Anemia

Dr. Bambang Mulyawan SpA

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 Definisi
 Sindroma Klinik yang disebabkan :
- Penurunan masa eritrosit total dalam tubuh
- Penurunan Hb, Ht, Eritrosit
 Definisi lain :
- Menurunnya jumlah hemoglobin dalam sel
darah merah sehingga oksigenasi ke jaringan
dan organ terganggu.
 Biasanya diikuti dengan penurunan Ht
 Kadar Hb dipengaruhi umur, jenis kelamin,
geofrafis dan metode pemeriksaan.
 Anemia : Not a diagnosis in itself.
An Objective Sign

Common problem in clinical practice.

It is defined as reduction in the conc. of Hb . Considered normal for
person’s age /sex group.
 Anemia
 Definisi
– Kadar Hb > 2 SD di bawah angka rata-rata
normal sesuai kelompok umurnya
 Angka normal bervariasi tergantung usia
anak
Age Newborn 2 wks 3 months 6m – 6 yrs 7-12 yrs

Hb 168 165 120 120 130

(137-210) (130-200) (95-145) (105-140) (110-160)
Hct 55 50 36 37 38
 WHO Criteria

Age/Sex group Hemoglobin level (g/dl)

Children 6 mon-5 years <11
Children 6 yrs -14 yrs <12
Adult males <13
Adult females (non pregnant) <12
Adult females (pregnant) <11
Single “cut off “ Hb value may underestimate the
true prevalence of anemia.
As RBC’s pass through the lungs the
hemoglobin in the red blood cell gives off
CO2 and picks up O2
 Anemia
Faktor penyebab :
1. Penurunan pembentukan sel drh merah

2. Peningkatan penghancuran
(HEMOLYSIS)

3. Kehilangan darah / perdarahan

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 1.Penurunan pembentukan sel drh merah
– deficiency
– bone marrow failure
– dyshematopoietic anemia
Penurunan ....
 Defect / kerusakan pembuatan heme
– Iron deficiency, anemia of chronic disease, lead
poisoning
 Defect / kerusakan pembentukan globin
– Alpha and beta thalassemia
 Defect pembuatan DNA
– Nutrient deficiencies (B12, folate)
 Kegagalan produksi epo
– Renal disease
Penurunan . . . .

 Gangguan sumsum tulang

– Aplastic anemia
 congenital (Fanconi)
 acquired
– Red cell aplasia
 Congenital (Diamond Blackfan)
 Acquired (Transient erythroblastopenia of childhood)
 Perubahan pd sumsum tulang
– Malignancy, myelofibrosis
Circulating Blood Cells
2 Peningkatan penghancuran

 Hemolytic Anemia
– corpuscular – extracorpuscular
 membrane defects  immune
– isoimmune
 enzyme defects
– autoimmune
 hemoglobin defects
 idiopathic
Peningkatan . . . .
 Extracellular
– Antibody mediated
– Microangiopathic; HUS, DIC
– Drugs, toxins
– Hypersplenism
Peningkatan . . . .
 Intracellular
– RBC membrane defects
 HS, HE
– Enzyme defects
 PK, G6PD
– Hemglobinopathies
 Sickle cell, thalassemia
 Anemia Classification
 Size of RBC’s
– Microcytic (Small)
– Macrocytic (Large)
– Normocytic (Normal Size)
 Concentration of Hgb
– Hypochromic (Less)
– Hyperchromic (More)
– Normochromic (Normal)
 Microcytic / Hypochromic
– Chronic Blood Loss, Iron Deficiency, Thalassemia
 Macrocytic (Megaloblastic) / Hyperchromic
– Vit B12 (Pernicious) or Folic Acid Deficiency
 Normocytic / Normochromic
– Hemolytic, Aplastic, Myelophthisic, Acute Blood Loss, Chronic Renal
Failure
 Anemia Hemolitik
 Anemia karena peningkatan destruksi
eritrosit
 Terjadi hiperplasi eritropoetik &
perluasan anatomis tulang
 SS tl : 6 – 8 xN
 Retikulosit meninggi
 Pembagian Anemia Hemolitik
1. Anemia hemolitik herediter/intrinsik:
a. Defek membran: sperositosis,eliptosit
b. Defek enzim/metabolik : G6PD, PK
c. Defek Hb : sickle sel, HbC, HbD, HbE,HbSC,HbM, H
Koln&Zurich, Thalasemia

2. Anemia hemolitik akuisita/ekstrinsik:

a. Autoimun : AIHA
b. Isoimun : Rx Tranfusi
c. Imun : Obat
d. Lain2 : zat kimia, mekanik, obat2an, infeksi defek
membran ekstrinsik/PNH
 Gambaran laboratorium
Anemia Hemolitik
1. Peningkatan destruksi eritrosit: bilirubin ,
urobilinogen urin , sterkobilinogen ,
haptoglobin serum –
2. Peningkatan produksi eritrosit: retikulositosis,
eritrosit hiperplasi
3. Sdm rusak : Morfologi (fragmentosit, sferosit,
mikrosit), fragilitas osmotic abn,
Autohemolitik, Umur SDM memendek.
4. OFT : abnormal
5. Usia sdm memendek
Perdarahan / kehilangan darah
 Acute hemorrhage
 Chronic blood loss
 Pemeriksaan fisik

 Pallor/pucat  peripheral edema

 Jaundice/kuning  splenomegaly
 tachycardia  glossitis
 tachypnea  gingival
 orthostatic pigmentation
hypotension
 venous hum
 systolic ejection
murmur
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 Penegakan Diagnosis
 detailed history/
anamnesis
 careful physical
examination
 peripheral blood  bone marrow
smear evaluation
– red cell morphology
 additional
– MCV
testing
– RDW
– WBC and platelet
morphology
 History / Anamnesis

 diet
 family history
 environmental exposures
 symptoms (headache, exertion dyspnea,
fatigue, dizziness, weakness, mood or
sleep disturbances, tinnitis)
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 Pemeriksaan laboratorium /
darah tepi
 RBC
 Hgb
 HCT
 MCV - a calculated value
 MCH
 RDW /lebar distribusi eritrosit
 Reticulocyte Count
 Determination of RBC Indices
 RBC count (RBC) - # RBC’s / 100 mL of Blood

 (NORMAL = 4.5-5.0 Million / 100 mL)

 Hematocrit (Hct) - % of (RB) Cells By Volume

 (NORMAL = 36-45%)

 Hemoglobin (Hgb) - mg / 100 ml of Blood

 (NORMAL = 13-15 mg/dL)

 Mean Corpuscular Volume (MCV)

– Hct/RBC - Normal = 90 (+or- 10) cubic microliter
 Mean Corpuscular Hemoglobin (MCH)
– Hgb/RBC - Normal = 30 (+or- 3) picograms
 Mean Corpuscular Hgb Concentration (MCHC)
 Diagnosis Lab :
1. Morfologi eritrosit ( Indeks Eritrosit )
- Mikro-Hipo ( MCV,MCH,MCHC )
- Normo ( MCV,MCH,MCHC N )
-Makro-Hiper ( MCV,MCH,MCHC )
2. Patofisiologi :
- Perdarahan ( Retikulosit > )
- Hemolitik (Retikulosit >, perdarahan -
)
- Ggn prod eri (Retikulosit < )
3. Kombinasi
 Anemia pasca perdarahan
 Akibat kehilangan darah : kecelakaan,
operasi, perdarahan usus, ulkus peptikum,
hemorrhoid, cacing ankilos/tambang, dll.
 Gejala ( jika 12 -15%) : pucat, transpirasi,
takikardi, tek.drh normal atau <.
Jika kehilangan drh 15-20% :tek.drh <,
syok  reversibel. >20%  syok
irreversible/menetap .
 Pengobatan : transfusi drh / plasma/infus
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 Pemeriksaan lab ;
1. Hb, Ht, Jmlh SDM, MCV, MCH, MCHC
2. SADT
3. Retikulosit
4. Sumsum Tulang
 Pemeriksaan Penunjang :
1. Tes Antiglobin (Coomb’s test direk & indirek)
2. Elektroforesis Hb
3. G6PD
4. Piruvat Kinase
5. Sucrose Water test
6. Ham test
7. Serum Feritin, B12, as folat
8. Hb uri, Uribilinogen uri,
Hiperbilirubinemia direk
 Indeks eritrosit
 MCV= Ht x 10 (Normal 80-97 fl)
eri
 MCH = Hb x 10 (Normal 27-31 pg)
eri
 MCHC= Hb x 100 (Normal 32-36 %)
Ht
MCV : Mikro/Makro
MCH , MCHC : Hipo / Hiper
Anemia Menurut morfologi SDM
1. Mikrositik hipokromik (MCH/MCV/MCHC
rendah):
anemia def. Besi, thalasemi, keracunan timah,
sideroblastik, peny kronis
2. Normositik normokromik (MCV/MCHC N):
anemia aplastik, anemia hemolitik, anemia
hemorragik)
3. Makrositik normokromik (MCV tinggi, MCHC N
a. Anemia Megaloblastik
- Def vit B12 / as folat
ANEMIA

