Sindroame hemoragipare 2016

HEMOSTAZA NORMALA

I. Etapa vasculara

II. Etapa trombocitara

III. Etapa coagulare

IV. Etapa fibrinoliza

HEMOSTAZA NORMALA

I. Endoteliul- functia

1. bariera de permeabilitate2. secretie:- F. Willebrand,

- trombomodulin - ataseaza trombina, proteina C, S

- fibronectina – inhibitorul activatorului tisular al plasminogenului - PGI2 , Endotelina

- adeziunea prin receptori Gp I - colagenul subendotelial

- fibronectin + f. Willebrand prin Gp IIb IIIa

- fibrinogen

II. Etapa trombocitara

- agregarea - ADP subendotelial - Tx A2

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

COAGULAREA - intrinseca - trombocite activate

colagenul subendotelial factorul XII

- XII XII a - XI XI a

- IX IX a

- X Xa

Ca, F3plachetar- fosfolipide,VIII

COAGULAREA - extrinseca

- tromboplastina tisulara

FT

- X Xa

Proteina C- VII

- fibrinogen fibrina +

fibrinopeptid A,B

COAGULAREA - calea comuna

- X Xa

- II IIa

Ca, F3plachetar,V

Proteina C

COAGULAREA

CLASIFICARE

- Etapa vasculara - Purpura vasculara- congenitala

- dobandita

- Etapa trombocitara - Purpura trombocitara

- trombocitopenie - trombopatii

- Etapa coagulare - Purpura deficienta factorilor de coagulare

- congenitala - dobandita

- Etapa reologica - Purpura ortostatica

- Etapa fibrinolizei - Purpura fibrinolitica

- Etapa activare sistem monocit-macrofag - Purpura CID

Purpure vasculare

- congenitaleEhler Danlos osteogeneza imperfectaRendu - Osler

- dobanditescorbutsenilaSindrom Henoch Schonleininfectioasa - meningococcica, viraledisglobulinemii - Waldenstrom, mielom,

disglobulinemie mixta

Boala Rendu Osler- congenitala

autosomal dominantadefect perete venos

(endoteliu, membrana bazala, adventice)

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

cerebral)

Telangiectazia ereditara

Telangiectazia ereditara

Manifestari clinice

1. telangiectazii cutanate, mucoase 2. epistaxis, hemoptizii, melena 3. anemie feripriva cr4. anevrisme arteriovenoase hepatice cu sindrom hiperkinetic cardiovascular 5. AHC – sugestive boala Rendu

Diagnostic diferential

1. Telangiectaziile sclerodermie (CREST)

2. Pete telangiectatice3. B Fabry (Angiokeratoma corporis

difusum) - boala a metabolismului glicolipidic (ceramide intramacrofagic)

- leziuni nodulare inchise la culoare ( aproape negre) periombilical,

scrotal, cardiac, sistem nervos

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 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 - tratament: Vit C iv

3. Purpure vasculare dobandite

- boli infectioase - boli de tesut conjunctiv

- hiper/disglobulinemii - Henoch Schonlein -cauze rare

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: infectioasa

- 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

Manifestari clinice1. purpura2. hemoragii retiniene3. nevrita periferica Tratament

1. Tratatamentul mielom, etc

2. Plasmafereza

Purpura hiperglobulinemica IgA+IgG - boala

Waldenstrom, mielom

Purpura hiperglobulinemica

Hemoragii subunghiale - crioglobulinemie

Purpura Henoch Schonlein- etiopatogenie

infectie streptococica (faringiana – 50%cazuri, respiratorie)

-alergii alimentare, medicamentoase – (chinidina, sulfamide)

membrana bazala capilara – - complexe imune IgA2

Purpura Henoch Schonlein

Manifestari clinice

Manifestari clinice1. purpura2. poliartralgii3. colica abdominala, melena,

rar perforatia intestinala

4. Hematurie, proteinurie – GNA ac mesangiala focala Prognostic

favorabil in generalevolutie cu “valuri purpurice”

Tratament1. Penicilina – infectie streptococica

2. Corticoterapie – 1mg/kg prednison

Prognostic

- favorabil in general- evolutie cu “recidive purpurice”

- IRA - perforatie intestinala

Complicatii

Purpure vasculare rare

- anticoagulante

- autoflagelare

- staza

Necroza cumarinica

Purpura trombocitopenicaI. Productie scazuta de trombocite- trombocitopenia < 100000/mm

