TROMBOTICKÁ MIKROANGIOPATIA TMA
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1 TROMBOTICKÁ MIKROANGIOPATIA TMA
2 TMA spektrum ochorení s podobnou klinickou manifestáciou tvorba trombov v mikrokapilárach trombocytopénia mikroangiopatická hemolytická anémia ischémia orgánov infarkty +
3 TMA PRÍČINY Genetické mutácie odlišných génov Získané Autoprotilátky namierené proti rozdielnym proteínom
4 klasifikácia zložitá 2 základné podtypy TMA Trombotické mikroangiopatie TTP HUS
5 TMA klasifikácia zložitá 2 základné podtypy Trombotické mikroangiopatie TTP systémová mikrovaskulárna agregácia TRC spôsobuje ischémiu mozgu a ostatných orgánov HUS Fibrínové tromby predominantne v renálnej cirkulácii
6 TMA-TTP Tromby multiméry vonwillebrandovho faktora bez fibrínu PRÍČINY Genetické deficit ADAMTS 13 Získané autoprotilátky proti ADAMTS 13
7 TMA Trombotické mikroangiopatie TTP HUS typický HUS atypický HUS
8 Hemolyticko-Uremický Syndróm HUS nie je HUS ako HUS...
9 HUS + & ahus 90% prípadov dojčatá a batoľatá krvavé hnačky E.coli O157:H žiadne relapsy relatívne dobrá prognóza 3% ESRD 10% prípadov dojčatá - dospelí bez prodromálnych hnačiek dramatický priebeh extrarenálne komplikácie časté relapsy zlá prognóza
10 zlá prognóza 30% má hnačky! ATYPICKÝ HUS až 90% detí poškodenie obličiek po 1. atake 25% končí fatálne už pri 1.atake 50% progreduje do ESRD 40-80% rekurencia štepe Zuber J et al. Nat Rev Nephrol, 2011 Taylor et al: Ped Neph, 2004
11 ATYPICKÝ HUS chronické ochorenie permanentná nekontrolovaná excesívna aktivácia komplementu SYSTÉMOVÁ KOMPLEMENT- MEDIOVANÁ TMA Noris, Remuzzi: Engl J Med, 2009
12 KEM1 Lektínová cesta Klírens IK opsonizácia Klasická ícesta C3 Alternatívna cesta Amplifikácia C5 prirodzené inhibítory Anafylaxia Zápal Trombóza C5a Anaphylatoxin chemotaxia prozápalovo aktivácia Lkc aktivácia endotelua protromboticky C5b-9 Membrane Attack Complex lýza buniek prozápalovo aktivácia TRC aktivácia Lkc aktivácia endotelu protromboticky Deštrukcia buniek Zápal Trombóza
13 Slide 12 KEM1 Adapted from: Rother/p1257/figure1 Figueroa/p363/figure1 Kose/p671 Kelly Moore;
14 Genetický defekt regulátorov komplementu vedie k životohrozujúcej systémovej komplement-mediovanej TMA TRC, endotelové bb. a Lkc chránia pred aktiváciou komplementu regulačné faktory Bez regulačných faktorov nekontrolovaná permanentná aktivácia komplementu Aktivuje TRC, endotelové bb. a Lkc Porvch buniek and inhibítory komplementu tekutej fázy Zápal a početné tromby s oklúziou malých ciev (systémová TMA) Náhle a progresívne poškodenie orgánov Noris M et al. CJASN,2010 Stahl A et al. Blood, 2008
15 ahus & Diagnostika G E N E T I K A! prognóza > heterozygótne mutácie nízka penetrácia
16 heterogénna skupina KOMPLEMENT & ahus prirodzené inhibítory komplementu 6 génov genetické mutácie má 50% až 70% chorých s ahus u 30% až 50% pacientov s ahus sa súčasnými genetickými testami mutácia nezistí!
