Post on 24-Feb-2018
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Hemostasis
• Definition: The mechanisms that ensure prevention andstoppage of beeding!
"! #rimar$ hemostasis:
– vesse %a
– pateets
– von &iebrand factor
'! (oaguation
) coaguation factors
*! Fibrino$sis
) pasmin
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• Disorders of hemostasis:
– Disorders of primary hemostasis: muco-cutaneousbleeding (petechiae, echymoses, epistaxis, gum
bleeding, etc)
– Disorders of coagulation: profound hemorrhage(hemarthrosis, hematomas, internal bleeding)
– Disorders of fibrinolysis:• Hyperfibrinolysis – bleeding• Hypofibrinolysis - thrombosis
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• #rimar$ hemostasis invoves: – +esse %a
– #ateets
– +on &iebrand factor
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Adventitia
edia!ntima -endothelium
+esse %a structure
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#ateets
ega"aryocyte
#ateets
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- ,$coipidic
membrane
- Membrane boundg$coproteins:
- ,#Ib
- ,# IIbIIIa
- ($topasmaticgranues:
- dense: AD#- STH
- apha: v&F- #D,F
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• +on &iebrand factor is secreted b$ endotheia asmonomer but is functiona on$ as mutimer
• Mutimers are eventua$ degraded b$ the v&Fceaving protease .ADAMTS"*/
• v&F circuates in a compe0 %ith coaguation factor+III .+III:RAg/
+on &iebrand
factor
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(oagen
Adventitia
Media ) fibre
muscuare
Endoteiu
Endoteiu intact ) suprafata netrombogena1orma endotheium 2 smooth- non)thrombogenic surface
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(oagen
Adventitia
Media ) fibre
muscuare
Endoteiu
3E4I51E +AS(53ARA
mecanica
fi6ica
chimicabioogica
+ascuar esion
mechanica
ph$sica
chemica
bioogica
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(oagen
Adventitia
Media ) fibre
muscuare
Endoteiu
+asoconstrictie ) cotractia fibreor
muscuare netede din tunica medie
+asoconstriction 2 contraction of smooth
musce fibers in the intima a$er
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d
AA ) T0A'
α
α
d#D,F
STH
AD#
,#
IIbIIIa
,#Ib
v&F
(oagen
Adventitia
Media ) fibre
muscuare
Endoteiu
Aderarea pachetara ) mediata de
,#Ib si v&F
#ateet adhesion 2 mediated
b$ ,#I and v&F
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dv&F
AA ) T0A'
α
α
d#D,F
STHAD#
,#IIbIIIa
Fbg
,#Ib
v&F
(oagen
Adventitia
Media ) fibremuscuare
Endoteiu
,#Ib
,#IIbIIIa
Agregarea pachetara) decansata de mediatorii umorai pachetari
) mediata de ,#IIbIIIa si Fbg
#atee aggregation 2 triggered b$
humora mediators and mediated
b$ ,#IIbIIIa and Fbg
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(oagen
Adventitia
Media ) fibre
muscuare
Endoteiu
Tromb pachetar #ateet thrombus
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(oagen
Adventitia
Media ) fibre
muscuare
Endoteiu
Retractia trombuui pachetar #ateet thrombus retraction
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• 3aborator$ tests that e0pore primar$
hemostasis: – 7eeding time: 89 min
– #ateet count: "9 ) ; < "= >
– #ateet functionait$ tests:• aggregation tests: AD#- thrombin- ristocetin
– v&F assessment 2 ?uantitative and?uaitative
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• (oaguation
• The process through %hich pasma is transformedfrom i?uid to soid!
– Essentia$ it consists of transformation of soube
fibrinogen in insoube fibrin po$mers under the cata$ticaction of thrombin .F II/!
– Thrombin is obtained from the inactive form @prothrombinat the end of a chain of en6$matic reactions Bno%n as the
@(OA,53ATIO1 (AS(ADE invoving severa en6$mes andcoen6$mes Bno%n as the (O,53ATIO1 FA(TORS!
– Most coaguation factors are produced in the iver- thereforeiver disorders have a profound impact on coaguation!