3

- Nr redus de megacariocite in maduva1. infiltrat medular : leucemii,

limfoame, mielom, metastaze, granuloame

2. hipoplazie medulara: idiopaticasecundara: radiatii, medicamente,

virusuri

4. anomalii congenitale: pancitopenia Fanconi, trombocitopenia autosomal recisiva, boala May Hegglin, infectii (rubeola)

3. sindr mielodisplazice: idiopaticasecundara: radiatii, medicamente,

virusuri

- scurtarea duratei de viata a trombocitelor

1. Distructie crescuta : - PTI autoimuna acuta, cronica

- purpura posttransfuzionala

- neonatala alloimuna- post medicamentoasa- autoimuna secundara

- trombocitopenia < 100000/mm

3

- nr crescut de megacariocite in maduva

II. Distructie crescuta trombocite:

Trombocitopenia autoimuna idiopatica

- terminologie- trombocitopenie imuna primara

- trombocitopenie imuna primara persistenta 3-12 luni

- trombocitopenie cronica

Trombocitopenia autoimuna idiopatica

- etiopatogenie- autoanticorpi in plasma si pe membrana trombocitelor

- distrugere prematura a trombocitelor in macrofagele splenice

Purpure trombocitopenica autoimuna idiopatica acuta

- etiopatogenie

- autoanticorpi antitrombocitari IgG

- antigene : virus gripal, rubeolic, hepatitic, HIV, Ebstein Barr,

Manifestari clinice

1. purpura2. poliartralgii3. colica abdominala, melena,

rar perforatia intestinala

4. Hematurie, proteinurie – GNA ac mesangiala focala

Manifestari clinice

- clinic- petesii fara splenomegalie

- paraclinic

- trombocitopenie- maduva: megcariocite numeroase

oprite in maturatie,

- TS prelungit

- 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

Tratament linia I la T‹ 30 0001.Corticoterapia

- Prednison 1-1,5 mg-kgc-zi - Dexametazona 40 mg 4 zile la 28 zile 1-4X - Metilprednisolon pulsterapie 500-1000mg 3 zile lunar 2.Imunoglobuline iv urgente, pre-splen. - Ig in doza mare 1g-kgc 2 zile sau 400mg 5 zile - Ig anti-D pacienti Rd pozitivi

Tratament linia II1.Splenectomia clasica sau laparoscopic-corticorezistenta 6 luni-recidivanti-se poate face la › 50 000 (corticoterapie, Ig.,agonisti ai receptorilor de trombopoietina)-in urgente dupa masa trombocitara - Vaccinare anti S. pneumoniae, N. meningitidis, Haemophilus influenzae

Tratament linia II2.Contraindicatii –refuz splenectomia-Azatriopina, Ciclofosfamida, Vincristin, Ciclosporina A-Danazol- Rituximab-in urgente dupa masa trombocitara -Agonistii receptorilor de trombopoietina Romiplostim s.c. Eltrombopag p.o.

Purpure trombocitopenica autoimuna idiopatica cronica

- etiopatogenie

- anticorpi antitrombocitari anti receptori IIb-IIIa, glicoproteina

Ib

- clinic

- astenie, petesii - “nepalpabile”, fara bule hemoragice, echimoze, - metroragii, sangerari digestive, - fara splenomegalie - paraclinic

- trombocitopenie- maduva: megacariocite tinere

Purpure trombocitopenica autoimuna idiopatica cronica

- femei / barbati = 3/1

- paraclinic

- trombocitopenie

- maduva: megacariocite tinere numeroase oprite in

maturatie,

- TS prelungit

Evolutie- cronica, remisiuni spontane f rare

Tratament- cortioterapie 1mg/kg/zi- 50% remisiune partiala,raspuns la 6 sap

- splenectomie – forme corticorezistente - agonisti de trombopoietina – forme corticorezistente

- imuran – 3 luni +/- vinblastin

- gama globulina iv – 3luni blocarea sistemului monocit-macrofag

- postnatala

- clinic- sindrom hemoragipar imediat dupa nastere

- manifestari grave la urmatorii copii

Purpure trombocitopenica alloimuna

- anticorpi antitrombocitari ce trec placenta

- anti sistemului PI

A1

- clinic

Purpure trombocitopenica posttransfuzionala

- la 7 zile de la transfuzie, masa trombocitara

- anticorpi antitrombocitari - anti sistemului PIA1

- tratament- corticoterapie, plasmafereza,

exanguinotransfuzie

- actiune maduva osoasa

Purpure trombocitopenica postmedicamentoasa

- arabinosid, daunorubicina,- tiazidice, estrogeni

- distructie imuna- antibiotice, sulfamide,

- chinidina, chinina- metildopa

- saruri de aur, - heparina

- mecanism

Purpure trombocitopenica postmedicamentoasa

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

- intreruperea medicatiei, corticoterapie, plasmafereza,

- tratament

- megacariocite normale, intens trombogene ( citoplasma granulata, azurofila, fara vacuole)

