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HEMOSTAZA NORMALA

I. Etapa vasculara
- vasoconstrictie - reflex axonic,
serotonina
II. Etapa trombocitara
III. Etapa coagulare
IV. Etapa fibrinoliza

HEMOSTAZA NORMALA
I. Endoteliul
- functia
1. bariera de permeabilitate
-2. secretie:
- F. Willebrand,
- trombomodulin ataseaza trombina, proteina C, S
- fibronectina
inhibitorul activatorului tisular al
plasminogenului
- PGI2 , Endotelina

HEMOSTAZA NORMALA
I. Endoteliul
- faeta luminala
- glicocalix

monocite

- molecule de adeziune aseaza neutrofile,


- imunoglobuline,
- selectine,

II. Etapa trombocitara


- adeziunea prin receptori Gp I
- colagenul

subendotelial
- fibronectin + f. Willebrand

prin

Gp IIb IIIa

- agregarea
- ADP subendotelial

- fibrinogen

- Tx A 2

- secretia
- Ca +2 , Factor 3, 4,

COAGULAREA - intrinseca

X a

- trombocite activate
colagenul subendotelial
factorul XII

- XII

XII a
- XI

XI a
- IX
Ca, F3plachetar,
VIII

- X

COAGULAREA - extrinseca
- tromboplastina tisulara
FT
- VII

Xa

- X

Proteina C

COAGULAREA - calea comuna

Xa

- X

Proteina C

IIa

- II

Ca, F3plachetar,
V

- fibrinogen

fibrina
+
fibrinopeptid

CLASIFICAR
E
- Etapa vasculara - Purpura
vasculara
- congeniala
- dobandita
- Etapa trombocitara - Purpura
trombocitara
trombocitopenie
- trombopatii

- Etapa coagulare - Purpura


deficienta
factorilor de
coagulare
- congenitala
-

dobandita
- Etapa fibrinolizei - Purpura
fibrinolitica
- Etapa reologica - Purpura
ortostatica
- Etapa activare
sistem monocit-macrofag Purpura CID

Purpure vasculare
- congenitale
Ehler Danlos
osteogeneza imperfecta
Rendu - Osler

- dobandite
scorbut

senila
Sindrom Henoch Schonlein
infectioasa - meningococcica, virale
disglobulinemii - Waldenstrom,
mielom, disglobulinemie mixta

Boala Rendu Osler


- congenitala
autosomal dominanta
defect perete venos
(endoteliu, membrana bazala,
adventice)

fistule arteriovenoase
(mucoasa digestiva, plaman, ficat, splina,
cerebral)

Telangiectatizia ereditara

Manifestari clinice
1. telangiectazii cutanate,
mucoase
2. epistaxis, hemoptizii, melena,
3. anemie feripriva cr
4. anevrisme arteriovenoase
hepatice cu sindrom hiperkinetic
cardiovascular
5. AHC sugestive boala Rendu

Diagnostic diferential
1. Telangiectaziile sclerodermie
(CREST)
2. Pete telangiectatice
3. B Fabry (Angiokeratoma
corporis
difusum)
- boala a metabolismului glicolipidic

(ceramide intramacrofagic)

- leziuni nodulare inchise la culoare


( aproape negre) periombilical,
scrotal,

CREST

Boala
Fabry

Pete telangiectatice

Tratament
1. Suportiv: tamponament nazal,
unguente ( dermatol),
cauterizari contraindicate
2. Trat anemiei : fier, ac folic,

vit B12 la 3 luni

3. Trat chirurgical al fistulelor mari


greu de
abordat

2. Purpure vasculare
anomalii dobandite
ale tesutului
conjunctiv

Purpura de staza

Purpura de senila

Scorbutul
Situatii etiologice
- alcoolism, copii hraniti exclusiv
cu lapte de vaca,
- patogenie:
- deficit vit C deficit de colagen
(hidroxiprolina)
- reduce adeziunea, agregarea
plachetelor,
- clinic :
- purura in jurul
foliculului pilos, durere
- hipercheratoza
- rar: HDS,
hemoragii musculare