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Factori de
contact:
<II
C,M
#C
Fbg
.I/
Fibrina
.F7/
(A3EA I1TRI1SE(A (A3EA E<TRI1SE(A
<I
<Ia
I< I<a
+III
F#*
(aDD
<<a
+
F#*
(aDD
II IIa
o#$ #$s
<III
<IIIa
AT III
#rot (
#rot S
TRM
FT
.III/
+II+IIaI<
I1STRI1SI( #ATH&A E<TRI1SI( #ATH&A
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<I
<Ia
<
II IIa
F7s
<IIIa
FT +II
FT)+IIa
<a
I<a
I<a)+IIIa+III
+
<
<a)+a
<III
I<
Fbg Fibrina
(urrent opinion: ' consecutive phases
) Initiation 2 #roduction of a sma ?uantit$ of thrombin- that
cannot activate fibrinogen- but can actiivate the other
coaguation factors .bacB activation/
) #ropagation 2 E0ponentia gro%th of the ?uantit$ ofthrombin 2 fibrin production
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• (oaguation testing
- routine tests – %&, A%&&, &&
- individual coagulation factor testing
A#TT 2 e0poresintrinsic path%a$
.*);s/
#T .T/ 2e0porese0trinsicpath%a$ ."")"9s/
TT) e0poresfibrin)formation."G)'s/
Deficit
1 proonged 1 Isoated F+II
deficit
proonged 1 1 F <II-<I-I<-+III
deficit
proonged proonged norma F <-+-II deficit- orgoba deficitAnticoaguants
proonged proonged proonged Fibrinogendeficit or gobadefect
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• Fibrino$sis – The fibrin cot
$sis – mediated
by pasmin – 3aborator$ tests
that e0pore
fibrino$sis• the diuted)bood
cot $sis time:
"9)* min
• FD# 2 D)dimers
Fbg
.I/
Fibrina
.F7/
o#$ #$s
#AI
Apha'
pasmin
inhibitor
#asminogen #asmina
t#At#A
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DISORDERS OF #RIMAR HEMOSTASIS
• +ESSE3 &A33 DISORDERS:
– Rendu)Oser disease .teeang$ectasia/• #athogenesis: Increased +E,F production 2 intima
proiferation %ithout media and adventitia @catching
up 2 resuts in thin arterioe and venue vesse %as• Autosoma dominant inheritance
• Muco)cutaneous vascuar diatations.teeangiectasias/ that rupture- eading to chronicbeeding and chronic iron deficienc$
•
Treatment: – Iron suppementation 2 ora iron usua$ not enough
– Transfusions
– Surgica hemostasis
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• Immunoogic and immuno)aergic
vascuitis: – (oagen diseases- chronic hepatitis-
$mphoproiferative disorders- idiopathic – 5sua$ s$metrica purpura %ith signs of
vascuar infammation organ invovement
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– Henoch)Schonein
purpura• 5sua$ affects chidren and
$oung aduts
• S$metric purpura arthritis
abdomina pain rena
impairment
• Sometimes associated %ith
streptococcus infection
• Treatment:
– 5sua$ spontaneous
remission
–If not 2 corticosteroids
– Streptococcus
eradication
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• #3ATE3ET DISORDERS
• uantitative and uaitative – uantitative: Thromboc$topenias are
probab$ the most common causes of
pathoogica beeding
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Thromboc$topenia .8"->/
•
7eeding rare$ occurs %hen pateets are 9->• Spontaneous beeding occurs at 8'->• (assification:
– (entra thromboc$topenia: megacar$oc$tes defectappearing in:
• apastic anemia .rare$ pure amegacar$oc$tosis/• acute and chronic euBemias• $mphomas• disseminated soid tumors• infection: tubercuosis
– #eriphera thromboc$topenia:• 1on)immune: se?uestration .spenomega$/• Immune:
– Idiopathic thromboc$topenic purpura .IT#- chronic- acute/ – Secondar$ autoimmune thromboc$topenia – (hronic IT# is more fre?uent in aduts! Acute IT# occurs most$ in
chidren!
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IDIO#ATHI( THROM7O(TO#E1I(
#5R#5RA .IT#/
• Definition: Thromboc$topeniacaused b$ immune-autoantibod$)mediated pateetdestruction
• Etioog$: unBno%n- as in most
autoimmune diseases• #athogenesis:
– Ig, autoantibodies against,#IIbIIIa!
