PB0902 - The effect of hypercortisolism on platelet function in dogs with Cushing's syndrome

Background: Cushing’s syndrome is a condition defined by endogenous hypercortisolism associated with an increased risk of coagulation disorders. Although patients with Cushing’s syndrome have a higher risk of hypercoagulopathy, a comprehensive study of platelet function in Cushing’s syndrome patients is lacking.

Aims: We aimed to determine the effect of hypercortisolism and its molecular basis on the regulation of platelet function in Cushing’s syndrome dogs.

Methods: We analyzed platelet functional responses in washed platelets from Cushing’s syndrome patients.

Results: Platelet counts were increased in Cushing’s syndrome patients compared to healthy controls. However, 2-MeSADP-induced secondary wave of aggregation was significantly inhibited in Cushing’s syndrome patients. Additionally, platelet aggregation and secretion induced by low-dose thrombin were inhibited in patients. It has been known that 2-MeSADP-induced secondary wave of aggregation and low-dose thrombin-induced platelet aggregation and secretion are affected by the positive-feedback effect of generated thromboxane A2 (TxA2), suggesting the defect in TxA2 generation in Cushing’s syndrome patients’ platelets. Moreover, the pre-incubation of prednisolone, a glucocorticoid, inhibited 2-MeSADP- and thrombin-induced platelet aggregation and secretion in healthy platelets to a similar extent as it did in platelets of Cushing’s syndrome patients, whereas no additional inhibitory effect of prednisolone was observed in Cushing’s syndrome patients’ platelets. Furthermore, platelet function was improved when trilostane, a Cushing’s syndrome treatment, was prescribed to Cushing’s syndrome patients, whereas platelet function was worsened when prednisolone was administered. Moreover, 2-MeSADP- and thrombin-induced platelet aggregation and secretion were significantly decreased at high post-cortisol levels, a positive indicator of Cushing’s syndrome, demonstrating a negative correlation between Cushing’s syndrome and platelet function. Finally, 2-MeSADP- and thrombin-induced TxA2 generation was inhibited in Cushing’s syndrome patients, confirming the effect of cortisol on TxA2 generation.

Conclusion(s): In conclusion, hypercortisolism impairs agonist-induced platelet aggregation and secretion by inhibiting TxA2 generation. These findings may lay the groundwork for improved treatment of dogs with Cushing’s syndrome.