Pathogenesis and treatment of immune thrombocytopenia: Are there fundamental differences between anti-GPlba- and anti-GPllbllla-mediated thrombocytopenia?

Platelets are small blood cells responsible for forming clots at the site of bleeding. They aggregate to form a cellular plug, strengthen the coagulation system when blood vessels are injured, and are critical in preventing blood loss. Autoimmune thrombocytopenia (ITP) is a disease that occurs when the immune system mistakenly produces antibodies that destroy a patient's own platelets. Thus, the patient cannot stop bleeding, which can lead to severe problems or death. The antibodies in this disease attack two proteins (antigens), called GPIIbIIIa and GPIb, on the surface of platelets. These proteins are responsible for binding platelets together and sticking to the vessel wall to stop bleeding. Approximately 70-80% of ITP patients have antibodies targeting GPIIbIIIa, 20-40% of patients have antibodies targeting GPIb, and some patients have antibodies targeting both. Currently, it is not clear whether the antibodies to GPIIbIIIa and GPIb cause ITP by the same mechanism, nor whether ITP caused by each of these proteins can be successfully treated by the same therapies. We also do not know whether some patients have more severe bleeding than others because of the specific type of antibodies in their blood (i.e. whether severity is related to the protein or the subsection of the protein that the antibody attacks). We propose to address these questions and investigate whether antibodies against GPIb and GPIIbIIIa may act differently by: i) changing platelet signaling activity, ii) changing the physical structure of GPIIbIIIa and GPIb proteins, or iii) affecting platelet generation. We think that different antibodies may affect platelet function in a different manner, which determines where platelets are destroyed and how patients respond to current clinical therapies (e.g. removing the spleen or IVIG treatment). This study has already and will continue to provide significant insights into development of new diagnostic and therapeutic methods to control this disease.

NI, Heyu

St. Michael's Hospital

Canadian Blood Services-CIHR Partnership Operating Grant Program

Ontario

378529.0