The DP receptor-dependence of inhibition of platelet aggregation (PA), degranulation, and TXA(2) synthesis, by PGD(2), in human whole blood, has not been established since selective antagonists have only recently been developed. Accordingly, the effects of PGD(2) (30 nM), were determined using the DP receptor antagonists AH6809 (50 µM) and 868C84 (0.5 µM), and results were compared with those obtained using the stable and DP receptor-specific agonist 572C85 (30 nM). With collagen at 0.3 µg/ml, PGD(2) markedly inhibited PA (6 vs 91% PA, p >0.03, n = 12) and both AH6809 and 868C84 alone also inhibited PA but less markedly (62 and 63% PA, respectively) and both antagonists largely prevented the antiaggregatory action of PGD(2) (57 and 52% PA, respectively). PGD(2) also markedly inhibited TXB(2), formation (reflecting inhibition of TXA(2) synthesis) (19 vs 48 nM TXB(2), p>0.03). AH6809 and 868C84 alone had little effect (both 45 nM) but both antagonists significantly reduced the inhibitory effect of PGD(2) on TXB(2) formation (35 and 33 nM, respectively, p> 0.03 vs PGD(2) alone). PGD(2) also inhibited β-thromboglobulin release, but only to a similar extent as with AH6809 and 868C84 alone. With collagen at 3.0 μg/ml, PGD(2) again inhibited PA (60 vs 96% PA, p >0.03), AH6809 and 868C84 alone had no effect on PA (98 and 96% respectively) but effectively abolished the antiaggregatory effect of PGD(2). PGD(2) also inhibited TXB(2) formation (194 vs 339 nM, p > 0.03) and this effect of PGD(2) was effectively abolished both by AH6809 and 868C84 (313 and 308 nM, respectively). Results obtained with 572C85 largely confirmed those obtained with PGD(2), and with collagen at 0.3 µg/ml, 868C84 effectively abolished inhibition of both PA and TXB(2) formation by 572C85. Thus, DP receptor-dependent inhibition of both aggregation and TXA(2) synthesis both by PGD(2) and the more selective DP receptor agonist 572C85, was established using the DP receptor antagonists AH6809 and 868C84. Results obtained for β-thromboglobulin release were inconclusive since both AH6809 and 868C84 inhibited release to a similar extent as did PGD(2), indicating that a limited effect either on aggregation or TXB(2) formation does not preclude a greater effect on degranulation.
We were concerned about the findings of Tigchelaar et al. in which ADP-induced platelet dysfunction was reportedly seen following cardiopulmonary bypass [1]. We are glad that they found HES to be a cost-effective plasma expander which neither caused bleeding nor perceptibly worsened platelet function, thus confirming previous work [2]. We were also pleased that they found that administration of gelatin solution during cardiopulmonary bypass was associated with decreased agglutination in response to ristocetin. This finding also gratifyingly confirms previous work [3] in which similar numbers of patients were studied using hirudinised blood and platelet rich plasma (PRP). We detected a specific impairment of vWF-dependent aggregation/agglutination by gelatin, an effect which was not seen with collagen-induced aggregation.We are disturbed by the choice of citrate as an anticoagulant since findings with ADP might be obscured by artefacts associated with low Ca 2 + concentrations. It has been shown that a low Ca 2 + level in plasma favours thromboxane A 2 formation and secretion in response to ADP [4,5]. The exaggerated response to ADP-induced aggregation might be more evident before cardiopulmonary bypass and since there is some impairment of largely ADP-dependent 'spontaneous' platelet aggregation in stirred normocalcaemic blood during and after cardiopulmonary bypass [3], haemodilution during cardiopulmonary bypass in addition to the 2-fold dilution of blood samples for aggregometry might have greatly exaggerated the degree of impairment of ADP-induced aggregation reported by Tigchelaar et al. [1].Although it is conventional to dilute whole blood 2-fold when using impedance aggregometry, it could markedly influence other results (as with ADP) when blood samples are taken following haemodilution. In the case of the 2L priming volume used by Tigchelaar et al. [1], there is likely to be a more marked effect on aggregation in whole blood than in PRP.Considering the above points, in which pre-cardiopulmonary bypass ADP-induced aggregation may have been exaggerated and the later effects could be attributed to haemodilution, we suggest that the change in aggregation was more apparent than real.
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