HELLP SYNDROME - elleventi.it · (Abraham et al. 2001, Vigil-De Gracia P et al 2001) ... STB EV...
Transcript of HELLP SYNDROME - elleventi.it · (Abraham et al. 2001, Vigil-De Gracia P et al 2001) ... STB EV...
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HELLP SYNDROME
Prof. A. Caruso
Convegno Microangiopatie Trombotiche,
Roma 19 Febbraio 2016
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Preeclampsia
Questa è la grande sfida: culturale, di capacità
professionali e organizzative
MORTALITA’ MATERNA
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HELLP
“H=HEMOLYSIS, EL: ELEVATED LIVER ENZYMES, LP= LOW PLATELETS”
Incidenza: 1-6 per 1000 (Abraham et al. 2001, Vigil-De Gracia P et al
2001)
Costituisce un’ urgenza ostetrica
Aggravante e/o variante della Preeclampsia severa
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Insorgenza antepartum: 70% (Sibai BM et al. 1993)
Insorgenza < 28 settimane: 20-30%
Esordio acuto e rapida progressione ( 30-50% della
conta piastrinica in 24 ore con diminuzione media
giornaliera di 40.000/L)
HELLP
“H=HEMOLYSIS, EL: ELEVATED LIVER ENZYMES, LP= LOW PLATELETS”
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Abildgaard U, 2013
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L’epoca gestazionale al parto ed il peso alla nascita sono i principali
determinanti della morbiditàneonatale
Murray, D et al.(2001), Singhal, N et al.(2004), Kandler, C et al.(1998)
Abildgaard U, 2013
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Modificato da De Stefano V. 2015
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Eziopatogenesi Stadio 1 –Prima metà della
gravidanza
Stadio 2 –Seconda metà
della gravidanza
Alterata
placentazione
Stress ossidativo
placentare ed
infiammazione
I due stadi della Preeclampsia
Nessun
sintomo
Segni clinici
evidenti
Effetti
FETALI
( IUGR)
Rilascio di fattori PLACENTARI
Risposta
infiammatoria
sistemica materna
Disfunzione
endoteliale
sistemica
Manifestazioni cliniche della preeclampsia
Adattato da Redman L, 2004
HELLP:
1.RUOLO DELLA PLACENTA
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Eziopatogenesi
..Ruolo centrale svolto
dal fegato anche nella
patogenesi di tale
sindrome
Nelle donne con HELLP si verifica un
aumento del rilascio nella circolazione
sistemica da parte della placenta del CD95
ligando (o Fas ligando) (Strand et al.2004)
L’interazione sulla superficie degli epatociti
del CD95L con la regione transmembranaria
della proteina CD95 (Fas) determina
apoptosi
Nelle donne con HELLP l’apoptosi
degli epatociti aumenta con il progredire
della severità della malattia
HELLP:
2.RUOLO DEL FEGATO
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Eziopatogenesi
..Similitudini tra HELLP
Syndrome e SIRS
(systemic inflammatory
response syndrome)
HELLP:
3. SINDROME INFIAMMATORIA
Leucocitosi proporzionale alla severità della
malattia
Aumentate concentrazioni plasmatiche
della anafilotossine C3a e C5a
Incremento della concentrazione delle
citochine circolanti
Ridotti livelli circolanti di VEGF e PlGF
(Martin et al.2006)
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Ultrastructructure of normal and pre-eclamptic
syncytial surface
Modified from Redman CWG et al, Placenta 2012
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What kind of placental debris is shed into
the maternal circulation?
Early EndosomeMultivesicular
Body
Exosomes30-100nm
Microvesicles100nm-1µm
Apoptotic Bodies1µm-4µm
Syncytial NuclearAggregates (20-500µm)(Syncytiotrophoblast)
Stimulus
Intracellular calcium
Cell membrane
Nucleus
Apoptosis
DNA Fragments
Syncytiotrophoblast extracellular vesicles (STB EV)
Tannetta et al 2014 Cell Mol Immunol
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STB EV FROM PRE-ECLAMPSIA PLACENTAS ARE
LARGER THAN THOSE FROM NORMAL
PLACENTAS
Tannetta D et al 2013
Shift from exosome to microvesicle release in pre-eclampsia?
