Post on 07-May-2015
INTRODUCTIONINTRODUCTION TO TO
HEMATOLOGYHEMATOLOGY
Erlinda E. Samson-Cruz, MD, FPCP, FPSHBTErlinda E. Samson-Cruz, MD, FPCP, FPSHBT
HEMATOLOGYHEMATOLOGY study of circulating blood components and blood study of circulating blood components and blood
forming tissuesforming tissues
Blood Blood 5 to 7 % of total BW5 to 7 % of total BW
functionfunction deliver nutrients, hormones and O2 to tissuesdeliver nutrients, hormones and O2 to tissues to collect and dispose of the wastes from cellular to collect and dispose of the wastes from cellular
metabolismmetabolism to deliver specialized cells to tissues for protection to deliver specialized cells to tissues for protection
against external environmentagainst external environment to prevent leakage of blood in blood vesselsto prevent leakage of blood in blood vessels
Elements of bloodElements of blood
Fluid elementsFluid elements WaterWater ElectrolytesElectrolytes ProteinsProteins
Cellular elementsCellular elements RBCRBC WBCWBC PlateletsPlatelets
Cellular elementsCellular elements
with an area of with an area of central pallor central pallor about a third of the about a third of the diameter of the celldiameter of the cell
shape of a normal shape of a normal red cell resembles a red cell resembles a disc that is thinner disc that is thinner in the centrein the centre
Normal red cellsNormal red cells
Cellular elementsCellular elements
Scanning Scanning electron electron micrograph of a micrograph of a red cellred cell
showing that it is showing that it is disc shaped with disc shaped with central thinningcentral thinning
Cellular elementsCellular elements
Normal white cellsNormal white cells
Cellular elementsCellular elements Normal Normal
neutrophil and neutrophil and normal small normal small lymphocytelymphocyte
Neutrophils Neutrophils have two to five have two to five
lobeslobes cytoplasm is cytoplasm is
very pale blue very pale blue and contains and contains small lilac-small lilac-staining staining granules, called granules, called neutrophilic neutrophilic granulesgranules
Cellular elementsCellular elements Normal Normal
eosinophil eosinophil
Eosinophils Eosinophils granules stain granules stain
orange and usually orange and usually pack the cytoplasmpack the cytoplasm
nucleus is most nucleus is most often bilobedoften bilobed
cytoplasm is weakly cytoplasm is weakly basophilic so when basophilic so when it is visible it stains it is visible it stains pale bluepale blue
Cellular elementsCellular elements Normal basophilNormal basophil Basophil Basophil
cytoplasm is cytoplasm is packed with large packed with large purple granules purple granules which often almost which often almost obscure the obscure the lobulated nucleuslobulated nucleus
Cellular elementsCellular elements
Normal small Normal small lymphocytelymphocyte
LymphocyteLymphocyte cell is round cell is round
with very scanty with very scanty cytoplasmcytoplasm
cytoplasm is cytoplasm is moderately blue moderately blue or basophilicor basophilic
high high nucleocytoplasmnucleocytoplasmic ratioic ratio
Cellular elementsCellular elements
Normal large Normal large lymphocytelymphocyte
Large lymphocyteLarge lymphocyte less condensed less condensed
chromatin and chromatin and more voluminous more voluminous irregular cytoplasm irregular cytoplasm than a small than a small lymphocytelymphocyte
cytoplasm is weakly cytoplasm is weakly or moderately or moderately basophilicbasophilic
Cellular elementsCellular elements Normal large Normal large
granular granular lymphocytelymphocyte
Large granular Large granular lymphocyte lymphocyte
large lymphocytes large lymphocytes containing a small containing a small number of number of azurophilic (light azurophilic (light purple) granulespurple) granules
cytoplasm is usually cytoplasm is usually weakly basophilicweakly basophilic
nucleolus may be nucleolus may be visiblevisible
Cellular elementsCellular elements Normal Normal
monocytemonocyte MonocyteMonocyte
largest normal white largest normal white cell found in the cell found in the bloodblood
irregular lobulated irregular lobulated nucleus and opaque nucleus and opaque grey-blue cytoplasm grey-blue cytoplasm containing fine containing fine azurophilic (light azurophilic (light purple) granulespurple) granules
cytoplasm is cytoplasm is sometimes sometimes vacuolatedvacuolated
Cellular elementsCellular elements Neutrophil band Neutrophil band
cellcell Neutrophil band Neutrophil band
cells or band forms cells or band forms
cells of neutrophil cells of neutrophil lineage with non-lineage with non-segmented nucleisegmented nuclei
less mature than less mature than segmented segmented neutrophilsneutrophils
increased number of increased number of band cells is band cells is referred to as a 'left referred to as a 'left shift'shift'
Cellular elementsCellular elements Normal plateletsNormal platelets Platelets Platelets
small anuclear small anuclear cytoplasmic cytoplasmic fragments fragments
small purple-small purple-staining granules staining granules
seen between the seen between the red cells in a blood red cells in a blood filmfilm
PRINCIPLES OF PRINCIPLES OF HEMATOLOGIC HEMATOLOGIC