3. Purpure vasculare
dobandite
- boli infectioase
- boli de tesut
conjunctiv
- hiper/disglobulinemii
- Henoch
Schonlein

Purpure vasculare
dobandite boli inflamatorii
- etiopatogenie
- complexe imune
circulante
- post infectii
bacteriene, virale, rickettsi
- medicamente penicilina, sulfamide,

allopurinol

Purpura infectioasa
- infectii (virusuri, meningococ, rickettsi)
- patogenie: complexe imune circulante

- clinic :
- purura bule hemoragice
purpura fulminans

tratament antiinfectios

Sindromul hemolitic uremic


- microtromboze exclusiv in vase renale
- etiologie: infectioasa

- patogenie:
- copii, adolescenti
- dupa infectii
(E Coli, Shigella)

- leziune de celule endoteliale,


microtromboze a. aferenta, glomerul

Sindromul hemolitic uremic


- microtromboze exclusiv in vase renale
- etiologie: infectiasa

- clinic:
- purpura
- insuf renala acuta
- HTA
- AH microangiopatica

- evolutie :
- deces prin IRA

- 10- 50% cazuri IRC


- tratament - dializa in IRA

Meningococcemie

Purpura fulminans
post zona zoster

Endocardita bacteriana

Vasculita poliartrita
reumatoida

Purpura hiperglobulinemica
IgA+IgG
- boala
Waldenstrom, mielom

Manifestari clinice
1. purpura

2. hemoragii retiniene
3. nevrita periferica
Tratament
1. Tratatamentul mielom, etc
2. Plasmafereza

Purpura hiperglobulinemica

Hemoragii subunghiale
- crioglobulinemie

Purpura Henoch Schonlein


- etiopatogenie
infectie streptococica
respiratorie)

(faringiana 50%cazuri,

-alergii alimentare, medicamnetoase


(chinidina, sulfamide)

membrana bazala capilara


- complexe imune IgA2

Manifestari clinice

Purpura Henoch Schonlein

Manifestari clinice
1. purpura
2. poliartralgii
3. colica abdominala, melena,

intestinala

rar perforatia

4. Hematurie, proteinurie
GNA ac

Prognostic
mesangiala
focala
favorabil in general

evolutie cu valuri purpurice

Tratament
1. Penicilina infectie

streptococcica

2. Corticoterapie 1mg/kg
Prognostic
prednison
- favorabil in general
- evolutie cu recidive purpurice

Complicatii
- IRA
- perforatie intestinala

Tratament
1. Penicilina infectie

streptococcica

2. Corticoterapie 1mg/kg
Prognostic
prednison
- favorabil in general
- evolutie cu valuri purpurice

Complicatii
- IRA
- perforatie intestinala

Purpure vasculare rare

- anticoagulante
- autoflagelare
- staza

Necroza cumarinica

Purpura trombocitopenica
I. Productie scazuta de
trombocite

- trombocitopenia < 100000/mm

- Nr redus de megacariocite in maduva

1. infiltrat medular : leucemii,


limfoame, mielom, metastaze,
granuloame

2. hipoplazie medulara: idiopatica


secundara: radiatii, medicamente,
virusuri

3. sindr mielodisplazice:
idiopatica
secundara: radiatii, medicamente,
virusuri
4. anomalii congenitale:
pancitopenia Fanconi,
trombocitopenia autosomal recisiva,
boala May Hegglin, infectii (rubeola)

II. Distructie crescuta trombocite:


3

- trombocitopenia < 100000/mm


- scurtarea duratei de viata a
trombocitelor
- nr crescut de megacariocite in
maduva

1. Distructie crescuta :

- PTI autoimuna acuta, cronica


- purpura
posttransfuzionala
- neonatala alloimuna

Purpure trombocitopenica
autoimuna idiopatica
- etiopatogenie

- autoanticorpi in plasma si pe
membrana trombocitelor
- distrugere prematura a
trombocitelor macrofagele
splinice

