Hematology Rivas2009lecture2

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<ul><li><p>RBC DisordersANEMIASAntonio Rivas PA-CLecture 2. 2009</p></li><li><p>ObjectivesDiscuss the etiology, pathogenesis, clinical features, laboratory evaluation, and management of:Aplastic anemiaIron deficiency anemiaMegaloblastic anemiaAnemia of chronic diseaseHemolytic anemiaSickle cell diseaseThalassemiasSideroblastic anemia</p></li><li><p>Disruption of the normal stem cell development can result in:- Underproduction of mature cells Aplastic anemia </p><p>- Overproduction of mature cells Myeloproliferative disease</p><p>- Failed differentiation with with production of increased immature cells Myelodisplasia Acute leukemia</p><p>Disorders of Hematopoiesis</p></li><li><p>Anemia classification-cell size</p><p>Microcytic anemia: Iron deficiency anemiaMacrocytic anemia: Megaloblastic anemiaNormocytic anemia: Anemia of chronic disease</p></li><li><p>Differential Dx.Anemias - MCVLow MCVThalassemiaIron def.Lead Pois.SideroblasticNormal MCVAcute B. lossAplastic A.Chronic Dis.Hemoglobinop-athiesHemolysis Iron def.High MCVAlcohol abuseAplastic A.B12 def.Folate defHemolysisHypothyroidismLiver DsMyelodysplastic s</p></li><li><p>Reticulocyte count vs Retic indexReticulocyte: young circulating Rbc that exhibits basophiliaRetic count: characterize the bone marrow attempt to compensate, if at all, for the anemia presentThe Retic. Index: more useful, corrects for the hematocrit abnormalities</p></li><li><p>Retic indexLess than 2 found:Hypoproliferative anemiasDis. Of heme or globin synthesis Iron deficiency and other metabolic anemiasB12 or folate deficiencyChronic dis.Lead poisoningThalassemias</p></li><li><p>Retic indexGreater than 2 found:Hyperproliferative anemiasAcute blood lossNutrient replacement(B12,folate,Iron) before resolution of the anemiaHereditary or acquired hemolysisPolycythemia </p></li><li><p>Pathophysiology Immune hemolytic anemiaWarm hemolytic anemia(IgG)Cold hemolytic anemia(IgM)Hemolysis causes extrinsic to RBCsMicroangiopathic hemolytic anemiainfectionHemolysis due to disorders RBC membraneInherited membrane abn.(HS,HE)Acquired membrane abn.(PNH,Spur cell anemia)Hemolysis due to disorders in RBC enzymesG6PD deficiencyHemoglobinopathiesSickle cell diseaseThalassemia(alpha,beta)</p></li><li><p>AnemiaReduction of RBC mass or HGB concentrationSymptoms reflect the rapidity of onsetPat. with acute hemorrhage/massive hemolysis may exhibit symptoms of hypovolemic shock Slowly established anemia produce few symptoms </p></li><li><p>Anemia SymptomsFatigueDecreased exercise toleranceDyspneaPalpitations</p></li><li><p>Anemia, physical examMajor sign is pallor of skin, and mucous membranesMay develop tachycardia Possible audible flow murmursPatients with hemolysis could present with jaundice and splenomegaly</p></li><li><p>Laboratory evaluationReticulocyte count differentiates between failure of RBC production (low retic) and increased RBC destruction (increased retic)</p><p>Peripheral blood smear provide clues to the cause of the anemia:Spherocytes in immune hemolysisSchistocytes in microangiopathic hemolysis</p></li><li><p>Laboratory eval. Cont.Sickle and target cell in hemoglobinopathiesTear drop cells and nucleated RBCs in myelofibrosis and marrow infiltrationIntracellular parasites in Malaria and BabesiosisPencil shape cells in severe iron deficiencyHypersegmented neutrophils and large plts. In megaloblastic anemiaImmature blasts in leukemias</p></li><li><p>Laboratory eval.cont.MCV is important in anemia with low retic count, to differentiate according to cell sizeBone marrow analysis helpful in patients with low retic count, provides information about causes of anemiaIf retic count is increased no need for bone marrow analysis, need to determine if decreased RBC mass is due to bleeding or hemolysis </p></li><li><p>Aplastic anemia(AA)Essentials of DiagnosisPancytopeniaNo abnormal cells seenHypo cellular bone marrow</p></li><li><p>AA - General considerationsHematopoietic stem cell failureRare disorderIncidence 1-5 cases per millionAffects young adults(20-25yo) and older adults (60-65yo)Three fold higher incidence in developing countries (Thailand and China)Most common cause: suspected autoimmune suppression of hematopoiesis by T-cell mediated cellular mechanism</p></li><li><p>AA. Acquired causesDrugs : dose related, chemotherapeutic agents, antibiotics (chloramphenicol , trimethoprim, sulfamethoxazole)Idiosyncratic(unproven): chloramphenicol, quinacrine, NSAIDS, cimetidine ,penicillamineToxins: benzene/hydrocarbons,insecticidesViral infections: hepatitis,EBV,HIVImmune mediated: GVHD ,immuno-deficiency/SLE, paroxysmal nocturnal hemoglobinuria(PNH)Radiation Pregnancy</p></li><li><p>AA-Congenital causesSmall proportion of the casesDefective genetic material (DNA ,gene mutations, etc.)Fanconis anemia(most common)Schwachmann-Diamond syndromeDyskeratosis congenita</p></li><li><p>AA- signs/symptomsClinical onset can be insidious or abruptEarly in the disease not all cell lines are always affectedWeakness-fatigue due to anemiaVulnerability to infections if leukopenia is presentMucosal/skin bleeding associated to thrombocytopenia</p></li><li><p>AA-Laboratory findingsPancytopeniaAnemia may be severe, always associated to decreased reticulocytesRBC morphology is unremarkableHypo cellular marrow analysisNo abnormal cells seen </p></li><li><p>AA-Differential DiagnosisFrom other causes of pancytopenias:Myelodisplasia/acute leukemia: exhibit morphologic abnormalities in the cells and increased blasts, or abn. Cytogenetics in bone marrowHairy cell leukemia: presence of splenomegaly and abnormal Lymphoid cells in bone marrowSLE, disseminated infection , or hypersplenism: normocellular bone marrow</p></li><li><p>AA-treatmentCurrent approaches geared to:Replacing defective marrow: Stem cell transplantorControlling an overactive immune response: using antithymocyte globulin (ATG) and other immunesuppresors such as Cyclosporine; Cyclophosphamide </p></li><li>AA-treatmentBased on severity of disease: mild cytopenias - monitor patient severe cases as indicated by blood count results showing: - anemia, with retic count &lt; 1% - neutrophil count </li><li><p>AA-treatmentSupportive care with broad-spectrum antibiotics, antifungals, and antivirals is warranted in advanced neutropenia RBC and Plt. Transfusions are helpful for very symptomatic patientsAllogeneic bone marrow transplant offers better outcome (75-90% survival rate) on patients 30 years of age and youngerImmunosuppressive therapy achieve restoration of marrow function in 70-80% of the patients, with a 90% survival rate in 5 years (patients older than 40 years of age) </p></li><li><p>Hypoproliferative anemias</p><p>Microcytic anemia: Iron deficiency anemiaMacrocytic anemia:Megaloblastic anemiaNormocytic anemia:Anemia of chronic disease</p></li><li><p>Iron deficiency anemiaEssentials of diagnosisSerum ferritin &lt; 12 mcg/LCaused by bleeding in adults unless proved otherwiseResponds to iron therapy</p></li><li><p>Iron deficiency anemiaMost common cause of anemia worldwideAverage american diet contains 10-15mg of iron per day (10% is absorbed)Iron Absorption in proximal small intestineBalanced daily iron absorption and loss at 1mg/day</p></li><li><p>Iron deficiency anemiaIron Bound to transferrin in plasmaSerum iron: men 50mg/kg, women 40 mg/kg60-75% found in HgbIron Stored as ferritin in the liver, spleen, BM,and musclePre-menopausal women could loose15mg of iron per month, and 900mg/pregnancyInvestigate GI blood loss in iron deficient men and postmenopausal women</p></li><li><p>Iron def.anemia, causesMost frequent cause of iron def. is blood lossDecreased iron absorption is rare, occasional after gastric surgeryHemoglobinuria in traumatic hemolysis due to prosthetic heart valveFrequent blood donors</p></li><li><p>Iron deficiency -symptomsIn severe cases, skin and mucosal changes:Smooth tongueBrittle