ANEMIA

Erythrocyte Indices
Blood Smear

MCV>100 MCV 80-100 MCV < 80

Macrocytic Normocytic Microcytic

 - Efek Kemotherapi
- Synd Mielodisplastik
b. Non Megaloblastik
- Alkoholisme
- Peny.hepar
- Hemolisis, perdarahan
- Hipotiroidisme
 Using MCV to Characterize
Anemia

 Hypochromic Microcytic
– Hemoglobin E trait
– Inborn errors of iron
– Iron deficiency anemia
metabolism
– Thalassemia
– Copper deficiency
– Sideroblastic anemia
– Severe Malnutrition
– Chronic infection
– Lead poisoning
 Using MCV to Characterize
Anemia
 Macrocytic

– Normal newborn – Obstructive jaundice

– Increased – Aplastic anemia
erythropoiesis – Hypothyroidism
– Post-splenectomy – Megaloblastic anemia
– Liver disease – Down’s syndrome
 Using MCV to Characterize
Anemia
 Normocytic

– Acute blood loss

– Infection – Disseminated
– Renal failure malignancy
– Connective tissue – Early iron deficiency
disorder – Aplastic anemia
– Liver disease – Bone marrow infiltration
– Dyserythropoietic
anemia
 Mean Cell Volume (MCV)
RBC size is measured indirectly by
The Mean Cell Volume (MCV) and RDW
MCV

Microcytic Normocytic Macrocytic

< 80 fl 80 -100 fl > 100 fl

< 6.5 µ 6.5 - 9 µ >9µ

 Mean Cell Volume (MCV)
MCV

Microcytic Normocytic Macrocytic

Iron Deficiency (IDA) Chronic diseases, CKD Megaloblastic anemias
Chronic Infections Early IDA Liver disease/alcohol
Thalassemias Hemoglobinopathies Hemoglobinopathies
Hemoglobinopathies Primary marrow disorders Metabolic disorders
Sideroblastic Anemia Combined deficiencies Marrow disorders
Increased destruction Increased destruction
 Using MCV and RDW

MCV Low MCV Normal MCV High

RDW Microcytic Normocytic Macrocytic
Normal Homogeneous Homogeneous Homogeneous
Heterozygous Normal Aplastic Anemia
Thalassemia Chronic disease Pre-leukemia
Chronic disease Chronic Liver Dz
Hemoglobinopathy (AS)
Transfusion
Chemotherapy
CML
Hemorrhage
Hered. Spherocytosis
 Using MCV and RDW

MCV Low MCV Normal MCV High

RDW Microcytic Normocytic Macrocytic
High Heterogeneous Heterogeneous Heterogeneous
Iron Deficiency Anemia Early iron or folate Folate Deficiency
S Beta-thalassemia Deficiency Vitamin B-12 Deficiency
Hemoglobin-H Mixed deficiencies Immune hemolytic
Red Cell Fragmentation Hemoglobinopathy Anemia
(SS,SC) Cold agglutinins
Myelofibrosis
S
Sideroblastic Anemia
 Differential diagnosis of
microcytosis
IRON LEAD
DEFICIENCY POISONING THALASSEMIA
Hgb Reduced Normal Reduced
MCV Reduced Normal Reduced
FEP Increased Increased Normal
Se Iron Reduced Normal Normal
TIBC Increased Normal Normal
Ferritin Reduced Normal Normal
 Anemia menurut etiologi
 Produksi/aktifitas menurun:
kegglan ssm tl : anemia aplastik, an
mielodisplastik
gizi : defis Fe,B12, as folat, toksin
 Destruksi meningkat:
anemia hemolitik (bawaan dan
akuisita)
 Kehilangan darah:
 Anemia defisiensi
 Disebabkan oleh kekurangan satu atau
lebih beberapa bahan yg diperlukan untuk
pematangan eritrosit :
a. Mikrositik hipokrom : kekurangan besi,
piridoksin , tembaga
b. Makrositik normokrom (megaloblastik):
kekurangan asam folat , vit.B12

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Blood cells are made in the
bone marrow
 Anemia defisiensi besi
 Etiologi :
 1. masukan kurang : KEP, def.diet relatif
 2. absorpsi kurang : KEP, diare kronis, sin-
droma malabsorpsi
 3. sintesis kurang transferin kurang
 4. kebutuhan bertambah : infeksi, pertum-buhan
yg cepat
 5. pengeluaran yg bertambah : cacing ankilos,
amubiasis kronis, polip, hemolisis intravask.
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 How to make a red blood
cell
Genes

Erythropoietin
(kidney)

Nutrients

Bone
marrow
Iron, Folate, B12
 Iron Deficiency Anemia
 causes
– Dietary deficiency – Blood loss
 gut problems
 gall bladder
– Increased demand
 lung
(growth)
 nose
 heart
– Impaired absorption  kidney
 menstrual problems
 trauma
 Anemia defisiensi Fe
 Anemia o.k cadangan besi berkurang
 Mikrositik hipokromik
 MCV,MCH,MCHC menurun
 Saturasi transferin menurun
 Kadar feritin serum menurun
 Hemosiderin ssm tulang menurun
 Gejala anemia def.besi
 Anak lemas, sering berdebar,lekas lelah, pucat, sakit
kepala, iritabel, dsb.
 Tidak tampak sakit o.k.perjalanan kronis.
 Pucat : mukosa bibir, faring, tapak tangan, dasar kuku,
konjungtiva okular kebiruan atau putih mutiara, papil
lidah atropi
 Jantung membesar, bising sistolik. Pada ankilost : perut
buncit,edema.
 Pada KEP : hepatomegali, diatese hemorrhgik

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 Iron Deficiency Anemia
 Symptoms
– GI – Cardiac
 anorexia  increased cardiac
 pica output
 atrophic glossitis  cardiac hypertrophy
 guaiac positive stool
– Musculoskeletal
– CNS  impaired exercise
performance
 fatigue
 radiographic changes
 irritability
 Iron Deficiency Anemia

 characteristics of peripheral blood

smear
– microcytic
– hypochromic
 Anemia def.besi ( pemeriksaan
laboratorium )
 Hb <10 g%, mikrositik hipokrom, poikilo-
sitosis, sel target. Lekosis dan trombosit
normal. Pemeriksaan sumsum tulang :
sistem eritropoetik hiperaktif.
 Serum iron (SI) merendah, Iron Binding
Capacity (IBC) meningkat.

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 Iron Deficiency Anemia

 additional diagnostic tests

– free erythrocyte protoporphyrin (elevated)
– serum ferritin (decreased)
– serum iron (decreased)
– Iron binding capacity (increased)
– Iron saturation (decreased)
Iron DeficiencyAnemia

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Etiologi anemia defisiensi Fe
 Kehilangan besi:
uterus : haid banyak
Sal. Cerna:varises oesophagus, ulkus peptikum,
carsinoma lambung/colon, hemorrhoid,
Cacingan, Ulcerative colitis,Hiatus hernia
 Kebutuhan meningkat:
kehamilan, menyusui, pertumbuhan
 Intake kurang:
diit buruk, malabsorbsi: gasterektomi,
coeliac disease
Diagnosis of iron deficiency
anemia
 RBC’s are hypochromic (pale) and
microcytic (small) although mild cases
will be normocytic
 Low serum iron, normal or high iron
binding capacity (TIBC, Transferrin)
 Low % saturation
 Low serum ferritin
 Absent iron stores in bone marrow
 Response to iron therapy
 Pem. Lab. Anemia def. Fe
 DT: mikrositik hipokromik, anisositosis
poikilositosis, sel pensil, target sel.
 MCV ,MCH ,MCHC
 Ssm tlg: eritroid hiperplasi, cadangan besi
 Serum feritin ( N : 10-500 ug/L)
 Retikulosit menurun, normal/naik
 Serum Fe menurun, TIBC meningkat
 Saturasi transferin menurun
 Free Eritrosit Protophorpirin
 Nilai normal :

 Serum Fe 60-180 mg/dl

 TIBC 200-410 mg/dl
 Serum feritin : 10-500 µg/L, <10 µg/L
cadangan besi tubuh menurun.
 Saturasi transferin = Fe/TIBC x100% =20-
45 %
 Diagnosis anemia def.besi
 Ditemukan penyebab defisiensi besi,
gambaran eritrosit mikrositik hipokrom, SI
rendah, IBC meningkat, tidak terdapat
besi dalam sumsum tulang, dan reaksi yg
baik terhadap pengobatan dengan besi.

