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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
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- (130- (95-145) (105-140) (110-
210) 200) 160)
Hct 55 50 36 37 38
As RBCs 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
Peningkatan penghancuran

Hemolytic
Anemia extracorpuscular
immune
corpuscular
isoimmune
membrane autoimmune
defects
idiopathic
enzyme defects
hemoglobin
defects
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 RBCs
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, Hb Koln&Zurich, Thalase

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/PN
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
Jaundice/kuning edema
tachycardia splenomegaly
tachypnea
orthostatic hypotension
glossitis
venous hum gingival
systolic ejection murmur pigmentation

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Penegakan Diagnosis
detailed history/
anamnesis
careful physical
examination
peripheral blood
smear bone marrow
red cell morphology evaluation
MCV additional
RDW testing
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) - # RBCs / 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)
Hgb/Hct - Normal = 33 (+or- 2) %
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 (Coombs 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
- 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


Increased jaundice
erythropoiesis Aplastic anemia
Post-splenectomy Hypothyroidism
Liver disease Megaloblastic
anemia
Downs syndrome
Using MCV to Characterize
Anemia
Normocytic

Acute blood loss


Infection Disseminated
malignancy
Renal failure
Early iron deficiency
Connective tissue
Aplastic anemia
disorder
Bone marrow
Liver disease
infiltration
Dyserythropoietic
anemia
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
Increased demand gall bladder
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
cardiac hypertrophy
atrophic glossitis
guaiac positive stool
Musculoskeletal
CNS impaired exercise
performance
fatigue
radiographic
irritability
changes
Iron Deficiency Anemia

characteristics of peripheral blood


smear
microcytic
hypochromic
Anemia def.besi
( pemeriksaan
Hb
laboratorium )
<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
RBCs 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 g/L, <10 g/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.
How to make a red blood
cell
Genes

Erythropoietin
(kidney)

Nutrients

Bone
marrow
Iron, Folate, B12
Folate and B12 Deficiency

Macrocytic anemia 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
5. Terapi obat antikonvulsan
6. Alkoholisme
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
Pem lain : tes gastrin & tes Shilling
Causes of Folate deficiency
Dietary deficiency (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)
Crohns 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<.
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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

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leukemia

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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.

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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

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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

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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.
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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

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Diagnosis
Gejalaklinis
Pemeriksaan darah tepi
Pemeriksaan sumsum tulang, limpa

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

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The most important first
step in the diagnosis of
Anemias.

107
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
bodies asplenia 108
?
Young women with
surgery as child
and was told that
she could be at risk
for developing
infections.
CBC normal

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

110
?
A 20 YO woman
presents with
increasing
weakness over six
weeks,fever and
Hb = 5.9 g/dl.,
white cells 18.0
x109/l., platelets
35 x109/l.

111
?
Young man with
recent travel
presents with fever
of unknown origin.
WBC 18K, HGB 8 g,
PLT 461,000

112
?
Elderly gentleman
presents with
fatigue, pallor and
SOB. WBC 3K, HGB
6g, PLT 566,000

113
?
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.
114
?
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

115
116
117
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 Aplastic Anemia Hypothyroidism
Anemia
Lead Poisoning Hemolytic Anemia Liver disease
Mixed Micro and MDS
Macrocytic
Anemia
118
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

119
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%

120
Case 1
Additional tests

121
SMEAR

122
Macrocytic Anemia
Abnormal maturation of nucleus in
RBC precursors

CAUSES:
- Alcoholism
Pernicious Anemia (Vit B12 deficiency)
Folic Acid deficiency
Tropical Sprue
Scandinavia - Fish tapeworm

123
Macrocytic Anemia
Megaloblastic
Vitamin B12 (Cobalamin) Deficiency
Folate Deficiency
MDS
Chemotherapy (Methotrexate,
Hydroxyurea, Azathioprine
SPURIOUS
Alcohol, Hypothyroidism, MM, Liver
disease, MDS, Aplastic Anemia 124
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

