3Causes of Pancytopenia 3. Paroxysmal nocturnal hemoglobinuria (PNH)4. Myelodysplastic syndrome5. Hypersplenism6. Vit B12 or folate deficiencies7. S. Lupus erythematosus8. Cytotoxic agents and antimetabolites9. Radiotherapy10. Overwhelming infections11. otherAplastic anemiaBone marrow infiltration byHematologic malignanciesNon-hematologic Tm met.Storage cell disordersOsteopetrosisMyelofibrosis
4Clinical features Related to Pancytopenia Or Underlying condition/disease
5Symptoms/Findings Related to pancytopenia The presenting symptoms are related to anemia or thrombocytopeniaLeukopenia may sometimes be life threatining (eg: late in the course of AA, severe neutropenia)Anemia develops slowly ( long life span of RBC’s)symptoms of gradual onset.
6Symptoms/Findings Related to pancytopenia Thrombocytopenic type bleeding may occur andseverity depends on the plt. number.eg: spontaneous bleeding indicates plt<20.000/mm3Infections are related to neutropenia , with severity depending on the decrease in neutrophyl counts.
7Symptoms/Findings Related to the cause of pancytopenia eg: Splenomegaly: Hypersplenism, lymphoma, leukemia, myelofibrosis etcLymphadenomegaly:Lymphoma , leukemia,SLE etcAtrophic glossitis: Megaloblastic anemiaOthers
8Investigation of Pancytopenia (Outline) History:Age , sex, occupation, dietChemical or drug or radiation exposureBone painFever, night sweats , malaise, weight lossSymptoms related to diseases that cause splenomegaly
9Investigation of Pancytopenia (Outline) Physical exam:SplenomegalyBone tendernessHepatomegalyLymph node enlargementGingival hypertrophySigns of liver failure or portal hypertensionEvidence of malignancy
11Investigation of Pancytopenia (Outline) Lab:Further investigations when requiredX-Rays: Bone, chest etcAlk. Phosp, acid. PhospSerum protein electrophoresisAnti-DNA, FANA, etcUrinary proteins (Bence-Jones)Lymph node or other biopsies
12Aplastic Anemia (AA) The term AA is first used by Ehrlich in 1888 Describes a disorder of unknown etiology characterized bypancytopenia withhypo or acellular bone marrow.It is one of the stem cell disorders.
13Classification of AA I-Inherited AA Dyskeratosis congenita Skin, nail and hair abnormalitiesTelangiectasiaAlopeciaAbnormal sweatingMental retardationGrowth failure and hypogonadismShwachman–Diamond syndromeI-Inherited AAFanconi’s anemia:Autosomal. recessive inheritanceSkeletal and renal defectsHyperpigmentationSmall statureHypogonadismChromosomal changesFamilial AA (non-Fanconi)Familial but without features of Fanconi’s anemia
14Somatic abnormalities in FA Abnormality % of patientsSkeletal (radial , hip, vertebral, scoliosis, rib)Skin pigmentation (café-au-lait, hyper- and hypopigmentation)Short statureEyes (microphthalmia)Renal and urinary tractMale genitalMental retardationGastrointestinal (e.g. anorectal, duodenal atresia)HeartHearingCentral nervous system (e.g. hydrocephalus)No abnormalities
15FAOccurrence of Pancytopenia: Age 7(med) 90% up to age 40Leukemia & other malignancyhepaticsquamous cell carcinomas of thevulva, oesophagus,head and neckImportant:Chromosomal breakage and hypersensitivity to the clastogenic effect of DNA cross-linking agentsdiepoxybutane (DEB) and mitomycin C (MMC)
18DC DC arises principally from an abnormality in telomerase activity A predisposition principally to chromosomal rearrangements rather than the gaps and breaks seen in FABM failure is likely to be a consequence of abnormalities in both haemopoietic stem cells and stromal cells
22Shwachman–Diamond syndrome Haematological abnormalities includes neutropenia (~60%), other cytopeniasApproximately 20% havepancytopenia, myelodysplasia andleukaemic transformation (~25%)
23Classification of AA II-Acquired AA Idiopathic Radiation Antineoplastic and cytotoxic drugsPesticidesSolvents and glues: benzene,toluene,xylene,naphtaleneDyes and industrial toxinsOthersII-Acquired AAIdiopathicRadiationDrugs/chemicalsChloramphenicolNSAID: (phenylbutasone,indomethacin,gold etc)Oral hypoglycemic drugs (chlorpropamide,tolbutamide)Antithyroid drugs, phenothiazines, antimalarials, diuretics,antiepileptics
24Classification of AA (continued) 5. Paroxysmal nocturnal hemoglobinuria(PNH)6. Immunologic disordersSLE, eosinophilic fasciitisGraft- versus- Host DiseaseHypoimmunoglobulinemiaThymoma7. Pregnancy8. Pancreatic insufficiency4. InfectionsHepatitisE.Barr virusRubellaCMVHIVParvovirusBrucellosisTbcToxoplasmosis
25Epidemiology of AA A disease of the young 1.5 – 2 /1.000.000-year Median age: about 25 y1.5 – 2 / yearEqual sex ratio
26Pathophysiology Defective stroma Stem cell damage Damage to stem cell DNA: Radiation, drugs etcLater progenitor cell damage: VirusesImmune mediatedInadequate production of growth factors?