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 Pengobatan anemia def.besi
 Makanan adekuat ( baik, cukup).
 Sulfas ferosus 3 x 10 mg/kgBB/hari
 Transfusi darah : jika HB < 5 g%
 Antihelmintik (obat cacing )

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 Iron Deficiency Anemia
 Treatment
– oral iron supplementation: 6mg/kg/day of
elemental iron
 for at least 3 months
 check retic count after 2 weeks
 side effects (educate family)
– goal: to replace iron stores, not just
circulating Hgb
 Dietary sources of iron

 Meat, poultry & fish, oysters

 Iron enriched cereal
 Beans
 Dried fruit
 Whole grains
 Egg yolk
Absorption increased by Vitamin C
 Iron Deficiency Anemia
 failure to respond to therapy
– non-compliance
– inadequate dose
– ineffective preparation
– unrecognized blood loss
– impaired GI absorption
– coexistence of disease
– incorrect diagnosis
 Iron Deficiency Anemia

 parenteral therapy
– indications
 poor compliance
 severe bowel disease
 intolerance of oral iron
 chronic hemorrhage
 acute diarrhea disorder
Dosing of Parenteral Therapies

– Iron Dextran
 provides 50mg/ml elemental iron
 for weight >15kg: dose (ml) =
0.0442 (desired Hgb - Observed Hgb) x LBW + (0.26 x LBW)
LBW (males)=50kg+2.3kg/inch of height over 5 ft.
LBW (females )=45.5kg+2.3kg/inch of height over 5 ft.

 For weight 5 - 15kg: dose (ml) =

0.0442 (desired Hgb - Observed Hgb) x W + (0.26 x
W)
W = wt in kg
Dosing of Parenteral Therapies

– Ferrlecit (sodium ferrous gluconate)

 each 10cc provides 125mg elemental iron
 dilute 10ml in 100ml 0.9NS and administer IV over
1 hour
 repeat for up to 8 sessions
 test dose recommended
 Anemia megaloblastik
Anemia dimana terjadi kelaianan pada sel dan
fungsi di sumsum tulang dan darah tepi yang
disebabkan sintesis DNA yang tidak sempurna
Penyebab:
1. Defisiensi B12 dan asam folat : yg penting utk
sintesa DNA, Defisiensi menimbulkan
pematangan inti terlambat(megaloblastik)
2. Abnormalitas metabolisme B12/as folat
3. Cacad sintesa DNA :
a. defisiensi enzim kongenital
b. Akuisita : terapi hidroksiurea,
sitosin arabinosa
 Macrocytic, normochromic red blood cells
are on the left, while normocytic
normochromic red blood cells are pictured
on the right.
 MACROCYTIC ANEMIA

Marrow Morphology

Megaloblastic Non-Megaloblastic

Serum Vitamins Reticulocyte Count

B12 def &/or Folate def

Increased N or Decreased
Diet
Hemolytic Anemia Hepatic Diseases
Hemorrhage Hypothyroidism
Poor Good Chronic Lung Disease

Dietary def Malabsorption

Pregnancy Tropical Sprue
Infancy Gastric Resection
 How to make a red blood
cell
Genes

Erythropoietin
(kidney)

Nutrients

Bone
marrow
Iron, Folate, B12
 Folate and B12 Deficiency

 Macrocyticanemia – MCV >100

and may be >120
 Hypersegmented neutrophils
 “Megaloblastic” bone marrow
 Sebab Defisiensi as Folat:
1. Nutrisional : Tua, Skorbut,Gastrektomi
parsial
2. Malabsorbsi : Peny. Crohn, Gastrektomi
parsial
3. Pemakaian berlebih :
- Fisiologis : kehamilan, laktasi
- Patologis : Hemolitik, Keganasan,Radang
(TBC, RA, Peny. Crohn,
Psoriasis )
4. Pembuangan As. Folat >> : Peny. Hati,
Jtg
Folic Acid (Folate) Sources
 Natural  Enriched
– Meat &Poultry (varies by country)
 Liver – Breakfast cereal
– Dark green veggies – Flour
 Spinach
– Bread
 Asparagus
– Pasta
 Broccoli
– Peas & Beans
– Fruit
 oranges
 Pemeriksaan An Megaloblastik
 Dt: makrositik normokromik
 Sdm : basofilik stipling, howell jolly,
eritrosit berinti, fragmentosit, Schistosit,
makrosit oval
 Netrofil hipersegmen
 Retikulosit turun
 MCV meningkat, MCHC normal
 Netrofil dan trombosit turun
 Sumsum tulang : Eritroid hiperplasi, seri
Myeloid ( btk Giant, granulosit
hipersegmen ), Megakariosit
 Serum B12 & As. Folat
 Causes of Folate deficiency
 Dietarydeficiency (not stored)
 Excess utilization (pregnancy,
hemolysis, cancer)
 Malabsorption
 Drugs (anticonvulsants)
 Vitamin B12
 Only in animal products – meat,eggs,dairy
 Body stores last 3-20 years – deficiency in
long-term vegans
 Fortified foods for vegans in developed
countries (veggie burgers, soy milk)
 Manure contamination in developing
countries (a problem when people
immigrate to more developed countries)
 Most B12 deficiency is due to
failure of absorption not dietary
deficiency
 Causes of B12 deficiency
 Pernicious Anemia/Gastric Atrophy
 Gastrectomy
 Blind Loop Syndrome (previous
intestinal surgery)
 Crohn’s Disease (terminal ileum)

Since absorption is the

problem, treatment is by
injection
 How to make a red blood
cell
Genes

Erythropoietin
(kidney)

Nutrients

Bone
marrow
Iron, Folate, B12
 Genetic Anemia
 Hemoglobinopathies (sickle cell
anemia)
 Thalassemias (alpha & beta)
 Membrane defects (elliptocytosis)
 Red cell enzymes (G6PD )

 Evolved in areas where malaria

endemic because these mutations
offer protection against malaria
 Talasemia

thalassemia

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 Merupakan penyakit anemia hemolitik herediter
yang diturunkan dari kedua orang tua kepada
anak-anaknya sera resesif, menurut hukum
Mendel.
 Pembagian (secara klinis) :
a. Talasemia mayor (bentuk homozygot)
Memberikan gejala klinis yg jelas
b. Talasemia minor
Biasanya tidak memberikan gjl.klinis

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 Gejala klinis dan laboratorium
 Anemia berat tipe mikrositik,retikulosit >
 Limpa dan hepar membesar
 Anak besar : gizi buruk
 Muka : fasies Mongoloid
 Apusan darah tepi : anisositosis, hipokrom
poikilositosis, sel target (fragmentosit dan
banyak sel normoblast)
 SI meninggi, IBC rendah/nol

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Gejala klinis dan laboratorium . .
 Kadar HbF tinggi >30%, kadang Hb patol.
 Umumnya pasien datang pd umur 4-6th,
padahal gejala sudah tampak sejak 3 bl.

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 Pemeriksaan radiologis
 Tulang : medula lebar, kortek tipis,
trabekula kasar.
 Tengkorak : diploe, brush appearance
 Sinus paranasalis : pneumatisasi rongga

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 Komplikasi
 Karena anemi berat dan lama  gagal
jantung / dekompensasi kordis
 Transfusi berulang dan hemolisis  kadar
besi dalam darah sangat tinggi  hepar,
limpa, kulit, jantung, dll  ggn fungsi alat
tsb / hemokromatosis.
 Limpa yg besar : mudah ruptur / pecah/
robek. Hipersplenisme:leukopeni,trombo<.

