HematologyHematologyBoard ReviewBoard Review

Jeremiah BolesJeremiah Boles6-4-086-4-08

AgendaAgenda► ITP – diagnosis and managementITP – diagnosis and management►Recognize Auer rods on peripheral smearRecognize Auer rods on peripheral smear►Brief overview of CML – specifically how to Brief overview of CML – specifically how to

diagnosediagnose►CLL – how to confirmCLL – how to confirm►Hyperhomocysteinemia and thrombosisHyperhomocysteinemia and thrombosis►AnemiaAnemia

Specifically Iron deficiency and how to Specifically Iron deficiency and how to diagnose/managediagnose/manage

ITPITP

► Immune mediated disorder of platelet Immune mediated disorder of platelet destructiondestruction Antibodies against glycoprotein IIb-IIIa, plt Antibodies against glycoprotein IIb-IIIa, plt

fibrinogen receptor and glycoprotein Ib.fibrinogen receptor and glycoprotein Ib. Blood smear – decreased numbers of platelets Blood smear – decreased numbers of platelets

with normal erythrocyte and leukocyte with normal erythrocyte and leukocyte morphologymorphology

► In adults, classically disorder of young In adults, classically disorder of young womenwomen

ITPITP

► Idiopathic thrombocytopenic purpura also Idiopathic thrombocytopenic purpura also known as immune thrombocytopenic known as immune thrombocytopenic purpura and ITPpurpura and ITP

►Goal of treatment is to provide a safe Goal of treatment is to provide a safe platelet count to prevent major bleeding platelet count to prevent major bleeding rather than correcting the underlying rather than correcting the underlying disease.disease.

►Major bleeding is rare in pts with >10,000Major bleeding is rare in pts with >10,000

ITPITP

►Autoimmune TCP not always idiopathicAutoimmune TCP not always idiopathic ~30% drugs, 30% underlying disease,30% ~30% drugs, 30% underlying disease,30%

idiopathic, 10% viralidiopathic, 10% viral►Underlying diseases – Connective tissue d/o (SLE), Underlying diseases – Connective tissue d/o (SLE),

lymphoproliferative d/o, hep C, HIVlymphoproliferative d/o, hep C, HIV TCP in such situations is referred to as secondary ITPTCP in such situations is referred to as secondary ITP

ITP DxITP Dx

►Careful peripheral smear examination – to Careful peripheral smear examination – to exclude morphologic abnormalities that exclude morphologic abnormalities that would suggest alternative dxwould suggest alternative dx

►Examination of BM is not necessary, but is Examination of BM is not necessary, but is recommended if patient age>60recommended if patient age>60

►?association with H.pylori – controversial?association with H.pylori – controversial

ITPITP

►General Treatment Goals: General Treatment Goals: - treat moderate to severe - treat moderate to severe thrombocytopenia who are bleeding or at thrombocytopenia who are bleeding or at riskrisk

- limit duration of treatment unless - limit duration of treatment unless symptoms persistsymptoms persist

- mild, asymptomatic thrombocytopenia - mild, asymptomatic thrombocytopenia should not be treated. should not be treated.

ITP – TreatmentITP – Treatment

► Individualized – American Society of Individualized – American Society of Hematology Hematology Rx when platelet count <30Rx when platelet count <30

► Initial therapy: prednisone 1 mg/kg/day, Initial therapy: prednisone 1 mg/kg/day, though some studies suggest treating initial though some studies suggest treating initial presentations with high dose presentations with high dose dexamethasone (40mg/kg/day for 4 days)dexamethasone (40mg/kg/day for 4 days)

►Most respond to steroidsMost respond to steroids

ITP – Treatment continuedITP – Treatment continued► Those who don’t respond or who require chronic Those who don’t respond or who require chronic

high dose steroids, consider 2high dose steroids, consider 2ndnd line therapy: line therapy: Splenectomy is classically second line – initially effective Splenectomy is classically second line – initially effective

in 85%, 66% in remission at 5 yearsin 85%, 66% in remission at 5 years► Remember, all splenectomy patients need vaccinations against Remember, all splenectomy patients need vaccinations against

encapsulated (encapsulated (H. influenzae H. influenzae andand N. meningitidis N. meningitidis – 2 weeks + – 2 weeks + prior to sx)prior to sx)

