Expression of Adhesion Molecules on the Surface of Activated Platelets is Diminished by PGI₂-analogues and an NO (EDRF)-Donor: A Comparison Between Platelets of Healthy and Diabetic Subjects

Abstract

Adhesion molecules such as P-selectin (CD 62), glycoprotein (CP) 53 (CD63) and thrombospondin play a decisive role in the thrombogenic transformation of platelets. Here we present evidence obtained using flow cytometric analysis that the PGI(2)-mimetics iloprost and taprostene, and an NO (EDRF)donor (SIN-1) are able to inhibit the expression of P-selectin, GP 53 and thrombospondin on human platelets activated by submaximal concentrations of thrombin. Since the half-maximal concentrations for inhibition of antigen expression (0.15 nM for iloprost, 3.0-5.3 nM for taprostene) are much lower than for activation of adenylate cyclase (1.4 nM for iloprost and 29.4 nM for taprostene) our data suggest that the occupation of a small number of PGI(2)-receptors is sufficient to inhibit the thrombogenic transformation and that spare PGI(2)-receptors are present on human platelets. In diabetes, the EC(50) for inhibition of expression of platelet antigens is shifted to higher concentrations suggesting that platelets from type 1 diabetic patients are partly resistant to PGI(2). Since the dose dependent increase in c-AMP by iloprost is not changed and intraplatelet c-AMP is elevated in platelets of diabetic patients, we assume that steps in the activation cascade subsequent to activation of adenylate cyclase are disturbed in diabetes.

Inhibition of platelet aggregation by prostaglandin E1 (PGE1) in diabetic patients during therapy with clopidogrel and aspirin

“…Similarly, VN platelet reactivity was higher in subjects with diabetes mellitus as compared to non-diabetic subjects. These findings may suggest a blunted inhibitory response of platelets from diabetics to PGE1, a finding that has previously been documented in platelets from diabetics subjects without antiplatelet therapy [15, 19, 21]. These previously published findings support an altered response of diabetic platelets to prostacyclin and reduced vasodilator response to prostaglandins.…”

“…Due to these qualities, it is used in the VerifyNow point-of-care P2Y12 platelet assay at a concentration of 22 nM along with ADP to suppress aggregation induced by P2Y1 and measure P2Y12 inhibition as previously described [18]. Diabetes mellitus is associated with altered response of platelets to prostacyclin in vitro , and also a blunted response to vasodilating properties of PGE1 in vivo [14, 15, 19–21], which suggests that DM patients may be less sensitive to the inhibitory effects of PGE1 in vitro .…”

Role of nitric oxide in regulation of leucocyte‐endothelial cell interactions

“…These data suggest that increased expression of P-selectin mediates the increase in leucocyte rolling associated with NO synthesis inhibition. The increased level of P-selectin expression and leucocyte rolling could be greatly reduced if an analogue of cGMP was added before L-NAME administration, further suggesting that cGMP may regulate P-selectin expression on endothelium, a concept supported by the known ability of increased levels of cGMP to inhibit surface expression of P-selectin on platelets (Rosen, Schwippert, Kaufman & Tschope, 1994). However, whether L-NAME acts directly on endothelium or on an intermediate cell to inhibit NO production remains unknown.…”

Relationships Between the Endothelin and Nitric Oxide Pathways

“…This suggests that it may also be that inhibition of NO synthesis is associated with changes at the level of the endothelium that makes it more adherent. In addition, NO mimetics decrease the expression of the adhesion molecules P‐selectin (CD62), glycoprotein 53 (CD63) and thrombospondin in platelets activated with thrombin 45 . However, in this latter case, in comparison with the endothelium the effect is more rapidly seen and is consistent with the ability of NO to inhibit rapidly the adhesion of platelets to the vascular endothelium.…”