Anemia and Abnormalities of Red Blood Cells: Approach to

Diagnosis and Treatment

Section of Hematology-OncologySection of Hematology-OncologyDepartment of MedicineDepartment of Medicine

University of Santo TomasUniversity of Santo TomasFaculty of Medicine and SurgeryFaculty of Medicine and Surgery

Case 1-01-01: 35 year old pre-menopausic female with menorrhagia

housewife housewife complains of progressive easy fatigability of complains of progressive easy fatigability of

about 3 months duration.about 3 months duration.(-) epigastric pain, (-) hematochezia nor (-) epigastric pain, (-) hematochezia nor melenamelenamenses – 28 days cycle, 7 days duration,menses – 28 days cycle, 7 days duration,3 days profuse flow , 5-6 fully soaked 3 days profuse flow , 5-6 fully soaked

pads/daypads/day (-) bruises/ecchymoses(-) bruises/ecchymoses P.E. Pale, no jaundiceP.E. Pale, no jaundice (-) hepatosplenomegaly(-) hepatosplenomegaly

Case 1-01-01

1.1. What other questions should you What other questions should you ask of this patient who presents ask of this patient who presents with pallor? with pallor?

2.2. What other findings should you What other findings should you look for in the physical look for in the physical examination?examination?

Case 1-01-01

3. What laboratory examinations 3. What laboratory examinations would you request in this case?would you request in this case?

4. What are red cell indices?4. What are red cell indices?

5. What information can you get from 5. What information can you get from the examination of the peripheral the examination of the peripheral smear?smear?

6. What is the significance of the 6. What is the significance of the reticulocyte count?reticulocyte count?

CBC: CBC: Hb: 60g/LHb: 60g/L Hct: .21 Hct: .21MCV: 80fLMCV: 80fL MCH: 25 pg MCH: 25 pg

MCHC: 28% MCHC: 28%WBC: 6 x 109/LWBC: 6 x 109/Lseg: 70%seg: 70% lymph: 25%lymph: 25%eos: 3%eos: 3% mono: 2%mono: 2%Platelets: adequatePlatelets: adequate

Reticulocyte count: 1.5 Reticulocyte count: 1.5 x 10x 10-3-3

Case 1-01-01:

Interpretation?

Microcytic (MCV low)Microcytic (MCV low) Hypochromic (MCH low)Hypochromic (MCH low) Normal WBCNormal WBC Platelets normal quantityPlatelets normal quantity Reticulocyte count normalReticulocyte count normal Peripheral smear: hypochromic, Peripheral smear: hypochromic,

microcytic red blood cells, varying sizes microcytic red blood cells, varying sizes (anisocytosis), varying shapes (anisocytosis), varying shapes (poikilocytosis), platelets adequate(poikilocytosis), platelets adequate

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Case 1

PatientPatient Normal valueNormal value

Serum ironSerum iron 1010 9 - 27 umol/L9 - 27 umol/L

50 – 150 50 – 150 μμg/dLg/dL

TIBCTIBC 6060 54 – 64 umol/L54 – 64 umol/L

300 – 600 300 – 600 μμg/dLg/dL

% transferrin % transferrin saturationsaturation

16.6%16.6% 25 – 50%25 – 50%

Serum ferritinSerum ferritin 8ug/L8ug/L 30 30 μμg/L(female)g/L(female)

100 100 μμg/L(male)g/L(male)

Interpretation?

Serum iron lowSerum iron low TIBC normalTIBC normal Transferrin saturation lowTransferrin saturation low Serum ferritin lowSerum ferritin low

Iron deficiency anemiaIron deficiency anemia

Anemia Reduction below normal in the Reduction below normal in the

concentration of hemoglobin or concentration of hemoglobin or RBC’s in the bloodRBC’s in the blood

Anemia is Anemia is not a diagnosisnot a diagnosis in itself, but in itself, but merely an merely an objective signobjective sign of disease of disease

First step in its diagnosis is detection of its First step in its diagnosis is detection of its presencepresence

Symptoms of moderate to severe anemia

FatigueFatigue BreathlessnessBreathlessness Loss of staminaLoss of stamina Palpitations, especially with physical exertionPalpitations, especially with physical exertion HeadacheHeadache VertigoVertigo Lack of mental concentrationLack of mental concentration DrowsinessDrowsiness TinnitusTinnitus ParesthesiasParesthesias PicaPica

History

Symptoms depend on:Symptoms depend on:1.1. Severity of the anemiaSeverity of the anemia2.2. Rapidity of onsetRapidity of onset3.3. Patient’s age and CV statusPatient’s age and CV status