TIH- sindrom protrombotic indus de un anticoagulant

Tip I primele 4 zile

- de cauza imuna, severa, progresiva - tromboze arteriale, venoase

Tip II dupa 5-15 zile

- datorata aglutinarii T, usoara, limitata

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

Purpure trombocitopenica autoimuna secundara

- LES - LLC, limfoame

- HIV

- tratament- zidovudin

Purpure trombotica trombocitopenica

- sarcina, anticonceptionale, infectii - Coxackie, micoplasme, - antibiotice

- morfopatologic

- context

- 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

- tratament

- IRA, sindr hemoragipar, rar sindrom neurologic

- prognostic- 50-80% mortalitate

- plasmafereza, exanguinotransfuzia

Sindroame hemoragipare prin

anomalii de coagulare si

fibrinoliza

- Etapa coagulare - Purpura deficienta factorilor de coagulare

- congenitala - dobandita

-Etapa fibrinolizei - Purpura fibrinolitica

- anomalii primare ale fibrinolizei- anomalii secundare: CID

COAGULAREA - intrinseca

colagenul subendotelial factorul XII

XII XII akininogenprecalicreina

XI XI a

IX IX a

X Xa

“Complex” la nivelul endoteliuui

COAGULAREA - intrinseca

XII XII akininogenprecalicreina

XI XI a

IX IX a

X Xa

COAGULAREA - extrinsecaVIIIa

Ca, F3plachetar

(1)factor tisular + F VII + Ca

VIII

colagenul subendotelial factorul XII

fibrinogen fibrina

Faza comuna a in coagularea intrinseca si extrinseca X Xa

II IIa

Fibrinoliza

+tPA

Pro UK

PAI

trombina

Plasminogen

Plasmina-

+

+

Fibrina

PD Fibrina

fibrinogen fibrina

Anticoagularea naturala

X Xa

II IIaInactiveaza Va

Proteina CProteina S

Proteina C a

Trombomodulina + trombina

Inactiveaza VIIIa

Antitrombina

Sindrom hemoragic prin anomalii de coagulare

1. Hemofilia A deficienta factor VIII

- anomalia genei F VIII – bratul lung cromozom X - mutatii punctiforme, deletii importante

- boala afecteaza aproape exclusiv barbatii, deoarece la femei heterozigote cromozomul X asigura sinteza necesara de f VIII

- incidenta 1/ 10 000

Hemofilia A - deficienta factor VIIIX

y xx

Xy

Xyx

xXy

Xy

Xy x

xx

xX Xy

xx

xxX

XX X

y

Generatia I

Generatia II

Generatia III

Generatia IV

X

Xy

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

- AND fetal

- Concentratie F VIII = scazuta

- Forme- severe …….. 1% activitate f VIII

- medii …….. 1-5% activitate f VIII

- usoare …….. 5% activitate f VIII

- f usoare .… 5 - 25% activitate f VIII

Tratament

• Profilactic de 2X pe saptamana• CurativKogenate 1000 UI 15 flOctanate 500 UI 13 fl• 1UI/kgc factor VIII creste concentratia

plasmatica cu 1%

Tratament

- crioprecipitat plasma Forme medii

Forme usoare

- desmopresin – creste nivelul F VIII

- EACA – inainte de extractii dentare inhibitor de fibrinoliza ( inhiba activatorul tisular plasminogen)

Tratament

- concentrat de factor VIII - prin absorbtie pe anticorpi monoclonali sau f VIII recombinat

- chirurgia majora, ortopedica - cu pretestarea inhibitorului FVIII – pentru nivel 50% a FVIII,2 sapt - adm la interval de 8 ore sau 12 ore

- profilactic - la simptome, fara hematoame, a redus hemartroza

Forme severe

1. Hemofilia B – boala Christmas deficienta factor IX

- Anomalia genei IX – bratul lung cromozom X

- mutatii punctiforme, 1/3 spontane- microdeletii

- 800 pattern- uri de anomalii moleculareex: factor IX Leiden – 11 mutatii punctiforme

- Factor IX - sinteza hepatica dependenta de vit. K

- 20% din hemofilii

1. Hemofilia B – boala Christmas deficienta factor IX

- Paraclinic – concentratia fact IX < 1%

- Tratament – plasma proaspata, - complex protrombinic liofilizat ( risc de tromboze)

