Grant: Foundation Grant

Platelets are small blood cells that aggregate and are responsible for bleeding arrest (hemostasis) at sites of injury. They are also key targets in many diseases. High platelet activity may result in heart attack and stroke (thrombosis), which are leading causes of death worldwide, while low platelet number may cause severe bleeding and miscarriages (thrombocytopenia). Our goal is to elucidate underlying mechanisms of these diseases and develop novel therapeutics. Platelet surface integrin alphaIIb beta3, is traditionally thought to exclusively bind fibrinogen (Fg)/VWF and mediate cross-linking of platelets (aggregation) during hemostasis/thrombosis. My discovery of Fg/VWF-independent thrombosis, proved that unidentified proteins ("X" ligands) bind beta3 integrin to support platelet aggregation. However, these ligands and their role in thrombosis still need to be delineated. We will use chemically engineered beads coupled with alphaIIb beta3 to pull down with high purity unidentified plasma and platelet proteins that bind alphaIIb beta3 (GPIIbIIIa). Specific alphaIIb beta3-protein interactions will be measured and the roles of new ligands in platelet biology, thrombosis and hemostasis will be studied using platelet function assays. We expect these ligands may affect both facets of platelets (activation and inhibition) and may be targeted to control many diseases. Immune-mediated thrombocytopenias involve targeting of self- or non-self (e.g. fetal)-platelet antigens by antibodies leading to platelet destruction known as autoimmune (ITP) and fetal/neonatal alloimmune thrombocytopenia (FNAIT), respectively. We have shown antibodies targeting different platelet surface receptors (i.e. GPIIbIIIa vs. GPIbalpha) can lead to very different disease outcomes and response to treatment. We will continue to explore these differences between the anti-GPIIbIIIa and GPIbalpha immune response in ITP and FNAIT to enhance treatment efficacy.