- capacity of the CV & pulmonary system - capacity of the CV & pulmonary system to compensate for the anemiato compensate for the anemia4.4. Associated manifestations of the underlying Associated manifestations of the underlying

disorderdisorder- Endocrine disorder- Endocrine disorder- Renal disorder- Renal disorder- Hepatic disorder- Hepatic disorder

History Onset & Duration of symptoms

insiduous or acute Previous prescription for hematinics &

response Medication history Occupation, household customs & hobbies Symptoms of hemolysis

jaundice, changes in urine color Symptoms of blood loss

melena, hematochezia, epigastric pain

History Obstetric & Gynecologic history

# of pads/day duration # of pregnancies, abortions -

interval Concomitant bleeding manifestations Dietary history Fever, Weight loss

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Vital signs Blood pressureBlood pressure

HypotensionHypotension Orthostatic hypotensionOrthostatic hypotension

Cardiac/pulse rateCardiac/pulse rate TachycardiaTachycardia

Respiratory rateRespiratory rate TachypneaTachypnea

Body temperatureBody temperature

Cardiac Signs

Hemic murmurs: mid or Hemic murmurs: mid or holosystolic often in the pulmonic holosystolic often in the pulmonic or apical area, due to increased or apical area, due to increased blood flow and turbulenceblood flow and turbulence

Gallop rhythmsGallop rhythms Tachycardia/CardiomegalyTachycardia/Cardiomegaly Strong peripheral pulses with wide Strong peripheral pulses with wide

pulse pressurepulse pressure

Pallor: <8 to 10 mg/dL hemoglobinPallor: <8 to 10 mg/dL hemoglobinAffected by:Affected by:

state of vasoconstriction/vasodilatationstate of vasoconstriction/vasodilatation degree & nature of pigmentationdegree & nature of pigmentation nature & fluid content of the nature & fluid content of the

subcutaneous subcutaneous tissuestissuesMost constantly detected in:Most constantly detected in: mucous membranes of the mouth, pharynx, mucous membranes of the mouth, pharynx,

conjunctivae, lipsconjunctivae, lips nailbedsnailbeds

* * Areas where vessels are close to the skin Areas where vessels are close to the skin surfacesurface

Skin

Skin

Dry, Shriveled skinDry, Shriveled skin Thinning, loss of luster, Thinning, loss of luster,

premature graying of hairpremature graying of hair Brittle, lackluster nails, spooningBrittle, lackluster nails, spooning

Gastrointestinal manifestations GlossitisGlossitis Atrophy of the papillae of the Atrophy of the papillae of the

tonguetongue DysphagiaDysphagia Oral ulcersOral ulcers Gingival hyperplasiaGingival hyperplasia HepatosplenomegalyHepatosplenomegaly

Sternal tendernessSternal tenderness LymphadenopathyLymphadenopathy Retinal hemorrhageRetinal hemorrhage

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Complete blood count Red cellsRed cells

HemoglobinHemoglobin HematocritHematocrit Red cell countRed cell count MorphologyMorphology Red cell indices: MCV, MCH, MCHCRed cell indices: MCV, MCH, MCHC

White blood cellsWhite blood cells Total countTotal count Differential countDifferential count

Platelet countPlatelet count

Changes in Normal Hemoglobin/Hematocrit Values with Age and Pregnancy

Age/Sex Hgb (g/dl) Hct (%)At birth 17 52Childhood 12 36Adolescence 13 40Adult man 16(+2) 47(+6)Adult woman 13(+2) 40(+6)(menstruating)Adult woman 14(+2) 42(+6)(postmenopausal)During pregnancy 12(+2) 37(+6)

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Red cell indices IndexIndex Normal Value Normal Value

Mean Cell Volume(MCV)Mean Cell Volume(MCV) (hematocrit x 10)/(red cell ct. x 106)(hematocrit x 10)/(red cell ct. x 106) 90 90 ++ 8 fL 8 fL Mean Cell Hemoglobin (MCH)Mean Cell Hemoglobin (MCH) (hemoglobin x 10)/ (red cell ct. x 106)(hemoglobin x 10)/ (red cell ct. x 106) 30 30 ++

3 pg3 pg

Mean Cell Hemoglobin ConcentrationMean Cell Hemoglobin Concentration 33 33 ++ 2% 2% (hemoglobin x 10)/ hematocrit, (hemoglobin x 10)/ hematocrit, or MCH/MCVor MCH/MCV

