Biomaterials Research - Manfred Maitz

HEMOSTAZA

ANTITROMBOTICELE HEMOSTATICELE
Grigor Viorel Asistent universitar
2/22/12

Biomaterials Research - Manfred Maitz

Hemostaz procesele ndreptate spre meninerea sngelui n patul vascular, prevenirea hemoragiei i restabilirea fluxului sanguin n caz de ocluzie vascular.

Biomaterials Research - Manfred Maitz

Stadiile procesului hemostatic

Dereglarea peretelui vascular Vazoconstrocie local Adghezia i activarea trombocitelor Formarea trombului trombocitar Stabilizarea trombului cu fibrin Liza trombului dup regenerearea peretelui vascular

Biomaterials Research - Manfred Maitz

Coagularea sngelui
Proprietatea organismului de a controla fluiditatea sngelui n lezarea vascular reprezint un factor important n supravieuire.

Biomaterials Research - Manfred Maitz

FIBRINOGEN o protein fibrilar solubil, reprezint 3% din proteinele plasmei sngelui

Biomaterials Research - Manfred Maitz

COAGULAREA
Thrombin Fibrin

Nucleul reaciei include dou molecule:

fibrinogen i trombin
Fibrinogen

Trombina scindeaz peptidele 2A i 2B, transformnd fibrinogenul n fibrin. Proteinele de fibrin se unesc, datorit afinitii a i b cu locusurile cleioase ale petidelor A i B dup scindare.

Biomaterials Research - Manfred Maina Rube Maitz

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 always handy in case opossum or the woodpecker gets sick and can't work.

Biomaterials Research - Manfred Maitz Sistema de coagulare

a sngelui amintete maina Rube Goldberg

Complexitate inevitabil?

Biomaterials Research - Manfred Maitz

De ce cascad?

Multitudinea etapelor cascadei amplific semnalul; Cascada crete eficacitatea procesului de coagulare; Datorit cantitii mari de proteaze active n preajma leziunii, cheagul se formeaz mai repede, crescnd ansele supravieuirii.

Etapele de coagulare a sngelui

Biomaterials Research - Manfred Maitz

1. Vascular 2. Trombocitar 3. Coagulaional

Biomaterials Research - Manfred Maitz VASCULAR PHASE

PLATELET PHASE

COAGULATION PHASE

Biomaterials Research - Manfred Maitz

Etapa vascular

Vasoconstricie local Adrenalin, noradrenalin, serotin, etc. Dezgolirea tisular (colagen) activeaz factorul tisular i declanleaz coagularea.

Tissue Factor

Biomaterials Research - Manfred Maitz

Etapa trombocitar

Endoteliul vascular prentmpin alipirea i agregarea trombocitelor. Leziunea vascular declaneaz adghezia i agregarea 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

FUNCIA TROMBOCITELOR
1. 2.

Biomaterials Research - Manfred Maitz

3.

4.

Adghezia la endoteliul lezat Pstrarea DP i altor proteine secretate la activarea lor; Agregarea cu alte trombocite; Asigurarea suprafeei (matrice fosfolipidic) pentru nfptuirea reaciilor de coagulare.

Biomaterials Research - Manfred Colman et al. Maitz

PDE- phosphodiesterase

Cyclic AMP

: , , .

Colman et al., Identification of Two Distinct Adenosine Diphosphate Receptors in Human Platelets, Trans. Am. Ass. Phys. 93:305, 306 (1980)

Biomaterials Research - Manfred Maitz

AGREGAREA TROMBOCITELOR:
Declanat de colagen i ADP. ADP amplific agregarea datorit creterii Ca++ i scderea AMPC. ADP determin schimbarea formei trombocitelor, ce d posibilitatea de a se cupla cu fibrinogenul. Ali factori: a. Tromboxan amplific agregarea. b. Prostaciclin diminuiaz agregarea.

1. 2.

3.

4.

Biomaterials Research - Manfred Maitz

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 i 2 Majoritatea factorilor fermeni n stare normal sunt inactivi i capabili de activare consecutiv

Biomaterials Research - Manfred Maitz

CALEA INTRINSEC
Toi factorii se afl intravascular Proces de coagulare lent Test de laborator:
()

CALEA EXTRINSEC
Factorul declanator se afl extravascular factorul tisular Coagulare rapid (secunde) Test de laborator:
Timpul protrombinic (TP) ()

Biomaterials Research - Manfred Maitz

Nomenclatura internaional a factorilor plasmatici ai coagulrii

Fibrinogen Protrombin Tromboplastina tisular, factorul tisular Ionii ++ Proaccelerin (factor labil) Proconvertin (factor stabil) Globulina antihemofilic A (Hemofilia A) Componentul plasmatic al tromboplastinei, f. Kristmas, factor antihemofilic B (Hemofilia B) Stiuart-Prauer, protrombinaza Predecesorul plasmatic al tromboplastinei, f. Rozental (Hemofilia C) Factorul Hageman, f. de contact Factorul fibrinstabilizant