DIAGNOSISDIAGNOSISHistoryHistory
Present illnessPresent illness Exposure to drugs or chemicalsExposure to drugs or chemicals Past med historyPast med history Family historyFamily history Review of symptomsReview of symptoms
Physical ExaminationPhysical Examination clues to the mechanisms of hematologic clues to the mechanisms of hematologic
disease/ anemia may be provided disease/ anemia may be provided
PRINCIPLES OF PRINCIPLES OF HEMATOLOGIC HEMATOLOGIC
DIAGNOSISDIAGNOSISPeripheral blood measurementsPeripheral blood measurements
CBC CBC PBSPBS Reticulocyte countReticulocyte count Iron studiesIron studies
BBone marrow aspirate or biopsy one marrow aspirate or biopsy
LABORATORY LABORATORY EVALUATIONEVALUATION
COMPLETE BLOOD COUNT COMPLETE BLOOD COUNT HemoglobinHemoglobin HematocritHematocrit RBC countRBC count red cell indicesred cell indices WBC count with cell differentialWBC count with cell differential Platelet countPlatelet count reticulocyte countreticulocyte count
LABORATORY LABORATORY EVALUATIONEVALUATION
RBC indicesRBC indices MCV in flMCV in fl
= hct/rbc ct x 1000= hct/rbc ct x 1000
MCH in pg per cellMCH in pg per cell = hgb/rbc ct x 1000= hgb/rbc ct x 1000
MCHC in grams MCHC in grams per literper liter
hgb/hct x 100hgb/hct x 100
average volume of average volume of individual red cellsindividual red cells
hgb content per red hgb content per red cellcell
hgb concentration of hgb concentration of the red cells the red cells
LABORATORY LABORATORY EVALUATIONEVALUATION
PERIPHERAL BLOOD SMEAR PERIPHERAL BLOOD SMEAR information about defects in red cell information about defects in red cell
productionproduction anisocytosis anisocytosis poikilocytosispoikilocytosis polychromasiapolychromasia
wbc immaturity or abnormalitywbc immaturity or abnormality
platelet number and morphologyplatelet number and morphology
LABORATORY LABORATORY EVALUATIONEVALUATION
AnisocytosisAnisocytosis variations in cell variations in cell
sizesize
AnisochromaAnisochromasiasia variation in staining variation in staining
from cell to cellfrom cell to cell Ida pt Ida pt
LABORATORY LABORATORY EVALUATIONEVALUATION
PoikilocytosisPoikilocytosis means an increased means an increased
variability in red variability in red cell shapecell shape
Classification of Classification of poikilocytespoikilocytes
LABORATORY LABORATORY EVALUATIONEVALUATION
PolychromasiaPolychromasia indicates the presence of indicates the presence of increased numbers of red increased numbers of red cells with a bluish tinge cells with a bluish tinge superimposed on the red superimposed on the red colour of haemoglobincolour of haemoglobin
increased numbers of increased numbers of polychromatic cells polychromatic cells correlates with an increased correlates with an increased reticulocyte countreticulocyte count
polychromatic cells are polychromatic cells are often larger than mature often larger than mature red cells and may then be red cells and may then be referred to as polychromatic referred to as polychromatic macrocytesmacrocytes
LABORATORY LABORATORY EVALUATIONEVALUATION
RETICULOCYTE COUNT RETICULOCYTE COUNT key to the initial classification of anemiakey to the initial classification of anemia
patient's reticulocyte count is compared with the patient's reticulocyte count is compared with the expected reticulocyte responseexpected reticulocyte response
Normally red cell production rate increases Normally red cell production rate increases to 2-3x normal within 10 days following the to 2-3x normal within 10 days following the onset of anemiaonset of anemia
In established anemia, a reticulocyte In established anemia, a reticulocyte response less than two to three times normal response less than two to three times normal indicates an inadequate marrow responseindicates an inadequate marrow response
LABORATORY LABORATORY EVALUATIONEVALUATION
ReticulocytesReticulocytes young red cells young red cells
newly released newly released from the bone from the bone marrowmarrow
identified by staining with a identified by staining with a supravital dye that supravital dye that precipitates the residual precipitates the residual ribosomal RNAribosomal RNA
precipitates appear as blue precipitates appear as blue or black punctate spotsor black punctate spots
residual RNA is metabolized residual RNA is metabolized over the first 24 to 36 h of over the first 24 to 36 h of the reticulocyte's lifespan in the reticulocyte's lifespan in circulationcirculation
reticulocyte count ranges reticulocyte count ranges from 1 to 2% and reflects the from 1 to 2% and reflects the daily replacement of 0.8 to daily replacement of 0.8 to 1.0% of the circulating red 1.0% of the circulating red cell populationcell population
RETICULOCYTE COUNT RETICULOCYTE COUNT 11stst CORRECTION CORRECTION
adjusts the reticulocyte adjusts the reticulocyte count based on the count based on the reduced number of reduced number of circulating red cellscirculating red cells
provides an estimate of provides an estimate of the retic ct corrected for the retic ct corrected for anemia anemia
corrected retic corrected retic
= retic % x (actual hgb = retic % x (actual hgb or hct /ideal hgb or hct ) or hct /ideal hgb or hct )
