explorarea hemostazei (1)
TRANSCRIPT
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EXPLORAREA HEMOSTAZEI
2009-2010
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DEFINITIE
Proces de formare a coagulului sanguin la locul de injurie a unui vas de sange pt a stopa pierderile de sange
Proces rapid, localizat si foarte bine reglat
Sangerari anormale sau tromboze pot sa apara cand elemente specifice ale acestui proces lipsesc sau sunt disfunctionale
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Elemente cheie
• Sistemul vascular – endoteliu
• Plachete
• Factori ai coagularii
• Sistemul fibrinolitic
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FAZE PROCES HEMOSTATIC
DIDACTIC: HEMOSTAZA PRIMARA dop plachetar instabil HEMOSTAZA SECUNDARA coagul fibrino-plachetar stabil
FIZIOLOGIC – 4 faze: Initierea si formarea dopului plachetar
Propagarea procesului de coagulare de catre cascada coagularii
Finalizarea coagularii prin interventia mecanismelor de control antitrombotice
Inlaturarea coagulului prin fibrinoliza
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Formarea dopului plachetar
Plachetele sunt activate la locul injuriei pt a forma dopul plachetar initial ce asigura efectul hemostatic si stopeaza sangerarile mici si moderate
Raspuns functional plachete: ADEZIUNE – depunere plachete pe matrixul subendotelial AGREGARE – coeziune plachete-plachete SECRETIE – eliberare continut granule ACTIVITATE PROCOAGULANTA – amplificarea formarii de trombina
Activare plachete – de catre numerosi stimuli fiziologici: ADP, epinefrina – activatori slabi trombina, colagen – activatori puternici
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Secvente normale hemostaza(4 pasi)
1. Vasoconstrictie arteriolara Reflex neurogenic
Reducere sangerare
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2. Expunere subendoteliu – formare dop plachetar
ECM, in special colagen
Plachetele adera si devin active
▪ Modificari forma▪ Eliberare continut granule
Agregare plachete pt formare dop plachetar
Secretie – eliberare continut plachetar
= hemostaza primara
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3. Factorul tisular eliberat la locul injureiei de catre celulele endoteliale Interactioneaza cu factorii eliberati de plachete Activeaza cascada coagularii pornind de la nivelul
plachetelor activate
• Este activata trombina• Sunt recrutate si activate alte plachete
In final – depunere fibrina = hemostaza secundara
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4. Formarea dopului fibrinoplachetar stabil
Previne hemoragia
Interventie mecanisme de control (t-PA) limiteaza formarea dopului fibrinoplachetar doar la nivelul injuriei
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Cascada coagularii
Conversia in cascada a unor serii de proenzime inactive in enzime active formare trombina
Trombina converteste fibrinogenul plasmatic solubil in fibrina insolubila
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FACTORII COAGULARII
1. Zimogeni sintetizati hepatic, vitamina K dependenti: F II – protrombina F VII - proconvertina F IX- Christmas (hemofilia B) F X – Stuart Prower Proteina C – anticoagulant, cofactor proteina S
! Formele activate ale fact VII, IX, X, asociaza cofactori specifici pt indeplinirea rolului in cascada coagularii: VIIa – factor tisular, IXa – VIIIa, Xa – Va.
! Trombina actioneaza direct asupra fibrinogenului ca fact procoagulant; in asociere cu trombomodulina anticoagulant prin activarea proteinei C.
