Hema intro anemia

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


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


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


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


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


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


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


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


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


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


PoikilocytosisPoikilocytosis means an increased means an increased

variability in red variability in red cell shapecell shape

Classification of Classification of poikilocytespoikilocytes


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


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


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


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

Sites of BMASites of BMA


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


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


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


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


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 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 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)


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


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


Trephine biopsy Trephine biopsy in Fanconi's in Fanconi's anaemiaanaemia

oiloil

Trephine biopsy Trephine biopsy in AA, acquiredin AA, acquired

lpolpo


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)

Hema intro anemia

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