Thromboinflammation in cardiovascular disease: lessons learned for the management of hypertension, heart failure, and aortic valve stenosis

Thromboinflammation has emerged as a new term to describe the interconnection between the simultaneous activation of the coagulation and the immune system. It is the flipside of immunothrombosis, an evolutionary highly conserved mechanism of innate immunity that has developed to allow trapping and compartimentalization of invaded pathogens and to improve host defence. In contrast to immunothrombosis, it occurs in the absence of a pathogen, but is triggered mainly by endothelial dysfunction. This may lead to release of pro-inflammatory cytokines as well as chemokines and adhesion molecules, activation of myeloid cells, decryption of tissue factor on the surface of neutrophils and monocytes, release of von Willebrand factor (vWF) from platelets and endothelial cell Weibel–Palade bodies, and netting of neutrophils with consecutive activation of the contact phase of the coagulation cascade and FXa/thrombin activation, implying both thrombin propagation via the FXI feedback activation and increased fibrin deposition.1 In cardiovascular diseases (CVDs), paradigmatic conditions of thromboinflammation are endothelial erosion as a mechanism of acute coronary syndrome in the absence of plaque rupture [Type II myocardial infarction (MI)],2 deep vein thrombosis induced by low flow,3 and atherogenesis propelled by a chronically activated coagulation cascade.4 In some indications, recent advances in pharmacotherapy were successful in ameliorating the disease burden evoked by thromboinflammation. For example, long-term FXa inhibition can reduce thrombosis-associated morbidity and mortality in cancer, when administered for primary prevention of venous thromboembolism in selected patients,5 and low-dose rivaroxaban in addition to aspirin can lower major adverse cardiovascular events and all-cause mortality in patients with coronary artery disease who had an MI in the past.6 These findings of the COMPASS trial merit special consideration, because one-fourth of the anticoagulant dose of rivaroxaban was efficient for reaching this endpoint including reduction in thrombotic events, which has been attributed to vascular protection mediated through protease-activated receptor inhibition instead of reducing thrombin and fibrin formation in this population of non-atrial fibrillation patiens. The identification of the thrombin-FXI feedback amplification loop for thrombin propagation holds promise to avoid blood clotting without abolishing haemostasis and has sparked the development of novel FXI(a) inhibitors for safer anticoagulation7 that seamlessly align into the concept of thromboinflammation (Figure 1).