Platelet aggregatory response to platelet activating factor (PAF), ex vivo, and PAF-acetylhydrolase activity in patients with unstable angina: effectof c7E3 Fab (abciximab) therapy

Objective: Platelet activation and aggregation is a dominant feature in the pathophysiology of unstable angina. The final step of platelet aggregation is mediated through the platelet integrin glycoprotein IIb/IIIa (GP IIb/II Ia), while abciximab (ReoPro) is one of the most potent inhibitors of this receptor. Platelet-activating factor (PAF) is a potent platelet agonist whi ch is degraded and inactivated by PAF-acetylhydrolase (PAF-AH). The plasma farm of PAF-AH is associated with lipoproteins. We studied the platelet res ponse to the aggregatory effect of PAF, ex vivo, in relation to the plasma PAF-AH activity in 32 patients with unstable angina, as well as the effect of abciximab therapy on the above parameters. Methods: Thirty two patients with unstable angina and 25 sex- and age-matched healthy controls participa ted in the study. On the day of admission (day 1) 17 patients received a bo lus of abciximab (0.25 mg/kg) followed by a 12-h infusion (10 mu g/min). Pl atelet aggregation to both PAF and ADP. in platelet rich plasma, was succes sively studied in both patients receiving abciximab or remaining untreated. The plasma and HDL-associated PAF-AH activity was also determined at the s ame times. Results: In the untreated patients, the PAF EC50 values were sig nificantly lower on the day of admission, whereas the maximal percentage of aggregation was significantly higher compared to controls (p<0.01 for both comparisons). Similar behaviour of the platelets was observed in the aggre gatory effect of ADP. This aggregatory response was not significantly alter ed 4 days, 7 days or 1 month afterwards. In the 17 patients who received ab ciximab, platelet aggregation to both PAF and ADP was inhibited by 90+/-5 a nd 96+/-3%, respectively, 1 h after bolus. At 2 and 3 days after treatment, platelet aggregation to both agonists was significantly recovered being si milar to controls. However, it was fully restored 6 days after bolus, still being significantly higher compared to controls (p<0.01 for PAF and p<0.00 3 for ADP). The total plasma PAF-AH activity in both patient groups was not different from that of controls, whereas the HDL-associated PAF-AH activit y was significantly lower. The total plasma or HDL-associated enzyme activi ty was not altered at any time interval studied, and it was not influenced by abciximab. Conclusions: The increased aggregatory response of platelets to PAF and the low plasma levels of HDL-cholesterol and HDL-associated PAF- AH activity in patients with unstable angina may contribute to the severe a therosclerosis and to acute thrombosis found in these patients. Abciximab t herapy may protect platelets from PAF action in vivo the first days after d rug administration, but it fails to permanently restore the enhanced aggreg atory response observed. (C) 1999 Published by Elsevier Science B.V. All ri ghts reserved.