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Nevtralizacija dabigatrana z idarucizumabom v pogojih in vitro
Krivec, Mojca (Author), Božič Mijovski, Mojca (Mentor) More about this mentor... This link opens in a new window

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Abstract
Neposredna peroralna antikoagulacijska zdravila (NO-AK) med katere sodi neposredni zaviralec trombina dabigatran (Pradaxa®), imajo številne prednosti pred antagonisti vitamina K, kot so manj številne interakcije z zdravili in hrano, širše terapevtsko okno, kar omogoča fiksni odmerek zdravila in s tem odsotnost potrebe po rednem laboratorijskem nadzoru. Prednost dabigatrana pred antagonisti vitamina K predstavlja tudi obstoj specifičnega antidota idarucizumaba (Praxbind®), ki veže dabigatran z bistveno večjo afiniteto kot trombin in na ta način zelo hitro izniči antikoagulacijski (AK) učinek zdravila. V raziskavo smo vključili 44 preiskovancev z atrijsko fibrilacijo (AF), ki so prejemali dabigatran. Vsem preiskovancem smo vzeli vzorec krvi pred in med uvedbo AK terapije, katerim smo nato dodali idarucizumab in vitro. Učinek dabigatrana in dodatka idarucizumaba in vitro smo preverjali s pomočjo presejalnih koagulacijskih preiskav (PČ, APTČ in TČ) ter s pomočjo spremljanja tvorjenja trombina (ang. Thrombin generation assays, TGA). Pri tem smo ugotovili, da so vrednosti APTČ, faza mirovanja ter čas do trombinskega vrha naraščale z višanjem koncentracije dabigatrana v plazmi preiskovancev v primerjavi z vzorci pred AK terapijo. Dabigatran ni imel nobenega statističnega vpliva na trombinski vrh. Vrednost PČ (%) se je statistično zmanjšala, prav tako površina pod krivuljo, zaradi zaviralnega učinka dabigatrana na trombin v primerjavi z vzorci pred AK terapijo. Z dodatkom idarucizumaba in vitro smo omogočili nevtralizacijo AK učinka dabigatrana, kar smo dokazali z normalizacijo PČ, APTČ, TČ, faze mirovanja in časa do trombinskega vrha, medtem, ko sta spremenljivki trombinski vrh in površina pod krivuljo ostali zvišani v primerjavi z vzorci, odvzeti pred AK terapijo.V raziskavi smo dokazali, da vzorci odvzeti v času AK terapije, ki vsebujejo dabigatran zaradi zaviralnega učinka na trombin podaljšuje APTČ, fazo mirovanja in čas do trombinskega vrha, ki jih z dodatkom idarucizumaba in vitro ne le popolnoma nevtraliziramo, ampak tudi statistično znižamo v primerjavi z vzorci pred AK terapijo. Podobne rezultate smo dobili tudi pri spremenljivkah tvorjenja trombina, razen pri času trombinskga vrha in površini pod krivuljo, ki sta ob prisotnosti dabigatrana statistično višji v primerjavi z vzorci pred AK terapijo in sta neučinkovita pri prepoznavanju AK učinka dabigatrana. Trombinski vrh in površina pod krivuljo sta ostala nespremenjena tudi po dodatku idarucizumaba in vitro, kar smo pripisali nastanku kompleksa (α2-makroglobulin-trombin), ki nastaja med tvorjenjem trombina in prispeva k cepitvi fluorogenega substrata in s tem posledično lažno zvišuje rezultate.

Language:Slovenian
Keywords:Dabigatran Idarucizumab Test tvorjenje trombina Presejalne koagulacijske preiskave (APTČ, PČ in TČ)
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2020
Views:207
Downloads:77
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Secondary language

Language:English
Title:In vitro neutralization of dabigatran with idarucizumab
Abstract:
Direct oral anticoagulants (DOACs) which include direct thrombin inhibitor dabigatran (Pradaxa®) have many clinical advantages over vitamin K antagonists, such as less interaction with drugs and food, a wider therapeutic window which enables a fixed dose regimen and requires no need for regular laboratory monitoring. The advantage of using dabigatran over vitamin K antagonists is the existence of specific reversal agent idarucizumab (Praxbind®) that binds dabigatran with higher affinity than thrombin, resulting in fast and complete neutralization of dabigatran anticoagulant activity. In this study we included 44 patients with atrial fibrillation (AF) treated with dabigatran. Blood samples were collected from all patients before and during dabigatran treatment, to which we later added idarucizumab in vitro. We determined the effect of dabigatran and addition of idarucizumab in vitro using coagulation tests (PT, APTT and TT) and with thrombin generation assay (TGA). The results show that dabigatran increases APTT, lag time and time to peak thrombin with increasing concentrations of dabigatran as compared to samples before anticoagulant therapy. Dabigatran had no significant effect on thrombin peak. PT (%) and area under the curve were significantly lower than those before anticoagulant treatment because of the inhibiting activity of dabigatran. The in vitro addition of idarucizumab fully neutralizes anticoagulant activity of dabigatran, which we proved with normalization of PT, APTT, TT, lag time and time to peak thrombin, meanwhile thrombin peak and area under the curve remained elevated compared to samples before dabigatran treatment. In this study we showed that samples collected during anticoagulant treatment with dabigatran which inhibits thrombin prolonged APTT, lag time and time to peak thrombin, however, the in vitro addition of idarucizumab did not restore but rather significant shortened coagulation times compared to samples with no dabigatran. We got similar results in variables of thrombin generation assay, except in thrombin peak and area under the curve, which were significantly higher compared to samples before dabigatran treatment and did not reflect anticoagulant activity of dabigatran. Thrombin peak and area under the curve were not affected by the addition of idarucizumab in vitro, which we attribute to formation of complex (α2-macroglobulin-thrombin) during thrombin generation and contributes to the splitting of fluorescent substrate and consequently falsely increases results.

Keywords:Dabigatran Idarucizumab Thrombin generation assay (TGA) Coagulation tests (APTT, PT and TT)

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