- Clinic – sindrom hemoragipar expresie fenotipica variabila

- ameliorare la pubertate, sub androgeni

1. Boala fon Willebrand- precursor F Willebrand sintetizat de endoteliu si megacariocite- functii F Willebrand

- adeziunea trombocit la endoteliu- transportor f VIII

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

- concentratia plasmatica: 10 mg/dl

- 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)- spectru normal al multimerilor la

electroforeza in agaroza

- activitatea F VIII scazuta

- 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

domeniul A2 – deficienta de secretie sau proteoliza a multimerilor vWF, - FvW si F VIII – concentratii normale

- BvW tip II b – descrestere FvW cu greutate moleculara mare, legare inadecvata de

plachete si eliminare a Pl+FvW anormal, cu trombocitopenie secundara

- mutatie in domeniul I ce se laga de glicoproteina Ib IX

- - FvW si F VIII – concentratii

normale

- 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:

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

- femei si barbati- hemoragii cutanate si mucoase

- Tratament: crioprecipitat, desmopresin

- forme:- usoare, medii, severe

- DG. paralinic:

- 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

- Tratament – plasma proaspata inghetata o infuzie/zi

- transmitere autosomal recesiva - mai frecventa la evrei din Ashkenazi

- Clinic – sangerare posttraumatica - menometroragii

Deficienta de factor V, VII. X si II

- Tratament – plasma proaspata inghetata o infuzie/zi

- transmitere autosomal recesiva - rare

- Clinic – sangerare posttraumatica - menometroragii

Afibrinogenemia si disfibrinogenemia

- Tratament – plasma proaspata inghetata

- Clinic – sangerare - tromboze in disfibrinogenemie (rar)

- Paraclinic- afibrinogenemie: scaderea concentratie de fibrinogen

- disfibrinogenemie: - Timp protrombina prelungit - Timp tromboplastina prelungit

- Timp trombina prelungit

1. Deficienta dobandita a factorilor de coagulare

- vitamina K -- plante- sintetizata de flora intestinala

vit K

epoxidaza

reductaza

vit K epoxid

Anticoagulanti cumarinici

- Deficienta vitamina K influenteaza -- f II- f VII- f IX- f 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

- Tratament - - plasma proaspata, sange proaspat - vit K parenteral – 10mg - restabileste depozitele hepatice in 8 -10 ore

- paraclinic -- TC – prelungit, T Quik - prelungit

- 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

PDF exces in microcirculatie

XII a

Tromboze

Fibrinoliza in excesActivare coagulare in microcirculatie

Sangerare difuza

XII a

PDF exces in microcirculatie

PDFcoagulare fibrinoliza

Tromboze Sangerare difuza

- neurologic : semne focar, convulsii, coma

- piele : ischemie focala, gangrena

- plaman : SDRA

- gastrointestinal : sangerare acuta

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

- petesii,- sangerare - pe mucoase -(gastrointestinala, hemoptizieepistaxis) - neurologica

Coagulare intravasculara diseminata

Coagulare intravasculara diseminata

CID – dg. paraclinic 1. trombocitopenie

2. AH microangiopatica

schizocite

3. TC >, aPTT >, TQ >

5. PDF+++4. Fibrinogen <

- Tratament

- tratamentul bolii de baza - reechilibrare hidroelectrolitica - heparina –1000 UI/ora, 5000 UI la 4ore - EACA = 4-6g/24 ore

( blocheaza PDF)

Coagulare intravasculara diseminatacronica

-hemangioame gigante-carcinoame metastatice-fetus mort

CID cronic– dg. paraclinic 1. Trombocite-N sau usor

2. AH microangiopatica

schizocite3. aPTT -N, TQ -N

5. PDF+++4. Fibrinogen -N

- Fibrinoliza

activator tisular plasminogen

plasminogen tromb

plasminafibrina

PDF

anti plasmina2

PAI

- Fibrinoliza primara

- deficitul anti plasmina2

- scade mult fibrinogenul

- sindrom hemoragipar

- aPTT, T Quick – aproape normale - trombocite normale

- paraclinic

- tratament - plasma proaspata, EACA

ELEMENTE CLINICE DIAGNOSTIC DIFERENTIAL

- varsta, sex - Sindromul hemoragipar

- conditii de declansare - purpura - localizare - leziuni palpabile, buloase,

micronecrotice - acuta, cronica

- hemoragii: mucoase, articulare, SNC

ELEMENTE PARACLINICE DIAGNOSTIC DIFERENTIAL

- Timp sangerare - Trombocite - Timp coagulare

- concentratie f VIII, IX, von willebrand

- aPTT - t Quick

- PDF - liza cheagului

- fibrinogen