наткнулся на интересные публикации, которые потенциально могут обьяснять, почему прямые ингибиторы тромбина (куда входят дабигатран и мелагатран) способны вызывать инфаркты: в низкой концентрации они оказывают прокоагулянтное действие (усиливают тромбинообразование) из-за того, что не дают активироваться системе тромбин-тромбомодулин/антикоагулянтный протеин С, ингибиторы фактора Х таким свойством не обладают:
Eur J Pharmacol. 2005 May 2;514(1):35-42. Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models.
Furugohri T, Shiozaki Y, Muramatsu S, Honda Y, Matsumoto C, Isobe K, Sugiyama N.
We compared the antithrombotic properties of a factor Xa inhibitor (DX-9065a) with those of a thrombin inhibitor (melagatran) in a rat disseminated intravascular coagulation model and a rat venous thrombosis model. Rat disseminated intravascular coagulation and venous thrombosis models were produced by injection of tissue factor and platinum wire placement, respectively. DX-9065a exerted antithrombotic effects dose dependently in both models. Melagatran was also effective in the venous thrombosis model, whereas it showed an aggravation in the disseminated intravascular coagulation model at low but not high doses.
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Thromb Haemost. 2011 Dec;106(6):1076-83.
Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system.
Furugohri T, Sugiyama N, Morishima Y, Shibano T.
There is increasing concern that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. We utilised an in vitro thrombin generation (TG) assay to determine if direct thrombin inhibitors could enhance TG in human plasma, and whether inhibition of the negative-feedback system [thrombin-thrombomodulin (TM)-protein C] contributed to the TG enhancement. TG in human plasma was assayed by means of the calibrated automated thrombography. In this assay, direct factor Xa (FXa) inhibitors such as edoxaban and antithrombin (AT)-dependent anticoagulants such as heparin did not increase, but simply suppressed TG. AT-independent thrombin inhibitors (melagatran, lepirudin, and active site blocked thrombin (IIai)) increased peak levels of TG (2.0, 1.6, and 2.2-fold, respectively) in the presence of 12 nM recombinant human soluble TM (rhsTM). Melagatran and lepirudin at higher concentrations began to suppress TG. In the absence of rhsTM, the enhancement of peak TG by melagatran decreased to 1.2-fold. Furthermore, in protein C-deficient plasma, AT-independent thrombin inhibitors failed to enhance TG. In addition, a human protein C neutralising antibody increased the peak height of TG in the presence of rhsTM. These results suggest that AT-independent thrombin inhibitors may activate thrombogenesis by suppression of the thrombin-induced negative-feedback system through inhibition of protein C activation. In contrast, direct FXa inhibitors are more useful than AT-independent thrombin inhibitors in terms of lower possibility of activation of the coagulation pathway.
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