► Splenectomy should be deferred for 4-6 weeks Splenectomy should be deferred for 4-6 weeks after diagnosisafter diagnosis

► Younger patients in general respond better to Younger patients in general respond better to splenectomysplenectomy

ITP – Treatment continuedITP – Treatment continued

►Splenectomy sparing therapies:Splenectomy sparing therapies: Anti-D immunoglubin (WinRho) if Rh+Anti-D immunoglubin (WinRho) if Rh+ IVIGIVIG Rituxan (chimeric anti-CD20 monoclonal Ab)Rituxan (chimeric anti-CD20 monoclonal Ab) Others: danazol, cyclophosphamide, Others: danazol, cyclophosphamide,

azathioprine, vincristineazathioprine, vincristine

ITP – TransfusionsITP – Transfusions

►Platelet transfusions are typically reserved Platelet transfusions are typically reserved for serious/severe bleeding.for serious/severe bleeding.

►Generally will see rise in platelet count for Generally will see rise in platelet count for up to 24 hours, but even if don’t see bump up to 24 hours, but even if don’t see bump in platelets, transfusions are often in platelets, transfusions are often hemostatically effectivehemostatically effective

Auer RodsAuer Rods

► These cytoplasmic inclusions were named by John These cytoplasmic inclusions were named by John Auer, an American physiologist (1875-1948)Auer, an American physiologist (1875-1948)

► They are clumps of azurophilic granular material They are clumps of azurophilic granular material that form elongated needles seen in the that form elongated needles seen in the cytoplasm of leukemic blasts. They are composed cytoplasm of leukemic blasts. They are composed of fused lysosomes and contain peroxidase, of fused lysosomes and contain peroxidase, lysosomal enzymes, and large crystalline lysosomal enzymes, and large crystalline inclusions inclusions

► Can be seen in the leukemic blasts of AMLCan be seen in the leukemic blasts of AML► Classically M1,M2,M3,M4Classically M1,M2,M3,M4

CMLCML

► Most common adult leukemia in Western worldMost common adult leukemia in Western world► Slight Male prodominanceSlight Male prodominance► Median age at presentation 50Median age at presentation 50► Prototypic myelproliferative syndrome (remember Prototypic myelproliferative syndrome (remember

others? ET, PCV, MF)others? ET, PCV, MF)► Philadelphia Chromosome Philadelphia Chromosome

Balanced translocation t(9:22) that creates BCR-ABLBalanced translocation t(9:22) that creates BCR-ABL BCR-ABL encodes protein that acts of tyrosine kinaseBCR-ABL encodes protein that acts of tyrosine kinase

► This translocation is diagnostic of CMLThis translocation is diagnostic of CML

CMLCML► In patient with CML – all cells of the In patient with CML – all cells of the

hematopoetic lineage contain t(9:22) –> hematopoetic lineage contain t(9:22) –> clonalityclonality

►Uncontrolled production of maturing Uncontrolled production of maturing granulocytes, predominantly neutrophils but granulocytes, predominantly neutrophils but also eosinophils and basophilsalso eosinophils and basophils

►3 phases of CML- chronic phase, 3 phases of CML- chronic phase, accelerated phase, and blast crisis.accelerated phase, and blast crisis.