ExampleExample
retic ct 9%retic ct 9% hemoglobin 7.5 g/dLhemoglobin 7.5 g/dL hematocrit 23%hematocrit 23%
corrected retic count corrected retic count
= 9 x (7.5/15) [or x = 9 x (7.5/15) [or x (23/45)](23/45)]
= 4.5%= 4.5%
RETICULOCYTE COUNT RETICULOCYTE COUNT 22ndnd CORRECTION CORRECTION
for longer life of for longer life of prematurely prematurely released released reticulocytes in the reticulocytes in the bloodblood
produces the produces the reticulocyte reticulocyte production indexproduction index
maturation time maturation time correction factorcorrection factor
RETICULOCYTE COUNT RETICULOCYTE COUNT 22ndnd CORRECTION CORRECTION
necessary to convert the corrected necessary to convert the corrected reticulocyte count to an index of marrow reticulocyte count to an index of marrow productionproduction
provides an estimate of marrow production provides an estimate of marrow production relative to normalrelative to normal +polychromatophilic macrocytes+polychromatophilic macrocytes
divided by 2 to account for the prolonged reticulocyte divided by 2 to account for the prolonged reticulocyte maturation timematuration time
-polychromatophilic cells -polychromatophilic cells second correction is not requiredsecond correction is not required
LABORATORY LABORATORY EVALUATIONEVALUATION
TESTS OF IRON SUPPLY AND STORAGE TESTS OF IRON SUPPLY AND STORAGE Serum ironSerum iron
normal serum iron ranges from 9 to 27 umol/L (50 to 150 normal serum iron ranges from 9 to 27 umol/L (50 to 150 ug/dL) ug/dL)
TIBC TIBC normal TIBC is 54 to 64 umol/L (300 to 360 ug/dL)normal TIBC is 54 to 64 umol/L (300 to 360 ug/dL)
Percent transferrin saturationPercent transferrin saturation derived by dividing the serum iron level (× 100) by the derived by dividing the serum iron level (× 100) by the
TIBCTIBC transferrin saturation ranges from 25 to 50%transferrin saturation ranges from 25 to 50%
Serum ferritin Serum ferritin to evaluate total-body iron storesto evaluate total-body iron stores
Bone marrow aspirationBone marrow aspiration
Bone marrow aspirationBone marrow aspiration
Sites of BMASites of BMA
LABORATORY LABORATORY EVALUATIONEVALUATION
BONE MARROW EXAMINATION BONE MARROW EXAMINATION CellularityCellularity M/E ratio 3-4:1M/E ratio 3-4:1 Morphology of cells Morphology of cells assessment of iron stores or iron in assessment of iron stores or iron in
developing red cellsdeveloping red cells bone marrow aspirate and needle bone marrow aspirate and needle
biopsy maybe useful in the diagnosis of biopsy maybe useful in the diagnosis of a marrow disorder a marrow disorder
How to examine How to examine a bone marrow a bone marrow
aspirate aspirate
Bone marrow aspirateBone marrow aspirate Macroscopic view Macroscopic view
of bone marrow of bone marrow filmfilm
Normal bone Normal bone marrow fragment marrow fragment in an adultin an adult
Bone marrow aspirateBone marrow aspirate
Megakaryocytes Megakaryocytes in bone marrowin bone marrow
without any without any associated associated megakaryocytesmegakaryocytes
Bone marrow aspirateBone marrow aspirate Normal mature Normal mature
megakaryocyte in the bone megakaryocyte in the bone marrowmarrow
megakaryocyte is the megakaryocyte is the largest normal bone largest normal bone marrow cellmarrow cell
has a large lobulated has a large lobulated nucleus and its cytoplasm nucleus and its cytoplasm contains fine azurophilic contains fine azurophilic granulesgranules
Normal Normal megakaryocytemegakaryocyte
Bone marrow aspirateBone marrow aspirate Bone marrow Bone marrow
iron stain, iron iron stain, iron deficiency deficiency
Bone marrow Bone marrow iron stain, iron stain, normalnormal
SITES OF SITES OF HEMATOPOIESISHEMATOPOIESIS
NORMAL CONDITIONSNORMAL CONDITIONS Fetal sites of HematopoiesisFetal sites of Hematopoiesis
Yolk sacYolk sac 3-12 wks AOG3-12 wks AOG
LiverLiver 5-6 weeks upto 6 months AOG to 2 weeks after birth5-6 weeks upto 6 months AOG to 2 weeks after birth
SpleenSpleen 4-8 months AOG4-8 months AOG
Bone marrowBone marrow 5 months AOG5 months AOG primary site by 7 monthsprimary site by 7 months
SITES OF SITES OF HEMATOPOIESISHEMATOPOIESIS
Post natal sites of hematopoiesisPost natal sites of hematopoiesis At birthAt birth
all BM cavities are hematopoieticall BM cavities are hematopoietic After 20 yearsAfter 20 years
axial skeletonaxial skeleton
Gross morphologic changesGross morphologic changes Red marrowRed marrow Yellow marrowYellow marrow
SITES OF SITES OF HEMATOPOIESISHEMATOPOIESIS
DISEASEDISEASE Fetal hematopoietic sitesFetal hematopoietic sites
Extramedullary site can serve as the Extramedullary site can serve as the primary sites of blood cell developmentprimary sites of blood cell development
Liver, spleenLiver, spleen
Adult medullary sites Adult medullary sites to help meet the demand for increased to help meet the demand for increased
blood cell productionblood cell production
Hematopoiesis Hematopoiesis
process by which the formed process by which the formed elements of the blood are producedelements of the blood are produced