27Immune mediated injury Blood and bone marrow of AA patients supress normal progenitor cell culturesCultured AA marrow recovers colony formation after removal of T-cellsImmunosupressive therapy is effective in about half of AA patientsViruses may cause an infection of the stem cell further leading to an immune response to permanent stem cell failure
28Clinical Features of AA History:BleedingSymptoms of anemiaInfectionsDrugs, chemicals or other etiologically important exposures have to be questioned.
29Clinical Features of AA Physical exam:Petechiae, ecchymosisRetinal bleedingPallorFever and other signs of infectionPresence of lymphadenomegaly and /or splenomegaly are unusual (indicate other diagnoses).
30Clinical Features of AA LAB:PancytopeniaReticulocytes: Low or absentRBC: normochrome-normocytic,or slight macrocytosisNeutropenia and relative lymphocytosisRed and white cell precursors are almost never seen in the peripheral smear
31Clinical Features of AA LAB: PNH tests may be positive (Ham’s or sucrose lysis tests,others)Serum iron is increasedBone marrow :Aspiration; Dry tapBiopsy; all three cell lines are reduced or absent, raplaced by fatty tissue, residual lymphocytes, increased iron stores,rarely hot spots of hematopoesis
32Course and prognosis of AA Definition of severe aplastic anaemia:1-hypocellular bone marrow2-neutrophils <500/mm33-platelets<20.000/mm34-reticulocytes<20.000/mm3 (<%1)Survival in severe disease is about 1 year if it is treated with transfusions only.Very severe AA:Severe AA criteria + Neutrophils:< 200/mm3
33Treatment of AA(1) Treatment alternatives: Allogeneic bone marrow/stem cell transplantationImmunosupressive treatmentAndrogensHematopoietic growth factorsSupportive therapy
34Treatment of AA (2) Stem cell transplantation: Young patients with severe AA and a HLA matched donor should undergo a stem cell transplantation(minimally transfused patients have a chance of > 80% survival )Risks: GVHD, engraftment failure, other
35Treatment of AA (3) Immunosupressive treatment ATG or ALG (antithymosit or antilymphocytic globulin )Cyclosporin APrednisolone(50% chance of recovery )Risks:Early:infectionsLate: MDS, PNH, leukemia, other malignancies,relapse
36Treatment of AA (4) Supportive treatment Hemopoetic Growth Factors: GM-CSF, G-CSF: efficiency ? (limited or not)Transfusions:Only when indicatedExclude family members as transfusion donorsCellular blood products must be irradiated before transfusionsMay cause:Iron overload (Repeated RBC’s), alloimmunization, infection transmission(eg : HIV,HCV,HBV,CMVetc),Infections: Preventive care, early diagnosis and treatment
37Pure Red Cell Aplasia Classification Anemia + Erythropoetic hypoplasia/aplasia occuring in a normocellular bone marrowClassificationCongenital (Diamond-Blackfan Syndrome)AcquiredDuring chronic hemolytic anemia (aplastic crisis)Infections(eg: Parvovirus B19)MalnutritionDrugs (Alpha Methyl Dopa, Azathioprine, Carbamazepine,Gold, NSAID,RMP ,Chloramphenicol etc)ThymomaMalignancyIdiopathic