Download - Anemia - UST 2007 (Revised)
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