Stem cells are capable of producing Stem cells are capable of producing red cells, all classes of red cells, all classes of granulocytes, monocytes, platelets, granulocytes, monocytes, platelets, and the cells of the immune systemand the cells of the immune system
Hematopoiesis Hematopoiesis
stem cells develop into differentiated cell stem cells develop into differentiated cell types through incompletely defined types through incompletely defined molecular events that are intrinsic to the molecular events that are intrinsic to the stem cell stem cell
Following lineage commitment Following lineage commitment hematopoietic progenitor and precursor hematopoietic progenitor and precursor cells come increasingly under the cells come increasingly under the regulatory influenceregulatory influence of growth factors of growth factors and hormonesand hormones
HEMATOPOIESISHEMATOPOIESIS
PLURIPOTENT STEM CELL
MYELOID MULTIPOTENT
STEM CELL
LYMPHOID MULTIPOTENT
STEM CELL
LYMPHOCYTESBFU-EYTHROIDMEG
PROGENITORCFU-MEG
GRAN/MONO PROGENITOR
CFU-GM
EO PROGENITOR
CFU-Eo
E PROGENITORCFU-E
RBC
PLATELET MONOCYTE NEUTROPHIL BASOPHIL EOSINOPHIL
ERYTHROPOIESISERYTHROPOIESIS
ERYTHROPOIESISERYTHROPOIESIS
critical elements critical elements
EPO productionEPO production iron availabilityiron availability proliferative capacity of the bone proliferative capacity of the bone
marrowmarrow effective maturation of red cell effective maturation of red cell
precursorsprecursors
ERYTHROPOIESISERYTHROPOIESIS
regulated process of red cell regulated process of red cell productionproduction
regulated by erythropoietin (EPO) regulated by erythropoietin (EPO) the hormone required for the the hormone required for the maintenance of committed erythroid maintenance of committed erythroid progenitor cells that, in the absence progenitor cells that, in the absence of the hormone, undergo apoptosisof the hormone, undergo apoptosis
ERYTHROPOIETINERYTHROPOIETIN produced and released by peritubular produced and released by peritubular
capillary lining cells within the kidneycapillary lining cells within the kidney
small amount is produced by hepatocytessmall amount is produced by hepatocytes
stimulus for EPO productionstimulus for EPO production Impaired O2 delivery to the kidney resulting to Impaired O2 delivery to the kidney resulting to
decreased red cell mass decreased red cell mass impaired O2 loading of the hemoglobin impaired O2 loading of the hemoglobin
molecule molecule impaired blood flow to the kidneyimpaired blood flow to the kidney
Physiologic regulation of red cell production
Anemia classificationAnemia classification
HYPOPROLIFERATIHYPOPROLIFERATIVE ANEMIAS VE ANEMIAS
HYPOPROLIFERATIVE HYPOPROLIFERATIVE ANEMIASANEMIAS
normocytic and normochromic red cells normocytic and normochromic red cells inappropriately low reticulocyte inappropriately low reticulocyte
response response includes:includes:
acute and chronic inflammationacute and chronic inflammation renal diseaserenal disease hypometabolic states such as protein hypometabolic states such as protein
malnutrition and endocrine deficienciesmalnutrition and endocrine deficiencies early iron deficiency early iron deficiency anemias from marrow damageanemias from marrow damage
ANEMIA OF CHRONIC ANEMIA OF CHRONIC DISEASE DISEASE
one of the most common forms of anemia seen one of the most common forms of anemia seen clinically clinically
includes the following:includes the following: inflammationinflammation infectioninfection tissue injurytissue injury cancer cancer
features:features: low serum ironlow serum iron increased red cell protoporphyrinincreased red cell protoporphyrin hypoproliferative marrowhypoproliferative marrow transferrin saturation in the range of 15 to 20%,transferrin saturation in the range of 15 to 20%, normal or increased serum ferritinnormal or increased serum ferritin
Cytokines effectCytokines effect
ANEMIA OF CHRONIC ANEMIA OF CHRONIC DISEASEDISEASE
Cytokines effectCytokines effect IL-1IL-1
directly decreases erythropoietin production in response to directly decreases erythropoietin production in response to anemiaanemia
IL-1 acting through accessory cell release of IFN-g suppresses IL-1 acting through accessory cell release of IFN-g suppresses the response of the erythroid marrow to erythropoietin — an the response of the erythroid marrow to erythropoietin — an effect that can be overcome by increased erythropoietin effect that can be overcome by increased erythropoietin administrationadministration
TNFTNF acting through the release of IFN-g by marrow stromal cells, acting through the release of IFN-g by marrow stromal cells,
also suppresses the response to erythropoietinalso suppresses the response to erythropoietin
HepcidinHepcidin made by the livermade by the liver increased in inflammation and acts to suppress iron increased in inflammation and acts to suppress iron
absorption and iron release from storage sitesabsorption and iron release from storage sites
TREATMENTTREATMENT
Treat underlying diseaseTreat underlying disease If reversals are not possibleIf reversals are not possible
Transfusions Transfusions Erythropoietin Erythropoietin
cancer up to 300 U/kg three times a weekcancer up to 300 U/kg three times a week Hgb levels of 10 to 12 g/dL are usually Hgb levels of 10 to 12 g/dL are usually
