani Hematology Oncology Medic Dept.of Internal Medicine Moh Hoesin General Hospital /Faculty of Medicine University Sriwijaya Palembang.
Polycythemia vera (PV) (ET) 2.Myeloproliferative disease arise from precursors of the "myeloid" lineage in the bone marrow 1. Essential thombocytosis 3. Myelofibrosis with myeloid metaplasia (MMM) Chronic Myelomonocytic leukemia (CMML) . 4.
Polycythemia vera 1892 : 1st described by Vaquez 1900 : Phlebotomy as treatment by Osler 1951 : Dameshek classified PV as a MPD 1967 : Wesserman defined of PV and treatment incidence etiology median age : : : 2 per 100.000 unknown 60 yrs. ( male ) .
Classfication of Polycythemia • I. Physiologycally in appropriate (normal tissue oxygenation ). Secondary Polycythemia A. . Physiologically appropriate ( decreased tissue oxygenation) B. Primary (autonomous) Polycythemia Vera • II.
pheochromocytoma Renal artery stenosis Adrenal cortical hypersecretion Exogenous androgens NS Bartter’s syndrome Renal cyst . hepatoma . uterine fibroid . hydronephrosis . renal . brain .Physiologycally inappropriate EPO Overproduction Tumors .
Physiologycally approprite (decreased tissue oxygenation) EPO Production secondary to hypoxia Lung disease High altitude Smoking Cyanotic Heart disease Methemoglobinemia High O2 affinity hemoglobin Cobalt .
vertigo Visual disturbance Conjunctival plethora Palpable splenomegaly 70% .Clinical Features .Head ache - Thrombosis common cause of death Pruritis ( aggravated by bathing ) 50% Erythromelagia Digital ischemia ( palpable pulse ) Joint pain Weight loss Headache .
hemat. increasing splenomegaly (extramed. with cytopenia .Clinical Features .) & collagen fibrosis of BM ) -BMP : hipersellarity .Risk to transform to acute leukemia spent phase ( Spent phase 40% 1.Lab : elevated leukocyte alkaline phosphatase ( LAP ) 70% elevated serum B12 .5 % 10-25% : normalization of red cell mass asso.
elevated RBC mass > 25% above mean normal predicted value.high O2 affinity Hb.truncated EPO receptor . Splenomegaly A4.5 g/dL (female ) A2. Endogenous erythroid colony formation in vitro . No cause of 2nd erythrocytosis. Clonal genetic abnormality other than Ph chromosome or BCR/ABL fusion gene in marrow cells A5.5g/dL ( Male ) Hb > 16.including: Absence of familial erythrocytosis No elevation of EPO from . .inappropiated EPO production by tumor A3.WHO criteria for diagnosis of Polycythemia Vera A1.hypoxia ( PaO2 92 % ) .or Hb > 18.
BM Biopsy showing panmyelosis with prominent erythroid & megakaryocytic proliferation B4. Thrombocytosis > 400.000 B3. B or > 99th percentile of method specific reference range of age . WBC > 12. A or A1+A2 and any 2 of cathegory.WHO criteria for diagnosis of Polycythemia Vera B1.000 B2.gender.altitude of residence . Low serum EPO levels Diagnosis : A1+A2 and any other of cathegory.
Arterial oxygen saturation ≥ 92 % 3.total red cell mass Male ≥36 ml/kg Female ≥32 ml/kg 2. Splenomegaly .Criteria Polycythemia Vera study group • Category A 1.
Increased leukocyte alkaline phosphatase (LAP) 4.• Category B 1. . Serum B12 > 900 pg/ml or B12 binding capacity > 2200 pg/ml Pv Diagnosis : when A1+A+2+A3 and any 2 from category B are present. Leukocytosis 12x 103/ul 3. Thrombocytosis > 400 x 10 3/ul 2.
PV & Secondary polycythemia Finding Splenomegaly Leukocytosis Thrombocytosis RBC volume arterial O2 sat B12 level LAP Bone Marrow EPO level Endogenous CFU-E growth PV + + + increased normal increased increased Panhyperplasia decreased + 2nd Polycythemia normal normal normal normal normal normal - .
important predictor of recurrent thrombotic events . & previous history of thrombosis . > 45% risk to thrombosis Death age > 70 yrs.Staging & Prognosis Hct.
based on risk of thrombosis Low risk -age < 60yr. thrombosis -CVD risk(smoking.Treatment aim . .000 -no CVD risk Intermediate risk High risk -age > 60yr. -Previous Hx.reduce thrombotic risk & slow leukemic transformation . ) . -no Hx thrombosis -Plt. < 1.500.
< 45 % in men . “ IFN –alfa “ use for cytoreduction in younger ( decreased risk to leukemic transformation of hydroxyurea ) . < 42% in women “ Hydroxyurea “ is supplemented to decreased Hct.Treatment Treatment of choice is “ Phlebotomy “ Hct.
erythromelalgia ) Anagrelide . with hydroxyurea intolerated Low dose ASA ( 40 mg ) . vertigo.Treatment Busulfan or P-32 in elderly pt. alleviate of microvascular sequelae ( headache. used in all MPD to lowering platelet count .visual disturbance .