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procoagulanti
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FACTORII COAGULARII2. Cofactori solubili: F V – proaccelerina F VIII – antihemofilic A F von Willebrand – molecula carrier pt FVIII Proteina S – anticoagulant, cofactor clivare si inactivare Va, VIIIa
3. Factori de contact: F XI – activat in vitro de F XII, in vivo nu necesita obligatoriu factorii de
contact, poate fi activat de trombina de pe supraf plachetara F XII - Hageman HMWK(kininogen) - Fitzgerald Prekalikreina- Fletcher
4. Cofactori celular asociati: Factorul tisular – TF (III, tromboplastina tisulara) factor major de initiere
coagulare in asociere cu VIIa
5. Fibrinogenul (F I)6. F XIII – stabilizator fibrina
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procoagulanti
Responsabili de activarea de contact a coagularii
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FACTORI INHIBITORI / REGLATORI
Inhibitorul caii factorului tisular- rol inhibitor pt fact Xa si VIIa/TF
Antitrombina III – ATIII- blocheaza situsurile active ale trombinei, fact Xa si IXa
Proteina C – sinteza hepatica, activata de complexul trombina-trombomodulina, actioneaza ca si cofactor pt proteina S in inactivarea factorilor Va, VIIIa
Proteina S – sintetizata hepatic, asociaza proteina C si Ca in reglarea coagularii
Trombomodulina- gp sintetizata de celula endoteliala, leaga -trombina schimbandu-I specificitatea de substrat
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MODEL CELULAR HEMOSTAZA
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CELULA TF+
VIITF, receptor pt F VII
VIIa/TF cx
Activare X trombinaActivare TrActivare VActivare VIIIActivare XI
Activare IX
Tr activat
VIIIa
XIa
IXa
X
Xa
Va
II
IIa
ADP
Tromboplastina intrinseca
adrenalina
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Caile coagularii
Doua cai de formare a fibrinei
• Intrinseca• Initiata de suprafete incarcate negativ
• Extrinseca• Initiata de injuria tisulara
Ambele converg catre cale finala comuna
• Protrombin a Trombina
• Fibrinogen Fibrina coagul
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Activarea in cascada a sistemului coagularii
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Controlul coagularii Antitrombine (e.g., antitrombina III)
Proteina C and S Sistemul fibrinoltic
• Plasminogen plasmina produsi de dgradare ai fibrinei (PDF) – D-dimer reprezentant major al PDF
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Anticoagulanti naturali
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Sistemul fibrinolitic
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Fibrinoliza
http://www.si.mahidol.ac.th/department/biochemistry/home/md/courseware_202/lec/hemostasis_lec.pdf
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Reglarea fibrinolizei
http://www.si.mahidol.ac.th/department/biochemistry/home/md/courseware_202/lec/hemostasis_lec.pdf
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Dezechilibru hemostaza
coagulare
antifibrinoliza
defect
Hemoragii
fibrinoliza
anticoagulare
defect
Tromboze
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Bleeding disorders
Vascular abnormalities
Platelet disordersClotting factorabnormalities
DIC
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Plasma Componenta non-
celulara a sangelui
Ser Plasma fara fibrinogen si Alti factori ai coagularii
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Evaluare de laborator
Timp vasculo-plachetar- numar trombocite
- teste functionale
agregare plachetara
activitatea ristocetinei
- timp de sangerare
- testul garoului (Rumpel-Leede)
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NUMAR TROMBOCITE Numarare manuala – imprecisa, consumatoare de timp Metode automate - rapid, precis
Metode optice Flow cytometrie
N = 150,000 - 450,000 /mcL - trombocitopenia – risc crescut de sangerare - trombocitoza- tromboze
TESTE FUNCTIONALE PLACHETARE Raportul numarului de plachete pt evaliuare functionala – raportul
intre numarul de plachete dintr-o proba de sange, inainte si dupa stimularea cu un agonist (ADP, epinefrina) evalueaza capacitatea de agregare corelat bine cu agregometria
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Agregometria plachetara implica o serie de teste efectuate pe sange integral sau plasma imbogatita in plachete , utilizand cativa agonisti.