125
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
127
128
FOLATE DEFICIENCY
Inadequate Intake
Malabsortion due to Sprue,
Celiac disease

129
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

130
FOLATE DEFICIENCY
Medications
6 thioguanine, azathiprine, 6
mercaptopurine
5 FU, cytosine, arabinoside
Hydroxyurea, procarbazine, AZT
Folate Antagonists - Methotrexate,
pentamidine, trimethoprim, triamterene,
pyrimethamine, Dilantin

131
COBALAMIN (VIT B12)
Cobalt cannot be synthesized - required in
diet !

ONLY SOURCE : Animal products (meat and


dairy)

Minimum daily requirement: 2.5


micrograms/day

132
133
COBALAMIN DEFICIENCY
Inadequate intake vegetarian
Malabsorption
Defective Release of Cobalamin from
Food
Inadequate Production of Intrinsic Factor

134
COBALAMIN DEFICIENCY
Disorders of the terminal ileum
Tropical and Non Tropical Sprue
Regional Enteritis, Crohns Disease
Intestinal Resection

Competition for cobalamin


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

135
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

136
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 137
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

138
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

139
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

140
141
FOLATE v COBALAMIN
DEFICIENCY STATES
Serum FOLATE COBALAMIN
Levels DEFICIENCY DEFICIENCY

Homocystein HIGH HIGH


e

Methylmaloni NORMAL HIGH


c Acid

142
TREATMENT
COBALAMIN DEFICIENCY
IM Cbl: 1000 g (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


143
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

144
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

145
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

146
Case 2
What is the next diagnostic test..

147
Case 2
Smear
Bone Marrow Biopsy
Ultrasound to evaluate Liver and
Spleen
Hepatitis / Viral panel

148
Case 2

149
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 Micromegakaryocyt
megakaryocytes esMononuclear
megakaryocytesMe
gakaryocytes with
seperated nuclei
150
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

151
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

152
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.
153
Myelodysplasia
IPSS Score
Low risk0
Intermediate risk 10.5 1
Intermediate risk 21.5 2
High risk >2.5

154
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

155
Erythropoietic Growth
Factors
Caution in patients with uncontrolled
hypertension
Risk of thrombosis
Lack of response
Survival benefit in patients with
malignancy

156
Myelodysplasia
High Risk MDS
-Refractory anemia/ thrmbocytopenia
and neutropenia
-Higher Blast percentage but less
than 20%
-Multiple Karyotypic abnormalities

157
Myelodysplasia
High Risk MDS
- Supportive Care
-Bone Marrow Transplant
-Hypomethylating Agents
--5 Azacitadine
--Decitabine

158
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?

159
Case 3
Serum Ferritin 15
Iron saturation 9%
TIBC 470
B12 and folate are normal
Retic 2.6%
Bone marrow biopsy

160
Iron DeficiencyAnemia

161
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 162
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
163
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
164
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

165
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.

166
Target cells: Seen in ETOH, Liver Disease, Hemoglobinopathies

167
168
THALASSEMIA
A Defect in Hemoglobin
Synthesis
Definition defect in Hemoglobin
subunit synthesis (2 and 2)

Inadequate hemoglobin accumulation


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

Three main variants: African, Asian,


Mediterranean

169
THALASSEMIA
TYPE (alpha)
TYPES:
Thalassemia alpha globin unit synthesis
decreased or absent
subunits will ppt

Four subtypes

Hydrops fetalis (4 loci)


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

170
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

171
THALASSEMIA
A Defect in Hemoglobin
Synthesis
Thalassemia - beta globin unit synthesis
Thalassemia - beta globin unit synthesis
decreased or absent, 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


172
THALASSEMIA
A Defect in Hemoglobin
Synthesis
Beta Major: These pts will be symptomatic only
after 4 6 months because in Fetal Hb (2 2), the
subunit is not replaced with the subunit until
after birth

173
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 174
THALASSEMIA
A Defect in Hemoglobin
Synthesis

175
176
THALASSEMIA
CHF/ CARDIOMEGALY
Chest radiograph typical of severe -
thalassemia. widening of the rib ends
and cardiac dilation.

