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HematopoiHematopoi
esisesisDepartment of Clinical Pathology
Blok 234
FK Unswagati Cirebon
1 !eptember 2"14
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TIK TIK
• De#nisi$ tempat ter%a&inya hematopoiesisDe#nisi$ tempat ter%a&inya hematopoiesis
• Komponen &an sel &arahKomponen &an sel &arah
• 'ahapan hematopoeisis 'ahapan hematopoeisis
• Faktor yang mempengar(hiFaktor yang mempengar(hi
hematopoiesishematopoiesis
• Peran sistem hematopoeitik &alamPeran sistem hematopoeitik &alam
pertahanan t(b(hpertahanan t(b(h
• )acam &an t(%(an pemeriksaan)acam &an t(%(an pemeriksaan
laboratori(m &arah r(tinlaboratori(m &arah r(tin
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ReferensiReferensi
1.1. Essential Hematology. AVEssential Hematology. AV
Hobrand, JE Pettit, PAH oss.Hobrand, JE Pettit, PAH oss.
!t" ed.!t" ed.
#.#. $enise Harmening.$enise Harmening.
Hematology and Hemostasis.Hematology and Hemostasis.
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$e%nisi Hematopoeisis
• Hematopoeisis
proses pembent(kan
sel*sel &arah
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Tempat ter&adinyaTempat ter&adinya
"ematopoiesis"ematopoiesis
A'E (ITE
Fet(s+ "*2months
,olk sac
2*months
-i.er$ spleen
/*0months
Bone marrow
nfants Bone marrow$ practically all bones
&(lts ertebrae$ ribs$ stern(m$ sacr(m
an& pel.is$ proimal en&s of fem(r• !el berkembang &an bergerak &ari s(ms(m t(langmelal(i sin(s*sin(s 5sirk(lasi mikro s(ms(m t(lang6sel*sel mat(r &i sirk(lasi (m(m•7ematopoiesis &im(lai &engan sel stem pl(ripoten
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Hematopoiesis
• Yolk sac phase - blood in 'islands' in yolk sac, no leukocytes• Hepatic phase - primitive nucleated RBCs, fetal hemoglobin• Bone marro phase - mature RBCs, leukocytes, !"# eeks• $dult phase - pelvis, vertebrae, skull, ribs, ends of long bones
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Komponen Darah Dan Sel-Sel Darah
%aringan konektif khusus
Komponennya
"& lasma
#& (el-sel
$& )ritrosit
B& *ekosit
i& $granulosit
ii& +ranulosit
& rombosit
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Sel-Sel Darah Dan Trombosit
)ritrosit . bagian /001 of blood cells by number
Hematokrit . packed red blood cell 2RBC3 volume 21 volume
darah3
*ifespan - 4eutrophils, only "#-"5 hours
latelets, !"6 days
RBCs, !5 months 2!"#6 days3
*ymphocytes, many years
Sel% dari volumedarah
per mikroliter (µl)
Eritrosit!56 - 761 283
!7 - 571 293
5, . 7,: ;uta 283
,0 - 7 ;uta 293
Lekosit !"1 ,7 . "6,7 < "6
Trombosit ="1 "76 - 576 < "6
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lasma
>ater !0"1
roteins !:1 $lbumin, globulins, fibrinogen?ons !"1 Bicarbonate 2#"-#7 m83
Calcium 2#-#&: m83
Chloride 205-""" m83
otassium 25&"-7&@ m83
(odium 2":-"5A m83
(mall 8olecules !"1 +lucose 2&5-7&@ m83
*actate 2"&6-"&A m83rea 2&5-@&: m83
*ipids ="1 Cholesterol 2&5-7 m83
9atty acids 2free3 26-6&0 m83
riglycerides 26&5-"7 g*3
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Erythro!ytes
• ransports D# 2bound to hemoglobin3
•
Converts CD# into HCD-
2transported in plasma3• Biconcave disk-shape, deformable, resilient, no organelles
• lasma membrane and spectrin cytoskeleton present
• roteins - mainly hemoglobin 2α#β#3 and glycolytic enEymes
• Fuality control - spleen removes old or damaged RBCs
T " H t i ti
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Ta"apan Hematopoietis)(tem * (el Progenitor
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Pl+ripotent)ial Hematopoieti-(tem ell
• 8i.e rise to the separatecell lineage
• 9act phenotype (nkown imm(nological testing+CD34:$ CD3;*
• ppearance <small=me&i(m si>elymphocyte
• Cell &i?erentiation occ(rsfrom the stem cell &ownthe erythroi&$ gran(locytic
an& other lineages .ia the committe& hematopoieticprogenitors cells restricte& in their&e.elopmental potential@
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• !C has the capability of self/rene0al cell(larity remains constant in anormal healthy stea&y state@
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• 1 ( -apable of prod+-ing1 ( -apable of prod+-ing 121233 mat+re blood -ells after #2 -ellmat+re blood -ells after #2 -ell
di4isions.di4isions.
