Research ArticleHypertension

Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension

See allHide authors and affiliations

Science Translational Medicine  01 Feb 2017:
Vol. 9, Issue 375, eaah4923
DOI: 10.1126/scitranslmed.aah4923

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Spotlight on factor XI

Hypertension, cardiovascular disease, and vascular inflammation are inextricably linked, often co-occurring. Kossmann et al. have now discovered a regulatory pathway linking these pathologies that could be inhibited to allow the control of treatment-resistant high blood pressure. In rats and mice with hypertension, the authors found that vascular disease is driven by an overactive thrombin-driven factor XI feedback loop on platelets. Inhibition of this feedback loop with an antisense molecule against factor XI reduced both the vascular pathology and hypertension. The authors show that this factor XI–dependent feedback loop also operates in patients with uncontrolled hypertension, raising the possibility that factor XI inhibition may prove a useful addition to our armamentarium for treating high blood pressure.


Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II–induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 expression and integrin αMβ2– and platelet-dependent leukocyte adhesion to arterial vessels. The resulting vascular inflammation and dysfunction was mediated by activation of thrombin-driven factor XI (FXI) feedback, independent of factor XII. The FXI receptor glycoprotein Ibα on platelets was required for this thrombin feedback activation in angiotensin II–infused mice. Inhibition of FXI synthesis with an antisense oligonucleotide was sufficient to prevent thrombin propagation on platelets, vascular leukocyte infiltration, angiotensin II–induced endothelial dysfunction, and arterial hypertension in mice and rats. Antisense oligonucleotide against FXI also reduced the increased blood pressure and attenuated vascular and kidney dysfunction in rats with established arterial hypertension. Further, platelet-localized thrombin generation was amplified in an FXI-dependent manner in patients with uncontrolled arterial hypertension, suggesting that platelet-localized thrombin generation may serve as an inflammatory marker of high blood pressure. Our results outline a coagulation-inflammation circuit that promotes vascular dysfunction, and highlight the possible utility of FXI-targeted anticoagulants in treating hypertension, beyond their application as antithrombotic agents in cardiovascular disease.

View Full Text

Stay Connected to Science Translational Medicine