nailsCheilosisDysphagia-esophageal webs (Plummer-Vinson syndromePica (ice,dirt)</p></li><li><p>Iron def.anemia laboratory Dx. Early Iron storage depletion stage - no changes on RBC morphologyDecreased total serum iron concentration Increased total iron binding capacity (TIBC) Decreased ferritin levelsAdvanced iron deficiency affects RBC morphology: microcytic - hypochromic cells, target cells, pencil shaped cells</p></li><li><p>Differential diagnosisAnemia chronic disease - NL or increased iron stores in bone marrow, NL or elevated ferritin level, low serum iron level, TIBC NL or low.Thalassemia - greater degree of microcytosis , changes on the RBC morphology occur earlier </p></li><li><p>Treatment of Iron deficiency Oral Ferrous sulfate (325mg TID)Improve compliance, gradually escalating the dose, taken with foodImprovement in 3 weeks, return to baseline in 2 months, continue for 3-6 months to replenish storesParenteral Iron in case of oral intolerance,possible anaphylactic reaction</p></li><li><p>Megaloblastic anemia-generalResults from block of synthesis of nucleotide precursors of DNAMaturation of cell nucleus is arrested, maturation of cytoplasm continuesMost common causes:Vitamin B12 (Cobalamin) deficiency, more commonFolate deficiencyMedications that inhibit DNA synthesis / block folate metabolismMyelodysplasia</p></li><li><p>B12 deficiency anemiaEssentials of diagnosisMacrocytic anemiaMacro-ovalocytes / hypersegmented neutrophils on peripheral smearSerum vitamin B12 level &lt; 100 pg/ml</p></li><li><p>B12 deficiency anemia-generalB12 absorbed from animal protein in the dietAbsorbed in the terminal ileum bound to intrinsic factor, a protein secreted by gastric parietal cellsB12 stored in the liver 3 years supply Daily losses 3-5 mcg, daily absorption 5mcgDietary B12 deficiency is rareVegans diet</p></li><li><p>B12 deficiency anemia- causesPernicious anemia:Autoimmune atrophy of gastric parietal cells ( most common)Gastrectomy Pancreatic insufficiency failure to inactivate competing binding protein</p></li><li><p>B12 deficiency anemia- causesBacterial overgrowth in the intestine Inflammatory bowel disease (crohns disease)Tapeworm infectionCongenital Intrinsic Factor or Transcobalamin II deficiency</p></li><li><p>Megaloblastic anemia symptomsOften severe anemia at presentation Insidious onset Yellowish of skin pallor and jaundiceMucosal changes glossitis, anorexia, diarrhea, cheilosisB12 deficiency leads to complex neurologic syndrome: paresthesias - early difficulty with balance - late</p></li><li><p>Megaloblastic anemia cont.Pernicious anemia patients present with atrophic gastritis - achlorhydriaassociated with increased risk for gastric carcinomaassociation with other autoimmune conditions such as: IgA deficiency and endocrine insufficiency</p></li><li><p>Laboratory findingsVariable severity anemiapossible pancytopeniaMCV: 110-140 flPeripheral smearlarge ovalocytes, hypersegmented neutrophils, and large plateletsHyper cellular bone marrowabnormally large precursorsIncreased bilirubin and lactate dehydrogenase enzyme (LDH)intramedullary destruction of RBCs</p></li><li><p>Laboratory findings Schilling test :Radioactive B12 given orally with a large parenteral dose of unlabeled B12.Oral absorption determine by: measuring radioactivity in the urine; B12+ IF + different isotope given at the same time, selective absorption of the B12+IF suggest pernicious anemia</p></li><li><p>Schilling test cont.If neither isotope is absorbed, possible bacterial overgrowth, treat with antibiotics and repeat testSupply pancreatic enzymes and repeat test to rule out pancreatic insufficiencyNew antibody tests for Anti-parietal cell AB , and Anti-IF AB now available</p></li><li><p>Differential diagnosisFolic Acid deficiency where:RBC folate is lowVitamin B12 levels in blood are normal</p></li><li><p>Treatment Intramuscular B12- 100mcg/dose daily for 7days, then weekly for a month, and monthly for lifeAccompanied with Folic acid 1-5 