– pateet destruction occursmost$ in spenic macrophages
– There coe0ists a decresedpateet production .antibod$attacB on megaBar$oc$tesJ/
,#IIbIIIa
Macrophage
#ateetFcR
Anti pateet
antibod$
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IT# ) (3I1I(A3 #I(T5RE: M5(O)(5TA1EO5S 73EEDI1,• #etechiae• Ech$moses• Epista0is• ,um beeding
• 1o spenomega$
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• 3aborator$ features: – #t 89-- often 8"->mm*
– &7(- Hgb usua$ norma
– 7one marro%: norma megacar$oc$tes-
sometimes megacar$oc$te h$perpasia
– Anti)pateet antibodies 2 o% specificit$
and sensitivit$ – A1A- HI+- H(+- H7+- Heicobacter #$ori 2
shoud be negative
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• Treatment: – (orticosteroids: #rednisone "mg>Bg 2 'mg>Bg up
to ')* months• compete response in 'K- partia response in most
patients
– If there is no significant response aftercorticosteroids: spenectom$
• compete response in GK of patients
– I+I, 2 ;mg>Bg *)9 da$s 2 temporar$ measure
– Thrombopoietin receptor agonists: etrombopag-romipostim
• #rognosis: good- even in the minorit$ ofpatients in %hich spenectom$ fais
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THROM7OTI( THROM7O(TO#E1I(
#5R#5RA .TT#/
• Definition' A rare disease defined by
reversible disseminated platelet
aggregation, bleeding, thrombosis, *
and renal disturbances – ' forms:
• congenital (extremely rare)
•
ac+uired
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• #athogenesis: – Abnorma persistence of high moecuar
%eight von &iebrand factor mutimers-due to absence of v&F ceaving protease.ADAMTS"*/
– Ac?uired form: antibodies against the v&Fceaving protease
– E0cess Fv& ) Disseminated pateet cots• both thrombosis and beeding ma$ occur
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Mutimer
v&F
ADAMTS"* ) en6ima de
civare a v&F
Anticorpi anti)ADAMTS"*
ADAMTS"*
Monomer
v&F
Mutimer
v&F
ADAMTS"* ) en6ima de
civare a v&F
ADAMTS"*
ormal &&%
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•
(inica picture: – abrupt onset – mucocutaneous bleeding – pallor aundice – thrombosis: cerebral, cardiac, etc – transient neuro-psychiatric symptoms – renal failure
• 3aborator$ features: – thrombocytopenia, sometimes severe – anemia, reticulocytosis, schisocytes – $., creatinine elevation
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• Treatment: – #asma e0change .#E</: pasmapheresis
massive pasma transfusion – orticosteroids, cyclophosphamide –
Aspirin – /ituximab – Dialysis
•
#rognosis: – used to be dismal, 012 mortality – no3adays mortality 4512 – sometimes debilitating se+uelae, relapses
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#t
#"
#L
#'
#*
#;
#9
##G
R"
#=
R'
R*
R;# N #asma e0change
R N Ritu0imab mg
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+O1 &I33E7RA1DS DISEASE
• Etioog$: Hereditary disease – autosomal dominant• (inica picture: muco-cutaneous bleeding – especially
6& – the s$mptom intensit$ tends to abate %ith age
•
3aborator$: – proonged beeding time- norma #T and A#TT – 3o% eves of v&F .+III:RAg/ – 3o% ristocetin cofactor activit$ – Sometimes associated %ith o% eves of coaguation factor
+III .+III:(/
• Treatment: – pasma- cr$oprecipitate transfusions – Factor +III:( v&F concentrate – Desmopressin
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(assification of von &iebrand disease:
T$pe ": Moderate v&F ?uantitative defect 2 dominant
inheritance .)GK of cases/
) associated %ith o%er eves of +III:( .but "K/
) mid>medium hemorrhage
T$pe ': uaitative defect .norma +IIIR:Ag eves/ 2
dominant inheritance 2 medium>mid .')'9K of cases/
) 'A- '7 2 poimeri6ation defect) 'M 2 defect of binding to pateets
) '1 2 defect of binding to +III:(
T$pe *: Severe ?uantitative defect 2 recessive inheritance
.")9K of cases/) severe hemorrhage
) associated %ith o% eves of +III:( .9)"K/
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THE HEMO#HI3IAS .F+III>I< deficit/
• Etioog$: hereditary 7-lin"ed diseases: both #8!!! and#!7 genes are found on chromosome 7 – 3omen arecarriers, men are sic" – Hemophiia A 2 Factor +III deficit .G9K/ – Hemophiia 7 2 Factor I< deficit ."9K/
• (inica picture: deep bleeding: – Hemarthrosis .Bnee- shouder- ebo%- hip/- hematomas-
hematuria – After minor>maPor surger$ or trauma – * cinica forms are described:
• severe: spontaneous hemorrhage .+III>I< ) 8"K/• medium : hemorrhage after minor trauma .+III>I< 2 ")9K/• mid: hemorrhage after trauma and surger$ .9)'9K/
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*evere hemophilia – 9nee hemarthrosis
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*evere hemophilia – muscle hematoma
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Hemophilia – uscle hematoma
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• 3aborator$: – #roonged A#TT
– 1orma #T- TT- 7T
– Specific dosage of +III>I< eves• Severe form: 8"K residua factor
• Moderate form: ")9K residua factor
•
Mid form: 9)'9K residua factor
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• Treatment: – Imobiisation- bed rest – #ainBiers – Substitution:
• Shoud be given as soon as possibe after event onset• (oncentrates +III and I< 2 '); units>Bg singe dose or
repeated if necessar$ at "' hours .+III/ or at '; hours .I</• Desmopressin in medium>mid forms• #roph$actic treatment 2 '); units>Bg ')* times>%eeB
in severe forms 2 practica$ transform severe formpatients into medium form patients
• Cineto)ph$siotherap$