Differential effects of novel anticoagulants: FXa versus FIIa inhibition on coagulation and inflammation

S. Nazir1, K. Shahzad1, I. Gadi1, M. Al-Dabet1, S. Kohli1, S. Ranjan1, F. Bock1,2, B. Isermann1 (1Magdeburg, Germany, 2Nashville, United States)

Basic Science
Date: 16.02.2017,
Time: 11:00 - 12:00

Objective: Thrombin is the key protease in regard to thrombus formation; the same is not true in regard to protease dependent signaling. Hence, we postulate that inhibition of either fXa or fIIa may have comparable effects in regard to coagulation, but convey different effects in regard to inflammation and receptor dependent regulation of cellular effects.

Methods: WT mice were either treated with low and high dose of dabigatran or Rivaroxaban for 1 week and then were analyzed for tail bleeding assay or for arterial injury induced thrombosis formation and LAD ligation (ischemic/reperfusion) induced myocardial infarction.

Results: Rivaroxaban and dabigatran have comparable dose-dependent effects in regard to bleeding and thrombosis in in vivo models. However, while fIIa inhibition abrogates the anti-inflammatory effect of fIIa already at low dosages, e.g. at dosages at which bleeding time is already prolonged, this is not the case when using the fXa inhibitor Rivaroxaban. Although Infarcted heart areas were similar in both groups, fxa inhibition abolished proinflammatory cytokines, IL-6, TNF-alpha and macrophages infiltration in infarcted heart tissue. In addition we observed higher levels of blood plasma endogenous activated protein C (aPC) in fXa inhibition group, as compared to in fIIa inhibition group. Western Blot analysis revealed NF-Kβ levels significantly less in fxa inhibited group as compared to fIIa inhibition.

Conclusion: Taken together, these results strongly support that inhibition of fIIa and fXa have similar profiles in regard to the regulation of hemostasis, but differ in their ability to modulate the inflammatory response, with fXa inhibition being superior.