A Nuclear Attack on Thrombosis and Inflammation

Thrombomodulin is a transmembrane glycoprotein expressed on the lumenal surface of endothelial cells, where it maintains vascular homeostasis via its anti-inflammatory, anticoagulant, and anti-fibrinolytic properties. These effects of thrombomodulin are achieved through dynamic interactions primarily with thrombin, protein C, thrombin activatable fibrinolysis inhibitor, complement components, and the proinflammatory danger signal high mobility group box 1 (HMGB1).1 When bound to thrombomodulin, thrombin loses its procoagulant/proinflammatory properties, while efficiently generating activated protein C and activated thrombin activatable fibrinolysis inhibitor. Activated protein C is a potent anticoagulant, anti-inflammatory and cytoprotective protease. Activated thrombin activatable fibrinolysis inhibitor inhibits fibrinolysis, and inactivates proinflammatory mediators and anaphylatoxins. The lectin-like domain of thrombomodulin also dampens inflammation by blocking HMGB1 and suppressing complement activation. Diminished expression of thrombomodulin is a feature of endothelial cell dysfunction, and it is a driver in the pathogenesis of several disorders, including venous thromboembolic disease, sepsis, disseminated intravascular coagulation (DIC), atherosclerosis, stroke, inflammatory arthritis and colitis, thrombotic microangiopathies, and diabetic nephropathy. To offset the imbalance associated with reduced thrombomodulin, and with the aim of preventing organ damage, systemic administration of recombinant forms of thrombomodulin has shown efficacy in several preclinical models of thrombosis and inflammation, and in humans with DIC and sepsis.2See accompanying article on page 361 Yang et al3 have taken a different approach to augment endothelial thrombomodulin and limit disease, particularly focusing on thrombosis. Going nuclear, they examined the role of 2 transcription factors, Nur77 and Nor1, members of the family of nuclear orphan NR4A receptors. These are constitutively active, early response genes that encode transcription factors that have multiple effects, …