►85% of pts present in the chronic phase85% of pts present in the chronic phase

CML- Chronic PhaseCML- Chronic Phase► Chronic Phase – years – phase with proliferative Chronic Phase – years – phase with proliferative

advantage of this clone – gain additional mutations advantage of this clone – gain additional mutations ► large increase in the pool of committed myeloid large increase in the pool of committed myeloid

progenitors leading to peripheral blood progenitors leading to peripheral blood leukocytosis and often thrombocytosis leukocytosis and often thrombocytosis

► Left shiftLeft shift► BasophilliaBasophillia► Splenomegaly, occasional hepatomegaly or Splenomegaly, occasional hepatomegaly or

adenopathy (myelofibrosis and extramedullary adenopathy (myelofibrosis and extramedullary hematopoiesis)hematopoiesis)

CML – Chronic PhaseCML – Chronic Phase

►Often asymptomaticOften asymptomatic►Symptoms include fatigue, malaise, weight Symptoms include fatigue, malaise, weight

loss, excessive sweating, abdominal loss, excessive sweating, abdominal fullness, early satiety, sternal tenderness, fullness, early satiety, sternal tenderness, gout, and bleeding episodes due to platelet gout, and bleeding episodes due to platelet dysfunction.dysfunction.

CML – Accelerated PhaseCML – Accelerated Phase

►Neutrophil differentiation becomes Neutrophil differentiation becomes progressively impaired and leukocyte progressively impaired and leukocyte counts are more difficult to control with counts are more difficult to control with myelosuppressive medsmyelosuppressive meds

CML –Blast PhaseCML –Blast Phase

►Blast Phase – mutations lead to loss of Blast Phase – mutations lead to loss of differentiation and progression into acute differentiation and progression into acute leukemia (may resemble ALL or AML)leukemia (may resemble ALL or AML)

CML – DiagnosisCML – Diagnosis

►Typically patient is noted to have Typically patient is noted to have leukocytosis on routine CBCleukocytosis on routine CBC May have fatigue, weight loss, splenomegaly, May have fatigue, weight loss, splenomegaly,

thromocytosisthromocytosis►Diagnosis confirmed by demonstrating Diagnosis confirmed by demonstrating

t(9:22) by FISH or PCR of blood or bone t(9:22) by FISH or PCR of blood or bone marrow aspiratemarrow aspirate

CML - TreatmentCML - Treatment► Imatinib meylate (Gleevec) STI 571Imatinib meylate (Gleevec) STI 571

Inhibits the tyrosine kinase BCR-ABLInhibits the tyrosine kinase BCR-ABL► Suppresses or eliminates CML cloneSuppresses or eliminates CML clone► Initial numbers: Gleevec vs previous standard therapy 95 vs Initial numbers: Gleevec vs previous standard therapy 95 vs

56% hematologic remession, 85 vs 22 complete cytogenetic 56% hematologic remession, 85 vs 22 complete cytogenetic remissionremission

► Longer f/u with determine durability of responseLonger f/u with determine durability of response► Allogenic stem cell transplant – best results in Allogenic stem cell transplant – best results in

early, chronic phaseearly, chronic phase► Blast phase – chemo to induce remission, if return Blast phase – chemo to induce remission, if return

to chronic phase - xplantto chronic phase - xplant

CML - RecapCML - Recap

►Myeloproliferative disorderMyeloproliferative disorder►Philadelphia Chromosome t(9:22)Philadelphia Chromosome t(9:22)►BCR-ABL Tyrosine KinaseBCR-ABL Tyrosine Kinase►Chronic Phase – years – gain mutationsChronic Phase – years – gain mutations►Blast Phase – loss of differentiation – Blast Phase – loss of differentiation –

resembers acute leukemiaresembers acute leukemia►Gleevec – Imatinib – tyrosine kinase Gleevec – Imatinib – tyrosine kinase

inhibitorinhibitor

CLL – Chronic Lymphocytic CLL – Chronic Lymphocytic LeukemiaLeukemia

► CLL and its lymphomatous cousin, small CLL and its lymphomatous cousin, small lymphocytic leukemia (SLL), are characterized by lymphocytic leukemia (SLL), are characterized by an abnormal accumulation of morphologically an abnormal accumulation of morphologically mature (chronic) appearing lymphocytesmature (chronic) appearing lymphocytes Characteristic phenotype: CD19,CD20, CD23+ B cells Characteristic phenotype: CD19,CD20, CD23+ B cells

and also CD5+ (Tcell assoc antigen)and also CD5+ (Tcell assoc antigen)► In blood (>5000/mm3), bone marrow, or lymph nodesIn blood (>5000/mm3), bone marrow, or lymph nodes