Acid arahidonic. Trombina ADP Epinephrine Collagen Ristocetin- necesita FWv si receptori membranari integrii
EVALUARE FUNCTIONALA PLACHETARA
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Agregometria plachetara Clasica – plasma imbogatita in plachete (obtinuta prin
centrifugare) stimulata cu ADP, epinefrina, ristocetina – evaluare agregate prin turbidimetrie
Depinde de functia normala a plachetelor, de concentratia de agonisti
nu poate detecta agregate formate din mai putin de 100 Tr
Agregometrie sange integral Prin impedanta electrica
Light scattering methods Analiza flow-citometrica a marimii particulelor
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Platelet function analyzer (PFA-100®)
Expunere plachete sange integral la un flux rapid (5000 to 6000/sec) prin tuburi capilare si monitorizarea scaderii fluxului pe masura formarii dopului hemostatic in centrul unei membrane acoperite cu ADP si colagen
Rezultatul testului exprimat ca timp de inchidere
Poate inlucui timpul de sangerare in vivo
Test screening pt evaluare functionala
Nu este speific unei anomalii
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EVALUAREA ACTIVARII PLACHETARE
MARKERI SOLUBILI AI ACTIVARII – factorul 4 plachetar, beta tromboglobulina, TX B2
Flow citometrie - CD62p, CD63, LAMP-1, CD40L, GpIIb/IIIa complex
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Agregarea Ristocetin indusa
Masoara afinitatea de legare a factorului vW la receptorul plachetar GP Ib
Plasare plachete pacient intr-o serie de eprubete in care se adauga concentratii joase de risatocetina (0.4 - 1.2 mg/mL)
Se urmareste formarea sau nu a agregatelor in fiecare tub
Ristocetina adaugata la sangele normal determina aglutinare
In boala von Willebrand, unde factorul von Willebrand este defect sau absent apare aglutinatinare anormala
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VWF antigen - ELISA
VWF activitate Activitatea cofactorului ristocetinic (VWF:RCo), "gold
standard" pt activitatea VWF
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Activitatea cofactorului ristocetinic si nivelul FvW in hemostaza primara
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Boala in cauza Activitatea CoF Ristocetinic
FvW
B von W tip III
B von W tipIIB prin consum
B von W tip I, IIA dg dificil, nivel FvWn
Pseudo-B von W prin consum
Sd. Bernard Soulier
N
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TIMPUL DE SANGERARE Metoda Duke (lobul urechii) Metoda Ivy (antebrat) Test de sange ce urmareste cat de repede se opreste sangerarea de
vase mici Islab reproductibil, invaziv, consumator de timp Cu toate acestea - screening test de prima intentia in clinica
Normal 2-10 minute (Ivy) Valori crescute - thrombocytopenia, disseminated intravascular coagulation
(DIC), Bernard-Soulier disease, Glanzmann's thrombasthenia, Aspirin
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EXPLORAREA GLOBALA A HEMOSTAZEI
1. TIMPUL DE SANGERARE TS METODA DUKE
Tehnica: dezinfectare lob ureche sau pulpa deget inelar, intepatura de 3-4 mm adancime, tamponare cu hartie de filtru din 30 in 30 de secunde pana la oprirea sangerarii.
Normal = 2-4 minute METODA IVY
Tehnica: incizie pe fata anterioara a antebratului sub o presiune constanta de 40 mm Hg obtinuta cu manson tensiometru, cronometrare timp necesar hemostazei; incizie standard greu de obtinut.
Normal = 4 – 10 minute
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TS:
•reproductibilitate dificila, standardizare dificila•este inconstant modificat in anomalii de vas•scade usor odata cu inaintarea in varsta•nu exista corelatii intre TS si pierderile de sange intravisceral•test primar de screening de ale carui limite trebuie sa tinem cont
• Testul de toleranta a aspirinei – prelungeste TS la cei la limita; discutabil
Semnificatie: TS alungit orienteaza catre o vasculopatie, trombocitopenie, alterare fct Tr (aspirina) si mai rar catre o coagulopatie.2. NUMAR SI FUNCTIE TROMBOCITARA
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1. EXPLORAREA REZISTENTEI VASCULARE PROBA VENTUZEI
• Tehnica: decompresiune a unei suprafete cutanate cu ajutorul unei palnii de sticla sau ventuze conectate la o pompa aspiratoare si manometru cu mercur - se determina momentul de aparitie si numarul de petesii aparute ca rezultat al decompresiunii.
• Rezistenta capilara normala nu apar petesii pana la o decompresiune de 20-25 mm Hg la adult, 30 mm Hg copil.
