Effect of Clopidogrel on Platelet Aggregation and Plasma Concentration of Fibrinogen in Subjects With Cerebral or Coronary Atherosclerotic Disease

To the Editor: We read the paper by Izaguirre-Avila and associates (1) with interest. These authors documented the platelet inhibitory action of clopidogrel (75 mg/day) in patients with coronary atherosclerosis disease (CAD, n = 41) or with cerebral vascular disease (CVD, n = 49) after 6 and 12 weeks of treatment. Izaguirre-Avila and associates (1) also showed that plasma fibrinogen levels did not change significantly in these patients after treatment with clopidogrel. However, ticlopidine (a drug that also acts on platelet adenosine diphosphate [ADP] receptors such as clopidogrel [2,3]) can decrease the plasma levels of this coagulation factor by about 10%. This effect may be an advantage because plasma fibrinogen is a powerful and independent predictor of vascular risk and an activator of platelets (2-4). The patients studied by Izaguirre-Avila and associates (1) showed a downward trend in fibrinogen concentration. This was especially evident in the CAD group with a decrease in fibrinogen concentration from 2.99 to 2.71 g/L (a decrease of 9.4%, which is similar to that seen with ticlopidine in other studies [2,3]). Do the authors know of a larger study that assessed the effect of clopidogrel on plasma fibrinogen levels? It may be that the numbers they studied were too small to show a significant decrease. Also, would cessation of ticlopidine administration for 1 week bring back the fibrinogen levels to pre-treatment levels in the 18 CVD patients who were taking this antiplatelet drug? We are puzzled by the collagen data (1). In Fig. 2, it is stated that 20 ,ug/mL of collagen was used to induce platelet aggregation. In the text, it is stated 120 mg/mL was used. The difference between these two values is 6,000 fold. Were there two misprints? Even the 20 Atg/mL dose is rather high because you can induce appreciable (e.g., 60%-75% aggregation) with as little 1 ,ug/mL in normal subjects (5,6). We would expect even more aggregation in patients with vascular disease (5). Therefore, it may be difficult to show inhibition when using very high agonist concentrations such as 20,g/mL of collagen. There is evidence that clopidogrel can inhibit platelet aggregation induced by collagen and other non-ADP agonists (e.g., thrombin and U46619, a thromboxane A2 analogue [7,9]). The mechanism responsible probably involves blocking the amplifying effect of ADP released by platelets during aggregation. Another reason why treatment with clopidogrel may inhibit platelet activation by agonists other than ADP may be a decrease in background platelet activity. Thus, other platelet inhibitors (e.g., aspirin and ticlopidine) can prolong the life span of platelets in humans (10,11). This probably means that platelet consumption is decreased, especially because the platelet half-life is shortened in patients with vascular disease (10,11). As far as we know, the effect of clopidogrel on platelet life span in humans has not been assessed. However, we would be very surprised if a prolongation was not reported following treatment with such an effective antiplatelet drug. This mechanism may explain why we found decreased aggregation in response to serotonin (5HT; 5-hydroxytryptamine) 2 hours after administering a loading dose of clopidogrel (300 mg) (unpublished results). Similarly, platelet shape change (PSC) was inhibited after clopidogrel (75 mg/day) on its own, or in combination with aspirin (75 mg/day), for 10 days in patients with peripheral arterial disease (PAD) (12). PAD is associated with platelet hyperactivity (13,14). PSC is an early phase of platelet activation that is aspirin resistant, at least in vitro (15-19). A global inhibition of platelet activity in vivo is supported by the finding of a prolonged bleeding time (p < .01) in the patients studied by Izaguirre-Avila and associates (1). Using a high-resolution channelyzer, we showed that ADP-induced PSC is significantly inhibited after adding ARC69931MX in vitro (19).