reached within 4 to 6 weeks if iron levels reached within 4 to 6 weeks if iron levels are adequateare adequate
only about 60% of patients may respondonly about 60% of patients may respond
ANEMIA OF RENAL ANEMIA OF RENAL DISEASEDISEASE
due to a failure to produce adequate amounts of due to a failure to produce adequate amounts of erythropoietin erythropoietin
reduction in red cell survivalreduction in red cell survival
normocytic and normochromic RBCnormocytic and normochromic RBC Reticulocytes are decreasedReticulocytes are decreased normal serum iron, TIBC, and ferritin levelsnormal serum iron, TIBC, and ferritin levels
Assessment of iron status provides information to Assessment of iron status provides information to distinguish the anemia of renal disease from the distinguish the anemia of renal disease from the other forms of hypoproliferative anemia and to guide other forms of hypoproliferative anemia and to guide managementmanagement
ANEMIA OF RENAL ANEMIA OF RENAL DISEASEDISEASE
EPOEPO 50-150 u/kg/wk iv or sc 1 to 3 x a wk50-150 u/kg/wk iv or sc 1 to 3 x a wk 11-12 g/dl target hgb11-12 g/dl target hgb Increase hgb by 1 to 2 g/dl over 4 week Increase hgb by 1 to 2 g/dl over 4 week
periodperiod
Iron supplementIron supplement<20 TS and < 100 ug/l serum ferritin<20 TS and < 100 ug/l serum ferritin
Give iron 50-100mg IV twice per weekGive iron 50-100mg IV twice per week
>50 TS and 800 ug/l serum ferritin>50 TS and 800 ug/l serum ferritin Withhold iron Withhold iron
ANEMIA OF ENDOCRINE ANEMIA OF ENDOCRINE DISORDERSDISORDERS
Anemia of HypothyroidismAnemia of Hypothyroidism
Thyroid hormonesThyroid hormones + effect on erythropoiesis+ effect on erythropoiesis controlling cellular oxygen requirements controlling cellular oxygen requirements
through their effects on the metabolic rates through their effects on the metabolic rates of the tissuesof the tissues
HypothyroidismHypothyroidism Normocytic or slightly macrocytic anemiaNormocytic or slightly macrocytic anemia Reponse of BM to decreased tissue oxygen Reponse of BM to decreased tissue oxygen
consumption that occurs in hypothyroidismconsumption that occurs in hypothyroidism Normal BM but rate of hematopoiesis is low bec of Normal BM but rate of hematopoiesis is low bec of
diminished release of EPO from kidneydiminished release of EPO from kidney 10% with macrocytosis10% with macrocytosis
ANEMIA OF ENDOCRINE ANEMIA OF ENDOCRINE DISORDERSDISORDERS
Anemia of HypopituitarismAnemia of HypopituitarismAndrogenAndrogen direct effect on BM stimulating production of direct effect on BM stimulating production of
EPOEPOmaking marrow cells responsive to EPOmaking marrow cells responsive to EPO
GH GH trophic effect on the BMtrophic effect on the BM
HypopituitarismHypopituitarism Normochromic normocyticNormochromic normocytic Reduced retic ctReduced retic ct Low EPO levelsLow EPO levels Hypocellular marrowHypocellular marrow
ANEMIA OF ENDOCRINE ANEMIA OF ENDOCRINE DISORDERSDISORDERS
Anemia of HyperparathyroidismAnemia of Hyperparathyroidism
PTHPTH Suppress erythropoiesis by Suppress erythropoiesis by
renal calcification (decreased EPO renal calcification (decreased EPO formation)formation)
marrow sclerosis ( decreased marrow sclerosis ( decreased proliferation of erythroid proliferation of erythroid precursors)precursors)
ANEMIA OF ENDOCRINE ANEMIA OF ENDOCRINE DISORDERSDISORDERS
TREATMENTTREATMENT
Correction of underlying endocrine Correction of underlying endocrine disorderdisorder
Hypoproliferative Anemias: Hypoproliferative Anemias: TreatmentTreatment
TransfusionsTransfusions Thresholds for transfusion based on the patient's Thresholds for transfusion based on the patient's
symptomssymptoms patients without serious underlying cardiovascular or patients without serious underlying cardiovascular or
pulmonary disease can tolerate hemoglobin levels pulmonary disease can tolerate hemoglobin levels above 8 g/dL and do not require intervention until the above 8 g/dL and do not require intervention until the hemoglobin falls below that levelhemoglobin falls below that level
Erythropoietin (Epo)Erythropoietin (Epo) useful in anemias in which endogenous EPO levels useful in anemias in which endogenous EPO levels
are inappropriately loware inappropriately low Iron status must be evaluated and iron repleted to Iron status must be evaluated and iron repleted to
obtain optimal effects obtain optimal effects Longer-acting preparations of EPO can reduce the Longer-acting preparations of EPO can reduce the
frequency of injectionsfrequency of injections
APLASTIC APLASTIC ANEMIAANEMIA
DEFINITIONDEFINITION
Aplastic anemiaAplastic anemia pancytopenia with bone marrow pancytopenia with bone marrow
hypocellularityhypocellularity
Acquired aplastic anemia Acquired aplastic anemia abrupt onset of low blood counts in a abrupt onset of low blood counts in a
previously well young adultpreviously well young adult seronegative hepatitis or a course of an seronegative hepatitis or a course of an
incriminated medical drug may precede incriminated medical drug may precede the onsetthe onset
DEFINITIONDEFINITION