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Morphology

Morphology

APPROACH TO THE DIAGNOSIS OF ANEMIA

Reticulocyte count Measure of bone marrow Measure of bone marrow

compensation for anemiacompensation for anemia Normal ValueNormal Value

0.5 – 1.5% (old)0.5 – 1.5% (old) 5 – 15 x 105 – 15 x 10-3-3 (SI) (SI)

Corrected Reticulocyte Corrected Reticulocyte ctct==Patient’s HctPatient’s Hct x x

Reticulocyte Reticulocyte 45 45 count (%) count (%)

Reticulocyte production Reticulocyte production indexindexCorrected ReticulocyteCorrected Reticulocyte 22

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Diagnosis of microcytic anemiasTestsTests Iron Iron

deficiencydeficiencyInflammatioInflammationn

ThalassemThalassemia ia

SideroblasSideroblastic anemiatic anemia

SmearSmear Micro/hypoMicro/hypo Normal, Normal, micro/hypomicro/hypo

Micro/hypo Micro/hypo with targetwith target

variablevariable

Serum Serum ironiron

<30<30 <50<50 Normal to Normal to highhigh

Normal to Normal to highhigh

TIBCTIBC >360>360 <300<300 normalnormal normlnorml

% % saturationsaturation

<10<10 10-2010-20 30-8030-80 30-8030-80

FerritinFerritin <15<15 30-20030-200 50-30050-300 50-30050-300

HemoglobHemoglobin patternin pattern

normalnormal normalnormal abnormalabnormal normalnormal

Adamson, J in Harrison’s Principles of Internal Medicine, 15th ed., 2001

Iron studies

Serum iron: amount of circulating iron Serum iron: amount of circulating iron bound to transferrinbound to transferrin

Total iron binding capacity: indirect Total iron binding capacity: indirect measurement of bound transferrinmeasurement of bound transferrin

Percent transferrin saturation: Percent transferrin saturation: Serum iron level x 100Serum iron level x 100

TIBCTIBC Serum ferritin: estimate of iron stores Serum ferritin: estimate of iron stores

Stages of Iron Deficiency

NormalNormal Negative Negative iron iron balancebalance

Iron deficient Iron deficient erythropoiesierythropoiesiss

Iron Iron deficiency deficiency anemiaanemia

Marrow iron Marrow iron storesstores

1–3+1–3+ 0-1+0-1+ 00 00

Serum ferritin Serum ferritin (ug/L)(ug/L)

50- 20050- 200 <20<20 <15<15 <15<15

TIBC (ug/dL)TIBC (ug/dL) 300-360300-360 >360>360 >380>380 >400>400

SI (ug/dL)SI (ug/dL) 50-15050-150 NLNL <50<50 <30<30

Saturation Saturation (%)(%)

30-5030-50 NLNL <20<20 <10<10

Marrow Marrow sideroblasts sideroblasts (%)(%)

40-6040-60 NLNL <10<10 <10<10

RBC RBC morphologymorphology

NLNL NLNL NLNL Microcytic Microcytic hypochromhypochromicic

Treatment

Severity and cause determine Severity and cause determine approach to treamentapproach to treament Elderly+/- cardiovasular Elderly+/- cardiovasular

instability: RBC transfusionsinstability: RBC transfusions Younger individuals with Younger individuals with

compensated anemia: iron compensated anemia: iron replacementreplacement

Optimal response occurs when about Optimal response occurs when about 200 mg of elemental iron given per day200 mg of elemental iron given per day

Absorption more complete on empty Absorption more complete on empty stomachstomach

With or after a meal, absorption With or after a meal, absorption decreases by 40 to 50%decreases by 40 to 50%

However gastric irritation is common, However gastric irritation is common, hence, advisingpt to take tablet hence, advisingpt to take tablet immediately after a meal may increase immediately after a meal may increase compliancecompliance

Optimal response occurs when about Optimal response occurs when about 200 mg of elemental iron given per day200 mg of elemental iron given per day

Absorption more complete on empty Absorption more complete on empty stomachstomach

With or after a meal, absorption With or after a meal, absorption decreases by 40 to 50%decreases by 40 to 50%

However gastric irritation is common, However gastric irritation is common, hence, advisingpt to take tablet hence, advisingpt to take tablet immediately after a meal may increase immediately after a meal may increase compliancecompliance

Oral Iron TherapyOral Iron Therapy

Absorption enhanced by orange juice, Absorption enhanced by orange juice, meat, poultry, fishmeat, poultry, fish

Absorption inhibited by cereals, tea, milkAbsorption inhibited by cereals, tea, milk Side Effects of Oral Iron: Side Effects of Oral Iron:

gastrointestinal: heartburn, nausea, gastrointestinal: heartburn, nausea, abdominal cramps, diarrheaabdominal cramps, diarrhea Related to doseRelated to dose

