Impaired cellular trafficking of a thrombomodulin mutant causes severe bleeding, thrombosis, and atypical hemolytic uremic syndrome.

Thrombomodulin (THBD) is an endothelial membrane protein that has anticoagulant and anti-inflammatory actions, inhibits fibrinolysis, and modulates innate immunity and complement activation. We report the characterization of a novel THBD mutation, C256S, homozygously expressed in an adolescent boy. The patient presented with a wide range of symptoms, including life-threating epistaxis, thrombotic microangiopathy, massive intraoperative bleeding, venous thromboses, and skin necrosis. THBD-C256S is predicted to prevent the formation of a critical disulfide bond within epidermal growth factor-like region 1. The mutant was nonfunctional when expressed in a zebra fish model. In patient-derived endothelial cells, THBD-C256S exhibited impaired glycosylation, increased intracellular retention, and reduced cell surface levels of THBD. Expression of the mutant led to decreased levels of other endothelial proteins, including platelet endothelial cell adhesion molecule-1 and vascular endothelial-cadherin. Our data suggest that misfolding of THBD-C256S disrupts normal THBD functions leading to the broad constellation of clinical abnormalities.