Current antithrombotic agents impair haemostasis, which increases the risk of bleeding. A new study now reveals a novel target with antithrombotic potential and with reduced risk of bleeding. “We have identified a pathway that regulates thrombosis, but not haemostasis,” says corresponding author, Daniel Simon. The pathway involves the interaction of the leukocyte integrin Mac-1 (also known as integrin αMβ2) with the platelet surface receptor GPIbα.
Previous work by this group showed that Mac-1 binds GPIbα, regulating inflammation in various models. Taking this work forward, the researchers now show that Mac-1–GPIbα interaction is critical for regulation of thrombosis. Mac-1 deficiency or mutations in the Mac-1 binding site for GPIbα delayed thrombus formation in mouse models of large-vessel (carotid artery) and small-vessel (cremaster microcirculation) arterial thrombosis, without affecting haemostasis parameters such as tail bleeding time. Adoptive transfer of wild-type leukocytes rescued the thrombosis defect. Mechanistically, Mac-1–GPIbα binding induced phosphorylation of protein kinase C-δ and downregulation of forkhead box protein P1 (FOXP1) in leukocytes. FOXP1 signalling contributed to thrombosis, as shown by delayed thrombosis in mice with monocyte and macrophage-specific overexpression of FOXP1.
Finally, in a set of experiments highlighting the therapeutic potential of targeting this pathway, Simon and colleagues showed that blocking Mac-1–GPIbα binding with an antibody or with the small-molecule glucosamine delayed thrombosis after carotid artery injury in mice, without altering haemostasis. The research team is now planning clinical studies to assess the anti-inflammatory and antithrombotic effects of the humanized antibody.
References
Wang, Y. et al. Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat. Commun. 8, 15559 (2017)
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Fernández-Ruiz, I. Novel target with antithrombotic potential and low bleeding risk. Nat Rev Cardiol 14, 444 (2017). https://doi.org/10.1038/nrcardio.2017.95
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DOI: https://doi.org/10.1038/nrcardio.2017.95