Constitutional Aplastic anemia Constitutional Aplastic anemia Fanconi's anemiaFanconi's anemia Dyskeratosis congenitaDyskeratosis congenita
frequently associated with typical physical frequently associated with typical physical anomalies and the development of anomalies and the development of pancytopenia early in life, can also present as pancytopenia early in life, can also present as marrow failure in normal-appearing adultsmarrow failure in normal-appearing adults
Iatrogenic marrow aplasiaIatrogenic marrow aplasia marrow hypocellularity after intensive marrow hypocellularity after intensive
cytotoxic chemotherapy for cancercytotoxic chemotherapy for cancer
EPIDEMIOLOGY EPIDEMIOLOGY
2 cases per million persons annually in 2 cases per million persons annually in Europe and Israel Europe and Israel
5 to 7 per million In Thailand and China5 to 7 per million In Thailand and China
men and women are affected with equal men and women are affected with equal frequencyfrequency
biphasic age distributionbiphasic age distribution major peak in the teens and twenties major peak in the teens and twenties second rise in the elderlysecond rise in the elderly
ETIOLOGY ETIOLOGY
ACQUIREDACQUIRED IdiopathicIdiopathic
SecondarySecondary Radiation Radiation
Marrow aplasia is a major acute sequela of Marrow aplasia is a major acute sequela of radiation radiation
Radiation damages DNARadiation damages DNA MDS and leukemia are late effects of MDS and leukemia are late effects of
irradiation irradiation
ETIOLOGY ETIOLOGY
SecondarySecondary Chemicals Benzene Chemicals Benzene
notorious cause of bone marrow failurenotorious cause of bone marrow failure aplastic anemia, acute leukemia, and blood and aplastic anemia, acute leukemia, and blood and
marrow abnormalitiesmarrow abnormalities
occurrence of leukemia is roughly occurrence of leukemia is roughly correlated with cumulative exposurecorrelated with cumulative exposure
employment history is importantemployment history is important
ETIOLOGY ETIOLOGY
Secondary Secondary Drugs Drugs
Dose dependent effectDose dependent effect Idiosyncratic reactionsIdiosyncratic reactions
Infections Infections Hepatitis is the most common preceding Hepatitis is the most common preceding
infectioninfection Rarely IM, EBVRarely IM, EBV
ETIOLOGY ETIOLOGY
Secondary Secondary Immunologic Diseases Immunologic Diseases
transfusion-associated graft-versus-host transfusion-associated graft-versus-host disease disease
eosinophilic fasciitiseosinophilic fasciitis systemic lupus erythematosussystemic lupus erythematosus
Pregnancy Pregnancy Rarely may occur and recur during pregnancy Rarely may occur and recur during pregnancy
and resolve with delivery or with spontaneous and resolve with delivery or with spontaneous or induced abortionor induced abortion
ETIOLOGY ETIOLOGY
Secondary Secondary Paroxysmal Nocturnal Hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria
acquired mutation in the PIG-A gene in a acquired mutation in the PIG-A gene in a hematopoietic stem cell resulting to clone of progeny hematopoietic stem cell resulting to clone of progeny deficient in glycosylphosphatidylinositol-linked cell deficient in glycosylphosphatidylinositol-linked cell surface membrane proteins surface membrane proteins
aplastic anemia/PNH syndrome is selection of the aplastic anemia/PNH syndrome is selection of the deficient clones, because they are favored for deficient clones, because they are favored for proliferation in the peculiar environment of immune-proliferation in the peculiar environment of immune-mediated marrow destructionmediated marrow destruction
ETIOLOGY ETIOLOGY
INHERITEDINHERITED Fanconi's anemiaFanconi's anemia
autosomal recessive disorderautosomal recessive disorder congenital developmental anomaliescongenital developmental anomalies progressive pancytopeniaprogressive pancytopenia increased risk of malignancyincreased risk of malignancy Chromosomes susceptibility to DNA cross-linking Chromosomes susceptibility to DNA cross-linking
agentsagents featuresfeatures
short statureshort stature cafe au lait spotscafe au lait spots anomalies involving the thumb, radius, and genitourinary anomalies involving the thumb, radius, and genitourinary
tracttract
ETIOLOGYETIOLOGY
INHERITEDINHERITED Dyskeratosis congenitaDyskeratosis congenita
characterized by mucous membrane leukoplasiacharacterized by mucous membrane leukoplasia dystrophic nailsdystrophic nails reticular hyperpigmentationreticular hyperpigmentation development of aplastic anemia during development of aplastic anemia during
childhoodchildhood
Shwachman-Diamond syndromeShwachman-Diamond syndrome marrow failure with pancreatic insufficiency and marrow failure with pancreatic insufficiency and
malabsorption malabsorption
PATHOPHYSIOLOGY PATHOPHYSIOLOGY
Bone marrow failure results from severe damage Bone marrow failure results from severe damage to the hematopoietic cell compartmentto the hematopoietic cell compartment
Aplastic anemia does not appear to result from Aplastic anemia does not appear to result from defective stroma or growth factor productiondefective stroma or growth factor production
