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HEMOSTAZA
ANTITROMBOTICELE
HEMOSTATICELE
Grigor ViorelAsistent universitar
16 septembrie 2013
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Hemostazprocesele ndreptate spre meninereasngelui n patul vascular, prevenirea
hemoragiei i restabilirea fluxuluisanguin n caz de ocluzie vascular.
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Stadiile procesului hemostatic
Dereglarea peretelui vascular
Vazoconstrocie localAdghezia i activarea trombocitelor
Formarea trombului trombocitarStabilizarea trombului cu fibrin
Liza trombului dup regenerearea peretelui vascular
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Coagularea
sngelui
Proprietatea
organismului de a
controla fluiditatea
sngelui n lezarea
vascular reprezint un
factor important n
supravieuire.
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FIBRINOGENo
protein fibrilar
solubil, reprezint
3% din proteineleplasmei sngelui
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Nucleul reaciei include dou molecule:fibrinogenitrombin
Fibrinogen Fibrin
Thrombin
Trombina scindeaz peptidele 2A i 2B, transformnd
fibrinogenul n fibrin. Proteinele de fibrin se unesc,
datorit afinitii a i b cu locusurile cleioase alepetidelor A i B dup scindare.
COAGULAREA
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Maina Rube Goldberg
Pentru ascuirea creioanelor
Open window (A) and fly kite (B). String (C) lifts small door(D) allowing moths (E) to escape and eat red flannel shirt
(F). As weight of shirt becomes less, shoe (G) steps on switch (H) which heats electric iron (I) and burns hole in pants
(J). Smoke (K) enters hole in tree (L), smoking out opossum (M) which jumps into basket (N), pulling rope (O) and
lifting cage (P), allowing woodpecker(Q) to chew wood from pencil (R), exposing lead. Emergency knife (S) is alwayshandy in case opossum or the woodpecker gets sick and can't work.
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Sistema de coagulare a sngelui
amintete maina Rube Goldberg
Complexitateinevitabil?
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De ce cascad? Multitudinea etapelor cascadei amplific semnalul;
Cascada crete eficacitatea procesului decoagulare;
Datorit cantitii mari de proteaze active npreajma leziunii, cheagul se formeaz mai repede,
crescnd ansele supravieuirii.
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VASCULAR PHASE
PLATELET PHASE
COAGULATION PHASE
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Etapa vascular
Vasoconstricie localAdrenalin, noradrenalin, serotin, etc.
Dezgolirea tisular (colagen) activeaz factorultisular i declanleaz coagularea.
Tissue Factor
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Etapa trombocitar
Endoteliul vascular prentmpin alipirea iagregarea trombocitelor.
Leziunea vascular declaneaz adghezia iagregarea trombocitelor.
Trombocitele dein receptori pentru f.Villebrand i fibrinogen.
Trombocitele: Fragmente acelulare a megacariocitelor
Secret factori de coagulare (reacie de eliberare)
i pot schimba forma i forma un cheag dens
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FUNCIATROMBOCITELOR1. Adghezia la endoteliul lezat
2. PstrareaDP i altorproteine secretate la
activarea lor;3. Agregarea cu alte
trombocite;
4. Asigurarea suprafeei(matrice fosfolipidic) pentru
nfptuirea reaciilor decoagulare.
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Colman et al. -
Colman et al., Identification of Two Distinct Adenosine Diphosphate Receptors in Human
Platelets, Trans. Am. Ass. Phys. 93:305, 306 (1980)
PDE- phosphodiesteraseCyclic AMP : ,
, .
A
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1. Declanat de colagen i ADP.2.ADP amplific agregarea
datorit creterii Ca++iscderea AMPC.
3.ADP determin schimbareaformei trombocitelor, ce dposibilitatea de a se cupla cufibrinogenul.
4.Ali factori:
a. Tromboxanamplificagregarea.
b. Prostaciclindiminuiazagregarea.