• ( -apable of responding to( -apable of responding to
"ematopoieti- gro0t" fa-tors"ematopoieti- gro0t" fa-tors
0it" in-reased prod+-tion of one0it" in-reased prod+-tion of one
or ot"er -ell line 0"en t"e needor ot"er -ell line 0"en t"e needarises.arises.
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5a6tor 7ang empengar+"iHematopoeisis
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Bone )arrow !troma
• !(itable en.ironment for!C growth A &e.@
• Compose& of stromalcells : micro.asc(larnetwork@
(tromal-ells8• a&ipocytes• Fibroblast• etic(l(mcella
• 9n&othelial
E9tra-ell+larmole-+les8• Collagen
• 8lycoprotein5#bronectin$
thrombospon&in6• 8lycosaminoglycans
5hyal(ronic aci& A
chon&roitin &eri.ates6• 8rowth factors for
se-rete
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7emopoietic 8rowth Factors
• 8lycoprotein hormones reg(lateproliferation A &i?erentiation of 7PC Af(nction of mat(re bloo& cells@
• Biological e?ects of 78F me&iate&thro(gh speci#c receptors on targetcells@
• ct+ . -ocally at the site where they are
pro&(ce by -ell/-ell -onta-t@
. Circ(late in plasma
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H'5H'5
• )ay bin& to 9C matri form niches towhich !C A P7C a&here@
• )a%or so(rces 5ecept erythropoietin6+
. '*lymphocytes
. )onocytes 5A macrophages6
. !tromal cells
• 9rythropoietin 0" synthesi>e& inki&ney
• 'hrombopoietin largely ma&e in li.er
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-e(kopoiesis also stim(lates by en&otoin
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'eneral "ara-teristi-s of yeloid and:ymp"oid 'ro0t" 5a-tors
• 8lycoprotein that act at .ery low concentration• ct hierarchically• Us(ally pro&(ce& by many cell types
• Us(ally a?ect more than 1 cell lineage• Us(ally acti.e on stem=progenitor cells an& on
f(nctional en& cells• Us(ally show synergistic or a&&iti.e interactions with
other growth factors
• ften act on the neoplastic eE(i.alent of a normal cell• )(ltiple actions+ proliferations$ &i?erentiation$mat(ration$ f(nctional acti.ation$ pre.ention ofapoptosis@
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Hematopoieti-
'ro0t"5a-tor
(ite of a-tion H'5
!tromal cell -*1$ 'F
Pl(ripotential stem cell !tem cell factor 5!CF6$ Flt ligan&5Flt*-6
)(ltipotential progenitorcell
-*3$ 8)*C!F$ -*G$ 8*C!F$thrombopoietin
Committe& progenitor 8*C!FH$ )*C!F$ -*/ 5eosinophil*
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!tem Cell Plasticity
• 9mbryonic !C totipotent generate alltiss(es@
• 9.i&ence a&(lts !C 5in&i?erent organs6 pl(ripotent@
• Bone marrow+ . 7ematopoietic !C
. )esenchymal !C clinicalapplication th=mesenchymal &isease
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poptosis
• 7omeostasis+
cell pro&(ction I cell &estr(ction• eg(late& process of physiological cell &eath
triggere& to acti.ate intracell(lar proteins lea&
to cell &eath@• )orphologically+
. Cell shrinkage . Con&ensation of n(clear chromatin . Fragmentation of the n(cle(s
. Clea.age of intran(cleosomal D• mportant proses for maintaining tiss(e
homeostasis in hematopoiesis A lymphocytes&e.elopment
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Pathway of apoptosis
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8rowth Factoreceptors A !ignal
'rans&(ction
Control hematopoiesis bygrowth factors+• Factors acts on cellsepressing thecorrespon&ing receptors@
• Bin&ing of 8F to its receptoracti.ates
by JKs then phosphorylate!''s
which translocate to then(cle(s an&
acti.ate transcription ofspeci#c
genes
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&hesion )olec(les
• 8lycoprotein• )e&iate the attachment of marrow
prec(rsors$ le(kocytes an& platelet to.ario(s components of the etracell(lar
matri to+ . 9n&otheli(m . ther s(rfaces . 9ach other
• n le(kocyte receptors interact withligan&• 3 main families+ mm(noglob(lin$ selectins$
integrin
"#$ l b Sk l t
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"#$ lasma embrane Skeleton
Resilientand fle
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&ree'e-ra!ture E o "#$ embrane"& 9reeEe-fracture
9reeEe and fracture
)
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Leuko!ytes
ranulo!ytes4eutrophil 2)3
Band 4eutro& 2?3
)osinophil 2G3
Basophil 2%3
*+ranulo!ytes
8onocyte 293*ymphocyte 2H3
latelets 2+3
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Leuko!ytes
Si'e - larger than erythrocytes 2"6 - "A Im diameter3