N STBM
PE STBM
Ves
icle
s/m
l (x1
06)
Diameter nm
4
2
1
3
06000 100 200 300 400 500
P<0.003
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Modified from Redman CWG et al, Placenta 2012
Danger molecules carried by STB EVs
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HELLPDiagnosi
15-20% dei casi si manifestano senza evidenza di
proteinuria ed Ipertensione (Sibai BM et al. 1993)
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HELLPDiagnosi
Anomalie Laboratoristiche
Anemia Emolitica Microangiopatica
Trombocitopenia
Disfunzione Epatica
La morbidità materna aumenta dall’11 ad oltre il 20% quando
ad una preeclampsia severa si associno piastrinopenia lieve,
rialzo dell’LDH (600 UI/L) e delle transaminasi (AST e/o ALT
40 UI/L)
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HELLP
Diagnosi
Stima della crescita fetale
Valutazione del Liquido amniotico
Studio doppler della circolazione materno-
fetale
L’iposviluppo fetale e le anomalie
velocimetriche della circolazione
fetale interessano dal 39% al 48% di
tali pazienti (Bush KD et al. 2001, Ertan AK et al. 2002,
Sibai BM et al 2004)
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HELLP
Diagnosi Differenziale
Importanza di
stabilire una
corretta diagnosi al
fine di definire la
migliore strategia
terapeutica
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“IMITATORS OF SEVERE PREECLAMPSIA”
SIBAI BM, 2009
Atrofia giallo acuta della gravidanza (AFLP)
Riacutizzazione del LES
APS catastrofica
Porpora trombotica trombocitopenica (TTP)
Sindrome Uremico Emolitica (SEU)
Sepsi virali sistemiche
Colangiti
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II/III TrimestreI/II Trimestre
Diagnosi Differenziale
Unica che può manifestarsi anche nel
primo trimestre (Sanchez-Lucheroz et al 2013)
II/III Trimestre
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Diagnosi Differenziale
Sibai BM et al. 2009
Incidenza e Gravità delle alterazioni laboratoristiche tra gli
“Imitators of severe Pre-eclampsia”
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Diversi autori (Lattuada et al. 2003, Hulstim JJJ et al. 2006) hanno segnalato
una riduzione dell’attività di ADAMTS-13 nelle donne gravide con
HELLP syndrome rispetto a donne con gravidanze a decorso fisiologico
Tuttavia l’attività di ADAMTS-13 seppur ridotta nella HELLP non
scende mai al di sotto del 5%
Criteri Laboratoristici
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HELLP
Diagnosi Differenziale
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Diagnosi Differenziale
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Delivery is at present the only efficient
treatment of HELLP syndrome and
preeclampsiaAbildgaar ,U et al. (2013)
HELLP
Management
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Ad un’epoca gestazionale non compatibile con la
viabilità del feto, si raccomanda atteggiamento
conservativo volto a stabilizzare le condizioni materne
34 settimane, parto immediato
<34 settimane, parto dopo completamento della
anticipazione della maturazione polmonare fetale
Management
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Non usare desametasone o
betametasone per il trattamento
dell’HELLP syndrome.
Migliorano la conta piastrinica ed
altri parametri laboratostici nel
breve termine, ma non hanno effetti
dimostrati a lungo termine nel
migliorare l’outcome materno-fetale
Cortisonici
Determinano miglioramento della conta piastrinica
ma non hanno effetti sulla morbidità e mortalità
materna e feto-neonatale
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Management
Prevenzione delle crisi epilettiche mediante
trattamento con Solfato di Magnesio
Terapia antipertensiva adeguata ad ottenere un
buon controllo pressorio
Non controindicazioni al supporto trasfusionale con
piastrine
Plasmaferesi terapeutica
( in puerperio: se l’emolisi, la trombocitopenia o la
disfunzione renale non migliorano 48-72 ore dopo il
parto)
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HELLP : NUOVE STRATEGIE TERAPEUTICHE
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Management
La modalità del parto è fortemente influenzata da:
Epoca gestazionale
Condizioni materno-fetali
Severità della malattia
Uso dei corticosteroidi
Il Taglio Cesareo si associa ad un incremento quasi doppio
della morbidità materna in termini di complicanze
cardiopolmonari, ematologiche ed infettive, rispetto al Parto
vaginale (Martin JN et al 1999)
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CONCLUSIONI
La tempestività del sospetto diagnostico
La diagnosi differenziale
La stima della progressione
La valutazione del rischio della madre del feto e neonato
La collaborazione interdisciplinare: ostetrico, ematologo
trasfusionista, neonatologo, anestesista ostetrico, rianimatore
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Tannetta et al 2013
WB
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Haram K et al.2009
HELLPHELLP
vera o
completa
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HELLP
It is critical to distinguish TTP/HUS
from HELLP syndrome as TTP/HUS
do not necessarily require pregnancy
discontinuation
Modified from Delmas,Y et al. (2015)
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Criteri Laboratoristici
Modificato da De Stefano V. 2015
HELLP Pregnancy Healthy
women
Range
vWF:Ag % 314 186 96 48-139
vWF:RCo % 243 140 89 46-142
vWF:CB % 208 152 94 51-155
ADAMTS13 % 31 71 101 47-152
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Tannetta et al 2015
STB EV from PE increase platelet
aggregation and activation