SINDROMUL ANTIFOSFOLIPIDIC - Baicuspancreatita acuta, infarct splenic, sd Budd-Chiari Manifestari...
Transcript of SINDROMUL ANTIFOSFOLIPIDIC - Baicuspancreatita acuta, infarct splenic, sd Budd-Chiari Manifestari...
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SINDROMUL ANTIFOSFOLIPIDIC
Simona CaraiolaMedicina interna Colentina
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DEFINITIE SAFL
SAFL-trombofilie dobandita cu patogenie autoimuna
SAFL-asocierea unor manifestari clinice caracteristice (tromboze recurente) cu prezenta anticorpilor antifosfolipidici patogeni: aCL, LA, ac antibeta2 glicoproteina I
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Manifestarile clinice sunt consecinta trombozelor arteriale si/sau venoase in vase mari si/sau mici
Tromboze vase mari, medii, mici-macroangiopatia trombotica
Tromboze arteriole, venule, capilare-microangiopatia trombotica
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FORME CLINICE SAFL
SAFL PRIMAR
lipsesc semnele unei boli concomitente
SAFL SECUNDAR
asociat unei boli-cel mai frecvent LES
SAFL CATASTROFIC
tromboze arteriale si/sau venoase multiple-mortalitate peste 50%
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CADRUL NOSOLOGIC
Afectare teritoriu vascular in SAFL-este SAFL o vasculita?
Bolile care afecteaza vasele:
Vasculite
Perivasculite
Vasculopatii
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VASCULITE/PERIVASCULITE vs VASCULOPATII
Vasculita
infiltrat inflamator in peretele vascular
eventual necroza perete vascular
Vasculopatie
edem endotelial (activare endoteliala)
lumen redus prin proliferare miointimala
ingrosarea, hialinizarea mediei
lamina interna intacta
fibrina, trombocite in peretele
vascular si/sau lumen
Perivasculita
infiltrat inflamator adventicial (perivascular)
SAFL ESTE O VASCULOPATIE, O BOALA “REUMATOVASCULARA”
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ETIOPATOGENIA SAFL-NECUNOSCUTA(I)
FACTORI DECLANSATORI= activarea de catre aFL a celulelor endoteliale, monocitelor si trombocitelor, interactiunea acestora cu proteine ale coagularii si cu sistemul complement
Centrul patogeniei=activarea celulei endoteliale
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ETIOPATOGENIA SAFL-NECUNOSCUTA(II)
Prezenta factorilor favorizanti:
boli colagen-vasculare
infectii: sifilis, HIV, HCV, septicemii
medicamente: propranolol, fenitoin, antiTNFalpha, amoxicilina
estrogeni
fumat...
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PREVALENTA AFL
aFL in populatia generala:
aCL -1-5%
LA - 0-4%
ac antibeta2 glicoproteina I - sub 2%
Framingham:
aCL - 10%-varsta sub 40 de ani
aCL - 40%-varsta peste 80 de ani
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MANIFESTARI CLINICE IN SAFL(I)
Tromboze in orice teritoriu vascular
Manifestari clinice extrem de polimorfe care pot afecta orice organ
Tromboze acute, dar si tromboze cu tendinta la cronicizare si cu potential de deteriorare functionala progresiva a oricarui organ afectat
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MANIFESTARI CLINICE IN SAFL(II)
Tromboza venoasa cea mai frecventa
tromboza venoasa profunda membre inferioare complicata/nu cu tromboembolism pulmonar
Tromboza arteriala cea mai frecventa
tromboza artere cerebrale: AVC, AIT
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MANIFESTARI CLINICE IN SAFL(III)
Tromboze periferice:
tromboze venoase profunde, superficiale mb. superioare, mb. inferioare
tromboze arteriale mb. superioare, mb. inferioare
Manifestari pulmonare: embolii, microtromboze, hemoragii, hipertensiune pulmonara
Manifestari neurologice
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MANIFESTARI CLINICE IN SAFL(IV)
Manifestari cardiace: trombi intracardiaci, infarct, angina, vegetatii valvulare
Manifestari digestive: ischemie esofag, mezenter, pancreatita acuta, infarct splenic, sd Budd-Chiari
Manifestari renale: tromboze vena, artera, glomerulara
Manifestari cutanate: necroze, ulceratii, gangrene, livedo reticularis, purpura
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MANIFESTARI CUTANATE(I)
LIVEDO RACEMOSA LIVEDO RETICULARIS
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BOLI ASOCIATE CU LIVEDO RETICULARIS
SAFL
LES
PANARTERITA NODOASA
CRIOGLOBULINEMII
SCLEROZA SISTEMICA
BOLI INFECTIOASE(tuberculoza, sifilis)
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MANIFESTARI CUTANATE(II)
ULCERATII NECROTICE GANGRENA DIGITALA
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MANIFESTARI CUTANATE(III)
LEZIUNI PSEUDOVASCULITICE MACULE ERITEMATOASE
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MANIFESTARI CLINICE IN SAFL(V)
Manifestari oftalmologice
Manifestari osoase: necroze
Manifestari hematologice: trombocitopenie, anemie hemolitica
Manifestari ORL: perforatie sept nazal
Manifestari obstetricale: avorturi spontane, eclampsie, preeclampsie, prematuri
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DIAGNOSTICUL DE LABORATOR
o multitudine de anticorpi antifosfolipidici descrisi
tinte antigenice variate: fosfolipide, proteine, complexe fosfolipide/proteine...
