Background: Thrombin is the key protease in regard to thrombus formation. However, in regard to protease dependent signaling other coagulation proteases, including fXa, likewise convey cellular effects.

Aims: We postulate that inhibition of fXa or fIIa conveys different effects in regard to inflammation despite comparable anticoagulant efficacy.

Methods: WT mice were treated with direct fIIa inhibitor (fIIai) or direct fXa inhibitor (fXai) at doses conveying a comparable anticoagulant effect in vivo (tail bleeding assay and FeCl₃-induced thrombosis). Myocardial ischemia-reperfusion injury (IRI) was induced via LAD ligation followed by reperfusion. To induce atherosclerosis ApoE-/- mice were fed high fat diet (HFD) for 20 weeks. 

Results: Doses of fIIai and fXai conveying comparable anticoagulant effect in vivo were established. Using equally potent dosages of fIIai and fXai we analyzed the impact of direct fIIa and fXa inhibition on myocardial infarction and atherosclerosis. fIIai and fXai inhibition resulted in comparable infarct. However, unbiased gene-expression analyses revealed marked differences, including pathways related to sterile inflammation. fXai and not fIIai conveyed anti-inflammatory effects, hallmarked by reduced expression of proinflammatory cytokines and less inflammasome activation. Mechanistically, aPC generation was higher in fXai as compared to fXai mice. 3K3A-aPC in addition to fIIai reduced the inflammatory response. Conversely, non-specific aPC-inhibition abolished the anti-inflammatory effect associated with fXa inhibition, while specifically inhibiting aPC’s anticoagulant function spared the anti-inflammatory effect. The anti-inflammatory effect observed with fXa inhibition reduced myocardial fibrosis post myocardial infarct. In addition, we observed smaller and more stable atherosclerotic plaques in fXai treated ApoE-/- HFD mice (more smooth muscle cells and less macrophages) , while in fIIai group plaques were also smaller but less stable (more macrophages and less SMC).

Conclusions: We reveal that specific inhibition of coagulation proteases via DOACs has differential effects in regard to gene-expression and inflammation, despite a comparable anticoagulant and infarct size and plaque size.
 

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/targeting-coagulation-factor-xa-and-iia-differentially-regulate-inflammation/