Soluble GPVI is elevated in injured patients: Shedding is mediated by fibrin activation of GPVI

Abstract

Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions.We assessed sGPVI levels togetherwith patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU) for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI wasmeasured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, andwas higher in patientswho developed sepsis. sGPVI levels were associated withsepsis, andthevalue forpredicting sepsiswas increasedincombinationwith platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlatedwith levels of D-dimer (a fibrin degradation product) in ICU patients and patientswith thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28- and 90-day mortality independent ofplatelet count. sGPVI levels in patientswith thermal injurywere associatedwith 28-daymortality at days 1, 14, and 21when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.