PROBA RUMPELL-LEEDE • Tehnica: tensiometru aplicat deasupra cotului si se ridica presiunea la o valoare intre
presiunea sistolica si cea diastolica timp de 5 minute.• Rezistenta capilara normala nu apar petesii. Fragilitate capilara cu atat mai mare cu
cat numarul si intinderea petesiilor sunt mai mari.
Intrucat rezistenta si permeabilitatea capilara depind de integritatea morfologica si functionala a vasului dar si de numarul si calitatea trombocitelor, proba ventuzei si Rumpell-Leede sunt pozitive atat in vasculopatii cat si in afectiuni plachetare.
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PT, INR PTT, aPTT
TT
ACT
Cascada coagularii
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EXPLORAREA TIMPULUI PLASMATICTIMPUL DE COAGULARE (TC)-Lee-White: timp coagulare sange venos in eprubeta hemostaza, la 370; n=8 – 12 min. Evalueaza calea intrinseca, sensibilitate scazuta.
TIMPUL HOWELL (TH) timp coagulare plasma decalcificata (recoltare pe sodiu citrat) dupa recalcificare, la 370 cronometrare timp formare cheag fibrinaEvalueaza calea intrinseca, punct de pornire FXII activat de supraf electronegativa a eprubetei (1,10-2,10 min) nu deceleaza tulburari minore coagulare
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Timpul de cefalina sau de tromboplastina partiala (PTT)
exploreaza coagularea intrinseca + comuna
timp recalcificare plasma saraca in trombocite cu suspensie cefalina (tromboplastina partiala ) n=70-110 s
valori normale in diateze hemoragice de natura plachetara (Tr este exclus din test, plasma saraca)
prelungire in deficit factori tromboplastinici sau al complexului protrombinic
PTTaPTT
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APTT – deficit factori coagulare IX, XI, VIII, XII, PK, HMWK, sau prezenta inhibitori
-aPTT descopera inhibitorii obisnuiti: anticoagulanti lupici, Ac anti-fosfolipid care interfera cu reactivul fosfolipidic folosit in reactie diluarea plasmei scade concentratia inhibitorilor si aPTT tinde sa scada
-aPTT folosit pt monitorizarea terapiei cu heparina: aPTT=1,5-2,5x timp referinta
Timpul de tromboplastina partiala activata (aPTT)
cefalina (tromboplastina partiala) + plasma cercetata expusa la suprafete incarcate negativ (activata) , aceasta fiind diferenta fata de PTTn=40-60 s
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EXPLORAREA ETAPELOR COAGULARII
I. TROMBOPLASTINOFORMAREA
Timp de consum de protrombina (TCP)= ser cercetat+tromboplastina calcica +plasma adsorbita (VIII, XI, V) sau fibrinogen n= 30 sec
investigheaza formarea protrombinazei pe cale intrinseca
este singurul test care se lucreaza pe ser si singurul la care valorile scazute sunt patologice
evidentiaza indirect deficite factori coagulare XI, IX, VIII
Mecanism: protrombina reziduala din ser se transf in trombina in prezenta tromboplastinei calcice. Deficit al formarii protrombinazei (IX, XI, VIII) face sa ramana cant mare de protrombina care in prezenta tromboplastinei calcice formeaza cheagul mai rapid.
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CALE INTRINSECA CALE EXTRINSECASuprafata incarcata negativ (in vitro-sticla, caolin, dextransulfat)
Factorul tisular
XII
XIa
XIIa
IX
XI
VIIIa
X
VaVVIII
I
II
XaIXa
IIa
VIIa-VII Ca2+
PK, HMWK
Ca2+
Ca2+
PL membranar
Ia
PL membranar
Ca2+
T. TrombinaT. Reptilaza(15 -20”)
TENAZA
PTT, aPTT (40-60 “)
TQ/TP(11-15 “)
TCP (30”)
PROTROMBINAZA
T Howell=1,1-2,1 min
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Teste de corectie
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• constau in refacerea timpului Howell si aPTT cu reactivi ce contin factorul considerat deficitar•Reactivii folositi sunt:
•plasma normala proaspata – contine toti factorii (PN) •plasma normala proaspata adsorbita pe sulfat de bariu – contine F VIII si XI (PAD)•ser vechi – contine F XI si IX (SV)•cefalina in suspensie (C) – daca se lucreaza T Howell, aici participa si Tr
eprubeta E1 E2 E3 E4
Reactiv PN PAD SV C Deficit de factor
Corectia testului
+ + - - VIIIHemofilia A
+ - + - IXHemofilia B
+ + + - XIHemofilia C
+/- - - + Fp3
- - - - Inhibitoriprotrombinaza
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II. TROMBINOFORMAREA
timpul Quick / timp protrombina = plasma de cercetat (citratata, fara Tr post centrifugare la 2500 g, 15 min) + tromboplastina calcica n= 11-15 sec.