Continue iron treatment 3 to 6 months Continue iron treatment 3 to 6 months after anemia resolvesafter anemia resolves Allows repletion of iron storesAllows repletion of iron stores

Absorption enhanced by orange juice, Absorption enhanced by orange juice, meat, poultry, fishmeat, poultry, fish

Absorption inhibited by cereals, tea, milkAbsorption inhibited by cereals, tea, milk Side Effects of Oral Iron: Side Effects of Oral Iron:

gastrointestinal: heartburn, nausea, gastrointestinal: heartburn, nausea, abdominal cramps, diarrheaabdominal cramps, diarrhea Related to doseRelated to dose

Continue iron treatment 3 to 6 months Continue iron treatment 3 to 6 months after anemia resolvesafter anemia resolves Allows repletion of iron storesAllows repletion of iron stores

Oral Iron TherapyOral Iron Therapy

PreparationPreparation SizeSize Iron Iron ContentContent

Usual Adult Usual Adult daily dosedaily dose

Ferrous sulfateFerrous sulfate

tablets (hydrated)tablets (hydrated) 300 mg300 mg 60 mg60 mg 3 tablets3 tablets

tablets (exsiccated)tablets (exsiccated) 200 mg200 mg 60 mg60 mg 3 tablets3 tablets

syrup & elixirssyrup & elixirs 40 40 mg/mlmg/ml

8 mg/ ml8 mg/ ml 25 ml25 ml

Ferrous gluconateFerrous gluconate 300 mg300 mg 37 mg37 mg 5 tablets5 tablets

Ferrous fumarateFerrous fumarate 200 mg200 mg

300 mg300 mg67 mg67 mg

100 mg100 mg3 tablets3 tablets

2 tablets2 tablets

Oral Iron PreparationsOral Iron Preparations

Indications for Parenteral Iron Unable to tolerate iron compounds orallyUnable to tolerate iron compounds orally Poor compliancePoor compliance Persistent loss of blood or iron at a rate too Persistent loss of blood or iron at a rate too

rapid for oral intake to compensate for the lossrapid for oral intake to compensate for the loss Disorder of GI tract e.g. ulcerative colitisDisorder of GI tract e.g. ulcerative colitis Malabsorption of ironMalabsorption of iron Inability of maintain iron balance during Inability of maintain iron balance during

treatment with hemodialysistreatment with hemodialysis Donating large amounts of blood for Donating large amounts of blood for

autotransfusionautotransfusion

Unable to tolerate iron compounds orallyUnable to tolerate iron compounds orally Poor compliancePoor compliance Persistent loss of blood or iron at a rate too Persistent loss of blood or iron at a rate too

rapid for oral intake to compensate for the lossrapid for oral intake to compensate for the loss Disorder of GI tract e.g. ulcerative colitisDisorder of GI tract e.g. ulcerative colitis Malabsorption of ironMalabsorption of iron Inability of maintain iron balance during Inability of maintain iron balance during

treatment with hemodialysistreatment with hemodialysis Donating large amounts of blood for Donating large amounts of blood for

autotransfusionautotransfusion

Computing for the dose of parenteral iron

= Body weight (kg) x 2.3 x (15 – = Body weight (kg) x 2.3 x (15 – patient’s Hgb, g/dL) + 500 or 1000 patient’s Hgb, g/dL) + 500 or 1000 mg (for stores)mg (for stores)

Case 1-02-01 75 year old female consulted because of progressive weakness 75 year old female consulted because of progressive weakness

and loss of balanceand loss of balance numbness and tingling sensation in all extremitiesnumbness and tingling sensation in all extremities no gastrointestinal complaintsno gastrointestinal complaints hypertensive on Felodipine 5 mg per day, but not a diabetichypertensive on Felodipine 5 mg per day, but not a diabetic Diet consists of vegetables and fish because of poor dentitionDiet consists of vegetables and fish because of poor dentition P.E. Vital signs: BP: 150/90, PR: 80/min, regular, RR: 21/min., P.E. Vital signs: BP: 150/90, PR: 80/min, regular, RR: 21/min.,

regular, Temp: 35.5’Cregular, Temp: 35.5’C pale, has slightly icteric scleraepale, has slightly icteric sclerae smooth, red tonguesmooth, red tongue no lymph nodes, nor anterior neck mass. no lymph nodes, nor anterior neck mass. regular rate and rhythm, no murmursregular rate and rhythm, no murmurs Lung examination is normalLung examination is normal no abdominal masses palpatedno abdominal masses palpated some problems with gait but has an otherwise normal some problems with gait but has an otherwise normal

neurologic examination neurologic examination

Case 1-02-01

1.1. What other questions should you What other questions should you ask of this patient who presents ask of this patient who presents with pallor? with pallor?

