Presentation Highlights

During Monday’s State-of-the-Art Session, Shaun Jackson, M.B.B.S., B.Med.Sci., Ph.D. presented his work on “Proinflammatory Function of Dying Platelets”, describing how these platelets are responsible for heterogenous disorders:

  • When patients become critically ill, they develop inflammatory and thrombotic mechanisms that can affect multiple organs.
  • A novel mechanism of occlusion in the lung involves white blood cells and dying platelets.
  • Therapeutic approaches that reduce platelet death may reduce microvascular obstruction in local and remote organs.

When people become critically ill, they often develop inflammation and thrombosis that can affect multiple organs. Jackson’s research is directed towards understanding why this thrombosis develops and he has identified a novel mechanism that begins in the gut, a key player in systemic immune responses.

Gut ischemia is common in critically ill patients and the inflammatory changes that occur in the gut associated with ischemia influence thrombosis in distant organs, in particular the lung. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. When gut ischemia occurs, the damage triggers an inflammatory response. In mouse models, gut ischemia induces a distinct pulmonary thrombotic disorder triggered by neutrophil macro-aggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and microvasculature.

A similar pulmonary neutrophil-rich thrombotic response occurs in humans with acute respiratory distress syndrome (ARDS). In ARDS, the immune response mechanism and thrombotic mechanism come together to affect the pulmonary vasculature. Jackson has found a novel mechanism of occlusion involving white blood cells and dying platelets in the lung. Intravital microscopy during gut ischemia/reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets. These platelet fragments bridge adjacent neutrophils to facilitate macro-aggregate formation. Specific deletion of cyclophilin D from platelets prevents neutrophil macro-aggregation and pulmonary thrombosis.

This research demonstrates the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.

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