Image by Volker Brinkmann
Researchers have found that hemorrhage occurs in the context of thrombocytopenia when neutrophils cross the endothelial barrier.
The team also identified ways to inhibit this diapedesis and prevent hemorrhage in mouse models.
If these results can be replicated in humans, such interventions could prevent bleeding in patients with immune thrombocytopenia and certain patients receiving chemotherapy or hematopoietic stem cell transplant.
Carina Hillgruber, PhD, of the University of Munster in Germany, and her colleagues conducted this research and detailed the results in the Journal of Experimental Medicine.
Previous studies showed that an absence of platelets alone was not sufficient to cause hemorrhage. Inflammation was required. But the exact cause of bleeding complications in thrombocytopenia was unknown.
With their research, Dr Hillgruber and her colleagues found that neutrophils are recruited to inflammatory sites to induce thrombocytopenic tissue hemorrhage. The process consists of Gαi2-mediated neutrophil transmigratory activity and opening of the endothelial barrier via VE-cadherin.
So the researchers speculated that preventing neutrophil diapedesis by either tightening the endothelial barrier or targeting neutrophil transmigratory activity would prevent hemorrhage.
The team showed they could inhibit the interaction between neutrophils and the endothelium by interfering with P-selectin, β2integrin-mediated adhesion, and chemokine signaling. This led to reduced inflammatory bleeding in thrombocytopenic mice.
The researchers also found they could interfere with Gαi signaling in neutrophils (which is critical for the cells’ transmigration) via treatment with pertussis toxin or gene ablation. And this protected thrombocytopenic mice from cutaneous hemorrhage.
Finally, the team showed that mice harboring the VE-cadherin mutation Y731F were protected from hemorrhage despite having low platelet counts and immune complex-mediated vasculitis.
The researchers said these findings suggest therapeutically targeting neutrophil diapedesis through the endothelial barrier could potentially prevent hemorrhage in patients with thrombocytopenia.
The team noted that platelets must seal the damage induced by neutrophil diapedesis, but they could only speculate as to how that occurs.
