An evolutionary conserved, immobility associated antithrombotic mechanism

Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a main cause of morbidity and mortality that causes tremendous health care costs. Short term immobility related conditions arising from hospitalization, acute trauma and forced bed rest are major risk factors for the development of VTE. In contrast, chronically paralyzed patients with post-spinal cord injury are protected from VTE despite immobilization. Similarly, free-ranging brown bears (Ursus arctos) that hibernate (immobilize) have adapted to this threat through yet to be discovered mechanisms and do not develop VTE. This suggests that long-term immobility can induce antithrombotic mechanisms that are evolutionarily conserved. Here we aimed to identify these adaptive mechanisms of VTE protection in a cross-species approach. Mass spectrometry-based proteomics identified platelet expressed heat shock protein 47 (Hsp47) as the most substantially downregulated protein during brown bear hibernation. In a clinical bed rest study and in spinal-cord injured humans, we likewise observed drastic reduction of platelet-expressed Hsp47. Genetic ablation and pharmaceutical inhibition of platelet Hsp47 attenuates deep vein thrombosis and thromboinflammatory responses in mice and human blood cells. This suggests that Hsp47 downregulation is an evolutionarily conserved mechanism that also protects immobilized patients from VTE. Our translational approach thus identified an antithrombotic signature that may give rise to novel antithrombotic therapeutics and prognostic markers.