98
 Pengobatan
 Tak ada obat yg menyembuhkan
 Transfusi : bila kadar Hb <6g%, atau
anak lemah tidak mau makan
 Mengeluarkan besi dari jaringan tubuh :
iron chelating agent (desferal) im/iv.
 Splenektomi : usia >2th, sbl tanda
hipersplenisme dan hemosiderosis.
 Vitamin : yg tidak mengandung besi

99
leukemia

100
 Definisi
 Leukemia merupakan penyakit keganasan
sel darah yang berasal dari sumsum
tulang, ditandai oleh proliferasi sel-sel
darah putih, dengan manifestasi adanya
sel-sel abnormal dalam darah tepi.
 Ada gangguan dlm pengaturan sel leukosit
 Leukosit dlm darah berproliferasi secara
tidak teratur dan tidak terkendali dan
fungsinyapun menjadi tidak normal.
101
102
 Klasifikasi / pembagian
 1. Leukemia sistem eritropoetik
 2. L. sistem granulopoetik : granulositik,
mielositik
 3. L. sistem trombopoetik : L. megakario-
sitik
 4. L . sistem limfopoetik : L. Limfositik
 5. L. RES

103
 Leukemia Limfositik Akut
 Paling sering yg terjadi pada anak.
 Etiologi : belum jelas, mungkin virus.
 Faktor lain : eksogen ( sinar X, radioaktif,
hormon, bhn kimia, infeksi virus/bakteri.
Edogen : ras (Yahudi), kelainan kromosom
(Down sindrom), herediter

104
105
Acute Lymphoblastic Leukemia
 Gejala klinis
 Pucat, panas, perdarahan, splenomegali,
hepatomegali, limfadenopati.
 Perdarahan : ekimosis, petekie, epistaksis,
perdarahan gusi.
 Gejala tidak khas : sakit sendi, tulang (spt
reumatik ).
 Infiltrasi sel leukemi ke alat tubuh :
purpura pd kulit, efusi pleura, kejang pd
leukemia serebral.
107
108
 Pemeriksaan laboratorium
 Darah tepi : pansitopeni, limfositosis, sel
blas (patognomonik utk leukemia)
 Sumsum tulang : monoton, hanya sel
limfopoetik patologis, lainya terdesak/
aplasia.
 Pemeriksaan lain : biopsi limpa, kimia
darah, CSS, sitogenetik

109
 Diagnosis
 Gejala klinis
 Pemeriksaan darah tepi
 Pemeriksaan sumsum tulang, limpa

110
 Pengobatan
 Transfusi darah ( bila Hb< 6 g%)
 Kortikosteroid
 Sitostatika
 Pengobatan infeksi sekunder
 Imunoterapi

111
112
The most important first
step in the diagnosis of
Anemias…….

113
 The Peripheral Smear
RBC Fragments Microangiopathic Hemolytic
(Schistocytes) Anemia, Valve Hemolysis, Burns
Spherocytes AIHA, Hereditary Spherocytosis
Target cells Alcoholics, Hemoglobinopathies
Sideroblasts Myelodysplasia, Alcoholics
Teardrop cells Myelofibrosis/Myeloid metaplasia,
Thalassemia
Burr cells Uremia
Howell Jolly Splenectomy, Functional asplenia
bodies
Hypersegmented Megaloblastic Anemia
PMN 114
 ?
 Young women with
surgery as child and
was told that she
could be at risk for
developing infections.
 CBC normal

115
?
 74 male presents with
neuropathy, loss of
balance, WBC 1.9,
HGB 7, PLT 120,000

116
 ?
 A 20 YO woman
presents with
increasing weakness
over six weeks,fever
and Hb = 5.9 g/dl.,
white cells 18.0
x10ˆ9/l., platelets 35
x10ˆ9/l.

117
 ?
 Young man with
recent travel presents
with fever of
unknown origin. WBC
18K, HGB 8 g, PLT
461,000

118
 ?
 Elderly gentleman
presents with fatigue,
pallor and SOB. WBC
3K, HGB 6g, PLT
566,000

119
?
 70 YO male admitted
to ICU with severe
pancytopenia,
bleeding,
hypotensive. Patient
is intubated
 PT 15, PTT 40, PLT
36,000, WBC 2.2,
HGB 8 g.

120
 ?
 46 YO presents with
history of alcohol
abuse, hypotension.
 WBC 3.2, HGB 10g,
PLT 72,000
 T. Bili 2.0, creatinine
4, BUN 68

121
122
123
 Anemia
Microcytic Normocytic Macrocytic
MCV <80 MCV 80-100 MCV >100
Iron Deficiency ACD B12 Deficiency

ACD Renal Failure Folate Deficiency

Thalassemias MDS Alcohol

Sideroblastic Anemia Aplastic Anemia Hypothyroidism

Lead Poisoning Hemolytic Anemia Liver disease

Mixed Micro and MDS

Macrocytic Anemia
124
 Case 1
 51 YO female presents with fatigue,
occasional tingling of her hand and feet.
She reports decrease in concentration and
memory
 PSHx: cholecystectomy, gastric bypass
 Social Hx: negative for drug, tobacco and
alcohol

125
 Case 1
 LABS:
WBC 1.7
HGB 8.9 G/DL
PLATELETS 109,000
MCV 109
SEGS 52%
LYMPHS 40%
MONO 5%
EOS 2%
METAMYELOCYTES 1%

126
 Case 1
 Additional tests……

127
SMEAR

128
 Macrocytic Anemia
 Abnormal maturation of nucleus in RBC
precursors

 CAUSES:
- Alcoholism
– Pernicious Anemia (Vit B12 deficiency)
– Folic Acid deficiency
 Tropical Sprue
 Scandinavia - Fish tapeworm
129
 Macrocytic Anemia
Megaloblastic
Vitamin B12 (Cobalamin) Deficiency
Folate Deficiency
MDS
Chemotherapy (Methotrexate,
Hydroxyurea, Azathioprine
SPURIOUS
Alcohol, Hypothyroidism, MM, Liver
disease, MDS, Aplastic Anemia 130
 MEGALOBLASTIC DISEASE
 Diagnosis: MCV> 100
 Macrocytosis may be blunted in presence of
Fe deficiency or thalasemia
 Low Reticulocyte count
 Neutropenia and Thrombocytopenia
 WBC :Hypersegmentation. Almost always
pathognomonic

131
 FOLIC ACID
 FOLIC ACID (pteroylmonoglutamic acid)
– Natural Source : fruits / vegetables
– May be destroyed by cooking
– Minimum daily requirement 50 micrograms/day
– Deficiency can develop within months
– FDA ordered Folic acid supplementation
(January, 1998) to all enriched grains

133
134
 FOLATE DEFICIENCY
 Inadequate Intake
 Malabsortion due to Sprue,
Celiac disease

135
 FOLATE DEFICIENCY
Increased Demand
– Cells with high rate of turnover
–Chronic hemolytic anemias
 Pregnancy
– Deficiency in first few weeks - - > neural tube
defects in fetus
 Malignancy
 Chronic Exfoliative Skin Disorders
 Hemodialysis pts

136
 FOLATE DEFICIENCY
Medications
– 6 thioguanine, azathiprine, 6 mercaptopurine
– 5 FU, cytosine, arabinoside
 Hydroxyurea, procarbazine, AZT
– Folate Antagonists - Methotrexate, pentamidine,
trimethoprim, triamterene, pyrimethamine, Dilantin

137
 COBALAMIN (VIT B12)
 Cobalt cannot be synthesized - required in diet !

 ONLY SOURCE : Animal products (meat and

dairy)

 Minimum daily requirement: 2.5 micrograms/day

138
139
 COBALAMIN DEFICIENCY
 Inadequate intake “vegetarian”
 Malabsorption
– Defective Release of Cobalamin from Food
– Inadequate Production of Intrinsic Factor

140
 COBALAMIN DEFICIENCY
– Disorders of the terminal ileum
 Tropical and Non Tropical Sprue
 Regional Enteritis, Crohn’s Disease
 Intestinal Resection

– Competition for cobalamin

 Fish Tapeworm (Scandinavian countries)
 Bacteria (“blind loop syndrome)
– Drugs
 p-aminosalicylic acid, colchicine, neomycin

141
 COBALAMIN DEFICIENCY
 Blood
– Macrocytic Anemia
– Pancytopenia, elevated LDH/ Indirect Bilirubin
– Clin Sx: weakness, dizziness, vertigo, tinnitus, angina,
palpitations and CHF
– Physical Exam: pale, icteric, rapid pulse, enlarged
heart, systolic flow murmur
 GI
– Based on rapidly proliferating GI epithelium
 SORE TONGUE
 ANOREXIA / WEIGHT LOSS
 DIARRHEA 142
 COBALAMIN DEFICIENCY
 NEURO (may be permanent)
– Demyelination -> axonal degeneration -> neuronal
death
– Peripheral nerves, spinal cord (posterior and lateral
columns) , cerebrum
– SX: EARLY: Numbness and parethesias in extremities
 LATER: weakness, ataxia, sphincter disturbances,
 Decreased vibratory sensation
 mild irritability --> dementia or psychosis
 NEURO SX MAY BE PRESENT IN A PATIENT WHO IS
NOT ANEMIC

143
 COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA
Autoimmune destruction or gastric mucosal atrophy
Etio: Lack of Intrinsic Factor (IF) secreted by parietal cells
EPIDEMIOLGY
 Males = females, often age >60
 See in pts from Northern Europe or African
Americans
OTHER DISEASE ASSOCIATIONS
Graves Disease Myxedema
Thyroiditis Vitiligo
Hypoparathyroidism Agammaglobulinemia
Adrenocortical Insufficiency
144
 PERNICIOUS ANEMIA
 ABNORMAL LABS
 Anti parietal cell antibody (anti Na,K ATPase (90%)
 Anti IF antibody (60%)
– RX; Glucocorticoids may reverse disease
– H Pylori does NOT cause parietal cell destruction
 ANATOMY: Gastric atrophy --> antrum is spared
 Tx: All reversible except neurological changes
 Complications : Gastric polyps 2x incidence of
cancer

145
 Schilling Test
(Cobalamin Deficiency verification)
 STAGE 1
 STAGE 2
– Give Radioactive Cobalamin bound to IF by mouth
– IM injection of nonradioactive B12
– Measure 24 hour urine
– Will still be diminished if
 Bacterial Overgrowth Syndrome, Blind Loop,
Pancreatic insufficiency, Celiac Sprue

146
147
 FOLATE v COBALAMIN
DEFICIENCY STATES
Serum FOLATE COBALAMIN
Levels DEFICIENCY DEFICIENCY

Homocysteine HIGH HIGH

Methylmalonic NORMAL HIGH

Acid

148
 TREATMENT
COBALAMIN DEFICIENCY
IM Cbl: 1000 µg (1 mg) every day x week,
followed by 1 mg every week x four weeks.
If the underlying disorder persists (PA) 1 mg
every month for life

Oral: 1000 to 2000 mcg/day.

