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DISORDERS OF HEMOSTASIS

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7/24/2019 9 Hemostasis

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DISORDERS OF

HEMOSTASIS

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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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 Aggregating platelets

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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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Rendu)Oser Teeang$ectasia

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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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+ascuitic purpura

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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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Sch$6oc$tes

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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$siotherap$

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•  (ompications:arthropath$ 2 various degrees of disabiit$

chronic hepatitis .7-(/- AIDS