Purpure trombocitopenica
autoimuna idiopatica acuta
- etiopatogenie
IgG

- autoanticorpi antitrombocitari

- antigene : virus gripal, rubeolic,


hepatitic, HIV, Ebstein
Barr,

Manifestari clinice

1. purpura
2. poliartralgii
3. colica abdominala, melena,

ntestinala

rar perforatia

4. Hematurie, proteinurie
GNA ac

mesangiala focala

- clinic

- petesii fara splenomegalie

- paraclinic
- TS prelungit
- trombocitopenie

- maduva: megcariocite numeroase


oprite in
maturatie,
- IgG antiitrombocitari

Maduva:

nu megcariocite
trombocitogene

- evolutie
- boala autolimitata cu vindecare,
- uneori cu purpura in valuri
- 20% cronicizare

- tratament

- cortioterapie in cazuri grave


- plasmafereza
in risc de hemoragie
cerebrala

Purpure trombocitopenica
autoimuna idiopatica cronica
- etiopatogenie
- anticorpi antitrombocitari
anti receptori IIb-IIIa,
glicoproteina Ib

Purpure trombocitopenica
autoimuna idiopatica cronica
- clinic
- femei / barbati = 3/1
- astenie, petesii - nepalpabile,
fara
bule hemoragice,
echimoze,
- metroragii,
sangerari digestive,
fara splenomegalie

- paraclinic

- trombocitopenie
- maduva: megacariocite tinere

- paraclinic
- TS prelungit
- trombocitopenie
- maduva: megacariocite
tinere
numeroase oprite in
maturatie,

- evolutie
rare

- cronica, remisiuni spontane f

- tratament
- cortioterapie 1mg/kg/zi
- 50% remisiune partaiala,
raspuns la 6 saptamani
- imuran 3 luni +/- vinblastin

- gama globulina iv 3luni


blocarea sistemului monocitmacrofag
- splenectomie forme
corticorezistente

Purpure trombocitopenica
alloimuna
- postnatala
- anticorpi antitrombocitari ce trec
placenta
A1

- clinic

- anti sistemului PI

- sindrom hemoragipar imediat dupa


nastere
- manifestari grave la urmatorii
copii

Purpure trombocitopenica
posttransfuzionala
- anticorpi antitrombocitari
A1

- anti sistemului PI

- clinic
- la 7 zile de la transfuzie, masa
trombocitara

- tratament

- corticoterapie, plasmafereza,
exanguinotransfuzie

Purpure trombocitopenica
postmedicamentoasa
- actiune maduva osoasa
- arabinosid, daunorubicina,
- tiazidice, estrogeni
- distructie imuna
- antibiotice, sulfamide,
- chinidina, chinina
- metildopa
- saruri de aur,
- heparina

Purpure trombocitopenica
postmedicamentoasa
- mecanism

1. complexe imune
anti
medicament + proteina
plasmatica
- absorbtie nespecifica a complexelor
pe trombocit inocent bystander
2. medicament fixat pe trombocit,
anticorpi anti
complex
medicament + trombocit

- clinic
- petesii, frecvent sindrom
hemoragic sever,
- aparut post
medicamentos

- paraclinic

- megacariocite normale,
intens trombogene ( citoplasma

granulata,

azurofila, fara vacuole)

- tratament

- intreruperea medicatiei,
corticoterapie,
plasmafereza,

Purpure trombocitopenica
autoimuna secundara
- LES

- LLC, limfoame

- HIV

- paraclinic
- trombocitopenie
- maduva: megcariocite normale,
anomalii morfologice
- tratament
- zidovudin

Purpure trombotica
trombocitopenica
- context
- sarcina, anticonceptionale, infectii
- Coxackie, micoplasme,
- antibiotice

- morfopatologic
- microtromboza hialina capilara,
arteriolara

Purpure trombotica
trombocitopenica
- clinic
- febra

- purpura
- anemie hemolitica
microangiopatica
- disfunctie renala severa,
- manifestari neurologice
- tratament
- CID

Sindrom hemolitic uremic


- clinic
- copii, tineri
- IRA, sindr hemoragipar, rar
sindrom
neurologic
- prognostic
- 50-80% mortalitate
- tratament
- plasmafereza,
exanguinotransfuzia

