The effect of rivaroxaban on the overall hemostatic potential

Hemostaza je fiziološki proces, ki z različnimi mehanizmi omogoči tvorbo trombocitnega strdka in s tem zaustavi krvavitev po poškodbi žile, sočasno pa aktivira njegovo razgradnjo in omogoči normalno prehodnost krvi v žili. Motnje hemostaze lahko privedejo do hiperkoagulabilnosti, le-te pa so zaradi mnogovrstnih vzrokov in mehanizmov pogostejše od krvavitev. Antikoagulanti so učinkovine, ki delujejo tako, da preprečijo strjevanje krvi. Omejitve tradicionalnih antikoagulacijskih zdravil so spodbudile razvoj tarčno specifičnih peroralnih antikoagulantov, ki neposredno zavirajo posamezne encime v koagulacijski poti. Ena teh učinkovin je rivaroksaban, ki neposredno zavira delovanje faktorja Xa. Zaradi predvidljive farmakokinetike in farmakodinamike rutinskega spremljanja rivaroksabana ne opravljamo, je pa laboratorijsko vrednotenje nepogrešljivo v nujnih primerih. Za oceno antikoagulacijskega učinka rivaroksabana trenutno uporabljamo klasični koagulacijski preiskavi protrombinski čas (PČ) in aktivirani parcialni tromboplastinski čas (APTČ), ki pa realnega hemostatskega stanja bolnikov ne odražata zadovoljivo. Razvoj je usmerjen v iskanje globalne hemostatske preiskave, katere rezultati bi korelirali s klinično sliko bolnika. Metoda celokupnega hemostatskega potenciala (CHP) temelji na spektrofotometričnem merjenju nastajanja in razgradnje fibrina v citratni plazmi v dveh paralelkah. Namen naloge je bil ovrednotenje uporabnosti te preiskave pri ex vivo vzorcih bolnikov, ki prejemajo rivaroksaban. Izmerili smo celokupni hemostatski potencial v vzorcih bolnikov v času pred zaužitvijo naslednjega odmerka in času največje absorpcije. Ocenili smo ponovljivost metode (KV=16,5 %) in preučili povezavo celokupnega hemostatskega potenciala s koncentracijo rivaroksabana v plazmi (R=0,148). Preučili smo tudi čas do začetka koagulacije in ugotovili, da se je s koncentracijo rivaroksabana povezoval enako dobro kot klasični koagulacijski preiskavi protrombinski čas (R=0,801) in aktivirani parcialni tromboplastinski čas (R=0,811), kar bi bilo smiselno podrobneje raziskati. Na osnovi naših rezultatov lahko zaključimo, da metoda CHP ni primerna za spremljanje zdravljenja z rivaroksabanom, predstavlja pa metodološki pristop k odkrivanju nove tehnike in prispeva k zavedanju zapletenosti procesa hemostaze. V prihodnosti pričakujemo intenziven razvoj metod za spremljanje učinkovitosti in varnosti zdravljenja z novimi oralnimi antikoagulanti.Hemostasis is a physiological process that with various mechanisms enables the formation of a platelet clot, thereby stopping the bleeding after the damage to the vessel, while simultaneously activating clot degradation and allowing normal blood flow. Hemostatic disorders can lead to hypercoagulability, which is more frequent than bleeding, due to multiple causes and mechanisms. Anticoagulants are substances that act to prevent blood clotting. Restrictions on traditional anticoagulant drugs have stimulated the development of target-specific oral anticoagulants that directly inhibit individual enzymes in the coagulation pathway. One of these active substances is rivaroxaban, which directly inhibits factor Xa. Due to the predictable pharmacokinetics and pharmacodynamics of rivaroxaban, routine measurements are not performed, but laboratory evaluation is indispensable in urgent cases. In order to evaluate the anticoagulation effect of rivaroxaban, classical coagulation screening assays such as prothrombin time (PT) and activated partial thromboplastin time (APTT) are currently used. Unfortunately they do not fully reflect the real hemostatic status of the patients. The development is aimed at finding a global hemostatic assay, the results of which would correlate with the clinical state of the patient. The method of overall hemostatic potential (OHP) is based on the spectrophotometric registration of fibrin formation and its degradation in citrate plasma in two parallels. To evaluate the usefulness of this assay in patients receiving rivaroxaban, sampling took place at the time just before next dose and at the maximum absorption time. Overall hemostatic potential in the patient samples was then measured. The reproducibility of the method was evaluated (CV=16,5 %) and the relationship between overall hemostatic potential and plasma concentration of rivaroxaban was studied (R=0,148). We also studied the time until the start of coagulation and found that it correlates with the concentration of rivaroxaban to the same extent as prothrombin time (R=0,801) and activated partial thromboplastin time (R=0,811). This finding could be worth exploring into more detail. Based on our findings we conclude that the method of overall hemostatic potential cannot be used to monitor treatment with rivaroxaban. Nevertheless, it represents a methodological approach in the search of a new method and contributes to the awareness of the complexity of hemostasis. In the future, we expect intensive development of methods for monitoring the efficacy and safety of treatment with new oral anticoagulants