mg /day, oralFolate alone will not correct neurological symptoms of B12 deficiency</p></li><li><p>Prognosis Rapid response to therapy, peak within 7-10 daysIncreased reticulocyte count 2 days after therapyMonitor patientHypo-kalemia,Hyper-urecemia,Hypo-phosphatemiaNeurologic manifestationsimprove slowly,some are irreversible</p></li><li><p>Anemia of chronic diseaseOccur in patients with:chronic inflammatory conditions (RA) Infectionsmalignant (cancer) autoimmune diseases (SLE)Usually normocytic-normochromicoccasionally microcyticCommon causes:EPO deficiency (chronic renal failure)Direct inhibition of erythropoiesisPoor iron incorporation to developing RbcsShortened erythrocyte survival</p></li><li><p>Symptoms Related to the underlying diseaseSLE: increased fatigue, susceptibility to infectionsRA: arthritis, Fatigue / decreased enduranceHIV:Fatigueweight losslymphadenopathy</p></li><li><p>Laboratory findingsLow serum iron levelTIBC is also reducedTransferrin saturation &gt;10%Ferritin level normal or increasedMCV normal or slightly reducedRBC morphology- non diagnostic</p></li><li><p>Treatment Mainstay EPO replacement in the case of chronic renal failureAnemia will improve if the underlying chronic condition is treated Some other conditions also respond to EPO treatment,good results in M.Myeloma,R.Arthritis,and HIV infection</p></li><li><p>EPO-TreatmentPurified recombinant erythropoietin (epo alfa) 30,000 units once weekly, SQVery expensive, used when quality of life clearly improve by hematologic response</p></li><li><p>Hemolytic anemiasGeneralPremature loss of RBCs by hemolysis either: extrinsic (reticuloendothelial system) intrinsic ( blood vessels)Reticulocytosis as a compensatory response of a normal bone marrowOnly other condition causing reticulocytosis in anemia is blood loss</p></li><li><p>Classification Hemolytic AnemiaImmune hemolytic anemiaIgG mediated - warm AIHAIgM mediated - cold Causes extrinsic to erythrocytesMicro-angiopathic (DIC,TTP,drugs,eclampsia, valvular hemolysis)Erythrocyte membrane disordersInherited - H.spherocytosis/elliptocytosis Acquired - PNH, Spur cell anemiaEnzymopathies G6PD deficiencyPKHemoglobinopathies Sickle cell diseaseThalassemia </p></li><li><p>Sickle cell anemia essential Dx.Sickled cells on blood smearPositive family history and lifelong history of hemolytic anemiaRecurrent painful episodesHemoglobin S, major Hgb present on Hgb electrophoresis</p></li><li><p>Sickle cell disease - generalBelongs to the hemoglobinopathies groupPoint mutation in DNA that results in substitution of valine for glutamine in the sixth position on the beta-globin chain of hemoglobin (beta-sickle chain)Homozygous genotype(SS)Resulting Hgb is called Hgb S (sickle) 2 alpha chain 2 beta sickle chain </p></li><li><p>Sickle cell disease - generalFound in African and Mediterranean populationOne birth out of 400 in american blacks will produce a child with sickle cell anemia Onset during the first year of lifewhen fetal Hgb is replaced by adult HgbHgb S is less soluble susceptible to polymerization and precipitationTrigger factors includeDehydrationHypoxia, acidosis, and high altitudes</p></li><li><p>Sickle cell anemia symptomsAnemia symptomsJaundiceHepatomegaly Splenomegaly in childrenEnlarged heart, systolic murmursPoorly healing ulcers over the lower tibiaIncreased susceptibility to encapsulated bacteria (strep. pneumoniae infections)Delayed puberty</p></li><li><p>Sickle cell anemia - symptomsAcute complications - vaso-occlusionPainful crises - ischemia (extremities,chest, abdomen, back)Acute chest syndrome - life threateningPriapism Cerebrovascular eventsThrombotic/hemorrhagic strokesAplastic crisisSplenic sequestrationosteomyelitis</p></li><li><p>Sickle cell anemia - symptomsChronic manifestationsChronic renal diseaseChronic pulmonary diseaseSickle hepatopathyRetinopathyAvascular necrosisSkin ulcers </p></li><li><p>Sickle cell anemia- Lab.findingsHematocrit 20-30%Increased WBC count...</p></li></ul>