Smudge cells on peripheral smear - reflect fragility of Smudge cells on peripheral smear - reflect fragility of cellscells

CLL - diagnosisCLL - diagnosis

►Characteristic phenotype Characteristic phenotype CD5+,CD19+,CD20+,CD23+ B cells by flow CD5+,CD19+,CD20+,CD23+ B cells by flow cytometry cytometry

►Flow often obviates need for BMBxFlow often obviates need for BMBx►Patients often noted to have lymphocytosis Patients often noted to have lymphocytosis

(>5000 lymphs) on routine CBC(>5000 lymphs) on routine CBC

CLL - diagnosisCLL - diagnosis

►1 point for each of below, 4-5 points 97% 1 point for each of below, 4-5 points 97% accurateaccurate

►Weakly positive surface immunoglobulin Weakly positive surface immunoglobulin stainstain

►CD5 +CD5 +►CD23+CD23+►CD79b or CD22 weakly +CD79b or CD22 weakly +►FMC7 negativeFMC7 negative

CLL – minimum diagnostic CLL – minimum diagnostic criteriacriteria

►ALC in the peripheral blood >10,000 with a ALC in the peripheral blood >10,000 with a preponderant population of morphologically preponderant population of morphologically mature appearing small lymphocytesmature appearing small lymphocytes

►Normo to hypercellular bone marrow with Normo to hypercellular bone marrow with lymphocytes accounting for >30% of all lymphocytes accounting for >30% of all nucleated cellsnucleated cells

► low levels of surface membrane low levels of surface membrane immunoglobulin, expression of 1 or more B immunoglobulin, expression of 1 or more B cell antigens, and expression of CD5cell antigens, and expression of CD5

CLL - MortalityCLL - Mortality►Major complications of CLL arise from Major complications of CLL arise from

cytopenias and immune dysfunction, cytopenias and immune dysfunction, anemia, and thrombocytopeniaanemia, and thrombocytopenia

► Infections lead to 50% of deaths from CLLInfections lead to 50% of deaths from CLL►Depressed immune function from Depressed immune function from

hypogammaglobulinemia can be improved hypogammaglobulinemia can be improved with IVIG for patients with pattern of with IVIG for patients with pattern of repeated infections, especially pneumonia repeated infections, especially pneumonia and sepsis.and sepsis.

CLL – Prognosis/TreatmentCLL – Prognosis/Treatment

► Important prognostic factors:Important prognostic factors: CytogeneticsCytogenetics Immunoglobulin mutational status – CLL with Immunoglobulin mutational status – CLL with

somatic mutations of immunoglobulin heavy somatic mutations of immunoglobulin heavy chain have particularly indolent course (median chain have particularly indolent course (median survival 25 years vs 8 without)survival 25 years vs 8 without)

Treatment options mirror those for Follicular Treatment options mirror those for Follicular lymphoma – indolent – very successful in lymphoma – indolent – very successful in inducing remission, but not cureinducing remission, but not cure

HyperhymocysteinemiaHyperhymocysteinemia► Hyperhymocysteinemia is associated with Hyperhymocysteinemia is associated with

increased risk of venous as well as arterial increased risk of venous as well as arterial thrombosisthrombosis

► Plasma homocysteine levels are determined by Plasma homocysteine levels are determined by genetic and environmental factorsgenetic and environmental factors Dietary intake of folic acid, b12, b6Dietary intake of folic acid, b12, b6

► Supplementation of these vitamins can lower Supplementation of these vitamins can lower plasma homocysteine levels, but it hasn’t been plasma homocysteine levels, but it hasn’t been shown if this reduces risk of recurrent vascular shown if this reduces risk of recurrent vascular eventsevents

AnemiaAnemia

►Deficiency in oxygen carrying capacity of Deficiency in oxygen carrying capacity of blood (decreased erythrocyte mass)blood (decreased erythrocyte mass) General Categories:General Categories:

