Håndtering av blødninger ved antikoagulasjon Pål Andrè Holme, Overlege, dr. med Avdeling for blodsykdommer OUS, Rikshospitalet
INR og blødningsrisiko INR Risiko/48t 2-2.9 1/4000 3-4.4 1/2000 4.5-6.9 1/500 >7.0 1/100 Etter ISCOAT; Palareti et al, Lancet 1996 INR > 5 og < 9: Risiko for major bleed neste 30 dager: 0,96% Garcia et al J AM Coll Cardiol 2006
BLØDNING UNDER PÅGÅENDE WARFARINBEHANDLING Mindre blødning: (hematom, neseblødning o.l.) Tiltak: Bør vurderes i sykehus/poliklinikk. Seponer Marevan i 2 dager. Gi 1-2 mg vitamin K1 peroralt. Vurder PCC (Prothromplex /Octaplex ) ved INR 4,5-6 Tannbehandling/epistaxis Cyklokapron 100 mg/ml lokalt på tampong Spongstan
BLØDNING UNDER PÅGÅENDE WARFARINBEHANDLING Alvorlig/livstruende blødning Tiltak: Skal behandles i sykehus ved alvorlig blødning og forhøyet INR, uansett INR nivå: Seponer Marevan Gi vitamin K1 10 mg langsomt i.v. Gjentas hver 12. time hvis INR ikke normaliseres Suppler med PCC (Octaplex / Prothromplex ) eller event plasma avhengig av det kliniske bildet.
Reversering av warfarineffekt med plasma /PCC (prothrombin complex concentrate) 60 FFP PCC Økning i faktornivå (IE/dl) 50 40 30 20 10 0 FII FVII FIX FX Plasma 800 ml og PCC 25-50 IE/kg Makris et al, Thromb Haemostas 1997;77:477-80
PKK- Prothromplex /Octaplex - dosering ved alvorlig warfarinblødning Octaplex Dosering ved alvorlig blødning i henhold til kroppsvekt og INR Prothromplex Dosering ved alvorlig blødning i henhold til kroppsvekt og INR Kg kroppsvekt INR<2 INR 2-3 INR>3 40-60 500 IE 1000 IE 1500 IE 60-90 1000 IE 1500 IE 2000 IE >90 1500 IE 2000 IE 2500 IE Kg kroppsvekt INR<2 INR 2-3 INR>3 40-60 600 IE 1200 IE 1800 IE 60-90 1200 IE 1800 IE 2400 IE >90 1800 IE 2400 IE 3000 IE Ukjent INR: 30-50 IE/kg Kontroller INR ca 10-15 min etter infusjon og siden etter et par timer Målverdi bør i begge tilfeller ligge < 1,5. Gi ytterligere PKK etter behov 10-20 IE/kg Prothromplex Hvert sett inneholder 600 IE målt som FIX: Human koagulasjonsfaktor FII 600 IE, FVII 500 IE, FIX 600 IE og FX 600 IE, protein C 400 IE, protein S 140-640 IE, heparin 0,5 IE per IE FIX Oppløsningsvæske: Vann til injeksjonsvæsker 20 ml. Octaplex Hvert sett inneholder 500 IE målt som FIX: Human koagulasjonsfaktor FII=480 IE, FVII 360 IE, FIX 500 IE, FX 480 IE, Protein C 140-620 IE, Protein S 140-640 IE, heparin 100-250 IE,
Blødinger ved Heparin Protaminsulfat: 1 mg nøytraliserer 100 IE standardheparin LMV heparin Protaminsulfat: 1 mg nøytraliserer 1 mg Klexane 1 mg nøytraliserer 100 IE Fragmin Pga subcutan administrering av LMV hepariner, kan gjentatte protamindoser (hver 4. time) være nødvendig. Anti FXa aktiviteten kan aldri fullstendig nøytraliseres ( maks 60%)
Monitoring of hemostafc funcfon Dabigatran: PT- insensitive aptt- curvilinear response (2 fold compared with control value at peak drug levels during chronic treatment TCT linear correlation with the dabigatran concentration TCT normal- low dabigatran concentration. Rivaroxaban: PT- linear dose response?, but assay dependent Apixaban: The Rotachrom anti-fxa assay may be useful in exceptional situations in which knowledge of apixaban exposure may help to inform clinical decisions, e.g. overdose PT- prothrombin time (INR) aptt -activated partial thromboplastin time TCT thrombin clotting time
New oral anfcoagulants
Suggestions for reversal of new oral anticoagulants Rivaroxaban Apixaban Dabigatran Oral activated charcoal Yes Yes Yes within 2 h Haemodialysis No No Yes PCC Partially reversed PT prolongation Shortened bleeding time in vivo Reversed rivaroxaban acivity in vivo but bleeding not reversed In vivo: Reversed PT prolongation and normalized ETP in healthy volunteers Improved some thrombin generation Prevented hematoma and reversed tail bleeding time In vivo: No effect on reversal in healthy volunteers In vitro: Increased ETP rfviia Rat and Baboon: Partial reversal of Thrombin generation in vitro Reduced clotting times, aptt and bleeding time in vivo In vitro: Only modified kinetic Imporved thromboelastography Ineffective in vitro and in vivo Reduced clot initation time to baseline in vitro apcc (FEIBA) Reduced clot initiation time to onethird of baseline in vitro Reduced bleeding time Partial neutralization of activity in vivo In vitro: Corrected all Specific antidotes Rabbit:pd-FXa/ rfxa Rabbit:pd-FXa/ rfxa Mab Clone 22 completely inhibited dabigatran activity in vitro and in vivo