Sindroame hemoragipare
prin
anomalii de coagulare
si
fibrinoliza

- Etapa coagulare - Purpura


deficienta
factorilor de
coagulare

dobandita

- congenitala
-

-Etapa fibrinolizei - Purpura


fibrinolitica
- anomalii primare ale fibrinolizei
-

COAGULAREA - intrinseca
colagenul subendotelial
factorul XII

XII
kininogen
precalicreina
Complex la nivelul
endoteliuui

XII a
XI

XI a
IX

IX a

COAGULAREA - extrinseca
colagenul subendotelial
factorul XII

XII

XII a
XI

kininogen
precalicreina

XI a
IX

IX a

COAGULAREA - extrinseca
VIII

VIIIa
Ca, F3plachetar

(1)factor tisular + F VII + Ca

Faza comuna a in coagularea


intrinseca si extrinseca
Xa

IIa

fibrina

II

fibrinogen

Fibrinoliza

Pro UK
+
tPA

Plasminogen

Plasmina

PAI

Fibrina

trombina
PD Fibrina

Anticoagularea naturala
X

Xa

Antitrombina

IIa
Inactiveaza
Va
Proteina C a
Proteina S

fibrina

II
Inactiveaza VIIIa

fibrinogen

Proteina C

Trombomodulina + trombina

Sindrom hemoragic prin


anomalii de coagulare
1. Hemofilia A
deficienta factor VIII
- anomalia genei F VIII

bratul lung cromozom X

- mutatii punctiforme, deletii importante


- incidenta 1/ 10 000
- boala afecteaza aproape exclusiv barbatii,
deoarece la femei heterozigote cromozomul X
asigura sinteza necesara de f VIII

Hemofilia A X

Generatia I

deficienta factor VIII


x

Generatia
II

x
X
x

xX
x

Generatia
III

Generatia
IV

x
X
Xx

x
X
x

Factorul VIII proteina 80 000 daltoni, pe

suprafata f. von Willebrand

F VIII sintetizat in ficat


- concentratie plasmatica = 10 g/l
- durata de
viata 8-12 ore
Hemostaza normala necesita activitate 25% f VIII

- Clinic
- copii - baieti, tineri
- hematoame, hemartroza,
- hemoragii: muschi,
orofaringe,
cerebrale

Hemofilia A

Hemartroze hemofilia A

- Diagnostic paraclinic
- T sangerare

= normal

- T coagulare

= prelungit

- T protrombina = normal

- T tromboplastina partial activata


=
prelungit
- Concentratie F VIII = scazuta

- AND fetal

- Forme
- severe .. 1%
- medii
- usoare

activitate f VIII

.. 1-5% activitate f VIII


.. 5% activitate f VIII

- f usoare . 5 - 25% activitate f VIII

Tratament
Profilactic de 2X pe saptamana
Curativ
Kogenate 1000 UI 15 fl
Octanate 500 UI 13 fl
1UI/kgc factor VIII creste concentratia
plasmatica cu 1%

Tratament
Forme medii
- crioprecipitat plasma
Forme usoare
VIII

- desmopresin creste nivelul F

- EACA inainte de extractii


dentare
inhibitor de fibrinoliza ( inhiba activatorul tisular
plasminogen)

Tratament
Forme severe
- concentrat de factor VIII
monoclonali

- prin absorbtie pe anticorpi


sau f VIII recombi

- chirurgia majora, ortopedica

ore sau 12 ore

- cu pretestarea inhibitorului F
pentru nivel 50% a FVIII,2 sa
- adm la interval d

- profilactic
- la simptome, fara
hematoame,

a redus

IX

1. Hemofilia B boala Christmas


deficienta factor
- 20% din hemofilii
- Factor IX - sinteza hepatica
dependenta de vit. K
- Anomalia genei IX bratul lung
cromozom X
- mutatii punctiforme, 1/3 spontane
- microdeletii

- 800 pattern- uri de anomalii moleculare


ex: factor IX Leiden 11 mutatii punciforme

IX

1. Hemofilia B boala Christmas


deficienta factor
- Clinic sindrom hemoragipar expresie
fenotipica variabila
- ameliorare la pubertate,
sub androgeni
- Paraclinic concentratia fact IX < 1%
- Tratament plasma proaspata,
- complex protrombinic liofilizat
( risc de tromboze)

1. Boala fon Willebrand


- precursor F Willebrand sintetizat de endoteliu si
megacariocite
- functii F Willebrand
- adeziunea trombocit la endoteliu
- transportor f VIII
- concentratia plasmatica: 10 mg/dl