replacement of the bone marrow by fat is replacement of the bone marrow by fat is apparent inapparent in the morphology of the biopsy specimen the morphology of the biopsy specimen magnetic resonance imaging (MRI) of the spinemagnetic resonance imaging (MRI) of the spine
cells bearing the CD34 antigen, are greatly cells bearing the CD34 antigen, are greatly diminisheddiminished
CLINICAL FEATURES CLINICAL FEATURES
HistoryHistory Abrupt/ insidious onsetAbrupt/ insidious onset
Bleeding is the most common early symptomBleeding is the most common early symptom
Symptoms of anemia are also frequentSymptoms of anemia are also frequent
restriction of symptoms to the hematologic restriction of symptoms to the hematologic systemsystem
CLINICAL FEATURES CLINICAL FEATURES
Physical Examination Physical Examination Petechiae, ecchymoses, retinal Petechiae, ecchymoses, retinal
hemorrhageshemorrhages Pallor of the skin and mucous membranes Pallor of the skin and mucous membranes Lymphadenopathy and splenomegaly are Lymphadenopathy and splenomegaly are
highly atypical highly atypical Cafe au lait spots and short stature suggest Cafe au lait spots and short stature suggest
Fanconi's anemiaFanconi's anemia peculiar nails and leukoplakia suggest peculiar nails and leukoplakia suggest
dyskeratosis congenitadyskeratosis congenita
CLINICAL FEATURESCLINICAL FEATURES
Fanconi's Fanconi's anaemiaanaemia
Hands of patient Hands of patient with Fanconi's with Fanconi's anaemia showing anaemia showing hypoplastic hypoplastic thumbsthumbs
CLINICAL FEATURESCLINICAL FEATURES
Abdomen of patient Abdomen of patient with Fanconi's with Fanconi's anaemia showing anaemia showing abnormal abnormal depigmented skindepigmented skin
as in many such as in many such patients the skin patients the skin abnormality abnormality worsened following worsened following bone marrow bone marrow
Abnormal skin in Abnormal skin in Fanconi's Fanconi's anaemiaanaemia
LABORATORY STUDIES LABORATORY STUDIES
Blood Blood smear shows large erythrocytes and a smear shows large erythrocytes and a
paucity of platelets and granulocytespaucity of platelets and granulocytes
MCV is commonly increasedMCV is commonly increased
Reticulocytes are absent or fewReticulocytes are absent or few
lymphocyte numbers may be normal or lymphocyte numbers may be normal or reducedreduced
LABORATORY STUDIES LABORATORY STUDIES
Bone Marrow Bone Marrow usually readily aspirated but appears usually readily aspirated but appears
dilute on smeardilute on smear
fatty biopsy specimen may be grossly pale fatty biopsy specimen may be grossly pale on withdrawalon withdrawal
<25% cellularity and shows mainly fat <25% cellularity and shows mainly fat
Residual hematopoietic cells should have Residual hematopoietic cells should have normal morphologynormal morphology
LABORATORY STUDIES LABORATORY STUDIES
Trephine biopsy Trephine biopsy in Fanconi's in Fanconi's anaemiaanaemia
oiloil
Trephine biopsy Trephine biopsy in AA, acquiredin AA, acquired
lpolpo
LABORATORY STUDIES LABORATORY STUDIES
Ancillary Studies Ancillary Studies Chromosome breakage studies of peripheral blood using Chromosome breakage studies of peripheral blood using
diepoxybutane (DEB) or mitomycin C should be performed diepoxybutane (DEB) or mitomycin C should be performed on children and younger adults to exclude Fanconi's on children and younger adults to exclude Fanconi's anemiaanemia
Chromosome studies negative in typical aplastic anemiaChromosome studies negative in typical aplastic anemia
Flow cytometric assays have replaced the Ham test for the Flow cytometric assays have replaced the Ham test for the diagnosis of PNHdiagnosis of PNH
Serologic studies may show evidence of viral infection, Serologic studies may show evidence of viral infection, especially Epstein-Barr virus and HIVespecially Epstein-Barr virus and HIV
Posthepatitis aplastic anemia is typically seronegativePosthepatitis aplastic anemia is typically seronegative
DIAGNOSIS DIAGNOSIS
pancytopenia with a fatty, empty bone pancytopenia with a fatty, empty bone marrowmarrow
bone marrow in constitutional aplastic bone marrow in constitutional aplastic anemia is indistinguishable morphologically anemia is indistinguishable morphologically from the aspirate in acquired diseasefrom the aspirate in acquired disease
diagnosis can be suggested by family diagnosis can be suggested by family history, abnormal blood counts since history, abnormal blood counts since childhood, or the presence of associated childhood, or the presence of associated physical anomaliesphysical anomalies
PROGNOSIS PROGNOSIS
natural history of severe aplastic anemia is rapid natural history of severe aplastic anemia is rapid deterioration and death deterioration and death
major prognostic determinant is the blood countmajor prognostic determinant is the blood count severe disease is defined by the presence of 2 of 3 severe disease is defined by the presence of 2 of 3
parameters: parameters: absolute neutrophil count <500/uLabsolute neutrophil count <500/uL platelet count <20,000/uLplatelet count <20,000/uL corrected reticulocyte count <1% corrected reticulocyte count <1%
Survival of patients who fulfill these criteria is about Survival of patients who fulfill these criteria is about 20% at 1 year after diagnosis with only supportive care20% at 1 year after diagnosis with only supportive care