*ll - contain non-specific aEurophilic 2primary3
granules that are eJuivalent to lysosomes
ranulo!ytes - contain specific 2secondary3 granules
that contain specific enEymes for each cell type*+ranulo!ytes - no specific granules present
+ranulocyte 4eutrophil !@61
)osinophil !51
Basophil ="1
$granulocyte *ymphocyte 2, B, 4K3 !#@1
8onocyte !01
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Leuko!ytes
Distribution - blood and C 2as transient or andering cells3&un!tion - immune protection, movement 2cell motility3
Diapedesis - movement out of blood into connective tissue
$hemota,is - movement directed by homing molecules
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eutrophil
• 8ost common leukocyte - 50-@:1 of leukocytes• $Europhilic granules - 4$GH o
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ha+osome and.or
E,tra!elluar spa!e
*DH
/,idase
$omple,
*DH
e-
&*D
Heme
Heme
/
-
0
/0 e-Supero,ide anion
*D1 1 H1
/
///-
pero,ynitriteanion
H0/0
H0/
1
/0
!atalase
/H-
hydro,yl
anion
&e01
&e21&enton ",n
H/$lhypo!hlorous a!id
$l-
/
/0$l
nitryl
!hloride
*TH/ES
ha+o!yti! $ell embrane
$ytoplasmi! spa!e
/0-
S/D
"ea!tive /,idants Kill atho+ens
hagocytic cells kill pathogens ith reactive o
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Eosinophil
• ?ntermediate abundance - #-71 of leukocytes• $Europhilic granules - lysosomal acid hydrolases•
(pecific granules 2eosinophilic3 - eosinophilic cationic protein,ma;or basic protein, eosinophilic pero
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#asophil
• *east common leukocyte - ="1 of leukocytes•
$Europhilic granules - lysosomal acid hydrolases• (pecific granules 2basophilic3 - histamine, heparin,
heparan sulfate, chemotactic factors for other granulocytes• 9unctions - similar to mast cells, upon stimulation it
releases preformed and nely synthesiEed secretory
products that initiate, maintain, and control inflammation
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ono!yte
• *argest cell in peripheral blood 2"A Im diameter3• $granulocyte - lysosomal acid hydrolases, myelopero
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Lympho!yte
• B lymphocyte - humoral immunity 2!#6-613• lymphocyte - cell-mediated immunity 2!@6-A613• 4atural killer 24K3 cell - cell-mediated immunity 2!7-"613
• $granulocyte - lysosomal acid hydrolases
latelets
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latelets
• Cell fragment - small 2!# Im3, irregular disk shape, no nucleus• (tructure - granules, mitochondria, glycogen, cytoskeleton• +ranules - alpha 2clotting factors3, dense core 2histamine3• 8egakaryocyte - produces platelets in bone marro sinus• 9unction - clot formation, bind to in;ured blood vessel all,
aggregate ith RBCs forms hemostatic plug 2stops bleeding3
HematopoiesisKiersEenbaum, 9ig& @-"@L
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Hematopoiesisg
(ee Ross 7th )d able "6&5
(C
Stem $ell #asi!s
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• (tem cell - asymmetric cell division yields cells ith different
fates 2one is stem cellL one is transient amplifying cell3• (elf-reneal - capacity of stem cell to regenerate itself • ransient amplifying cells - symmetric cell division yields
daughter cells ith same fate 2transient amplifying cells3
• Gifferentiated cells - cells e
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Hematopoieti! Stem $ells
luripotent hematopoieti! stem !ell (HS$)
ndifferentiated cell producing blood cells of all lineages,
capable of self-reneal
ultipotent HS$
ndifferentiated cell producing cells of multiple lineages,
limited self-reneal 2e&g&, myeloid (C, lymphoid (C3
$ommitted pro+enitor - undifferentiated cell capable of
producing cells of one lineage, colony forming units 2C9s3
2e&g&, erythroid C9, granulocyte-macrophage C93
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roerythroblast
Basophilic
erythroblast
olychromatophilic
erythroblast
Drthochromatic
erythroblast
2normoblast3
Reticulocyte
)rythrocyte
)arly ?ntermediate *ate
Sta+es in Erythropoiesis
Er thropoiesis
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Erythropoiesis
roerythroblast
2pronormoblast3
active rR4$ and ribosome synthesis 2nucleoli visible3
active gene e
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Leukopoiesis - yeloid Linea+e
KiersEenbaum
9ig& @-#6L
(ee Ross 7th
)d able "6&5
Band (tage
yeloid Linea+e (eutrophili!)