TS - prelungit
agregare plachetara la ristocetina= absenta
APTT normal, T Quik-normal
concentrataia de F Willebrand - scade

- tratament: crioprecipitat, desmopresin

- Boala Von Willebrand


- 1 la 100 500 persoane este cea mai
comuna anomalie mostenita de sangrare
- FvW - glicoproteina multimerica
heterogena secretata de endoteliu si
plachete
1. favorizeaza adeziunea plachetelor la
receptori subendoteliali
2. transportor plasmatic al F VIII
- nivel palsmatica 10mg/L
reduceri modeste FvW sau modificare
moleculara
determina S hemoragipar

Boala von Willebrand:


- boala autosomal dominanta, forma
heterozigota vWf este produs de gena normala

- BvW tip I - nivel descrescut cu 50% al


FvW

- Clinic: sangerare la traumatisme, chirurgie,


epistaxis, hemoragii mici mucoase, subcutanate
- Diagnostic:
- TS >
- nivel plasmatic vWF <
- aglutinare la ristocetina< (activitate biologica)
in

- spectru normal al multimerilor la electroforeza


agaroza

- Boala von Willebrand:


- BvW tip II - nivel noraml FvW
disfunctional
pentru multimerii cu greutate
moleculara mare si medie, fenomen detectat la
electroforeza in agaroza

- BvW tip II a -

deficienta a FvW cu greutate


moleculara mare sau medie, mutatie in

deficienta de secretie sau


proteoliza
a multimerilor vWF,
- FvW si F
VIII concentratii normale
domeniul A2

- BvW tip II b descrestere FvW cu greutate


moleculara mare, legare inadecvata de
plachete si eliminare a Pl+FvW anormal, cu
trombocitopenie secundara

- BvW tip III


- autosomal recesiva
- incidenta 1 la 1 milion
- parinti heterozigoti pentru defecte diferite
sau
homozigoti pentru acelasi
defect
FvW absent + F VIII redus
Clinic: sangerari de mucoase + hemartroze

- BvW tip IIn


- defect legare FvW de F VIII

- Clinic:
- femei si barbati
- hemoragii cutanate si mucoase
- forme:
- usoare, medii, severe

- DG. paralinic:

- TS - prelungit
- Agregare plachetara la ristocetina= absenta
- APTT normal, T Quik-normal
- Concentratia plasmatica F Willebrand - scade
-

Tratament: crioprecipitat, desmopresin

- Tratament
- concentrate de F VIII
- menoragia
contraceptive orale
- DDAVP sau desmopresina (vaspresina)
creste retentia de
fluide stimuleaza
eliberarea FvW

- nu in tipul IIa !!!

Deficienta factor XI
-

transmitere autosomal recesiva


- mai frecventa la evrei din Ashkenazi

- Clinic sangerare posttraumatica


- menometroragii
- Tratament
plasma proaspata inghetata o infuzie/zi

Deficienta de factor V, VII. X si

II
-

transmitere autosomal recesiva


- rare

- Clinic sangerare posttraumatica


- menometroragii
- Tratament
plasma proaspata inghetata o infuzie/zi

Afibrinogenemia si disfibrinogenemia
- Clinic

sangerare
- tromboze in
disfibrinogenemie (rar)
- Paraclinic
- afibrinogenemie: scaderea concentratie de fibrinogen
- disfibrinogenemie:
- Timp
protrombina prelungit
- Timp tromboplastina prelungit

- Tratament
- Timp trombina prelungit

plasma proaspata inghetata

1. Deficienta dobandita a
factorilor de coagulare
- vitamina K - plante
- sintetizata de flora intestinala

epoxidaza
vit K epoxid

vit K
reductaza

Anticoagulanti
cumarinici

Deficienta vitamina K influenteaza -

f
f
f
f

II
VII
IX
X

- proteina C si S

- Cauze deficienta vitamina K aport insuficient


- antibioterapie per os
- sindr biliar obstructive- f X
- boli hepatocelulare grave
-