very severe diseasevery severe disease defined by an absolute neutrophil count <200/udefined by an absolute neutrophil count <200/u fare even more poorlyfare even more poorly
TREATMENT TREATMENT
can be cured by replacement of the can be cured by replacement of the absent hematopoietic cells by stem absent hematopoietic cells by stem cell transplantcell transplant
can be ameliorated by suppression can be ameliorated by suppression of the immune system to allow of the immune system to allow recovery of the patient's residual recovery of the patient's residual bone marrow functionbone marrow function
TREATMENT TREATMENT
Bone Marrow Transplantation Bone Marrow Transplantation
best therapy for the young patient with best therapy for the young patient with a fully histocompatible sibling donor a fully histocompatible sibling donor
allogeneic transplant from fully allogeneic transplant from fully matched siblings, long-term survival matched siblings, long-term survival rates for children are 80% rates for children are 80%
TREATMENT TREATMENT
Immunosuppression Immunosuppression
ALG or antithymocyte globulin (ATG) ALG or antithymocyte globulin (ATG) induces hematologic recovery in about induces hematologic recovery in about 50% of patients50% of patients
addition of cyclosporine to either ALG or addition of cyclosporine to either ALG or ATG has further increased response rates ATG has further increased response rates to about 70% and especially improved to about 70% and especially improved outcomes for children and for severely outcomes for children and for severely neutropenic patientsneutropenic patients
TREATMENT TREATMENT
ATG is given at 40 mg/kg per day for 4 daysATG is given at 40 mg/kg per day for 4 days anaphylaxis is a rare but occasionally fatal complicationanaphylaxis is a rare but occasionally fatal complication ATG binds to peripheral blood cells; therefore, platelet and ATG binds to peripheral blood cells; therefore, platelet and
granulocyte numbers may fall further during active treatmengranulocyte numbers may fall further during active treatmen Serum sickness, a flulike illness with a characteristic cutaneous Serum sickness, a flulike illness with a characteristic cutaneous
eruption and arthralgia, often develops about 10 days after eruption and arthralgia, often develops about 10 days after initiating treatmentinitiating treatment
Most patients are given methylprednisolone, 1 mg/kg per day Most patients are given methylprednisolone, 1 mg/kg per day for 2 weeks, to ameliorate the immune consequences of for 2 weeks, to ameliorate the immune consequences of heterologous protein infusionheterologous protein infusion
ALG is administered at 3.5 mg/kg per day for 5 daysALG is administered at 3.5 mg/kg per day for 5 days
Cyclosporine is administered orally at an initial dose of Cyclosporine is administered orally at an initial dose of 12 mg/kg per day in adults (15 mg/kg per day in 12 mg/kg per day in adults (15 mg/kg per day in children), with subsequent adjustment according to children), with subsequent adjustment according to blood levels obtained every 2 weeksblood levels obtained every 2 weeks
TREATMENT TREATMENT
Supportive Care Supportive Care
infection in the presence of severe neutropenia must be infection in the presence of severe neutropenia must be aggressively treated by prompt institution of parenteral, aggressively treated by prompt institution of parenteral, broad-spectrum antibioticsbroad-spectrum antibiotics
Granulocyte transfusions using G-CSF-mobilized Granulocyte transfusions using G-CSF-mobilized peripheral blood have been effective in the treatment of peripheral blood have been effective in the treatment of overwhelming or refractory infections in a few patientsoverwhelming or refractory infections in a few patients
Hand washing, the single best method of preventing the Hand washing, the single best method of preventing the spread of infectionspread of infection
Total reverse isolation does not reduce mortality from Total reverse isolation does not reduce mortality from infections infections
TREATMENT TREATMENT
Supportive Care Supportive Care
transfusions once or twice weekly in order to maintain the transfusions once or twice weekly in order to maintain the platelet count >10,000/uLplatelet count >10,000/uL
Menstruation should be suppressed either by oral Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating hormone/luteinizing estrogens or nasal follicle-stimulating hormone/luteinizing hormone (FSH/LH) antagonistshormone (FSH/LH) antagonists
Aspirin and other nonsteroidal anti-inflammatory agents Aspirin and other nonsteroidal anti-inflammatory agents inhibit platelet function and must be avoidedinhibit platelet function and must be avoided
Red blood cells should be transfused to maintain a normal Red blood cells should be transfused to maintain a normal level of activity, usually at a hemoglobin value of 70 g/L level of activity, usually at a hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary (90 g/L if there is underlying cardiac or pulmonary disease)disease)