17 FAKTOR H 25% prípadov ahus C3 nízke u 30-67% pacientov /homozygoti takmer 100% rekurencia posttx zlá prognóza (70-80% ESRD alebo smrť)
18 Transplantácia áno/nie?
19 atypický HUS & Tx Riziko rekurencie po nemodifikovanej transplantácií Proteín Gén Rekurencia Faktor H CFH > 80% Faktor I CFI > ~ 80% MCP MCP ~ 20% Faktor B CFB? C3 C3? Anti-FH- Ab CFHR1/CF HR3 Neznáma mutácia 30%? Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009
20 ahus & Liečba PLAZMAFERÉZA proteíny systému komplementu tekutej fázy sú v plazme (faktor H, faktor I) náhrada bielkovín komplementového systému odstránenie protilátok Caprioli, et al. Blood,2006
21 ahus & Liečba Nové možnosti Biologická liečba! purifikovaný a rekombinantný faktor H monoklónová protilátka/pôsobí na mieste činu ECULIZUMAB blokuje komplement na úrovni C5 tlmí lytickú schopnosť komplementu
22 Aktivácia komplementu ahus D + B C3a C3 C3bBb C3b Ba C3b C3bi CR3 Opsonizácia I K C5-convertáza C5 C5a C5b C6 C7 C8 C9 C5b-9 Terminal Complement Complex ahus Hemolýza Aktivácia Endotelu Zápal Aktivácia TRC TMA Trombóza ESRD Vazokonstrikcia QoL/ Mortalita
23 ECULIZUMAB ahus a KOMPLEMENT Liečba Efekt aj po Tx celoživotná liečba
24 Kazuistika # Mirka 12-ročná Mirka december 2009 opakované vracanie, hematúria, bledosť OA: p.h. 3650g apendektómia v r.2005, inak zdravá, respiračné infekty HDC RA: bez pozoruhodností
25 Kazuistika # Mirka Vstupné laboratórne parametre Hb: 82, Ery: 3.2, HTK: 0.25, TRC:30 Ret: 1.71% bil c: 49, bil k: 6.2 Urea: 27, Kreat: 250, K: 4.6, Na: 135 LDH: 36.9, haptoglobín:0.03 C3: 0.40 (N = ), C4: 0,13 moč: sed: Ery: 250, Leu: 0, Val: 0
26 Kazuistika # Mirka Kreatinin [µmol/l] Trombocyty [µl -1 ] TPE LDH TPE 1x/2T kreat TRC TPE 1x/1T TPE 1x/2T TPE 1x/1T dec jan feb mar apr maj jun jul aug sep oct LDH [µkat/l]
27 Imunogenetika Innsbruck homozygotná delécia génu pre factor H related protein-1 (CFHR-1) pozitívne autoprotilátky proti faktoru H titer 417 AU/ml (N<100 AU/ml)
28 Kazuistika # Mirka predĺženie intervalu TPE na 1x/2T vždy spojené s dramatickým relapsom 4 relapsy za 2 roky MMF bez efektu IVIG bez efektu
29 4. relaps... Kazuistika # Mirka TPE 1x/T po dobu 12 mesiacov bez hemolytickej mikroangiopatickej anémie permanentná aktivácia systému komplementu CKD, GFR 70ml/ min., proteinúria Hypertenzia LVH
30 ECULIZUMAB Kazuistika # Mirka 05/ mg..1200mg i.v. á 2 týždne TPE STOP extrakcia permcathu 5 mesiacov bez TPE
31 Výsledky Kazuistika # Mirka KO:Hb:12.6, Ery:4.7, TRC:287 LDH:3.4 urea:4.5, kreat:90 KVP:0.5g/d C3:0.9 Agen x Tritace TK:120/80 torr (90.percentil) PROGNÓZA?
32 Z Á V E R TMA Atypický HUS TTP
33
34 TMA- Dif. Dg. v Thrombocytopenia 1,7 TRC <150,000 + MiKROANGIOPATICKÁ HEMOLÝZA Schistocyty haptoglobín LDH hemoglobín CNS Porucha vedomia Kŕče Obličky Kreatinín GFR Močové abnormality GIT hnačky+/- krv nausea/vracanie bolesti brucha ADAMTS13 Aktivita a Shiga-toxin/EHECTest 5% ADAMTS13 Aktivita >5% ADAMTS13 Aktivita Shiga-toxin/EHEC pozit TTP ahus STEC-HUS* Caprioli et al. Blood 2006 Neuhaus et al. Arch Dis Child 1997 Al-Akash et al. Pediatr Nephrol. 2011
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