May not be effective for PA (malabsorption)
Do not use timed release preparations

Transfusion- watch for CHF

149
COBALAMIN DEFICIENCY
Laboratory response
+ Anemia--- reticulocytosis in 3-4 days+ Severe
Anemia--- serum iron and LDH levels fall

Hypokalemia
Hypersegmented neutrophils disappear at 10 to 14
days.
Neurologic abnormalities often improve but may not
reverse fully

150
 TREATMENT
Folate Deficiency

– Exclude Cobalamin deficiency !!

– A dose of 1 mg/day is usually sufficient,

even if malabsorption is present.
– Neuro symptoms may be exacerbated with
therapy

151
 Case 2
 70 YO male presents with fatigue, weight
loss, palpitations
 Unremarkable PMHx, PSHx
 WBC 1.9, HGB 8, PLT 79,000, MCV 100,
ANC 1.0
 Normal B12/folate and iron levels

152
 Case 2
 What is the next diagnostic test…..

153
 Case 2
 Smear
 Bone Marrow Biopsy
 Ultrasound to evaluate Liver and Spleen
 Hepatitis / Viral panel

154
Case 2

155
 Case 2
Lineage Blood Marrow

Erythroid Oval macrocytes Abnormal nuclear

shape and chromatin
pattern
Basophilic stippling
Ring sideroblasts

Myeloid Hypogranular Hypolobated forms

neutrophils
Megakaryocytic Agranular Micromegakaryocytes
megakaryocytes Mononuclear
megakaryocytesMega
karyocytes with
seperated nuclei
156
 Myelodysplasia
 Clonal stem cell disorder resulting in
multilineage dysplasia
 Can transform to acute leukemia
 Under diagnosed disorder
 Can be secondary to therapy
 Multiple bone marrow biopsies required
 Cytogenetic abnormalities

157
 Myelodysplasia
 WHO system includes:
 Refractory anemia (RA)
 Refractory anemia with ringed sideroblasts
(RARS)
 Refractory cytopenia with multilineage dysplasia
(RCMD)
 Refractory cytopenia with multilineage dysplasia
and ringed sideroblasts (RCMD-RS)
 Refractory anemia with excess blasts I and II
 5q- syndrome
 Myelodysplasia unclassifiable (seen in those cases
of megakaryocyte dysplasia with fibrosis and
others

158
 IPSS SCORE
 Unfavorable cytogenetics 1
 Age > 60 years 2
 Hgb <10 (g dl-1) 1
 Plt <50 2
 Plt >50 -250 1
 1BM blasts >4% 1
 diploid and 5q only were favorable cytogenetic,
all others were considered as unfavorable
cytogenetics.
159
 Myelodysplasia
 IPSS Score
 Low risk0
 Intermediate risk 1 0.5 – 1
 Intermediate risk 2 1.5 – 2
 High risk >2.5

160
 Myelodysplasia
 Low Risk MDS

-Neutropenia or thrombocytopenia

-symptomatic anemia is usually the initial problem

- Erythropoietin: highest response rate seen in patients with lower

endogenous erythropoietin levels (< 500 IU) and lower
transfusion requirements.

-low-dose granulocyte colony-stimulating factor (G-CSF)

-Erythropoietin resistance

-Red blood cell transfusions

161
 Erythropoietic Growth Factors
 Caution in patients with uncontrolled
hypertension
 Risk of thrombosis
 Lack of response
 Survival benefit in patients with
malignancy

162
 Myelodysplasia
 High Risk MDS
-Refractory anemia/ thrmbocytopenia and
neutropenia
-Higher Blast percentage but less than
20%
-Multiple Karyotypic abnormalities

163
 Myelodysplasia
 High Risk MDS
- Supportive Care
-Bone Marrow Transplant
-Hypomethylating Agents
--5 Azacitadine
--Decitabine

164
 Case 3
 47 YO African American Female presents
with fatigue, heavy menstrual bleeding,
body aches.
 FHx: anemia of unknown etiology
 Social Hx, PMHx is unremarkable
 WBC 5K, HGB 9.8 g, PLT 166,000, MCV 56
 How do you approach this case?

165
 Case 3
 Serum Ferritin 15
 Iron saturation 9%
 TIBC 470
 B12 and folate are normal
 Retic 2.6%
 Bone marrow biopsy

166
Iron DeficiencyAnemia

167
 Iron Deficiency Anemia
Etiology
1. Dietary deficiency
2. Malabsorption (Subtotal gastrectomy,
celiac sprue)
3. Bleeding (Gastrointestinal, Genitourinary,
Hemoptysis, Epistaxis, Pregnancy)
4. Intravascular hemolysis (PNH, Trauma,
Hemosiderinuria)
5. Chronic renal failure
168
 Iron DeficiencyAnemia
Poor correlation between hemoglobin level and
symptoms

Symptoms may include:

Pica - geophagia, pagophagia, amylophagia
Pallor
Smooth tongue
Stomatitis
Cheilosis
Koilonychia (spoon nails)
Paresthesias
Splenomegaly
169
 Iron DeficiencyAnemia
LABORATORY
Low iron, high TIBC, low ferritin, high serum
transferrin receptor
Absent marrow iron
Thrombocytosis

TREATMENT
1. Oral
2. Parenteral:
Iron dextran < 70% utilized
Need Test dose
Total dose (mg) = deficit in Hb (gm/100ml) x weight
(lb) + 1000mg
Watch for anaphylaxis
3. Treat underlying
170
 Case 3
 Patient was treated with oral iron for 3
months and follow-up labs showed
– WBC 5.2, HGB 11, MCV 60, PLT 222,000

– What is your next step

171
 Case 3
 Patient was treated with oral iron for 3
months and follow-up labs showed
– WBC 5.2, HGB 11, MCV 60, PLT 222,000

– Ferritin 50, TIBC 300, Saturation 15%

– What is the next step…….

172
Target cells: Seen in ETOH, Liver Disease, Hemoglobinopathies

173
174
 THALASSEMIA
A Defect in Hemoglobin Synthesis
Definition – defect in Hemoglobin subunit
synthesis (2α and 2β)

Inadequate hemoglobin accumulation 

Hypochromia/microcytosis and a host of
clinical manifestations.
Severe anemia will present in childhood

Three main variants: African, Asian,

Mediterranean

175
 THALASSEMIA
TYPE a (alpha)
TYPES:
a-Thalassemia – alpha globin unit synthesis
decreased or absent
b subunits will ppt

Four subtypes

Hydrops fetalis (4 loci)

Hemoglobin H (3 loci)
a-Thalassemia Minor (2 loci) mild anemia,
microcytosis
a-Thalassemia Minima (1 loci) no significant anemia

176
 Thalassemia
Alpha Beta
Thalassemia Thalassemia
MCV 74+/- 4 63 +/- 4

HGB A2 2.2 +/- 0.6 3.3+/- 0.2

MCH 24 +/-2 27 +/- 2

177
 THALASSEMIA
A Defect in Hemoglobin Synthesis
b-Thalassemia - beta globin unit synthesis decreased
or absent, a subunits will ppt

Beta – two Loci/ one Gene

Major – Homozygous – Severe Anemia, Jaundice,
Hepatosplenomegaly, Fe Overload (High Ferritin),
CHF
Onset: first year of life, transfusion dependent)

Minor – Heterozygous – Hypochromic, Often Mild

Microcytic Anemia; HgB A, HgB F, HgB A2

178
 THALASSEMIA
A Defect in Hemoglobin Synthesis
Beta Major: These pts will be symptomatic only after 4 –
6 months because in Fetal Hb (a2 d2), the d subunit is not
replaced with the b subunit until after birth

179
 THALASSEMIA
Clinical Manifestations
 Skeletal-
– Osteoporosis – vertebral compression Fx (next
slide)
– Skull has a “hot cross bun” configuration
– Pneumatization of the sinuses is delayed (next
slide)
 Distortion of the maxillary bones, as well as
poor development of the sinus cavities
 Hand: Metacarpals. Metatarsals, phalange
make it look rectangular and convex shaped.
180
 THALASSEMIA
A Defect in Hemoglobin Synthesis

181
182
 THALASSEMIA
CHF/ CARDIOMEGALY
Chest radiograph typical of severe β-
thalassemia. widening of the rib ends and
cardiac dilation.