►Production DefectsProduction Defects►Maturation DefectsMaturation Defects►Survival DefectsSurvival Defects►SequestrationSequestration►Blood LossBlood Loss

Anemia – Production DefectsAnemia – Production Defects

►Anemia of Chronic DiseaseAnemia of Chronic Disease Most common cause of anemia in hospitalized Most common cause of anemia in hospitalized

patientpatient Impaired iron utilization despite normal or Impaired iron utilization despite normal or

increased iron storesincreased iron stores Epo levels are usu lower than expected for Epo levels are usu lower than expected for

degree of anemiadegree of anemia Chronic rheumatic, infectious, neoplastic d/o Chronic rheumatic, infectious, neoplastic d/o

usually at playusually at play

Anemia – Production DefectsAnemia – Production Defects

►Anemia of Renal DiseaseAnemia of Renal Disease Normochromic and normocytic with low retic countNormochromic and normocytic with low retic count For epo to be effective – need normal iron stores - For epo to be effective – need normal iron stores -

(ferritin >100 and %sat >20)(ferritin >100 and %sat >20)

►Anemia of Hypometabolic StatesAnemia of Hypometabolic States Hypothyroid, Addison (deficient glucocorticoid), Hypothyroid, Addison (deficient glucocorticoid),

hypogonadism, panhypopit (low growth hormone)hypogonadism, panhypopit (low growth hormone)

►Anemia from bone marrow damageAnemia from bone marrow damage Aplastic anemia, marrow infiltrative disorders Aplastic anemia, marrow infiltrative disorders

Anemia – Maturation DefectsAnemia – Maturation Defects

• Can further divide into Cytoplasmic and NuclearCan further divide into Cytoplasmic and Nuclear►CytoplasmicCytoplasmic

• Impaired hgb synthesis – iron deficiencyImpaired hgb synthesis – iron deficiency• Protoporphyin deficiency – sideroblastic anemiaProtoporphyin deficiency – sideroblastic anemia• Globin synthesis deficiency - thalassemiasGlobin synthesis deficiency - thalassemias

►NuclearNuclear• DNA synthesis defects – folate,b12DNA synthesis defects – folate,b12

Iron Deficiency AnemiaIron Deficiency Anemia

► Very low ferritin(<10ng/ml) diagnostic of iron deficiencyVery low ferritin(<10ng/ml) diagnostic of iron deficiency► Ferritin - acute phase reactant - thus it may be falsely Ferritin - acute phase reactant - thus it may be falsely

normal or elevatednormal or elevated► Serum ferritin>100ng/ml is rare in iron deficient patientsSerum ferritin>100ng/ml is rare in iron deficient patients► Serum iron (<35), TIBC (>300), and %TS (<10%) are Serum iron (<35), TIBC (>300), and %TS (<10%) are

helpful when ferritin10-100ng/ml and iron deficiency is still helpful when ferritin10-100ng/ml and iron deficiency is still suspectedsuspected

► Bone marrow iron stores is the gold standard Bone marrow iron stores is the gold standard ► Iron Deficiency is a symptom – once diagnosed – find the Iron Deficiency is a symptom – once diagnosed – find the

causecause► Most common cause of thrombocytosis in adultsMost common cause of thrombocytosis in adults

Iron Deficiency vs AOCDIron Deficiency vs AOCDFe DeficiencyFe Deficiency AOCDAOCD

MCVMCV <85<85 72-10072-100

MCHCMCHC <32<32 <36<36

FEFE Low (<60)Low (<60) Low (<60)Low (<60)

TIBCTIBC High (>400)High (>400) Low (<250)Low (<250)

TIBC satTIBC sat Low <15 (usu <10%)Low <15 (usu <10%) Low to normal (2-20%)Low to normal (2-20%)

FerritinFerritin Low (<15)Low (<15) Normal to High (>35)Normal to High (>35)

