Adenosine diphosphate-induced aggregation is enhanced in platelets obtained from patients with thrombotic primary antiphospholipid syndrome (t-PAPS): Role of P2Y12 -cAMP signaling pathway

Abstract

Background: Thrombotic antiphospholipid syndrome (t-PAPS) is characterized by arterial, venous, or microvascular occlusions, which are explained, in part, by the presence of antiphospholipid (aPL) antibodies. Although there is much evidence indicating that isolated aPL antibodies increase the activity of platelets obtained from healthy volunteers, platelet function in t-PAPS has not been as widely studied.

Objective: To evaluate platelet reactivity in t-PAPS patients.

Methods: Platelet aggregation, protein expression, and cyclic nucleotide levels were carried out in platelet rich plasma (PRP) or washed platelets (WPs) obtained from t-PAPS or healthy volunteers.

Results: ADP-induced aggregation was significantly higher in PRP obtained from t-PAPS than obtained from the control. The protein expression of P2Y₁₂ receptor and Gs alpha was significantly higher and lower, respectively in WPs from t-PAPS patients. In PRP incubated with iloprost or sodium nitroprusside, the residual platelet reactivity induced by ADP was still higher in PRP from t-PAPS than from the control. Lower intracellular levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) were observed in unstimulated PRP from t-PAPS patients. The protein expression of soluble guanylate cyclase subunits and phosphodiesterases types 3 and 5 did not differ. The antiplatelet activity of ticagrelor was similar between the groups and cilostazol significantly potentiated this response. Isolated aPL antibodies obtained from t-PAPS patients potentiated ADP-induced aggregation in healthy platelets but did not affect the inhibitory responses induced by iloprost or sodium nitroprusside.

Conclusions: The overexpression of P2Y₁₂ receptor, accompanied by lower levels of cAMP and cGMP levels produced greater amplitude of ADP aggregation in platelets from t-PAPS patients.

Keywords: P2Y12 receptor; adenosine diphosphate; antiphospholipid syndrome; cilostazol; cyclic nucleotides; platelet; ticagrelor.