A comparison of the abilities of acetylsalicylic acid, flurbiprofen and indomethacin to inhibit the release reaction and prostaglandin synthesis in human blood platelets.

1 A quantitative comparison has been made of the abilities of acetylsalicylic acid, flurbiprofen and indomethacin to inhibit the adenosine diphosphate (ADP)-induced platelet release reaction and to inhibit the synthesis of prostaglandins from arachidonic acid. 2 Experiments were carried out on human platelets that had been incubated with the agents in vitro and on platelets obtained from volunteers who had ingested standard doses of the drugs. 3 The results obtained for acetylsalicylic acid show that there is a close relation between the release reaction and the synthesis of prostaglandins in platelets. 4 Flurbiprofen and indomethacin appear to inhibit the release reaction rather more effectively than they inhibit the synthesis of prostaglandins. It is possible that these agents inhibit the release reaction by another mechanism.

Pseudo grey platelet syndrome--grey platelets due to degranulation in blood collected into EDTA.

We have studied a woman with a history of mild bruising and bleeding, with a normal platelet count and normal clotting factors, who had platelets that appeared grey when stained and viewed under the microscope. Unlike the grey platelet syndrome, the abnormality was only evident when blood had been collected into EDTA and not when citrate or heparin was used as anticoagulant. This 'pseudo grey platelet syndrome' was associated with platelet dense body and alpha granule secretion with no aggregation and occurred on removal of extracellular Ca2+. We discovered that a plasma factor was responsible which could be an immunoglobulin but which is clearly different from the EDTA-sensitive antibodies which cause platelet aggregation and agglutination. We were not able to demonstrate a relationship between the mild bleeding tendency and the in vitro abnormality.

Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis.

The capacity of venous tissue for prostacyclin synthesis was determined in 68 patients undergoing surgery for removal of varicose veins. A single dose of aspirin (81 mg or 300 mg) taken 14 h preoperatively strongly inhibited its synthesis, and the effect of 300 mg was still evident 48 h after ingestion. A single dose of 40 mg aspirin taken 14 h preoperatively had no effect on prostacyclin synthesis. The capacity of blood platelets to synthesise thromboxane (measured as malondialdehyde) was determined in volunteers before and at various times after ingestion of 300 mg or 40 mg aspirin. Both doses had an inhibitory effect that lasted for at least 96 h. The length of time for which the amount of thromboxane synthesised was insufficient to support platelet aggregation and the platelet release reaction depended on both the donor and the dose of aspirin. If prostacyclin and thromboxane are important in the pathogenesis of thrombosis, then doses of aspirin much lower than those used previously should be tested. The long-lasting effect of 300 mg aspirin on both venous tissue and platelets indicates that this dose is unlikely to produce a favourable prostacyclin/thromboxane balance.

Effects of dazoxiben and low-dose aspirin on platelet behaviour in man.

1 We have studied the effects on platelet behaviour of ingestion of the thromboxane synthetase inhibitor dazoxiben (UK 37248), by healthy subjects, and compared the results with the effects of a low dose of aspirin (a cyclo-oxygenase inhibitor), and of a combination of dazoxiben and a low dose of aspirin. 2 Dazoxiben ingestion prevented the release reaction induced by sodium arachidonate (NaAA) in platelet-rich plasma (PRP) from some individuals ("responders") but not in PRP from others ("non-responders"). In vitro testing of PRP from the same subjects, incubated with 10(-4)M dazoxiben, correlated with the effect of dazoxiben ingestion on NaAA-induced release. Platelets from "non-responders" tended to undergo a more extensive release reaction than platelets from "responders" even in the absence of any drug although there was some overlap between the results in the two groups. Platelets from "non-responders" required significantly lower concentrations of NaAA to induce release reaction than platelets from "responders". Platelets from "responders" and "non-responders" did not differ in the amount of malondialdehyde (MDA) produced or in the effectiveness with which dazoxiben ingestion inhibited MDA production. 3 Low dose aspirin had comparable effects on NaAA-induced release to dazoxiben, but in contrast to dazoxiben, the effectiveness of low-dose aspirin in inhibiting NaAA induced release reaction was related to its effectiveness in inhibiting MDA generation. 4 Neither dazoxiben nor low-dose aspirin significantly affected the release reaction induced by adenosine diphosphate (ADP), although both drugs significantly inhibited adrenaline-induced release. 5 A combination of dazoxiben and low dose aspirin had a greater effect on platelet behaviour in response to NaAA, ADP, and adrenaline than either drug alone.

A regimen for low-dose aspirin?

The effects of different regimens of 40 mg aspirin on platelet thromboxane A2 synthesis and vascular prostacyclin synthesis were determined in patients who were undergoing elective surgery for removal of varicose veins. Aspirin 40 mg taken at intervals of 48 hours consistently reduced platelet thromboxane A2 synthesis to a level at which it failed to support platelet aggregation and the associated release reaction. This effect lasted for at least 36 hours. In contrast, aspirin 40 mg every 72 hours did not have the same consistent effect. Both dose regimens led to a reduction in vascular prostacyclin synthesis 12 hours after the last dose, but 36 or 72 hours after the last dose prostacyclin synthesis was not reduced; thus the inhibition of prostacyclin synthesis was short lived. If the balance between platelet thromboxane A2 and vascular prostacyclin synthesis is important in thrombosis 40 mg aspirin every 48 hours may have the maximum antithrombotic effect.

Platelet aggregation in whole blood from patients with Glanzmann's thrombasthenia.

We examined platelet aggregation in platelet-rich plasma (PRP) and in whole blood from two patients with Glanzmann's thrombasthenia. In PRP, aggregation was measured by monitoring the changes in light absorbance that occurred in response to aggregating agents; to measure platelet aggregation in whole blood, we used a platelet counting technique. In PRP, the patients' platelets showed defective aggregation in response to ADP, adrenaline, arachidonic acid (AA), and collagen, but normal agglutination occurred in response to ristocetin. In whole blood, however, platelet aggregation in response to the aggregating agents appeared to be either very similar to that which occurred in blood from normal subjects or only slightly reduced. There was a reduced response to all concentrations of ADP and to low concentrations of collagen but a normal response to all concentrations of adrenaline, AA, and higher concentrations of collagen. Conversely, there seemed to be an increased agglutination response to ristocetin. The abnormality in our two patients with Glanzmann's thrombasthenia probably lies in the inability of their platelets to form large, macroscopic aggregates rather than in platelet aggregation per se.

The effects of dietary supplementation with fish oil in patients with psoriasis.

Ten patients with psoriasis resistant to conventional topical treatment were given dietary supplements of fish oil, providing approximately 12 g of eicosapentaenoic acid daily for a period of at least 6 weeks. In eight patients there was a modest improvement in their psoriasis, the principal effects being a diminution of erythema and scaling. The dietary treatment resulted in a substantial inhibition of leukotriene B4 production by the peripheral blood polymorphonuclear leukocytes in vitro. The discrepancy between the high degree of inhibition of leukotriene B4 synthesis and the modest therapeutic effect suggests that leukotriene B4 is not the only mediator involved in the development of the psoriatic lesion. Furthermore, the in vivo cutaneous levels of leukotriene B4 might not have been inhibited to the same extent as the polymorphonuclear leukocyte levels in vitro. Further studies on the use of fish oil supplements, both on their own and in conjunction with other forms of treatment in psoriasis are warranted. It will also be important to determine whether the altered profile of 5-lipoxygenase products found in the blood is also seen in the skin.