2.2. What other findings should you What other findings should you look for in the physical look for in the physical examination?examination?

Case 1-02 CBC: CBC:

Hb: 80 g/L Hct: .26Hb: 80 g/L Hct: .26MCV: 102fL MCH: MCV: 102fL MCH: 36 pg MCHC: 38%36 pg MCHC: 38%WBC: 9 x 109/LWBC: 9 x 109/L

seg:seg: 74% 74% lymph: lymph: 20% 20% eos: eos: 2% 2%mono:mono: 4% 4%platelets: adequateplatelets: adequate

Case 1-02-01

3. What laboratory examinations 3. What laboratory examinations would you request in this case?would you request in this case?

4. What other differential diagnoses 4. What other differential diagnoses should be considered?should be considered?

> 36

macrocytes

32-36normochromic

normocytic

< 32 hypoochromic

microcyticReticulocyte count

Increased Normal/Decreased

• prior hemolysis• prior hemorrhage• treated disease • deficiency of - Vit. B12 - Folate

bone marrowmegaloblastic

• deficiency of Vit. B12, Folate• disorders of DNA synthesis - drug-induced - inherited

YES NO• hypothyroidism• hypoplastic marrow and misc.

INCREASED NORMAL/DECREASED

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Diagnostic Tests: Megaloblastic Anemia Reticulocyte indexReticulocyte index Unconjugated bilirubin may be increasedUnconjugated bilirubin may be increased LDH may be increasedLDH may be increased Serum levels of Serum levels of

Cobalamin (Vitamin B12) (NV: 300 – 900 Cobalamin (Vitamin B12) (NV: 300 – 900 pg/mL)pg/mL)

Folate (6 – 20 mg/mL)Folate (6 – 20 mg/mL) Red cell folate levels Red cell folate levels

not subject to fluctuations in folate intakenot subject to fluctuations in folate intake better indication of folate storesbetter indication of folate stores

Bone marrow findings: Megaloblastic anemia

HypercellularHypercellular Decreased Decreased

myeloid/erythroid ratiomyeloid/erythroid ratio Abundant stainable ironAbundant stainable iron RBC precursors abnormally RBC precursors abnormally

large, nuclei less mature large, nuclei less mature (nuclear-cytoplasmic (nuclear-cytoplasmic asynchrony)asynchrony)

Nuclear chromatin more Nuclear chromatin more disperse and condenses in disperse and condenses in a fenestrated patterna fenestrated pattern

Abnormal mitosisAbnormal mitosis Granulocyte precursor Granulocyte precursor

larger than normal with larger than normal with giant bands and metasgiant bands and metas

Megakaryocytes decreased, Megakaryocytes decreased, abnormalabnormal

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Interpretation?

MCV high (macrocytic)MCV high (macrocytic) MCH high (hyperchromic)MCH high (hyperchromic) PS: macrocytic red cells, some PS: macrocytic red cells, some

hyperchromic red cells, hyperchromic red cells, hypersegmented neutrophilshypersegmented neutrophils

Macrocytic anemia, probably Macrocytic anemia, probably megaloblastic anemiamegaloblastic anemia

Megaloblastic anemia

disorder caused by impaired DNA disorder caused by impaired DNA synthesissynthesis

Cells primarily affected: blood Cells primarily affected: blood cells, GI epithelial cellscells, GI epithelial cells

slowed nuclear cell division with slowed nuclear cell division with normal progression of cytoplasmic normal progression of cytoplasmic maturation maturation megaloblastosis megaloblastosis in bone marrowin bone marrow

Causes of Megaloblastic anemia

Cobalamin deficiencyCobalamin deficiency Inadequate intake (vegans)Inadequate intake (vegans) MalabsorptionMalabsorption

Gastric achlorydia, partial gastrectomy, Gastric achlorydia, partial gastrectomy, drugs that block acid secretiondrugs that block acid secretion

Pernicious anemia, total gastrectomyPernicious anemia, total gastrectomy Terminal ileal disease: sprue, enteritis, Terminal ileal disease: sprue, enteritis,

resection, tumorsresection, tumors Competition of cobalamin: fish Competition of cobalamin: fish

tapeworm, “blind loop” syndrometapeworm, “blind loop” syndrome

Causes of megaloblastic anemia

Folic acid deficiencyFolic acid deficiency Inadequate intake: unbalanced diet (alcoholics, Inadequate intake: unbalanced diet (alcoholics,

teenagers, some infants)teenagers, some infants) Increased requirementsIncreased requirements