177
THALASSEMIA
Clinical Manifestations
Shortened RBC survival
DECREASED MCV
Iron- normal !!
Heart Cardiomegaly
Growth + Development is retarded
both skeletal and dental ages.
Secondary Iron Overload

178
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.

179
THALASSEMIA
Therapy
Trait None indicated

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

180
THALASSEMIA
Therapy
Genetic Counseling
recommended.
Autosomal
Recessive pattern
of inheritance

181
Hemolytic Anemia
Hemoglobinopathies
Sickle Cell Disease (HgB SS)
1 in 400 American Blacks
Valine for Glutamate at position #6 in
Chain
Gelation of HgB Deoxygenation
Sickled Irreversibly
Electrophoresis Required for
Differentiation
Trait- often no clinical symptoms
182
183
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
184
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

185
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

186
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

187
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

188
Case 5
Iron studies are normal except for
ferritin 988
B12/Folate are normal
Additional laboratory data requested

189
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%

190
Hemolytic Anemia

Increased RI, LDH, Indirect Bilirubin


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

191
Hemolytic Anemia
Acquired

Type Mechanism Disease States Diagnostic


tests
Immune Antibodies to Drugs, Spherocytes
mediated RBC surface Malignancy, +DAT
antigens AIHA
Microangiopat Destruction TTP, HUS, DIC, Schistocytes
hic of RBC in Pre-eclampsia,
circulation Prosthetic
valves
Infectious Malaria, Positive blood
Babesia, cultures
Clostridia
Bartonella
192
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

193
Hemolytic Anemia
Immune Mediated

194
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

195
Hemolytic Anemia
Autoimmune
Warm Antibody IgG or < IgA
Inefficient C3 & C4 Fixation
Active at 37oC, Nonagglutinating
Evans 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

196
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

197
Hemolytic Anemia
Autoimmune
Cold Antibody IgM
Efficient Complement Fixation (C3)
Active at 4oC, Agglutinate; Dissociate at 32 oC
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

198
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 RBCs (Schistocytes),
PT/PTT, Fibrin Split Products (FSP), Mod.
Hemolysis
Severe disease usually with low Plasma
Fibrinogen Level
TREATMENT: Underlying Disorder

199
Hemolytic Anemia
Hereditary

Type Mechanism Triggers Diagnostic


tests
Hemoglobin Thalassemia - Hemoglobin
-opathies Sickle Cell electrophore
Disease sis
Membrane Hereditary - Spherocytes,
dysfunction Spherocytosi Family
s, history,
Elliptocytosis negative DAT
Enzyme G6PD Infections, Abn G6PD
mediated Deficiency Drugs, Fava activity
beans
200
Hemolytic Anemia
Microangiopathic TTP
Thrombotic Thrombocytopenic Purpura
(TTP)
Etiology Unclear; Immunologic, Microaneurysm
Anemia with Fragmented RBCs, 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

201
Transfusion Reactions
Type Onset Laborator Treatments
y
Acute hemolytic Within + DAT IVF, Stop
hours transfusion
Delayed hemolytic 2-12 days + DAT (Also IVF
Indirect +)
Febrile Within - DAT Supportive
nonhemolytic hours
Anaphylactic Within IgA Epinephrine
minutes deficiency
Posttransfusion 5-12 days Seen with IVIG
Purpura plt
transfusion
Urticarial Within - DAT Diphenhydrami
minutes ne
202
Can continue
Hemolytic Anemia
Microangiopathic TTP
Thrombotic Thrombocytopenic
Purpura (TTP)
Pentad: FAT-RNs
40% Present with Pentad

30% of patients will relapse

203
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%
204
205
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;107:34813485
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;24:38953903.
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, OBrien S, et al. Results of a phase 12 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 leukemianew
agents. Semin Hematol. 2006;43:96106.
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): 242940.

