Hamostaseologie 2021; 41(S 01): S17
DOI: 10.1055/s-0041-1728112
Oral Communication
Mechanisms of Disease I

Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury

I Gadi
1   University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry und Molecular Diagnostic, Leipzig
,
S Fatima
1   University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry und Molecular Diagnostic, Leipzig
,
S Kohli
1   University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry und Molecular Diagnostic, Leipzig
,
A Elwakiel
1   University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry und Molecular Diagnostic, Leipzig
,
B Isermann
1   University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry und Molecular Diagnostic, Leipzig
,
K Shahzad
1   University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry und Molecular Diagnostic, Leipzig
› Author Affiliations
 

Objective While thrombin is the key protease in regard to thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially disjunct receptors. Hence, we postulate that inhibition of fXa or fIIa conveys different effects in regard to inflammation in myocardial ischemie-reperfusion injury (IRI), despite comparable anticoagulant efficacy.

Material and Methods Mice were treated with direct fIIa inhibitor (fIIai; dabigatran) or direct fXa inhibitor (fXai; rivaroxaban) at doses conveying a comparable anticoagulant effect in vivo (tail bleeding assay and FeCl3-induced thrombosis). Myocardial IRI was induced via LAD ligation. We determined volumes of infarct size and in vivo aPC generation and conducted gene-expression using an unbiased approach, immunoblotting and ELISA. The signaling-only 3K3A aPC variant and inhibitory antibodies blocking all or only the anticoagulant function of aPC were used to determine the role of aPC for differential effects between fIIai and fXai.

Results Doses of fIIai and fXai conveying comparable an anticoagulant effect in vivo were established and used subsequently in animals challenged with myocardial IRI. fIIai and fXai resulted in a comparable reduction of infarct size. However, unbiased gene-expression analyses revealed marked differences, including pathways related to sterile inflammation and inflammasome regulation. fXai, but not fIIai, conveyed anti-inflammatory effects, hallmarked by reduced expression of proinflammatory cytokines and reduced NF-κB and inflammasome activation. The anti-inflammatory effect observed with fXai reduced myocardial fibrosis 28 days post myocardial IRI. Mechanistically, in vivo generation of cytoprotective aPC was higher with fXai as compared to fIIai. Inhibition of aPC`s anticoagulant and signaling properties abolished the anti-inflammatory effect associated with fXai, while inhibiting only aPC’s anticoagulant function spared the fXai-associated anti-inflammatory effect. Concurrently, 3K3A-aPC in addition to fIIai reduced the inflammatory response, mimicking the fXai-associated effect.

Conclusion Here we show that specific inhibition of coagulation via DOACs has differential effects in regard to gene-expression and inflammation, despite a comparable anticoagulant effect and infarct size.

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Publication History

Article published online:
18 June 2021

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