The chaperone protein HSP47: a platelet collagen binding protein that contributes to thrombosis and haemostasis

Sasikumar, P., AlOuda, K. S., Kaiser, W. J., Holbrook, L. M., Kriek, N., Unsworth, A. J., Bye, A. P. ORCID: https://orcid.org/0000-0002-2061-2253, Sage, T., Ushioda, R. W., Nagata, K., Farndale, R. W. and Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352 (2018) The chaperone protein HSP47: a platelet collagen binding protein that contributes to thrombosis and haemostasis. Journal of Thrombosis and Haemostasis, 16 (5). pp. 946-959. ISSN 1538-7933 doi: 10.1111/jth.13998

Abstract/Summary

Objective: Heat shock protein 47 (HSP47) is an intracellular chaperone protein that is vital for collagen biosynthesis in collagen secreting cells. This protein has also been shown to be present on the surface of platelets. Given the importance of collagen and its interactions with platelets in triggering haemostasis and thrombosis, in this study we sought to characterise the role of HSP47 on these cells. Approach and Results: The deletion of HSP47 in mouse platelets or its inhibition in human platelets reduced their function in response to collagen and the GPVI agonist (CRP-XL), but responses to thrombin were unaltered. In the absence of functional HSP47, the interaction of collagen with platelets was reduced, and this was associated with reduced GPVI-collagen binding, signalling and platelet activation. Thrombus formation on collagen, under arterial flow conditions was also decreased following the inhibition or deletion of HSP47, in the presence or absence of the eptifibatide, consistent with a role for HSP47 in enhancing platelet adhesion to collagen. Platelet adhesion under flow to von Willebrand Factor was unaltered following HSP47 inhibition. Laser-induced thrombosis in cremaster muscle arterioles was reduced and bleeding time was prolonged in HSP47 deficient mice or following inhibition of HSP47. Conclusions: Our study demonstrates the presence of HSP47 on the platelet surface where it interacts with collagen, stabilises platelet adhesion and increases collagen mediated signalling and therefore thrombus formation and haemostasis.