AGREGAREA
TROMBOCITELOR:
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Etapa de coagulare
Dou ci principale Intrinsec Extrinsec
Ambele converg ntr-un punct
13 factori solubili implicai n procesul de coagulare
Biosinteza acestor factori depinde de vitamina 1 i2
Majoritatea factorilorfermeni n stare normal sunt inactivi i capabili de activare
consecutiv
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CALEA
INTRINSEC Toi factorii se aflintravascular
Proces de coagularelent
Test de laborator: ()
CALEA
EXTRINSEC Factorul declanator se
afl extravascularfacto rul t isu lar
Coagulare rapid(secunde)
Test de laborator: Timpul protrombinic
(TP) ()
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Nomenclatura internaional a factorilorplasmatici ai coagulrii
I Fibrinogen
II Protrombin
III Tromboplastina tisular, factorul tisular
IV Ionii ++
V Proaccelerin (factor labil)
VII Proconvertin (factor stabil)
VIII Globulina antihemofilic A (Hemofilia A)
IXComponentul plasmatic al tromboplastinei, f. Kristmas, factorantihemofilic B (Hemofilia B)
X Stiuart-Prauer, protrombinaza
XIPredecesorul plasmatic al tromboplastinei, f. Rozental(Hemofilia C)
XII Factorul Hageman, f. de contact
XIII Factorul fibrinstabilizant
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Factor F X
F IXaF IX
F XIaF XI
Contact cu osuprafa strin:colagen
F XIIaF XII
Intrinsec
Ca2+
Ca2+
Ca2+
Cascada coagulrii
Factor F X
F VIIF VIIa
F III (Tissue
Thromboplastin)
Defect tisular/ celular
Extrinsec
Ca2+
Ca2+
FibrinogenFibrinmonomersFibrinpolymers
ThrombinProthrombin I
Factor F Xa
Ca2+
Platelet Factor 3
Cheag fibrinic
F XIIIa F XIII
F VF Va
F VIIIaF VIII
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FIBRINOLIZA
Preparate exogene Streptokinaza product bacterian (posibilereacii imune)
Urokinaza produs tisular uman (fr reaciiimune)
Activatorul tisular al plasminogenului (tPA)produs prin clonare genic (fr reacii imune,
scump) Inhibitorii fibrinolizei
Analogi lizinici
Acidul aminocapronic, a. Tranexemic
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Efectele III / Heparin
FibrinogenFibrinmonomers
Prothrombin I Thrombin
Factor F XaFactor F X Factor F X
F VIIF VIIa
F IXaF IX
F XIaF XI
Surface ContactCollagen
FXII activator
F XIIaF XII
F III (Tissue
Thromboplastin)
Tissue/Cell Defect
Intrinsic Extrinsic
Platelet Factor 3
Ca2+
Ca2+
Ca2+
Ca2+ Ca2+
FibrinpolymersCrosslinkedFibrin Meshwork
F XIIIa F XIII
F VF Va
F VIIIaF VIII
Ca2+
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Timpul trombinic (TT)
FibrinogenFibrinmonomers
Prothrombin I Thrombin
Factor F XaFactor F X Factor F X
F VIIF VIIa
F IXaF IX
F XIaF XI
Surface ContactCollagen
FXII activator
F XIIaF XII
F III (Tissue
Thromboplastin)
Tissue/Cell Defect
Intrinsic Extrinsic
Platelet Factor 3
Ca2+
Ca2+
Ca2+
Ca2+ Ca2+
FibrinpolymersCrosslinkedFibrin Meshwork
F XIIIa F XIII
F VF Va
F VIIIaF VIII
Ca2+
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Timpul protrombinic dup Quick
FibrinogenFibrinmonomers
Prothrombin I Thrombin
Factor F XaFactor F X Factor F X
F VIIF VIIa
F IXaF IX
F XIaF XI
Surface ContactCollagen
FXII activator
F XIIaF XII
F III (Tissue
Thromboplastin)
Tissue/Cell Defect
Intrinsic Extrinsic
Platelet Factor 3
Ca2+
Ca2+
Ca2+
Ca2+ Ca2+
FibrinpolymersCrosslinkedFibrin Meshwork
F XIIIa F XIII
F VF Va
F VIIIaF VIII
Ca2+
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()
FibrinogenFibrinmonomers
Prothrombin I Thrombin
Factor F XaFactor F X Factor F X
F VIIF VIIa
F IXaF IX
F XIaF XI
Surface ContactCollagen
FXII activator
F XIIaF XII
F III (Tissue
Thromboplastin)
Tissue/Cell Defect
Intrinsic Extrinsic
Platelet Factor 3
Ca2+
Ca2+
Ca2+
Ca2+ Ca2+
FibrinpolymersCrosslinkedFibrin Meshwork
F XIIIa F XIII
F VF Va
F VIIIaF VIII
Ca2+
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Stabilirea dereglrilor de
coagulareCrescut Patologia cii interneNormal TP (cascada de coagulare)
Normal Patologia ciiexterneCrecut TP
Crescut Patologia ambelorciCrescut TP
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Coagulograma
510
24
200400 1091 84122
6080
() 46
IV-V
() 3545
VIII 60140%
V 58190%
VII 83117%
92109%
() 1214
24 /
() 2832
1D-
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Tromboza
Arterial Tromb alb:
Alipirea trombocitelor la endoteliul arterial;
Infarct miocardic, AVC, ischemii tisulare. Venoas
Tromb rou:
Se formeaz n zone de staz sanguin; Tromboza venelor profunde, insuficien cardiac
cronic, tumori, postintervenii chirurgicale.