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yeloid Linea+e (eutrophili!)
"& romyelocyte
5& Band 9orm
& 8etamyelocyte
#& 8yelocyte
KiersEenbaum, 9ig& @-#"
l id Li
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yeloid Linea+e
8yeloblast2do not identify
in lab3
active rR4$ and ribosome synthesis 2nucleoli visible3,active gene e
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Leukopoiesis -
Lymphoid Linea+e
• *ymphoid stem cell gives rise to
-lymphocyte and B-lymphocyte
lineages• -cell maturation - thymus
• B-cell maturation - bone marro
•
lasma cells - present in marro,lymphatic tissue, connective tissue
stem cell
(ee Ross 7th )d able "6&5
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Hematopoieti! ro3th &a!tors
Erythropoietin 2)D3 - ma;or regulator of erythropoiesis,
stimulates erythroid C9 cells and proerythroblasts
Thrombopoietin 2D3 - increases platelet production,
stimulates megakaryocyte C9 cells
ranulo!yte $S& 2+-C(93 - increases production of
neutrophils, stimulates granulocyte-macrophage C9 cells
ranulo!yte-ma!ropha+e $S& 2+8-C(93 - increases
macrophage production, stimulates granulocyte-macrophage C9 cells
4nterleukins - stimulate B- and -cell formation, function
together ith +-C(9 and +8-C(9
#one arro3
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• Bone marro cavity - marro proper and venous sinuses• Bone marro cells - stromal cells, adipocytes, endothelial
cells, macrophages, hematopoietic cells• Blood vessels - nutrient arteries supply marro cavity• (tem cells and early precursor cells do not leave marro
KiersEenbaum,9ig& @-"5
#one arro3
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#one arro3
*nemia
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*nemia
"edu!ed "#$ rodu!tion
9actor Geficiency?ron - reJuired for heme synthesis
itamin B"# - reJuired for G4$ synthesis
9olate - reJuired for G4$ synthesis
Gietary limitations - most common cause
Hematopoietic Cell Gamage
Grugs
Radiation
?nfections
o
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e+aloblasti! *nemia
Gefect in hematopoiesis
eripheral blood - macroovalocytes 2large oval RBCs3
Bone marro - megaloblasts
$nemia - autohemolysis of megaloblasts, short life span
of macroovalocytes
Causes - usually deficiency of folic acid or vitamin B-"#,
hich are reJuire for G4$ synthesis during cell division
Dther causes - leukemia, myelofibrosis, multiple
myeloma, hereditary disorders, chemotherapy drugs
2that affect G4$ synthesis, e&g&, methotre
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e+aloblasti! *nemia
eripheral blood - macroovalocytes and hypersegmented neutrophileripheral blood - macroovalocytes and hypersegmented neutrophil
e+aloblasti! *nemia
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8egaloblasts in8egaloblasts in
bone marrobone marro
4ormal erythroids4ormal erythroids
in bone marroin bone marro
e+aloblasti! *nemia
Leukemia
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Leukemia• roliferation of leukocytes from hemopoietic tissue
•
9our ma;or forms $cute 8yelogenous *eukemia 2$8*3
$cute *ymphocytic *eukemia 2$**3
Chronic 8yelogenous *eukemia 2C8*3
Chronic *ymphocytic *eukemia 2C**3
• 8yelogenous - proliferation of cells of myeloid lineage
• *ymphocytic - proliferation of cells of lymphoid lineage
• $cute - rapidly progressing, cells are immature and do not
carry out their normal functions
• Chronic - progresses sloly, more developed cells that
carry out normal functions
• Blood test - measure leukocyte alkaline phosphatase 2*$3
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Any;+estions
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T"an6 7o+ Very +-"T"an6 7o+ Very +-"