PregnancyPregnancy InfancyInfancy MalignancyMalignancy Increased hematopoiesis (chronic hemolytic Increased hematopoiesis (chronic hemolytic

anemias)anemias) Chronic exfoliative skin disordersChronic exfoliative skin disorders HemodialysisHemodialysis

MalabsorptionMalabsorption Impaired metabolismImpaired metabolism

Other causes of megaloblastic anemia

Drugs that impair DNA metabolismDrugs that impair DNA metabolism Purine antagonists: 6 mercaptopurine, Purine antagonists: 6 mercaptopurine,

azthioprineazthioprine Pyrimidine antagonists: 5FU, cytosine Pyrimidine antagonists: 5FU, cytosine

arabinoside, othersarabinoside, others Others: procarbazine, hydroxyurea, zidovudineOthers: procarbazine, hydroxyurea, zidovudine

Metabolic disorders (rare)Metabolic disorders (rare) Hereditary orotic aciduriaHereditary orotic aciduria Lesch Nyhan syndromeLesch Nyhan syndrome

Megaloblastic anemia of unknown etiiologyMegaloblastic anemia of unknown etiiology Refractory megaloblastic anemiaRefractory megaloblastic anemia DiGuglielmo’s syndromeDiGuglielmo’s syndrome Congenital dyserythropoietic anemiaCongenital dyserythropoietic anemia

Treatment of Megaloblastic anemia Treat the causeTreat the cause Cobalamin deficiencyCobalamin deficiency

IM cyanocobalamin: 1000 mcg IM cyanocobalamin: 1000 mcg per week for 8 weeks then per week for 8 weeks then monthlymonthly

Oral cobalamin: 2 mg crystalline Oral cobalamin: 2 mg crystalline B12 per dayB12 per day

Folic acid: 1 mg/day poFolic acid: 1 mg/day po

Case 1-03-01 50 year old female was referred for evaluation of 50 year old female was referred for evaluation of

anemiaanemia easy fatigability about 5 weeks easy fatigability about 5 weeks cough and fever and was diagnosed to have cough and fever and was diagnosed to have

pneumonia. She was given antibiotics which included pneumonia. She was given antibiotics which included Cefuroxime 500 mg BIDCefuroxime 500 mg BID

other symptoms other symptoms passage of highly colored urinepassage of highly colored urine weight loss of about 5 lbs in the last 2 monthsweight loss of about 5 lbs in the last 2 months

P.E. Vital signs: BP: 120/70, PR: 110/min, regular, RR: P.E. Vital signs: BP: 120/70, PR: 110/min, regular, RR: 23/min, regular, Temp: 37’C23/min, regular, Temp: 37’C pale palpebral conjunctivae, icteric sclerae, small pale palpebral conjunctivae, icteric sclerae, small

cervical lymph nodes on both sides, cervical lymph nodes on both sides, no hepatomegaly and slight splenomegalyno hepatomegaly and slight splenomegaly

Case 1-03 CBC: CBC:

Hb: 70 g/L Hct: .21 Hb: 70 g/L Hct: .21 MCV: 98fL MCH: MCV: 98fL MCH: 35pg35pgMCHC: 36%MCHC: 36%WBC: 13x 109/LWBC: 13x 109/Lseg: 80%seg: 80% lymph: lymph: 20%20%platelets: adequateplatelets: adequate

Reticulocyte count: Reticulocyte count: 80 x 1080 x 10-3-3/L/L

Case 1-03-01

1.1. What other questions should you What other questions should you ask of this patient who presents ask of this patient who presents with pallor? with pallor?

2.2. What other findings should you What other findings should you look for in the physical look for in the physical examination?examination?

Case 1-03-01

3. What is the most likely problem 3. What is the most likely problem in this patient?in this patient?

4. What diagnostic tests are 4. What diagnostic tests are important in this patient?important in this patient?

Diagnostic tests for hemolytic anemia Peripheral smearPeripheral smear Direct Coomb’s test (antiglobulin test)Direct Coomb’s test (antiglobulin test)

Clue to immune (antibody-mediated) Clue to immune (antibody-mediated) hemolysis of RBChemolysis of RBC

Ham’s test (acid hemolysis); sucrose Ham’s test (acid hemolysis); sucrose hemolysis test screens for paroxysmal hemolysis test screens for paroxysmal nocturnal hemoglobinurianocturnal hemoglobinuria Flow cytometry diagnosticFlow cytometry diagnostic

