Role of Thrombin Compared With Factor Xa in the Procoagulant Activity of Whole Blood Clots

Abstract

These results indicate that factor Xa is primarily responsible for the procoagulant activity of clots in vitro and suggest a potential molecular mechanism for the observed efficacy of inhibitors of factor Xa in preventing recurrent thrombosis after coronary thrombolysis.

Prolonged Activation of Prothrombin on the Vascular Wall After Arterial Injury

“…Our previous findings document the observation that conditions which induce more extensive mural vascular injury and platelet-rich thrombosis (ie, high shear, electrical injury) cause considerably more Xa/Va activity to be associated with the thrombus, leading to marked local generation of thrombin. 4,8,10,11 Persistence of Bound Xa/Va Activity After Arterial Injury Data from previous experimental and clinical studies are consistent with our observation that Xa/Va activity persists for long periods of time after initial arterial injury. For example, using assays similar to those we used, Barry et al 19 have shown that a 2-hour infusion of hirudin attenuates arterial wallassociated thrombin activity at 24 hours but that bound thrombin activity increases by 48 hours.…”

“…We hypothesized that the Xa/Va complex expressed by platelets that bind to the vascular wall after injury may be an important determinant of thrombin elaboration. 8,10,11 Accordingly, the objectives of this study were to characterize the functional activity of Xa/Va and thrombin associated with the vascular wall after balloon-induced injury to the rabbit aorta and the extent to which the activity of these factors contributes to procoagulant activity over time. In addition, we characterized the extent to which aspirin and heparin attenuate vascular wall-associated procoagulant activity after injury.…”

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors V. A Series of New Derivatives Containing a Spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one Scaffold

“…[23][24][25][26] Direct inhibition of FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [27][28][29][30][31][32][33] In a previous paper, 4) we reported the synthesis and evaluation of compounds in a series of spiro [5H-oxazolo[3,2-a] (Table 1).…”

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors IV. A Series of New Derivatives Containing a Spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one Skeleton

“…[21][22][23][24] Direct inhibition to FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [25][26][27][28][29][30][31] In preceding papers, 1,2) we reported the synthesis and evaluation of compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, of which M55113 (1) 4--2-piperazinecarboxylic acid were found to be potent inhibitors of FXa (IC 50 ϭ60 nM, 31 nM, 6 nM, respectively) with high selectivity for FXa over trypsin and thrombin.In more recent investigations, fixation of the conformation of testing compounds is believed to affect the strength of interaction between such compounds and the target enzyme. Accordingly, in the next stage of investigation our interest was focused on the synthesis of compounds containing a rigid structure in the central part of the compound (2, 3), and on comparison of the inhibitory activities of the compounds thus synthesized for FXa with those of previously reported compounds.…”

“…[21][22][23][24] Direct inhibition to FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [25][26][27][28][29][30][31] In preceding papers, 1,2) we reported the synthesis and evaluation of compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, of which M55113 (1) 4-…”