183
 THALASSEMIA
Clinical Manifestations
 Shortened RBC survival
 DECREASED MCV
 Iron- normal !!
 Heart – Cardiomegaly
 Growth + Development – is retarded – both
skeletal and dental ages.
 Secondary Iron Overload

184
 THALASSEMIA –
Clinical Manifestations
 Liver – Hepatomegaly due to extramedullary
hematopoiesis.

Later in disease hepatomegaly is associated with

cirrhosis.
Iron deposited in Kupffer cells  may look like
idiopathic hemochromatosis.

 Viral Hepatitis may augment liver damage.

185
 THALASSEMIA
Therapy
Trait – None indicated

Splenectomy –
Chelation:Deferoxamine / Fe Chelation
(Keep Iron Saturation <50%)
Iron Supplementation Contraindicated

186
THALASSEMIA
Therapy
 Genetic Counseling
recommended.
 Autosomal Recessive
pattern of inheritance

187
 Hemolytic Anemia
Hemoglobinopathies

 Sickle Cell Disease (HgB SS)

– 1 in 400 American Blacks
– Valine for Glutamate at position #6 in b Chain
– Gelation of HgB  Deoxygenation  Sickled
Irreversibly
– Electrophoresis Required for Differentiation
– Trait- often no clinical symptoms

188
189
 What is Sickle cell disease
 An inherited disease of red blood
cells
 Abnormal hemoglobin.
 Sickle-shaped red cells interrupt
blood flow by blocking small blood
vessels
 Tissue damage due to lack of blood
flow and severe pain due to tissue
hypoxia

190
 Hemolytic Anemia
Sickle Cell Disease
– Microinfarction
 Pulmonary (Acute Chest), Avascular Necrosis, CVA,
CHF, RF, Skin ulcerations
– Pain
 Joint, Musculoskeletal, Abdominal
– Asplenism
– Sepsis, Recurrent Infection
– Fetal loss, high Maternal Morbidity
– Aplasic Crisis - Infection, Folate Deficiency
– Sequestration Crisis -  HgB, Retics.,
Hepatosplenomegaly

191
 Hemolytic Anemia
Sickle Cell Disease - TREATMENT
 Treatment
 PAIN CRISIS
– Supportive, Conservative & Expectant
– Treat Infections Early; Pneumococcal Vaccine
– Folate Supplementation Daily
– Opiod Analgesics PRN; Dependence Common
in advanced Stages

192
 Hemolytic Anemia
Sickle Cell Disease - TREATMENT
 Treatment
 CHEST SYNDROME
– Supportive, Conservative & Expectant
– Folate Supplementation Daily
– Opiod Analgesics
– Oxygen / Hyperbaric
– Correct Dehydration
– Hypertransfusion in Crisis
– Hydrea- reduce ulcers, transfusion, crises

193
 Case 5
 36 YO female presents with history of URI
symptoms, ear ache, fever.
 Unremarkable past medical history
 WBC 11 K, HGB 5 g, PLT 202,000
 What is the next step……

194
 Case 5
 Iron studies are normal except for ferritin
988
 B12/Folate are normal
 Additional laboratory data requested

195
 Case 5
 Iron studies are normal except for ferritin
988
 B12/Folate are normal
 Peripheral Smear
 Additional laboratory data requested
 LDH 1000, Haptoglobin 5, T.Bili 3, Retic
12%

196
 Hemolytic Anemia

Increased RI, LDH, Indirect Bilirubin

Decreased Haptoglobin
Urine Hemoglobin- severe cases
Direct Antiglobulin test
Indirect Antiglobulin test
Peripheral Smear

197
 Hemolytic Anemia
Acquired

Type Mechanism Disease States Diagnostic tests

Immune Antibodies to Drugs, Spherocytes

mediated RBC surface Malignancy, AIHA +DAT
antigens

Microangiopathi Destruction of TTP, HUS, DIC, Schistocytes

c RBC in Pre-eclampsia,
circulation Prosthetic valves
Infectious Malaria, Babesia, Positive blood
Clostridia cultures
Bartonella

198
 Hemolytic Anemia
Immune

 Antibodies to Red Cell or Drug Interaction

 Direct Coombs – Detects IgA/G or
Complement (C3)
 Indirect Coombs – Detects Antibody in
Serum of Recipient Against Donor

199
Hemolytic Anemia
Immune Mediated

200
 Hemolytic Anemia
Alloantibody Immune
 Transfusion Reactions
– Recipient Antibody to Donor Antigen
– Increased Risk with Transfusions
– Single Donor Donation Decreases
 Erythroblastosis Fetalis – IgG-Anti-Rh
– Rh- Mother Carrying Rh+ Fetus
– RhoGam (IgM-Anti-Rh) at Delivery/Miscarry

201
 Hemolytic Anemia
Autoimmune
 Warm Antibody – IgG or < IgA
– Inefficient C3 & C4 Fixation
– Active at 37oC, Nonagglutinating
– Evan’s Syndrome- associated thrombocytopenia
– Symptoms: Inc RI, SM, Spherocytosis
– Destruction in Spleen
– Idiopathic 20%
 CLL 20%, Lymphoma 10%, Misc. 10%
 Collagen Vascular 15%, Thyroid Disease 10%
 GI Diseases (UC) 10%
– Treatment
 Steroids, Immunosuppression, Splenectomy 202
 Case 5
 36 YO female presents with history of URI
symptoms, ear ache, fever.
 Unremarkable past medical history
 WBC 11 K, HGB 5 g, PLT 202,000

203
 Hemolytic Anemia
Autoimmune
 Cold Antibody – IgM
– Efficient Complement Fixation (C3)
– Active at 4oC, Agglutinate; Dissociate at 32oC
– Destruction in Liver, Intravascular
 Mycoplasma (5-10 days post recovery),viral illnesses
 Lymphoproliferative, Often Chronic
 MGUS
– Treatment
 Acute - Usually Self Limited, Warm Environment
 Chronic – Steroids, Splenectomy not Helpful; Immune
Suppression

204
 Hemolytic Anemia
Acquired – DIC
Microangiopathic
Disseminated Intravascular Coagulation (DIC)
 Obstetrical, Bacterial Sepsis, Carcinoma,
Trauma
 Diffuse Microthrombi Followed by
Fibrinolysis Consuming Coagulant Proteins
 Extensive Hemorrhage, Thrombocytopenia,
Fragmented RBC’s (Schistocytes),
PT/PTT, Fibrin Split Products (FSP), Mod.
Hemolysis
 Severe disease usually with low Plasma
Fibrinogen Level
 TREATMENT: Underlying Disorder
205
 Hemolytic Anemia
Hereditary

Type Mechanism Triggers Diagnostic

tests
Hemoglobin- Thalassemia - Hemoglobin
opathies Sickle Cell electrophoresis
Disease
Membrane Hereditary - Spherocytes,
dysfunction Spherocytosis, Family history,
Elliptocytosis negative DAT
Enzyme G6PD Infections, Abn G6PD
mediated Deficiency Drugs, Fava activity
beans

206
 Hemolytic Anemia
Microangiopathic – TTP
Thrombotic Thrombocytopenic Purpura
(TTP)
 Etiology Unclear; Immunologic, Microaneurysm
 Anemia with Fragmented RBC’s, Retics, Moderate
Thrombocytopenia, Jaundice, Petechiae < ITP
 PT, PTT, Fibrinogen, FSP usually near NL
 Fever, Abdominal Pain, Arthralgias
 Bleeding Unusual; Course Days to Weeks
 Death Due to Renal Failure, Cerebral Ischemia
 Plasmaphoresis, Steroids

207
 Transfusion Reactions
Type Onset Laboratory Treatments
Acute hemolytic Within hours + DAT IVF, Stop
transfusion
Delayed hemolytic 2-12 days + DAT (Also IVF
Indirect +)
Febrile nonhemolytic Within hours - DAT Supportive

Anaphylactic Within IgA deficiency Epinephrine

minutes
Posttransfusion 5-12 days Seen with plt IVIG
Purpura transfusion

Urticarial Within - DAT Diphenhydramine

minutes Can continue Tx
208
 Hemolytic Anemia
Microangiopathic – TTP
Thrombotic Thrombocytopenic Purpura
(TTP)
Pentad: FAT-RNs
40% Present with Pentad