Osmotic fragility testOsmotic fragility test Hemoglobin electrophoresis for Hemoglobin electrophoresis for

hemoglobinopathies (e.g. thalassemia)hemoglobinopathies (e.g. thalassemia)

Morphology in hemolytic anemias

Target cells: thalassemias

Spherocytes: hereditary spherocytosisAutoimmune hemolytic anemia

Schistocytes: microagiopathic hemolyticAnemia, intravascular prostheses

Causes of HemolysisAbnormalities of RBC interiorAbnormalities of RBC interior

Enzyme defectsEnzyme defectsHemoglobinopathiesHemoglobinopathies

INTRACORPUSCULARINTRACORPUSCULAR RBC membrane abnormalitiesRBC membrane abnormalitiesHereditary spherocytosis, etcHereditary spherocytosis, etcParoxysmal nocturnal Paroxysmal nocturnal

hemoglobinuriahemoglobinuriaSpur cell anemiaSpur cell anemia

Extrinsic factorsExtrinsic factorsHypersplenismHypersplenism ACQUIREDACQUIRED

EXTRACORPUSCULAREXTRACORPUSCULAR Antibody: immune hemolysisAntibody: immune hemolysisMicroangiopathic hemolysisMicroangiopathic hemolysisInfections, toxins, etc.Infections, toxins, etc.

HEREDITARYHEREDITARY

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HEMOLYTIC ANEMIA

COOMB’S TEST

NEGATIVE POSITIVE

EXTRACORPUSCULAR

AUTOIMMUNE HEMOLYTIC ANEMIAPrimarySecondary (CT disease, drugs)Isoimmune Hemolytic Disease

Rh,ABO, mismatched transfusion

HEMOLYTIC ANEMIA

COOMB’S TEST

NEGATIVE POSITIVE

CORPUSCULAR EXTRACORPUSCULAR

HemoglobinopathiesEnzymopathiesMembrane Defects

MorphologyAutohemolysisOsmotic Fragility

IdiopathicSecondary

DrugsInfectionMicroangiopathic

Immune-mediated hemolysis Usually due to IgG or IgM antibodies with Usually due to IgG or IgM antibodies with

specificity to antigens on red cell specificity to antigens on red cell membrane(autoantibodies) or with membrane(autoantibodies) or with alloantigens on transfused RBC alloantigens on transfused RBC (alloantibodies)(alloantibodies)

Diagnostic tool: Coomb’s antiglobulin testDiagnostic tool: Coomb’s antiglobulin test Direct: ability of anti-IgG or anti-C3 sera Direct: ability of anti-IgG or anti-C3 sera

to agglutinate patient’s RBCto agglutinate patient’s RBC Indirect: serum of patient incubated with Indirect: serum of patient incubated with

normal RBC & antibody is detected with normal RBC & antibody is detected with anti-IgGanti-IgG

Hemolysis due to Antibodies Warm-Antibody Warm-Antibody

Immunohemolytic Immunohemolytic anemiaanemia IdiopathicIdiopathic LymphomasLymphomas SLE & other collagen SLE & other collagen

vascular diseasevascular disease DrugsDrugs

Alpha methyl dopaAlpha methyl dopa PenicillinPenicillin QuinidineQuinidine

Postviral infectionsPostviral infections Other tumorsOther tumors

Cold-Antibody Cold-Antibody Immunohemolytic AnemiaImmunohemolytic Anemia Cold-agglutinin diseaseCold-agglutinin disease

Acute: Mycoplasma, Acute: Mycoplasma, infectious infectious mononucleosismononucleosis

Chronic: idiopathic, Chronic: idiopathic, lymphomalymphoma

Paroxysmal cold Paroxysmal cold hemoglobinuriahemoglobinuria

Treatment: Autoimmune hemolytic anemia Glucocorticoids: PrednisoneGlucocorticoids: Prednisone SplenectomySplenectomy Immunosuppressive drugsImmunosuppressive drugs Blood transfusion for severe Blood transfusion for severe

anemiaanemia

Case 1-04-01

48 year old male farmer with 48 year old male farmer with progressive weakness and pallorprogressive weakness and pallor

no jaundice nor no jaundice nor hepatosplenomegaly hepatosplenomegaly

petechiae noted on both L.E.’spetechiae noted on both L.E.’s

Case 1-04 CBC:CBC:

Hb:7 gm/dl Hct: 21Hb:7 gm/dl Hct: 21WBC: 3,000WBC: 3,000

lymph: 48% lymph: 48% segs: segs: 52%52%Platelet count: Platelet count: 80,00080,000

Reticulocyte Reticulocyte CountCount::5 x 105 x 10-3-3

Interpretation?