Anticorpi antifosfolipidici utilizati ca si“criterii de clasificare”-deci “diagnostici”: aCL, LA, ac antibeta2 glicoproteina I
SAFL “seronegativ”: tromboze clasice recurente cu aFL “diagnostici” absenti
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Anticorpii anticardiolipinici
Antigen=fosfolipidele anionice din membrana endoteliala
cardiolipina=difosfatidilglicerol
Relatie cu infectia!!!!
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LUPUS ANTICOAGULANT(I)
Nu are un singur antigen: protrombina, alti factori ai coagularii
Nu este un anticorp, ci EXISTA ACTIVITATE DE TIP LUPUS ANTICOAGULANT DEMONSTRATA IN LABORATORUL DE COAGULARE
LA ALUNGESTE IN LABORATOR TIMPII DE COAGULARE FOSFOLIPID-DEPENDENTI
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LUPUS ANTICOAGULANT(II)
Efect anticoagulant in vitro si efect procoagulant in vivo
Asociat atat cu tromboze arteriale, cat si cu tromboze venoase-predominant venoase
Determinat prin teste de coagulare : aPTT, timpul de caolin...
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PRINCIPIUL TESTELOR DE IDENTIFICARE A LA
PAS 1: TEST ALUNGIT: deficit factori ai coagularii SAU prezenta lupus anticoagulant
PAS 2: SE ADAUGA PLASMA PROASPATA:
daca testul se normalizeaza=deficit de factori ai coagularii
daca testul nu se normalizeaza=activitate tip LA
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Anticorpii antibeta2 glicoproteina I
antigenul=beta2 glicoproteina I
beta2 glicoproteina I:
proteina plasmatica
anticoagulant natural
complexul antigen/anticorp are afinitate crescuta catre celulele endoteliale
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EVALUAREA ANTICORPILOR ANTIFOSFOLIPIDICI
Probleme in practica:
teste nestandardizate
pot fi fals negative in timpul episodului de tromboza acuta
LA poate fi modificat in timpul terapiei anticoagulante orale
LA-variabilitate importanta
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APRECIEREA RISCULUI DE TROMBOZA
LA - cel mai puternic predictor al riscului de tromboza
persistenta aCL poate fi asociata cu tromboza
titrurile aCL peste 40-60 GPL/MPL
PREZENTA UNUI NUMAR MAI MARE DE AFL CRESTE RISCUL DE TROMBOZA=DUBLA/TRIPLA POZITIVITATE:
1 AC-27.6%; 2 AC-38.8%; 3 AC-66.7%
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CRITERIILE DE CLASIFICARE SAFL SYDNEY 2006(I)
CRITERII CLINICE:Tromboze: unul/mai multe episoade clinice de tromboza arteriala, venoasa sau de
vase mici in orice tesut sau organ CONFIRMATA prin metode imagistice, Doppler sau histopatologice (fara inflamatie semnificativa)
Morbiditate legata de sarcina (morfologie normala ecografic sau ex direct):
3/mai multe avorturi spontane consecutive sub saptamana 10 de sarcina
moarte fetala la peste 10 saptamani de sarcina
prematuritate sub 34 saptamani de sarcina datorata preeclampsiei sau eclampsiei sau insuficientei placentare
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CRITERIILE DE CLASIFICARE SAFL SYDNEY 2006(II)
CRITERII DE LABORATOR:
aCL IgG/IgM titru mediu/mare(peste 40 GPL) la cel putin 2 determinari la minim 12 saptamani distanta
lupus anticoagulant detectat la cel putin 2 determinari la minim 12 saptamani distanta
ac antibeta2 glicoproteina I IgG/IgM prezenti la cel putin 2 determinari la minim 12 saptamani distanta
21/1/19
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DIAGNOSTICUL SAFL
PT DIAGNOSTIC=MINIM 1 CRITERIU CLINIC PLUS 1 CRITERIU DE LABORATOR
DAR EXISTA SITUATII PARTICULARE CLINICE SI DE LABORATOR CARE NU SE INCADREAZA IN CRITERII…
21/1/19
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ASPECTE CLINICE “NON-CRITERII”
Criterii de evidenta redusa:
tromboza venoasa superficiala
migrena
convulsiile
Criterii de evidenta moderate:
trombocitopenia
leziuni valvulare
coreea
mielita transversa
21/1/19