Soluble Transferrin Soluble Transferrin ReceptorReceptor

High High NormalNormal

Stainable Marrow IronStainable Marrow Iron AbsentAbsent PresentPresent

Iron Deficiency AnemiaIron Deficiency Anemia

Increased iron requirements:Increased iron requirements: Blood loss: menstruation, GI bleeding, chronic blood Blood loss: menstruation, GI bleeding, chronic blood

donation donation Intravascular hemolysis (PNH, hemolysis secondary to Intravascular hemolysis (PNH, hemolysis secondary to

prosthetic valve) prosthetic valve) Pregnancy, lactationPregnancy, lactation

Inadequate iron supply:Inadequate iron supply: Poor nutritionPoor nutrition Malabsorption: gastric bypass surgery, achlorhydria, Malabsorption: gastric bypass surgery, achlorhydria,

celiac diseaseceliac disease

Iron Deficiency Anemia - TreatmentIron Deficiency Anemia - Treatment

► Replacement doses: Recommended - 200mg of Replacement doses: Recommended - 200mg of elemental iron per dayelemental iron per day

► Ferrous sulfate: 66mg of elemental iron per 325mg Ferrous sulfate: 66mg of elemental iron per 325mg tablettablet

► Niferex® (iron polysaccharide) contains 150mg of Niferex® (iron polysaccharide) contains 150mg of elemental ironelemental iron

► Better absorption in a more acidic environment – Better absorption in a more acidic environment – empty stomach, absence of antiacid (ppi etc), empty stomach, absence of antiacid (ppi etc), vitamin C, OJ - but usually not significant enough vitamin C, OJ - but usually not significant enough to justifyto justify

Iron Deficiency Anemia - TreatmentIron Deficiency Anemia - Treatment

►Reticulocytosis in 4-7 daysReticulocytosis in 4-7 days► Increased hemoglobin in first several weeks Increased hemoglobin in first several weeks

(4-6 classically)(4-6 classically)►Anemia usually resolves in 4-6 months Anemia usually resolves in 4-6 months

(depending on etiology of iron deficiency)(depending on etiology of iron deficiency)►Continue oral replacement for several Continue oral replacement for several

months after anemia has resolved to replete months after anemia has resolved to replete iron storesiron stores

Iron Deficiency Anemia - TreatmentIron Deficiency Anemia - Treatment

►Reasons for failure of oral iron:Reasons for failure of oral iron: Non-compliance ***Non-compliance *** Incorrect diagnosisIncorrect diagnosis Malabsorption: celiac disease, chronic Malabsorption: celiac disease, chronic

giardiasis, small bowel infiltrative process, h/o giardiasis, small bowel infiltrative process, h/o small bowel or gastric resection.small bowel or gastric resection.

Iron Deficiency Anemia – Treatment Iron Deficiency Anemia – Treatment FailuresFailures

► What to do if No Response and have iron What to do if No Response and have iron deficiency confirmed as diagnosisdeficiency confirmed as diagnosis Attempt to Improve compliance: decrease number of Attempt to Improve compliance: decrease number of

pills, treat constipation, take with foodpills, treat constipation, take with food Oral iron challenge to determine if absorbing ironOral iron challenge to determine if absorbing iron Parenteral iron: Parenteral iron:

► Iron dextran: can give total dose replacement in single dose, Iron dextran: can give total dose replacement in single dose, rate of anaphylaxis 0.6%rate of anaphylaxis 0.6%

► Ferrlecit® (Sodium Ferric Gluconate): Usually do not give as a Ferrlecit® (Sodium Ferric Gluconate): Usually do not give as a single dose as total replacement can cause hypotension from single dose as total replacement can cause hypotension from excess of free ironexcess of free iron

Anemia – Survival DefectsAnemia – Survival Defects

►Further Divided into:Further Divided into: Intrinsic (inheritied defects)Intrinsic (inheritied defects)

►Membrane cytoskeleton - spherocytosis, Membrane cytoskeleton - spherocytosis, elliptocytosiselliptocytosis