206
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

207
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

208
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
209
210
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

211
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 (Dont forget vaccinations!)
Lifelong Folate

212
213
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
214
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

215
216
217
218
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
219
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

220
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

221
Other Anemias
Blooms 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
222
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


223
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
224
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, Fanconis
anemia
Symptoms: of Anemia, SM, increased MCV,
Hyposegmented PMNs (Pelger Huet anomaly)
Treatment: SCT, Growth factors, Chemotherapy,
Transfusions
225
Leukemia/Lymphoma

CLL
CML
AML
ALL
Non-Hodgkins Lymphoma
Hodgkins Lymphoma

226
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 227
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
Richters Tranformation 228
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.

229
CHRONIC MYELOGENOUS LEUKEMIA

230
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
231
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 232
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
233
FAB Classification
FAB Morphology Frequency
Subtype (%)
M0 Agranular myeloblasts 2-3
M1 Acute myeloblastic 20
leukemia without
maturation
M2 Acute myeloblastic 25 30
leukemia
with maturation
M3 Acute promyelocytic 8 15
leukemia
M4 Acute myelomonocytic 20 25
234
leukemia Bennett et al, Br J Haematol, 1976
FAB Classification
FAB Morphology Frequency
Subtype (%)
Myelomonoblasts with
M4E0 5
abn eos
M5 Acute monocytic 10
leukemia monoblasts,
promonocytes or
monocytes comprise 80%
of nonerythroids
M6 Erythroleukemia 5
>50% of nucleated cells
erythroid
M7 Acute megakaryocytic 1-3
leukemia 235
Bennett et al, Br J Haematol, 1979
Leukemic Auer Rod in
Myeloblast Leukemic Myeloblast

236
M4 M5

237
M6
238
AML- Acute Myelogenous Leukemia

Risk factors

Ionizing radiation
Chemical exposure: benzene
Previous chemotherapy:
Melphalan, Cyclophosphamide, Etoposide
Genetic factors:
Downs syndrome, Klinefelters, Fanconis
anemia
MDS
239
AML- Acute Myelogenous Leukemia

Prognosis

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

240
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%. 241


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

242
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
243
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)

244
Chloroma

Gingival
Hyperplasia in
M5

245
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

246
Common Induction Regimen

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

Cytarabine 100 mg/m2/d CI x 7 days

247
Tumor Lysis Syndrome
Rapid cell turnover
Prevent with Fluids, Allopurinol,
Sodium Bicarbonate
Test Result
Uric Acid Increased
Potassium Increased
Phosphate Increased
Calcium Decreased
248
PLASMA CELL DISORDERS
Multiple Myeloma
Plasmacytoma
MGUS (Monoclonal Gammopathy of
Undetermined Significance)
POEMS (Polyneuropathy w/Organomegaly,
Endocrinopathy, M-Protein production, and
Skin changes)
Waldenstroms Macroglobulinemia
Amyloidosis (ASSOCIATED WITH FACTOR X
DEFICIENCY) types- AA, AL, Familial, Dx:
Fibers stain with Congo Red- Apple green
Birefringence
Cryoglobulinemia 249
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)

250
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, 251
Bisphosphonates (watch for osteonecrosis of jaw)
MULTIPLE MYELOMA

252
MM Monoclonal Band

253
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
254
Immunoglobulins
Multiple Myeloma

Lytic lesions

255
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)

256
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
257
Thalassemia Screening

MCV Fl MCH Hb
pg pattern
> 78 > 27 A+A2 <
3%
< 78 < 27 A+F(0.1-7%) + A2 > -THAL
3.5% Carrier

258