PB1378 - Complex Phenotypic Expression of an ADP Receptor (P2Y12) Defect in Greater Swiss Mountain Dogs

Background: Congenital defects of the platelet ADP P2Y12 receptor are rare, and affected patients experience highly variable bleeding severity. A naturally occurring bleeding disorder in Greater Swiss mountain dogs (GSMD) has been associated with a mutation in the P2Y12 gene (P2RY12). Canine breeds are large kindreds that facilitate study of rare human disease through combined phenotypic and genotypic studies.

Aims: To define bleeding severity and ADP receptor function in a GSMD pedigree segregating a P2RY12 deletion mutation.

Methods: Clinical histories were compiled from GSMD owners using an on-line survey questionnaire and volunteers were requested to submit blood samples from their dogs. Hemostasis testing for GSMD and paired control dogs included coagulation and von Willebrand factor (VWF) assays, platelet count, and a platelet flow cytometric assay to detect phosphorylation status of vasodilator stimulated phosphoprotein (VASP). All dogs were genotyped for an in-frame 3-bp deletion (P2Y12 p.delSer176).

Results: All GSMD (n=44) had normal platelet count, coagulation, and VWF test results. Overall P2RY12 mutation frequency was 0.34, with abnormal bleeding reported for 5 of 23 GSMD carrying the mutation (Table 1). Marked decrease in ADP receptor function was a consistent finding for all homozygous GSMD, whereas heterozygotes had values that overlapped with wild-type GSMD and control dogs (Figure 1).

Conclusion(s): Although homozygosity for the GSMD P2Y12 p.delSer176 mutation impairs signaling through the ADP receptor, it is not predictive of bleeding severity. The GSMD platelet defect provides a large animal model to further explore platelet ADP signaling pathways and to identify modifying factors that influence bleeding severity.