30% of patients will relapse

209
 Hemolytic Anemia
Microangiopathic – HUS
Hemolytic Uremic Syndrome (HUS)
 ASSOCIATED WITH E.COLI: O-157-H7
infection
(5-10% of infections)
 Intracorpuscular Defect Acquired in Stem Cells
 Viral Prodrome, Young Children
 Acute Hemolytic Anemia, Thrombocytopenic
Purpura, Oliguria, Venous Thrombosis
 Blood Smear & Coagulation Studies Similar ITP
 Neurologic Deficits Uncommon
 Dialysis, Transfusion
 Mortality 5% to 20%
210
211
 REFERENCES
References for Hematology lecture dated 9/25/08
1. Myelodysplasia, Blood, 1 August 2008, Vol. 112, No. 3, pp. 479.
2. BMJ 1998 / B12 Deficiency
3. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood.
2006;107:3481–3485
4. Silverman LR, McKenzie DR, Peterson BL, et al; Cancer and Leukemia Group B. Further analysis of
trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221
by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–3903.
5. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in
patients with refractory or relapsed acute leukemia. Blood. 2003;102:2379.
6. Faderl S, Gandhi V, O’Brien S, et al. Results of a phase 1–2 study of clofarabine in combination
with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105:940
7. Burnett AK, Mohite U. Treatment of older patients with acute myeloid leukemia—new agents.
Semin Hematol. 2006;43:96–106.
8. Greenberg et al. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes.
Blood 1997;89:2079-2088.
9. Silverman LR, Demakos EP, Peterson BL, et al (2002). "Randomized controlled trial of azacitidine
in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B". J.
Clin. Oncol. 20 (10): 2429–40.

212
 Malaria
 Clinical Manifestation
– 1 to 6 weeks after Innoculation
– P. vivax & P. ovale Recurrent 6 – 12 Months
– Chills, Fever, Myalgia, Splenomegaly, Anemia;
Leukocytosis Rare
– P. falciparum – Encephalitis, ARDS
– Blackwater Fever – Massive Immune Hemolysis, Renal
Failure
 Treatment
– P. falciparum - Chloroquine Resistant; Quinine &
Doxycycline
– Others - Chloroquine Responsive
– P. vivax & P. ovale; Add Primaquine
 Prophylaxis – Chloroquine, Mefloquine 213
 Hemolytic Anemia
Infectious - Babesiosis
 Malaria-Like Intraerythrocyctic Parasite
 Eastern and Western Seaboard,
 Ixodidae Ticks; Rodents, Pets
 Symptoms: Febrile Hemolytic Anemia
Incubation 1-3 weeks
Flu like Symptoms, Myalgias, Dark Urine
Asplenic individuals can have overwhelming
disease
Often co-infection with Borrelia burgdoferi

214
 Hemolytic Anemia
Infectious - Babesiosis

 Diagnosis – Blood Smears

– Similar to P Falciparum (Malaria) but these
organisms produce no pigment.
– “Maltese Cross”
 Therapy – Clindamycin & Quinine
 Exchange Transfusion when Severe
Disease
215
216
 Hemolytic Anemia
Congenital
DAT negative

 Membrane Abnormalities
– Hereditary Spherocytosis
 Hemoglobinopathies
– Sickle Cell Anemia
– Hemoglobin C & SC Disease
– Thalassemia
– Defective Metabolism
– Glucose-6-phosphate Dehydrogenase Deficiency
217
 Hemolytic Anemia
Membrane Abnormality
 Hereditary Spherocytosis
– Common Hemoglobinopathy in Whites
– Defective Fragile Red Cell Membrane; Spherocytes
– Hemolysis in Spleen; Splenomegaly, Common
Skin Ulcers Over Ankles
– Mildly Reduced HgB, Increased Retics.
– Occasional Jaundice, +Gallstones, Anemia is mild to
severe, Increased MCHC, Aplastic Crisis in Viral Infection
or Folate
– Splenectomy Curative (Don’t forget vaccinations!)
– Lifelong Folate
218
219
 Hemolytic Anemia
Acquired Nonimmune
Paroxysmal Nocturnal Hemoglobinuria

Acquired stem cell disorder

Susceptible to complement due to two missing
membrane components of the complement
system.
Look for Specific assays for CD 55 and CD59 by
Flow Cytometry
Complication: Thrombosis
Treatment: Steroids, Transfusions, Iron and folate
replacement
220
 Hemolytic Anemia
Enzyme Deficiencies
 Glucose-6-Phosphate Dehydrogenase
–  Glutathione-SH (in a series of biochem rxns)
– GSH Protects Oxidation Cysteine in Cell Wall,
Oxidation MethHgB (Fe3+  Fe2+)
– X - Linked, > 250 Variants
– Acute Hemolysis 2-4 days after drug exposure
– American Blacks – African Variant (A-)
 13% Males; 20% Female Carriers, Variable Affect
 Self-Limited; Retics NL G-6-PD Activity
 May Confer Malarial Protection
– Italian/Greek – Mediterranean, More Severe

221
222
223
224
 Hemolytic Anemia
G6-PD Deficiency – What causes a
crisis?
 Oxidative Drug-Induced Hemolysis
– Sulfonamides, Dapsone; Nitrofurantoin
– Antimalarials; Primaquine, Chloroquine
– Vitamin K (Water Soluble), Probenecid
– Occasional - Infection, Diabetic Ketoacidosis

 Mediterranean Variant
– Quinine, Quinidine; Aspirin
– Favism – Exposure to Fava Bean or Pollen
225
 Hemolytic Anemia
G6-PD Deficiency
 Laboratory Studies
– Heinz Bodies (Precipitated GS-SG HgB)
– Bite cells
– NL 50% Enzyme Decline in 120d RBC Life
 Black Variant (A-); RBC Survival, w/o Anemia
 Mediterranean; Survival, Anemia w/o Exposure
 G6PD enzyme normal with active hemolysis
– Acute Phase
 RBC,  25% in A-, > Mediterranean
 Plasma HgB, Uncong. Billi., Haptoglobin
 ± Hemoglobinuria
 Heinz Bodies Cleared After Day 1  Bite Cells
226
 Hemolytic Anemia
G6-PD Deficiency

 Treatment – Maintain Hydration

– Black Variant Self-Limited
– Mediterranean
 Splenectomy not Effective
 RBC Transfusion Rarely Indicated
– Prevention
 Screening - Avoid Oxidant Drugs
 Prompt Treatment Infection

227
 Other Anemias
Bloom’s Syndrome: AR, Ashkenazi Jews,
Mild anemia, stunted growth,
Photosensitivity, Mental Retardation,
Facial erythema, Infertility (men)

Dyskeratosis congenita: Marrow aplasia,

Dystrophic nails, Skin hyperpigmentation,
Leukoplakia, Continuous lacrimation,
Testicular atrophy

228
 Acute Intermittent Porphyria
AD, presents in adulthood

Defect of porphobiligen deaminase activity,

accumulate Aminolevulinic acid and
porphobilinogen in urine

Symptoms: Abdominal pain, Autonomic (HTN,

Tachycardia) and Peripheral Neuropathy,
Hyponatremia, MS changes, Psychosis, Seizures,
(No Skin changes like other porphyrias)

Treatment: High carb diet, IV Glucose, Hematin 229

 Myeloproliferative Disorders

Polycythemia Vera
Low EPO, Inc RBC Mass, SM.Treat w/Phlebotomy, Hydrea, ASA
Symptoms: HA, Visual Changes, Fatigue, Pruritus, Epistaxis, DVT,
High B12 levels
If Hct >54- rule out secondary causes- Hypoxia, Carboxyhem,
Tobacco, EPO tumors). SHOULD GET BM BIOPSY

Myelofibrosis
Essential Thrombocythemia
CML
230
 MYELODYSPLASTIC DISORDERS
MDS- Refractory anemia, RA with ringed
sideroblasts, RA with excess blasts, RA with
excess blasts in transformation, CMMOL

Causes: Environmental exposures, post

chemotherapy, Aplastic anemia, Fanconi’s anemia
Symptoms: of Anemia, SM, increased MCV,
Hyposegmented PMNs (Pelger Huet anomaly)
Treatment: SCT, Growth factors, Chemotherapy,
Transfusions
231
 Leukemia/Lymphoma

CLL
CML
AML
ALL
Non-Hodgkins Lymphoma
Hodgkins Lymphoma

232
 CHRONIC LYMPHOCYTIC LEUKEMIA

 Most common form of Leukemia in US

 Usually seen in pts > 50 yrs old
 Most pts are asymptomatic at presentation

 Diagnosis made by flow cytometry

 Abnormal cells resemble mature small
lymphocytes
 Symptoms: LA, SM, Anemia, Thrombocytopenia
 Associated with Autoimmune disorders
 Median Survival > 10 years
233
 CHRONIC LYMPHOCYTIC LEUKEMIA
Infections and Indications for Rx
 Hypogammoglobulinemia- Can give IVIG
– Staph Pneumoniae
– Staph Aureus
– Hemophilus influenza

 Indications for Treatment

– Anemia Hb < 10
– Thrombocytopenia Platelets < 100,000
– Constitutional Symptoms
– Bulky Lymphadenopathy
– Richter’s Tranformation
234
CHRONIC MYELOGENOUS LEUKEMIA
 15 to 20 percent of cases of leukemia in adults
 Annual incidence of 1 to 2 cases per 100,000
 Male predominance
 Median age at presentation- 50 years
 Uncontrolled production of maturing
granulocytes, predominantly neutrophils, but
also eosinophils and basophils.
 Three phases: Chronic phase (85% at
Diagnosis), Accelerated phase, Blast crisis.