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ANTITROMBOTICE
Clasa Reprezentant Aciune Efect
Anticoagulant
parenteral
Heparin Inactivarea factorilor
de coagulareProfilaxia
trombozelor venoase
Anticoagulant
enteral
Varfarin Inhib sinteza
factorilor de coagulare
Antitrombocitare Asprin Scade agregarea
trombocitelor
Trombolitice Actilyse Fibrinoliz Liza trombilor
Profilaxia
trombozelor venoase
Profilaxia
trombozelor arteriale
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Clasificarea
Antitrombocitarelor
Preparate ce inhib adghezia
Preparate ce inhib agregarea
Inhibitorii ciclooxigenazei (aspirin,sulfinpirazon)
Inhibitorii tromboxansintetazei(diazoxiben, pirmagrel)
Antagoniti dublu aitromboxanului 2 (ridogrel)
Blocatori ai complexuluiglicoproteic IIb/IIIa (abciximab,tirofiban, epifibatid)
Modulatorii sistemeiadenilatciclazei/Pc(dipiridamol)
Preparate cu alte mecanisme deaciune(ticlopidin, clopidogrel)
Anticuagulante
Aciune directDependente de III Heparinp nefracionat Heparine fracionateIndependente de III
Hirudina (bivalirudin,ghirughen) Oligopeptide (argatroban,
inogatran, novostan,efegartan)
Aciune indirect Derivai de cumarin
(varfarin)
Derivai indandione(fenindion)
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Heparina
Greutate molecular diferit
Activ in vitro i in vivo
Se indic parenteral NU se administreaz i/m!
Numai i/v sau s/c!
Timpul de njumatire 1-5 ore Monitorizarea
Efecte nedoritehemoragiiAntidot protamin sulfat
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Heparina
1916 McLean descoper heparina
1939 Brinkhous descrie prezena cofactoruluiheparinei
1968 Abildgaard izoleaz cofactorul heparineiantitrombina III
1978 i 79 Rosenberg i Lindahl descriuinteraciunea heparinei i III.
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I hibit ii t il GP IIb/III
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Inhibitorii receptorilor GP IIb/IIIa
1983Coller descrie rolul receptorilor glicoproteici ai
trombocitelor
Anii 90cercetarea apoi implimentarea activ a abciximabului,tirofibanului i epifibatidei
Rezultate nesatisfctoare n practic toate studiile cu blocatoriGP orali.
A ti l t i di t
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Anticoagulante indirecte
1929epidemie de diatez hemoragic la gini
descrierea rolului vitaminei K
1939obinerea dicumarolului
1941nceputul testrii clinice aanticoagulantelor indirecte.
Anii 90renoirea interesului ctre tratamentulcu varfarin lrgirea indicaiilor
A ti l t i di t
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Anticoagulante indirecte
Inhib activitatea epoxidreductazei-K,
micoreaz rezervele de vit. K
Scade sinteza factorilor de coagulare K-dependeni (II, VII, IX, X)
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Anticoagulante enterale
Cumarinevarfarin, dicumarol Dup structur asemntoare vit. K
Inhib producerea factorilor de coagulare
Absorbie rapid, se leag cu albumina
Klirens lent 36 ore.
Aciunea ncepe trziu, 8-12 ore. La supradozare infuzia vitaminei
Trec bariera placentarnu se utilizeaz
n perioadele tardive ale graviditii
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Antitrombocitare
Aspirin Inhib agregarea/adghezia trombocitelor
Utilizare clinic
Profilactica trombozelor arteriale Infarct miocardic, AVC, valve protezate
Alte preparate
Dipiridamol, ticlopidin, clopidogrel
A id til li ili
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Acid acetilsalicilic
1899Goffman sintetizeaz AAS, nceputul producerii
industriale a aspirinei de concernul Bayer.
1967 descrierea efectelor antiagregante a AAS de
Weiss iAledort
Anii 70-80 ai sec. XXo serie de cercetri clinice ceau confirmat eficacitatea aspirinei n afeciunileaterosclerotice ale vaselor.
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Mecanism de aciune
Aspirina inhib ciclooxigenaza (COX)
COX enzima chee, implicat n sintezade tromboxan2
Inhib agregarea trombocitelor
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Aspirin
A. ARAHIDONIC
CICLOOXIGENAZA
PgG2 i PgH2 (endoperoxizi ciclici)
Tromboxansintetaza
Tromboxan 2
Agregarea trombocitelor
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Utilizarea profilactic a aspirinei
Doze mici (180 g/zi) Previne atacurile ischemice i infarctul
miocardic 335 /ziscade riscul coronarian la pacienii
mai n vrst de 50 ani
Mai mult 1000 /ziefectul lipsete Dozele mari inhib sinteza prostaciclinei ceniveleaz proprietile antiagregante aleaspirinei.
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Fibrinolitice
Altteplazarecombinat (tPA, Actilyse)
50 i/v
Streptokinaza (Kabikinase, streptase)
Parenteral: 250000 - 1.5 million Un/fl i/v
Urokinaza (Abbokinase) Parenteral: 250000 Un/fl i/v, 5000 Un/ml
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Procoagulante
Vitamin (Phytonadione (K1), Mephyton) Enteral: 5 , past.
Factori plasmatici hemofilia Factor antihemofilic (VIII, AHF)
Parenteral
Factor IX complex (konyne HT, proplex T) Parenteral
Din cauza riscului de infestare HIV au nceput autiliza preparate recombinate
Ex. capre transgenice se secret n lapte factori aicoagulrii
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Hemostatice
Administrare sistemic: - (Amicar)
Ac. Tranexamic (cyclokapron)
Vitamina K Locale
Burete de gelatin (Gelfoam)
Pelicul gelatinoas Celuloz oxigenat (Oxycel)
Colagen microfibrinic (Avitene)
Trombin
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