Pancytopenia (anemia, leukopenia, Pancytopenia (anemia, leukopenia, thrombocytopenia)thrombocytopenia)

Reticulocyte index lowReticulocyte index low Peripheral smear: normocytic, Peripheral smear: normocytic,

slightly hypochromic RBC, slightly hypochromic RBC, leukopenia, platelets nilleukopenia, platelets nil

Bone marrow failureBone marrow failureBack to algorithm

Case 1-04-01

What examination will establish What examination will establish the diagnosis in this case?the diagnosis in this case?

Diagnosis of hypoproliferative anemias

TestsTests Iron Iron deficiencydeficiency

InflammatioInflammationn

Renal Renal diseasedisease

HypometaboliHypometabolic statesc states

anemiaanemia Mild-Mild-severesevere

mildmild Mild-Mild-severesevere

mildmild

MCV (fl)MCV (fl) 70-9070-90 80-9080-90 9090 9090

morphologmorphologyy

Normo-Normo-micromicro

normonormo normonormo normonormo

Serum IronSerum Iron <30<30 <50<50 normalnormal normalnormal

TIBCTIBC >360>360 <300<300 normalnormal normalnormal

SaturationSaturation%%

<10<10 10-2010-20 normalnormal normalnormal

Serum Serum ferritinferritin

<15<15 30-20030-200 115-150115-150 normalnormal

Iron storesIron stores 00 2-4+2-4+ 1-4+1-4+ normalnormalAdamson, J in Harrison’s Principles of Internal Medicine, 15th ed., 2001Back to Case 1-04-01

Bone marrow examination

Bone marrow Bone marrow aspirationaspiration Smear for Smear for

morphologymorphology Flow cytometryFlow cytometry CytogeneticsCytogenetics

Bone marrow Bone marrow biopsybiopsy cellularitycellularity

Fatty marrow: Aplastic anemia

Normal bone marrow

Classification of Aplastic Anemia AcquiredAcquired

SecondarySecondary RadiationRadiation Drugs/chemicalsDrugs/chemicals VirusesViruses

• EBVEBV• Hepatitis (non-A, Hepatitis (non-A,

non-B, non-C)non-B, non-C)• Parvovirus B19Parvovirus B19• HIV1HIV1

Immune diseasesImmune diseases• Eosinophilic fascitisEosinophilic fascitis• HypoimmunoglobuliHypoimmunoglobuli

nemianemia• Thymoma/thymic caThymoma/thymic ca• GVHDGVHD

PNHPNH PregnancyPregnancy

IdiopathicIdiopathic

InheritedInherited Fanconi’s anemiaFanconi’s anemia Dyskeratosis congenitaDyskeratosis congenita Shwachman-Diamond Shwachman-Diamond

syndromesyndrome Reticular dysgenesisReticular dysgenesis Amegakaryocytic Amegakaryocytic

thrombocytopeniathrombocytopenia Familial aplastic Familial aplastic

anemiasanemias

Treatment: Aplastic Anemia Treatment of identifiable causeTreatment of identifiable cause Supportive careSupportive care

Blood component therapyBlood component therapy Treatment of infectionsTreatment of infections

Severe acquired AA:Severe acquired AA: Stem cell transplantationStem cell transplantation ImmunosuppressionImmunosuppression

ALG or ATG + cyclosporineALG or ATG + cyclosporine ModerateModerate

AndrogensAndrogens

Summary History and Physical examination are essential in the History and Physical examination are essential in the

assessment of a patient who may have anemiaassessment of a patient who may have anemia CBC, done and reported correctly is an important tool in CBC, done and reported correctly is an important tool in

anemiaanemia Confirms presence of anemiaConfirms presence of anemia Clues to the type and possible etiology of anemiaClues to the type and possible etiology of anemia

Additional tests indicated depending on type of anemiaAdditional tests indicated depending on type of anemia Bone marrow examinationBone marrow examination Iron studiesIron studies Hemoglobin electrophoresisHemoglobin electrophoresis Blood chemistriesBlood chemistries Vitamin levels: B12, folic acidVitamin levels: B12, folic acid Coomb’s testCoomb’s test OthersOthers

Treatment depends on the causeTreatment depends on the cause

Acknowledgements:

This presentation has been the This presentation has been the collective effort of the following collective effort of the following members of the staff of the members of the staff of the Section:Section:

Gina V. Panuncialman, MDGina V. Panuncialman, MD Priscilla B. Caguioa, MDPriscilla B. Caguioa, MD Irene D. Castillo, MDIrene D. Castillo, MD