235
CHRONIC MYELOGENOUS LEUKEMIA

236
CHRONIC MYELOGENOUS LEUKEMIA
Symptoms:
SM (60%), leukocytosis, thrombocytosis, Blast
crisis- fever, night sweats, bone pain,
ecchymoses
Diagnosis:
Philadelphia chromosome (9;22) translocation

Treatment:
Tyrosine kinase inhibitors (Imatinib, Desatinib)
Hydroxyurea
Interferon Alpha with or without cytarabine
Stem Cell Transplant 237
 CHRONIC LYMPHOCYTIC LEUKEMIA

 Most common form of Leukemia in US

 Usually seen in pts > 50 yrs old
 Most pts are asymptomatic at presentation

 Diagnosis made by flow cytometry

 Abnormal cells resemble mature small
lymphocytes
 Symptoms: LA, SM, Anemia, Thrombocytopenia
 Associated with Autoimmune disorders
 Median Survival > 10 years
238
 AML
Definition, Manifestations, Outcome
 Uncontrolled clonal proliferation and
accumulation of neoplastic hematopoietic
precursors
 Inhibition of normal hematopoiesis
 Defective maturation
 Multilineage
 Extramedullary disease
 Outcome has improved in younger adults, but
much less so for older adults
239
 FAB Classification
FAB Morphology Frequency
Subtype (%)
M0 Agranular myeloblasts 2-3

M1 Acute myeloblastic leukemia 20

without maturation
M2 Acute myeloblastic leukemia 25 – 30
with maturation
M3 Acute promyelocytic leukemia 8 – 15

M4 Acute myelomonocytic 20 – 25
leukemia
240
Bennett et al, Br J Haematol, 1976
 FAB Classification
FAB Morphology Frequency
Subtype (%)
Myelomonoblasts with abn
M4E0 5
eos
M5 Acute monocytic leukemia 10
monoblasts, promonocytes
or monocytes comprise 80%
of nonerythroids

M6 Erythroleukemia 5
>50% of nucleated cells
erythroid
M7 Acute megakaryocytic 1-3
leukemia
241
Bennett et al, Br J Haematol, 1979
Leukemic Auer Rod in
Myeloblast Leukemic Myeloblast

242
M4 M5

243
M6
244
AML- Acute Myelogenous Leukemia

Risk factors

Ionizing radiation
Chemical exposure: benzene
Previous chemotherapy:
Melphalan, Cyclophosphamide, Etoposide
Genetic factors:
Downs syndrome, Klinefelter’s, Fanconi’s anemia
MDS

245
AML- Acute Myelogenous Leukemia

Prognosis

Age
Performance status
Secondary AML
Previous chemotherapy
WBC >20,000/µL

246
1)Good prognosis features:
cytogenetic interpretation (t15:17, t8:21 or i16)
60% of patients are cured with multiple cycles of high
dose AraC

2)For patients with normal cytogenetics (intermediate risk)

approximately 70% achieve a complete remission and
40% of complete responders (i.e. 28% overall) are cured.

3)Poor prognostic features for AML include WBC>10,000 or

platelets <40,000.

-CALGB AML Study (>1200 patients)

1)5-year survival for good risk cytogenetics= 55%.
2)5-year survival for intermediate risk= 24%.
3)5-year survival for poor risk= 5%.
247
Clinical Presentation

Fatigue, dyspnea, pallor

Petechiae, hematoma, bleeding
Recurrent infections
Not common to see splenomegaly
Leptomeningeal involvement
Neurologic abnormalities- may be signal of
intracranial bleed
Tumor lysis syndrome

248
 Major Clinical Features
 Incidence/Prevalence
Estimated new cases in US in 2002: 10,600
80% >15 years old; median age 70 years
Estimated deaths in US in 2002: 7,400
Mortality in US = 7/100,000/year

 Pancytopenia

 Extramedullary disease
Skin, gingiva – M5
CNS – M5, ? Increased in M4EO
Orbit – M2 with t(8;21) and CD56 expression
249
 Major Clinical Features
 Hyperleukocytosis
– microgranular APL, monocytic differentiation
– 11q23 and inv(16)(p13;q22)
– >100,000 myeloblasts/L
– leukostasis (obstruction, vascular injury,
hypoxemia)
– leukaphoresis, hydroxyurea, RT, chemotherapy
 Coagulation abnormalities
– abn plt function
– consumption: APL > M5, M4
 Metabolic abnormalities
– tumor lysis syndrome
– renal tubular dysfunction
 Typhlitis (mimics appendicitis)
250
Chloroma

Gingival
Hyperplasia in
M5

251
Diagnosis

Peripheral smear
Identification of myeloblasts
Bone Marrow Biopsy

CBC: WBC can be high or low

Blast count high or low
Thrombocytopenia
Anemia

Increased LDH, Uric Acid, K, PO4

252
Common Induction Regimen

 Daunorubicin 45-60 mg/m2/d IV x 3 days

 Cytarabine 100 mg/m2/d CI x 7 days

253
 Tumor Lysis Syndrome
Rapid cell turnover
Prevent with Fluids, Allopurinol, Sodium
Bicarbonate
Test Result
Uric Acid Increased
Potassium Increased
Phosphate Increased
Calcium Decreased
254
 PLASMA CELL DISORDERS
Multiple Myeloma
Plasmacytoma
MGUS (Monoclonal Gammopathy of Undetermined
Significance)
POEMS (Polyneuropathy w/Organomegaly,
Endocrinopathy, M-Protein production, and Skin
changes)
Waldenstrom’s Macroglobulinemia
Amyloidosis (ASSOCIATED WITH FACTOR X
DEFICIENCY) types- AA, AL, Familial, Dx: Fibers
stain with Congo Red- Apple green Birefringence
Cryoglobulinemia
255
 PLASMA CELL DISORDERS
If Suspected:

1. Quantitate Immunoglobulin production-

SPEP, SIFE, UPEP, UIFE
2. BM Biopsy
3. Skeletal survey, Abdominal Fat Pad
Biopsy if MM present (r/o Amyloid)

256
 MULTIPLE MYELOMA
 Second most common hematologic malignancy
 More common in African Americans

Associated with
 Monoclonal Spike
 Lytic Lesions – increased risk of fracture, Cord Compression
 Renal insufficiency
 Bence Jones Proteinuria
 Hypercalcemia
 Hyperviscosity
 Peripheral Smear: Rouleaux Formation
 Increased Risk of Bacterial Infections

Treat with Stem Cell Transplant, Thalidomide, Thalidomide

derivatives, Melphalan, Steroids, Bisphosphonates (watch for
osteonecrosis of jaw)
257
MULTIPLE MYELOMA

258
MM – Monoclonal Band

259
 Multiple Myeloma
Major 1. Plasmacytoma
Criteria 2. BM with >30%
Plasma cells
3. M protein
Dx made
with 1M IgG >3.5 g/dL
+1m or IgA >2.0 g/dL
3m
minor 1.BM with >10-30%
criteria Plasma cells
2. M protein less than
above
3. Lytic bone lesion
4. Decreased 260
 Multiple Myeloma

Lytic lesions

261
 Severe aplastic anemia
 Disease of bone marrow – etiology either
toxin, genetic, or autoimmune
 Incidence: 3 per million per year
 Genetic include Fanconi anemia –
accounts for 20%
 Radiation, chemicals, or viruses for toxin
(Benzene, Radiation, Parvo B19, Hepatitis)

262
 Treatment of SAA
 Bone Marrow Transplant – if matched
related donor around 70-85% cure and
little chance of leukemia.
 Immunosuppressive therapy – cyclosporin,
antithymocyte globulin, and prednisone
 May add erythropoietin, and Neupogen
 Supportive with transfusion and chelation

263
 Thalassemia Screening

MCV Fl MCH pg Hb pattern

> 78 > 27 A+A2 < 3%

< 78 < 27 A+F(0.1-7%) + A2 > 3.5% β-THAL Carrier

264