Suggestions for reversal of new oral anticoagulants Rivaroxaban Apixaban Dabigatran Oral activated charcoal Yes Yes Yes within 2 h Haemodialysis No No Yes PCC Partially reversed PT prolongation Shortened bleeding time in vivo Reversed rivaroxaban acivity in vivo but bleeding not reversed In vivo: Reversed PT prolongation and normalized ETP in healthy volunteers Improved some thrombin generation Prevented hematoma and reversed tail bleeding time In vivo: No effect on reversal in healthy volunteers In vitro: Increased ETP rfviia Rat and Baboon: Partial reversal of Thrombin generation in vitro Reduced clotting times, aptt and bleeding time in vivo In vitro: Only modified kinetic Imporved thromboelastography Ineffective in vitro and in vivo Reduced clot initation time to baseline in vitro apcc (FEIBA) Reduced clot initiation time to onethird of baseline in vitro Reduced bleeding time Partial neutralization of activity in vivo In vitro: Corrected all Specific antidotes Rabbit:pd-FXa/ rfxa Rabbit:pd-FXa/ rfxa Eerenberg et al. Circulation, 2011 Mab Clone 22 completely inhibited dabigatran activity in vitro and in vivo
Suggestions for reversal of new oral anticoagulants Rivaroxaban Apixaban Dabigatran Oral activated charcoal Yes Yes Yes within 2 h Haemodialysis No No Yes PCC Partially reversed PT prolongation Shortened bleeding time in vivo Reversed rivaroxaban acivity in vivo but bleeding not reversed In vivo: Reversed PT prolongation and normalized ETP in healthy volunteers Improved some thrombin generation Prevented hematoma and reversed tail bleeding time In vivo: No effect on reversal in healthy volunteers In vitro: Increased ETP rfviia Rat and Baboon: Partial reversal of Thrombin generation in vitro Reduced clotting times, aptt and bleeding time in vivo In vitro: Only modified kinetic Imporved thromboelastography Ineffective in vitro and in vivo Reduced clot initation time to baseline in vitro apcc (FEIBA) Reduced clot initiation time to onethird of baseline in vitro Reduced bleeding time Partial neutralization of activity in vivo In vitro: Corrected all Specific antidotes Rabbit:pd-FXa/ rfxa Rabbit:pd-FXa/ rfxa Eerenberg et al. Circulation, 2011 Mab Clone 22 completely inhibited dabigatran activity in vitro and in vivo
Suggestions for reversal of new oral anticoagulants Rivaroxaban Apixaban Dabigatran Oral activated charcoal Yes Yes Yes within 2 h Haemodialysis No No Yes PCC Partially reversed PT prolongation Shortened bleeding time in vivo Reversed rivaroxaban acivity in vivo but bleeding not reversed In vivo: Reversed PT prolongation and normalized ETP in healthy volunteers Improved some thrombin generation Prevented hematoma and reversed tail bleeding time In vivo: No effect on reversal in healthy volunteers In vitro: Increased ETP rfviia Rat and Baboon: Partial reversal of Thrombin generation in vitro Reduced clotting times, aptt and bleeding time in vivo In vitro: Only modified kinetic Imporved thromboelastography Ineffective in vitro and in vivo Reduced clot initation time to baseline in vitro apcc (FEIBA) Reduced clot initiation time to onethird of baseline in vitro Reduced bleeding time Partial neutralization of activity in vivo In vitro: Corrected all Marlu et al. Thromb Haemost 2012, 108 Specific antidotes Rabbit:pd-FXa/ rfxa Rabbit:pd-FXa/ rfxa Mab Clone 22 completely inhibited dabigatran activity in vitro and in vivo
Alvorlig blødning ved bruk av NOAC Vurder Fdspunkt for siste legemiddelinntak- Blødningskilde?, BT- Hemodynamisk stabil? Hb, Trc, nyrefunksjon, APTT og INR. Blodtrykk stabiliseres Generelle 'ltak Mekanisk kompresjon av blødningssted Medisinsk kull (mindre enn 2 Fmer erer inntak) Monitorere hemodynamisk status Volumerstatning SAG, FFP, TRC- spes Fl pas på anfplatebehandling Alvorlige/livstruende blødninger Intensiv overvåkning Hemodynamisk størebeh Dabigatran: apcc 50-80 U/kg Rivaroxaban/Apixaban: PCC 30-50 U/kg event apcc Stø7ebehandling: Hemodialyse ved dabigatran? Desmopressin Traneksamsyre
Tiltak ved utvikling av livstruendeblødning/hjerneblødning under behandling med NOAC Vurder tidspunkt for siste legemiddelinntak og pasientetterlevelse. Ta hemoglobin, trombocytter, kreatinin, ALAT, bilirubin, APTT og INR. Blodtrykk stabiliseres. Ved behandling med dabigatran: gi aktivert protrombinkomplekskonsentrat (apcc) 50-80 IE/kg (Feiba (Baxter) Ved behandling med apiksaban eller rivaroksaban: gi PCC 30-50 IE/kg (Prothromplex (Baxter) / Octaplex (Octapharma) / Confidex (CSL Behring), eventuelt gi aktivert protrombinkomplekskonsentrat (apcc) 50-80 IE/kg (Feiba (Baxter) rfviia-konsentrat 90 µg/kg (Eptacog alfa Novoseven Novo Nordisk) i.v. kan forsøkes, men dokumentasjon mangler pr. i dag. Eerenberg et al. Circulation 2011; 124:1573-79 Marlu et al. Thromb Haemost 2012;108:217-24 Siegal et al. J Tromb Thrombolysis 2013; online Siegal D and Crowther MA, Eur Hea J 2013: 34 489-500