►Metabolic enzymes – G6PDMetabolic enzymes – G6PD►Hemoglobinopathies – Sickle CellHemoglobinopathies – Sickle Cell

Extrinsic (acquired)Extrinsic (acquired)►Antibody or complement mediated – Autoimmune Antibody or complement mediated – Autoimmune

hemolysis, malariahemolysis, malaria►Microangiopathy –DIC, vascular hemolysisMicroangiopathy –DIC, vascular hemolysis

Anemia - SequestrationAnemia - Sequestration

►Sequestration – hypersplenism usually from Sequestration – hypersplenism usually from portal hypertension or splenic sequestration portal hypertension or splenic sequestration crisescrises

Anemia – Blood LossAnemia – Blood Loss

►Self explanatory – when loss exceeds Self explanatory – when loss exceeds marrow production – may result in a marrow production – may result in a maturation defect (iron, b12, folate)maturation defect (iron, b12, folate)

Microcytic AnemiasMicrocytic Anemias► Iron deficiencyIron deficiency► Beta thal:Beta thal:

Trait hgb usually 9-11Trait hgb usually 9-11 Hemoglobin electrophoresis: persistent elevation of hgbF, variable Hemoglobin electrophoresis: persistent elevation of hgbF, variable

levels of hgbA2, and absent HgbA.levels of hgbA2, and absent HgbA.► Alpha thal: Alpha thal:

One gene absent RBC normalOne gene absent RBC normal Two genes absent: mild anemia with hypochromic/microcytic red Two genes absent: mild anemia with hypochromic/microcytic red

cellscells Electorphores is normal. Globin chain analysisElectorphores is normal. Globin chain analysis

► Sideroblastic anemia: rare, hereditary disorder, X-linked Sideroblastic anemia: rare, hereditary disorder, X-linked mutation in ALA synthase.mutation in ALA synthase.

► Lead poisoningLead poisoning

Macrocytic AnemiasMacrocytic Anemias

► Vitamin deficiency: B12 and folateVitamin deficiency: B12 and folate► Medications: hydroxyurea, methotrexate, 6MP, Medications: hydroxyurea, methotrexate, 6MP,

AZT, phenytoinAZT, phenytoin► Alcoholism: direct toxic effect or via folate Alcoholism: direct toxic effect or via folate

deficiencydeficiency► Liver diseaseLiver disease► Myelodysplastic syndromeMyelodysplastic syndrome► HypothyroidismHypothyroidism► ReticulocytosisReticulocytosis

Peripheral SmearPeripheral SmearFindingFinding MeaningMeaningShistocytes/RBC Shistocytes/RBC fragmentsfragments

Microangiopathic hemolytic Anemia (MAHA) – TTP, HUS, HELLP, DICMicroangiopathic hemolytic Anemia (MAHA) – TTP, HUS, HELLP, DICBurnsBurnsValve hemolysisValve hemolysis

SpherocytesSpherocytes Autoimmune hemolytic anemiaAutoimmune hemolytic anemiaHereditary spherocytosisHereditary spherocytosis

Target CellsTarget Cells Liver disease, also in thalassemia and other hemoglobinopathiesLiver disease, also in thalassemia and other hemoglobinopathies

Teardrop CellsTeardrop Cells Myelofibrosis and other infiltrative bone marrow processesMyelofibrosis and other infiltrative bone marrow processesSometimes seen in thalassesemiaSometimes seen in thalassesemia

Burr Cells (echinocytes)Burr Cells (echinocytes) Uremic patientsUremic patients

Spur Cells Spur Cells (acanthocytes)(acanthocytes)

Liver diseaseLiver disease

Howell-Jolly bodiesHowell-Jolly bodies Splenectomy or functionally asplenic patients – result of fragmentationof Splenectomy or functionally asplenic patients – result of fragmentationof nucleas – occurs normally and usually removed by spleennucleas – occurs normally and usually removed by spleen

Hypersegmented PMNSHypersegmented PMNS Megaloblastic anemia (PA, b12, folate)Megaloblastic anemia (PA, b12, folate)