ADP Signaling Defect in Children with Severe Acquired Aplastic Anemia: A Potential Common Pathway for Development of Aplastic Anemia.

Severe Acquired Aplastic Anemia is a rare disease with an incidence in British Columbia of 6.9 per million/year in Eastern/Southeastern Asians, 7.3 per million/year in South Asians and 1.7 per million/year in those of White/mixed ethnic descent. Two children presented with mucosal bleeding >4 years after achieving complete remission with immune suppressive therapy (antithymocyte globulin, cyclosporin A and prednisone). Evaluation revealed normal routine coagulation profiles and normal platelet numbers but mildly prolonged bleeding times (patients 8.5 - 11.0 minutes; control 3.0 – 8.0 minutes) and abnormal platelet aggregation as measured by aggregometry (optical and luminescence) after ADP stimulation. The patients had normal aggregation and ATP secretion after stimulation with thrombin (ATP secretion only), collagen, epinephrine, arachidonic acid, and ristocetin (1.125, 1.0, and 0.5 mg/mL concentrations, optical aggregation only) but showed abnormal aggregation with ADP (2.5, 5.0, and 10 μM). An additional 4 aplastic anemia patients were tested >1 year after successful immune suppressive therapy with no bleeding history: 1 of the 4 had the identical defect in platelet aggregation and ATP release after ADP stimulation, with no other defects on aggregometry. All 3 patients with abnormal platelet aggregation were of South or East Asian background, and the 3 with normal aggregation were of Caucasian/mixed ethnicity. Of the patients with an abnormal ADP platelet response, one has subsequently developed ulcerative colitis. Based on these observations we hypothesize that some patients with severe acquired aplastic anemia have an underlying defect in a signaling pathway shared by platelets, T cells, and B cells. ADP-induced signaling in platelets is induced through the surface molecule P2Y12, which is not expressed on lymphocytes. P2Y12 signaling occurs in association with a G protein Galphai2, an important signaling molecule in T and B cells and associated with development of ulcerative colitis in Galphai2 knock out mice. The specific signaling defect in platelets is currently being elucidated in these patients, and the incidence of these defects in aplastic anemia patients must be characterized.