Novel mechanism of platelet activation in haemolytic diseases

Haemolytic diseases with genetic (e.g. sickle cell disease) or infectious (e.g. shigatoxin–producing Escherichia coli-induced haemolytic uremic syndrome) origins are characterised by thrombocytopenia, a hypercoagulable and proinflammatory states, vessel obstruction and organ damage, regardless of aetiology.

My unpublished data demonstrate that in haemolytic diseases, haem released from lysed red blood cells mediates a novel pathway of platelet activation that promotes inflammation and thrombosis.

I have discovered that haem mediated activation of human platelets is blocked by inhibitors of Src and Syk kinases and by recombinant CLEC-2, and that activation is abolished in CLEC-2-deficient mice platelets. In addition, I show a partial role for GPIb in supporting activation.

I propose to further investigate the mechanism of interaction between haem and platelet CLEC-2 and GPIb in vitro and in in vivo clinically relevant experimental models, and determine its contribution to the pathophysiology of haemolytic diseases.

The results will provide a basis for selecting and re-purposing clinically approved kinase inhibitors for prevention of thrombosis and inflammation in haemolytic diseases.