Understanding the role of damage-associated molecular patterns Heme and S100A8/A9 in platelet function

Colicchia, Martina ORCID: 0000-0002-5622-6565 (2024). Understanding the role of damage-associated molecular patterns Heme and S100A8/A9 in platelet function. University of Birmingham. Ph.D.

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Abstract

Platelets are small blood cell fragments, derived from the megakaryocytes, essential for adequate haemostasis at the site of vascular injury, but also drivers of pathological processes such as thrombosis. In the context of both sterile and infection-driven inflammation, platelets interact with immune and endothelial cells supporting immunothrombosis which can subsequently lead to thromboinflammation and organ damage. The contribution of platelets is not solely dependent on their classical activation and aggregation, but also relies on the development of different platelet subpopulations including procoagulant platelets. Those drive different pathways fuelling thromboinflammation. The mechanisms leading to platelet activation and the formation of procoagulant platelets under pathogenic conditions remains poorly understood.

Damage-associated molecular patterns (DAMPs) are danger molecules released by injured and/or activated host cells which bind and activate pattern recognition receptors on different cells. Once secreted extracellularly, DAMPs drive both immunothrombosis and thromboinflammation. Moreover, multiple DAMPs have been proposed as biomarkers of immunothrombosis and their plasma levels correlate with disease severity. In this thesis, we propose that the two DAMPs, S100A8/A9 and heme, which are primarily released from neutrophils and damaged erythrocytes respectively, lead to direct platelet activation and support immunothrombosis and thromboinflammation.

We identify S100A8/A9-GPIb axis as a novel pathway mediating platelet activation. We show that S100A8/A9 levels are elevated in the plasma of patients with COVID-19 and sustained high levels correlate with adverse outcome. We demonstrate that S100A8/A9 induces non-classical platelet activation and the formation of procoagulant platelets accelerating fibrin generation at venous shear. However, S100A8/A9 does not induce platelet aggregation. The effect of S100A8/A9 on platelets is regulated by the platelet adhesion receptor GPIbα with a supportive role for CD36. These data shed light on a new immune-driven mechanism of thrombosis.

We next identify heme as a novel agonist leading to platelet activation. We describe that the mechanism driving platelet aggregation is regulated by the levels of free heme whereby low concentrations induce classical aggregation whilst high concentrations induce platelet death and agglutination. At low concentrations, as observed in patients with haemolytic diseases, heme induces platelet activation and aggregation through the receptor CLEC-2, independent of heme-driven oxidative stress. These data identify a new mechanism by which haemolysis induces platelet activation and aggregation through CLEC-2. We demonstrate that both S100A8/A9 and heme-mediated platelet activation are resistant to classic anti-platelet drugs targeting cyclo-oxygenase and P2Y12 and raise the need to develop new therapies to limit the effect of these DAMPs on platelets.

Taken together, these results highlight the importance of heme and S100A8/A9 in platelet activation and immunothrombosis. These data underline the importance of finding novel molecules or repurposing known compounds to complement current anti-platelet therapies and address the immune- and damage-driven thrombotic pathways regulating immunothrombosis.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Rayes, Julie UNSPECIFIED orcid.org/0000-0003-0499-6880 Thomas, Mark R. UNSPECIFIED orcid.org/0000-0001-7048-7764 Rainger, George Edward UNSPECIFIED orcid.org/0000-0002-1592-9854 Watson, Steve P. UNSPECIFIED orcid.org/0000-0002-7846-7423
Licence:	All rights reserved
College/Faculty:	Colleges (former) > College of Medical & Dental Sciences
School or Department:	Institute of Cardiovascular Sciences
Funders:	Wellcome Trust
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General) R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology
URI:	http://etheses.bham.ac.uk/id/eprint/15593

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