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ASPECTE DE LABORATOR “NON-CRITERII”
ALTI ANTICORPI ANTIFOSFOLIPIDICI “NON-DIAGNOSTICI”:
aCL/ac antibeta2 glicoproteina I izotipul IgA
ac antibeta2 glicoproteina I – domeniul I
ac anticomplex fosfatidilserina/protrombina
ac antifosfatidiletanolamina
ac antianexina V
21/1/19
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aFL “nondiagnostici” in SAFL seronegativ si manifestarile clinice asociate
aFL “non-diagnostici” Manifestari clinice
ac. antiprotrombina/fosfatidilserina tromboze
ac. antianexina V/rezistenta la anexina A5
tromboze si/sau complicatii sarcina
ac. anticomplex vimentina/CL tromboze arteriale
ac. antifosfatidiletanolamina pierderi fetale si/sau tromboze
ac. antiacid fosfatidic pierderi fetale
ac. antifosfatidilserina pierderi fetale
ac. antifosfatidilinozitol pierderi fetale
ac. IgA aCL si IgA aβ2GPI tromboze
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DIAGNOSTIC DIFERENTIAL
Trombofilie cu manifestari venoase sau arteriale
Endocardita infectioasa
Coagulare intravasculara diseminata
Purpura trombotica trombocitopenica
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TROMBOZE VENOASE-diagnostic diferential
Deficit proteina C, S, antitrombina
Factor V Leiden
Sindrom nefrotic
Contraceptive orale
Paraneoplazii
Boala Behcet
Hemoglobinurie paroxistica nocturna
Tromboza postheparinica
21/1/19
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TROMBOZE ARTERIALE-diagnostic diferential
Ateroscleroza
Vasculitele
Homocistinuria
Bolile mieloproliferative
Deficit proteina C, S, antitrombina
Purpura trombotica trombocitopenica
Coagulare intravasculara diseminata
21/1/19
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RELATIA SAFL-LES
LES:
30% (25-50%) au anticorpi antifosfolipidici
15% (12-30%) au SAFL secundar
Alte boli autoimmune
8% au SAFL
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NEFROPATIA din SAFL
LES
HTA, proteinuria minima, IRA/IRC
LA prezent de obicei, livedo reticularis
Biopsia renala este cea care stabileste daca este nefropatie lupica SAU nefropatie in cadrul SAFL
21/1/19
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SAFL CATASTROFIC
afectare trombotica simultana/consecutive a cel putin 3 organe in decurs de zile-saptamani
debut/oricand in evolutia SAFL primar/secundar
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FACTORI PRECIPITANTI SAFL CATASTROFIC
necunoscuti - 45%
infectii - 20%
trauma - 14%
terapie anticoagulanta neadecvata - 7%
neoplazii - 5.5%
LES activ - 3%
alte boli autoimune - 5.5%
21/1/19
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ASPECTE HISTOPATOLOGICE(I)
Vas calibru mediu cu tromboza recenta, coloratie hematoxilin eozina
Vase mici cu tromboze recente, coloratie van Gieson
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ASPECTE HISTOPATOLOGICE(II)
Vas mediu tromboza in organizare, coloratie hematoxilin eozina
Vas mic tromboza recenta, coloratie hematoxilin eozina
V
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TRATAMENTUL SAFL
Heparina
nefractionata
cu greutate moleculara mica
Antivitamine K
Hidroxicloroquina
Antiagregante plachetare
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PRINCIPII GENERALE
⚫identificarea factorilor asociati cu risc inalt de tromboze sievenimente obstetricale
⚫screeningul si managementul factorilor de risccardiovascular, dar si a celor pentru tromboze venoase
⚫educatia pacientului in ceea ce priveste aderenta latratament, monitorizare INR, protocolul perioperatorheparina/AVK, consiliere despre utilizarea contraceptivelororale, terapiei hormonale postmenopauza si planingul desarcina
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Factori asociati cu risc inalt de tromboze/evenimente obstetricale
⚫profilul aFL:
− profil de risc inalt: LA de cel putin ori la 12 saptamani distantaSAU dubla SAU tripla pozitivitate SAU persistenta titrului inaltde aFL
− profil de risc scazut: aCL sau ac antibeta2GPI in titrumic/mediu, mai ales daca se pozitiveaza trazitoriu
⚫factori de risc aditionali: prezenta unor boli autoimune,istoric de SAFL trombotic sau obstetrical, prezentafactorilor traditionali de risc cardiovascular
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TROMBOFILAXIA PRIMARA-recomandari
• purtatorii asimptomatici cu profil aFL de risc inalt –profilaxie cu Aspirina 75-100 mg/zi
• pacientii cu LES cu profil aFL de risc inalt – profilaxie cu Aspirina 75-100 mg/zi
• femeile cu SAFL pur obstetrical IN AFARA SARCINII -profilaxie cu Aspirina 75-100 mg/zi DOAR DUPA EVALUARE RISC/BENEFICIU
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TROMBOFILAXIA SECUNDARA-recomandari(I)
- pacientii cu SAFL si tromboza venoasa:
AVK cu INR intre 2 si 3; durata tratamentului cu AVK este delunga durata
DOAC nu se vor utiliza la pacientii cu tripla pozitivitate dincauza riscului inalt de recurenta trombotica
- pacientii cu SAFL si tromboza venoasa recurenta sub AVK cuINR=2-3:
verificarea aderentei la AVK, testare mai frecventa
AVK cu INR=2-3 PLUS Aspirina 75-100 mg/zi SAU crestereaINR=3-4 SAU schimbare cu HGMM
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TROMBOFILAXIA SECUNDARA-recomandari(II)
- pacientii cu SAFL si tromboza arteriala:
tratament cu AVK cu INR=2-3 sau INR=3-4, in functie de riscul individualde tromboza recurenta/risc hemoragic; uneori de luat in discutie AVK cuINR=2-3 PLUS Aspirina 75-100 mg/zi
DOAC nu se vor utiliza pacientii cu tripla pozitivitate aPL din cauzariscului mare de recurenta trombotica
- pacientii cu SAFL si tromboza arteriala recurenta sub AVK:
evaluare cauze suplimentare de tromboza
crestere INR=3-4 SAU AVK PLUS Aspirina 75-100 mg/zi SAU schimbare cuHGMM
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TRATAMENT SAFL CATASTROFIC-recomandari
Glucocorticoizi PLUS Heparina PLUS plasmafereza sau imunoglobulinei.v.
Tratamentul factorilor precipitanti
SAFL catastrofic refractar - Rituximab sau medicatie inhibitoare acomplementului
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Research agenda(I)
⚫Stratificarea riscului
⚫Preventia trombozei primare
− impactul asupra riscului trombotic al managementuluiintensiv al factorilor traditionali de risc cardiovascular
−HCQ in preventia trombozei primare la subiectii cuprofil aFL de risc inalt?
− Statinele sau coenzyme Q10 ?
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STRATIFICAREA RISCULUI DE TROMBOZA IN SAFL
⚫ GAPSS
− clinice:
⚫ dislipidemia 3 puncte
⚫ HTA 1 punct
− laborator:
⚫ aCL IgM/IgG 5 puncte
⚫ ac antibeta2GPI IgM/IgG 4 puncte
⚫ ac antifosfatidilserina/protrombina IgM/IgG 3 puncte
⚫ LA 4 puncte
⚫ GAPSS ajustat: fara ac antifosfatidilserina/protrombina
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Research agenda(II)
⚫Preventia trombozei secundare
− RCT cu AVK cu INR 3-4 vs AVK cu INR 2-3 plus Aspirina doza micapentru pacientii cu SAFL cu un prim episod de tromboza arteriala
− RCT AVK vs AVK PLUS HCQ pentru pacientii cu SAFL cu un primepisod de tromboza arteriala
− RCT cu terapii pentru tromboze arteriale recurente sub AVK cu INR 3-4
− SISTAREA AVK la pacientii care devin negativi pt aPL la determinarirepetate ?
− terapii adjuvante pentru tromboze arteriale recurente: HCQ,vitamina D, statine, alte terapii antiplachetare
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Research agenda(III)
⚫SAFL obstetrical
−RCT Aspirina doza mica PLUS heparina vs AspirinaPLUS Heparina PLUS HCQ la femeile cu patologieobstetricala recurenta
−Aspirina 150 mg/zi vs 100 mg/zi
− statine la pacientele cu SAFL catre dezvolta in timpul sarcinii preeclampsie sub Aspirina doza mica si heparina?