I II III IV V VII VIII IX X XI XII XIII

Biomaterials Research - Manfred Maitz

Cascada coagulrii
Intrinsec Extrinsec

Contact cu o suprafa strin: F colagen F XII XIIa F XI Ca2+ F XIa F IX

F VIII Ca2+

Defect tisular/ celular F Ca2+ F VIIa VII F IXa

Ca2+

F VIIIa Platelet Factor 3

Factor F X

Factor F Xa F Va

Ca2+ FV

F III (Tissue Thrombopla stin) Factor F X

Cheag

Prothro Ca2+ mbin I F F XIII XIIIa Fibrin Fibrin polym mono

Thromb in Fibrin

Biomaterials Research - Manfred Maitz

FIBRINOLIZA Preparate exogene

Streptokinaza product bacterian (posibile reacii imune) Urokinaza produs tisular uman (fr reacii imune) Activatorul tisular al plasminogenului (tPA) produs prin clonare genic (fr reacii imune, scump) Inhibitorii fibrinolizei Analogi lizinici

Acidul aminocapronic, a. Tranexemic

Efectele III / Heparin

Intrinsic Extrinsic
Tissue/Cell Defect F XIIa F XI F XIa
Ca2+

Biomaterials Research - Manfred Maitz

Surface Contact Collagen FXII activator F XII

F VIIa

Ca2+

F VII

Ca2+

F IX
F VIII

F IXa

F VIIIa Platelet Factor 3

F III (Tissue Thromboplastin) Factor F Xa

F Va

Factor F X

Ca2+

Ca2+ FV

Factor F X

Prothrombin I F XIIIa Crosslinked Fibrin Meshwork F XIII Fibrin polymers

Ca2+

Thrombin

Fibrin monomer

Fibrinoge n

Biomaterials Research - Manfred Maitz

Timpul trombinic (TT)

Intrinsic Extrinsic
Tissue/Cell Defect F XIIa F VIIa F XIa
Ca2+

Surface Contact Collagen FXII activator F XII F XI

Ca2+

F VII

Ca2+

F IX
F VIII

F IXa

F VIIIa Platelet Factor 3

F III (Tissue Thromboplastin) Factor F Xa

F Va

Factor F X

Ca2+

Ca2+ FV

Factor F X

Prothrombin I F XIIIa Crosslinked Fibrin Meshwork F XIII Fibrin polymers

Ca2+

Thrombin

Fibrin monomer

Fibrinoge n

Timpul protrombinic dup Quick

Intrinsic
Surface Contact Collagen FXII activator

Biomaterials Research - Manfred Maitz

Extrinsic
Tissue/Cell Defect

F XII F XI

F XIIa F XIa
Ca2+

F VIIa

Ca2+

F VII

Ca2+

F IX
F VIII

F IXa

F VIIIa Platelet Factor 3

F III (Tissue Thromboplastin) Factor F Xa

F Va

Factor F X

Ca2+

Ca2+ FV

Factor F X

Prothrombin I F XIIIa Crosslinked Fibrin Meshwork F XIII Fibrin polymers

Ca2+

Thrombin

Fibrin monomer

Fibrinoge n

Biomaterials Research - Manfred Maitz

Intrinsic
Surface Contact Collagen FXII activator F XII F XI F XIIa

()
Extrinsic
Tissue/Cell Defect F VIIa F VII

Ca2+

Ca2+

F XIa
Ca2+

F IX
F VIII

F IXa

F VIIIa Platelet Factor 3

F III (Tissue Thromboplastin) Factor F Xa

F Va

Factor F X

Ca2+

Ca2+ FV

Factor F X

Prothrombin I F XIIIa Crosslinked Fibrin Meshwork F XIII Fibrin polymers

Ca2+

Thrombin

Fibrin monomer

Fibrinoge n

Stabilirea dereglrilor de coagulare

Crescut Normal TP Normal Crecut TP Crescut Crescut TP Patologia cii interne (cascada de coagulare) Patologia cii externe

Biomaterials Research - Manfred Maitz

Patologia ambelor ci

Biomaterials Research - Manfred Maitz

()

Coagulograma
510 24 200400 109 1 84122 6080 46 IV-V 3545 60140% 58190% 83117% 92109% 1214 24 / 2832 1
<400 /

() VIII V VII () () D- -XIII -III

75125% 85120%

Biomaterials Research - Manfred Maitz

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.