evalueaza factorii II, V, VII, X, trombino, fibrinoformarea cale extrinseca
- deficit II, V, VII, X, deficit vit K, hipo/afibrinogenemii
INR= International Normalized Ratio protrombine time ratio (PTR)=timp protrombina pacient/timp martor (PTR =1 la n, =1,5-2,5 la cei cu anticoagulante orale)
INR = PTRISI = 0,5-1,5 (ISI – index international de sensibilitate)
T QUICKVII
X
II
V
FIBRINOGEN> 1,5 - hiopcoagulabilitateINR=2-3 la subiecti sub anticoagulant< 2 – risc tromboza>3 – risc hemoragie
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Testul Koller = vitamina K parenteral la subiecti TQ + determinare TQ
TQ normal deficit aport sau absorbtie vitamina K
TQ alungit defect de utilizare
Timp Quick si timp partial tromboplastina in paralel = cale extrinseca + intrinseca
F II – protrombinaF VII - proconvertina F IX- Christmas (hemofilia
B)F X – Stuart Prower
Vit K
Testul generarii de tromboplastina:
plasma normala adsorbita (V, VIII, XI, XII)
ser normal (IX, X, XI, XII)
plachete (factorul III lipoproteic)
2 din reactivii de mai sus + 1 componenta pacient identificare defect in ser, plasma, trombocit
+ Ca tromboplastina
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Algoritm de diagnostic utilizand teste de coagulabilitate globala
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aPTT TQ (timp protrombina)
Deficit de factori
N CALE INTRINSECAXII, XI, IX, VIII
N CALE EXTRINSECAVII (parahemofilia Alexander)
CALE COMUNAX, V, II, IDEFICIT MULTIPLU (coagulopatie dobandita)
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dozare fibrinogen plasmatic (gravimetric, colorimetric)
- hepatopatii severe, leucoze, fibrinolize primare, secundare
- infectii, hemopatii maligne, colagenoze, etc
activitate factor XIII- dizolvare cheag cu acid monocloracetic
cheag>2 ore – normal, < 5-15 min-lipsa factor XIII
III. FIBRINOFORMAREA
timpul de trombina = timp coagulare plasma oxalatata + exces trombina= timp de conversie fibrinogen fibrina
- deficit sau exces (inhiba activitatea trombinica) de fibrinogen; fibrinogen n cu anomalii fct.; inhibitori fmare fibrina: substante heparin-like (neoplazii), exces PDF
plasma normala corecteaza TT in hipo si afibrinogenemii, partial in fibrinoliza acuta
timpul de reptilaza
reptilaza coaguleaza fibrinogenul si este insensibila la anticoagulanti
in prezenta inhibitori polimerizare fibrina, normal in caz anticoagulanti antitrombinici
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Algoritm de diagnostic in investigarea fibrino-formarii
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FIBRINOGENEMIA TIMP TROMBINA
TIMP REPTILAZA
DIAGNOSTIC
HIPOFIBRINOGENEMIE
N DISFIBRINOGENEMIE
N N ANTICOAGULANTI CIRCULANTI
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Retractia cheagului
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• metoda de explorare a timpului trombodinamic• investigheaza indirect si hemostaza primara, depinde de activarea trombocitara, se desfasoara normal in functie de numarul si functia trombocitelor• recoltare 5 ml sange, eprubeta in baie de apa la 37 grade, se apreciaza retractia cheagului la 2 si la 24 ore prin cantitatea de ser expulzat• n= 30% ser expulzat la 2 ore si 45% dupa 24 ore
• varianta: apreciere retractie pe lama timpul necesar pt aparitia unei picaturi de ser pe lama cu o pic sange• n=30 min
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EVALUAREA FIBRINOLIZEI
