Platelet aggregatory response to platelet activating factor (PAF), ex vivo, and PAF-acetylhydrolase activity in patients with unstable angina: effect of 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/IIIa), while abciximab (ReoPro) is one of the most potent inhibitors of this receptor. Platelet-activating factor (PAF) is a potent platelet agonist which is degraded and inactivated by PAF-acetylhydrolase (PAF-AH). The plasma form of PAF-AH is associated with lipoproteins. We studied the platelet response 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 participated in the study. On the day of admission (day 1) 17 patients received a bolus of abciximab (0.25 mg/kg) followed by a 12-h infusion (10 micrograms/min). Platelet aggregation to both PAF and ADP, in platelet rich plasma, was successively studied in both patients receiving abciximab or remaining untreated. The plasma and HDL-associated PAF-AH activity was also determined at the same times.


RESULTS
In the untreated patients, the PAF EC50 values were significantly 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 aggregatory effect of ADP. This aggregatory response was not significantly altered 4 days, 7 days or 1 month afterwards. In the 17 patients who received abciximab, platelet aggregation to both PAF and ADP was inhibited by 90 +/- 5 and 96 +/- 3%, respectively, 1 h after bolus. At 2 and 3 days after treatment, platelet aggregation to both agonists was significantly recovered being similar 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 < 0.003 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 activity was significantly lower. The total plasma or HDL-associated enzyme activity 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 atherosclerosis and to acute thrombosis found in these patients. Abciximab therapy may protect platelets from PAF action in vivo the first days after drug administration, but it fails to permanently restore the enhanced aggregatory response observed.
Tselepis
A D
AD
Department of Chemistry, Medical School, University of Ioannina, Greece.
Goudevenos
J A
JA
Tambaki
A P
AP
Michalis
L
L
Stroumbis
C S
CS
Tsoukatos
D C
DC
Elisaf
M
M
Sideris
D A
DA
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000077284:Abciximab; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000789:Angina, Unstable / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D000911:Antibodies, Monoclonal; D008076:Cholesterol, HDL; D007140:Immunoglobulin Fab Fragments; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014280:Triglycerides; D002784:Cholesterol; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000077284:Abciximab