Biomaterials Research - Manfred Maitz

ANTITROMBOTICE
Aciune Inactivarea factorilor de coagulare Inhib sinteza factorilor de coagulare Efect Profilaxia trombozelor venoase Profilaxia trombozelor venoase

Clasa Anticoagulant parenteral

Anticoagulant

Reprezentant Heparin

Varfarin

enteral

Antitrombocitare

Asprin

Scade agregarea trombocitelor Fibrinoliz

Profilaxia trombozelor arteriale Liza trombilor

Trombolitice

Actilyse

Biomaterials Research - Manfred Maitz

Clasificarea
Anticuagulante

Antitrombocitarelor Preparate ce inhib adghezia Preparate ce inhib agregarea Inhibitorii ciclooxigenazei (aspirin, sulfinpirazon) Inhibitorii tromboxansintetazei (diazoxiben, pirmagrel) Antagoniti dublu ai tromboxanului 2 (ridogrel) Blocatori ai complexului glicoproteic IIb/IIIa (abciximab, tirofiban, epifibatid) Modulatorii sistemei adenilatciclazei/Pc (dipiridamol) Preparate cu alte mecanisme de aciune (ticlopidin, clopidogrel)

Aciune direct
Dependente de III Heparinp nefracionat Heparine fracionate Independente de III Hirudina (bivalirudin, ghirughen) Oligopeptide (argatroban, inogatran, novostan, efegartan)

Aciune indirect
Derivai de cumarin (varfarin) Derivai indandione (fenindion)

Biomaterials Research - Manfred Maitz

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 nedorite hemoragii Antidot protamin sulfat

Biomaterials Research - Manfred Maitz

Heparina

1916 McLean descoper heparina 1939 Brinkhous descrie prezena cofactorului heparinei 1968 Abildgaard izoleaz cofactorul heparinei antitrombina III 1978 i 79 Rosenberg i Lindahl descriu interaciunea heparinei i III.

Biomaterials Research - Manfred Maitz

Inhibitorii receptorilor GP IIb/IIIa

Biomaterials Research - Manfred Maitz

1983Coller descrie rolul receptorilor glicoproteici ai trombocitelor Anii 90 cercetarea apoi implimentarea activ a abciximabului, tirofibanului i epifibatidei Rezultate nesatisfctoare n practic toate studiile cu blocatori GP orali.

Biomaterials Research - Manfred Maitz

Anticoagulante indirecte

1929 epidemie de diatez hemoragic la gini descrierea rolului vitaminei K 1939 obinerea dicumarolului 1941 nceputul testrii clinice a anticoagulantelor indirecte. Anii 90 renoirea interesului ctre tratamentul cu varfarin lrgirea indicaiilor

Biomaterials Research - Manfred Maitz

Anticoagulante indirecte

Inhib activitatea epoxidreductazei-K, micoreaz rezervele de vit. K Scade sinteza factorilor de coagulare Kdependeni (II, VII, IX, X)

Biomaterials Research - Manfred Maitz

Anticoagulante enterale

Cumarine varfarin, 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 placentar nu se utilizeaz n perioadele tardive ale graviditii

Biomaterials Research - Manfred Maitz

Antitrombocitare

Aspirin Inhib agregarea/adghezia trombocitelor Utilizare clinic Profilactica trombozelor arteriale Infarct miocardic, AVC, valve protezate Alte preparate Dipiridamol, ticlopidin, clopidogrel

Biomaterials Research - Manfred Maitz

Acid acetilsalicilic

1899Goffman sintetizeaz AAS, nceputul producerii industriale a aspirinei de concernul Bayer. 1967 descrierea efectelor antiagregante a AAS de Weiss i Aledort Anii 70-80 ai sec. XX o serie de cercetri clinice ce au confirmat eficacitatea aspirinei n afeciunile aterosclerotice ale vaselor.

Biomaterials Research - Manfred Maitz

Mecanism de aciune

Aspirina inhib ciclooxigenaza (COX) COX enzima chee, implicat n sinteza de tromboxan 2 Inhib agregarea trombocitelor

Biomaterials Research - Manfred Maitz

Aspirin

A. ARAHIDONIC

CICLOOXIGENAZA

PgG2 i PgH2 (endoperoxizi ciclici)

Tromboxansintetaza

Tromboxan

Agregarea trombocitelor

Biomaterials Research - Manfred Maitz

Utilizarea profilactic a aspirinei

Doze mici (180 g/zi) Previne atacurile ischemice i infarctul miocardic 335 /zi scade riscul coronarian la pacienii mai n vrst de 50 ani Mai mult 1000 /zi efectul lipsete Dozele mari inhib sinteza prostaciclinei ce niveleaz proprietile antiagregante ale aspirinei.

Biomaterials Research - Manfred Maitz

Fibrinolitice

Altteplaza recombinat (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

Biomaterials Research - Manfred Maitz

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 a utiliza preparate recombinate

Ex. capre transgenice se secret n lapte factori ai coagulrii

Biomaterials Research - Manfred Maitz

Hemostatice

Administrare sistemic: - (Amicar) Ac. Tranexamic (cyclokapron) Vitamina K Locale Burete de gelatin (Gelfoam) Pelicul gelatinoas Celuloz oxigenat (Oxycel) Colagen microfibrinic (Avitene) Trombin