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Plasminogen
Plasmina
Extrinsec: t-PA, urokinaza
Intrinsec: factor XIIa, HMWK, kallikrein
Exogeni: streptokinaza
Fibrina, fibrinogen
Fibrina, fibrinogen, produsi degradare
1. Timpul de liza a cheagului euglobulinic2. Evidentierea produsilor de degradare fibrina
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1. Timpul de liza a cheagului euglobulinic- TLCE
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• plasma de cercetat citratata, fara plachete (inlaturare prin centrifugare la viteza inalta, deoarece contin inhibitor-1 al plasminogenului) diluata cu apa distilata pt a scadea puterea inhibitorilor fibrinolizei + acid acetic precipitare fractiune euglobuline (factori ai coagularii, t-PA, complex activator tisular plasminogen-inhibitor1 al activatorului tisular al plasminogenului)• dizolvare precipitat in mediu tamponat• coagulare prin adaos de trombina cheag euglobulinic• liza cheagului euglobulinic in 60 minute• interpretare:
• TLCE - sindrom fibrinolitic – supraacut < 15 min, acut 15-30 min, subacut 30-60 min• nu poate face diferenta intre un sindrom fibrinolitic primar (crestere t-PA, scadere inhibitor t_PA) si unul secundar (CID)
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2. Evidentierea produsilor de degradare fibrina-PDF
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• PDF exista in ser in cant foarte mici, nedecelabili prin metode obisnuite• cresterea concentratiei se face fie prin cresterea productiei, fie prin scaderea degradarii si eliminarii lor
• reactie de hemaglutinare: aglutinare particule de latex acoperite cu Ac anti-fibrinogen
• daca testul foloseste Ac policlonali, nu se face diferenta intre monomeri si D-dimeri fibrina• test cu Ac monoclonali metoda dozare D-dimeri
• n: PDF – monomeri <10 mcg/ml; D-dimeri <250 mcg/ml
•Nivele crescute PDF:•CID, fibrinoliza primara, ciroza hepatica (asociaza un grad de CID dar si scaderea eliminare PDF), tumori solide, tromboza venoasa periferica, TEP
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Algoritm de interpretare valori PDF
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CID FIBRINOLIZA PRIMARA
CIROZA HEPATICA, TUMORI SOLIDE, LEUCEMII
TROMBOZA VENOASA PERIFERICA
PDF D-dimeri
PDFD-dimeri --
PDFD-dimeri
D-dimeri (nivele detectabile)
Diagnostic diferential CID – fibrinoliza primara
TLCE TQ aPTT Tr T. TROMBINA
FIBRINOGEN
PDF D dimeri
CID
FIBRINOLIZA PRIMARA
n n
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Cauze ce determina anomalii ale testelor de hemostaza
Partial Thromboplastin
Time (aPTT)
Prothrombin Time (PT)
Thrombin Time (TT)
Bleeding Time (BT)
Factor deficiency (except VII)
VII, X, V, II, fibrinogen deficiency
Low or absent fibrinogen
Thrombocytopenia
Antibodies to clotting factors
Antibodies Dysfibrinogenemia, hypofibrinogenemia
Von Willebrand’s disease
Heparin Warfarin; Vit K defficiency (mild to severe)
Heparin Drugs (Aspirin, NSAIDs, high dose penicillins, etc.)
Excessive Warfarin Excessive Heparin Cirrhosis, Uremia, PLTs dysfunction
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TESTE SCREENING:
Numar trombocite
Timp partial tromboplastina activata / PTT, aPTT
INR, timp protrombina/TQ
Timp trombina
Timp sangerare
Fibrinogen, dimeri
Retractia cheagului
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Test Purpose
Formation of initial platelet plugs
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