- antagonisti de vit K

- Clinic - sindrom hemoragipar functie de

deficienta de vit K
- forme usoare - severe

- paraclinic - TC prelungit, T Quik - prelungit

- Tratament - plasma proaspata, sange proaspat


- vit K parenteral 10mg
-10 ore

- restabileste depozitele hepatice in 8

- Cauze de sangerare
in boli de ficat
- scade sinteza : fibrinogen,

protrombina, fact V, VII, IX, X,


- scade sinteza: proteina C,S,
antitrombina III - CID
- vit K - scade absorbtia si metabol
- monocit - macrofag
insuficient functional
- fibrinoliza sistemica primara
- trombocitopenie

Coagulare intravasculara diseminata


Sindrom clinicopatologic caracterizat prin
formarea unor retele de fibrina intravascular.

Coagulare intravasculara diseminata


Mecanism:
-generarea necontrolata de trombina
-expunerea la nivele patologice de FT
-supresia mecanismelor anticoagulante fiz.
-fibrinoliza anormala

Coagulare intravasculara diseminata


Insuficienta organica multipla:
-depozite de fibrina in vasele mici si medii
-afectarea circulatiei:F,R, creier,plaman
-ischemie
-hemoliza intravasculara

Coagulare intravasculara diseminata


Consumul trombocitelor si factorilor de coag.
- sangerare difuza
-fibrinoliza
-PDF, d-Dimeri

Coagulare intravasculara diseminata


- infectii sistemice: stafilo,
meningococ, B Gram neg
- sindr obstetricale: avort, eclampsie,
dezlipire placenta
- neoplazii: LAM, adenocarcinoame
- hemoliza intravasculara
- distructii tisulare: traumatisme, arsuri, etc
- leziuni endoteliu: SHU, GNA, hemangiom
cavernos
- ciroza

Factori etiologici
XII a
coagulare

PDF

fibrinoliza

PDF exces inPDF


microcirculatie
exces in microcirculatie

Activare coagulare in
microcirculatie

Tromboze

XII a

Fibrinoliza in exces
Sangerare difuza

Tromboze

- neurologic : semne focar,


convulsii, coma
- piele : ischemie focala, gangrena
- plaman : SDRA

Sangerare difuza
- petesii,
- sangerare - pe mucoase (gastrointestinala, hemoptizie
epistaxis)
- neurologica

- gastrointestinal : sangerare acuta

- laborator : trombocite <, F VII, V<, Fibrinogen<, PDF> 4g/dl,


AH microangiopatica

Coagulare intravasculara
diseminata

Coagulare intravasculara
diseminata

CID dg. paraclinic


1. trombocitopenie
2. AH microangiopatica
schizocite

3. TC >, aPTT >, TQ


>
4. Fibrinogen <
5. PDF+++

- Tratament
- tratamentul bolii de baza

- reechilibrare hidroelectrolitica
- heparina 1000 UI/ora, 5000 UI la 4ore
- EACA = 4-6g/24 ore

( blocheaza PDF)

Coagulare intravasculara diseminata


cronica
-hemangioame gigante
-carcinoame metastatice
-fetus mort

CID cronic dg. paraclinic


1. Trombocite-N sau
usor
2. AH microangiopatica
3. aPTT -N, TQ -N
4. Fibrinogen -N
5. PDF+++

schizocite

- Fibrinoliza
activator tisular plasminogen
PAI

plasminogen
tromb

2 anti plasmina

plasmina
fibrina
PDF

- Fibrinoliza primara
- deficitul 2 anti plasmina
- sindrom hemoragipar
- paraclinic
- scade mult fibrinogenul
- aPTT, T Quik aproape normale
- trombocite normale

- tratament
- plasma proaspata, EACA

ELEMENTE CLINICE
DIAGNOSTIC DIFERENTIAL
- Sindromul hemoragipar
- varsta, sex
- conditii de declansare
- purpura
- localizare
- leziuni palpabile, buloase,
micronecrotice
- acuta, cronica
- hemoragii: mucoase, articulare, SNC

ELEMENTE PARACLINICE
DIAGNOSTIC
- TimpDIFERENTIAL
sangerare
- Trombocite
- Timp coagulare
-

fibrinogen
aPTT
t Quik
concentratie f VIII, IX,
von willebrand

- PDF
- liza cheagului

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Sarcom
Kaposi