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We have evaluated the influence of NBT, vitamin E, and the combination of NBT and vitamin E on the fine structure and biochemistry of platelets during incubation, and the effects of these compounds on the aggregation and secretion of platelets stimulated by collagen, thrombin, epinephrine, and ADP. Results demonstrate that NBT and vitamin E, rather than injuring platelets, appear to protect them during incubation. Togheter NBT and vitamin E blockedaggregation by epinephrine, collagen, and thrombin, but permitted a small first wave stimulated by ADP. This pattern of response to aggregating agents was similar to reactions observed in platelets pretreated with aspirin and indomethacin, both potent inhibitors of platelet prostaglandin synthesis. The findings support the concept that conversion of arachidonic acid to an activated state is an important step in prostaglandin synthesis and that electron transfer or oxidation--reduction reactions are intimately involved in the development of platelet stickiness. Although vitamin E alone does not block prot to regulate formation of endoperoxides and thromboxanes.

The reaction of ferrous iron and oxygen to oxidize arachidonic acid has been studied to aid in understanding the mechanism of PGG2 formation. Based on these results we have presented a novel concept of heme-arachidonic acid interaction in PG synthesis.

Platelet aggregation studies were performed on 10 pediatric patients with acute lymphoblastic leukemia (ALL) receiving induction therapy with vincristine, prednisone, and L-asparaginase. An isolated abnormality in platelet aggregation in response to collagen was found in all patients during the course of therapy. Platelet aggregation in response to collagen normalized following the discontinuation of L-asparaginase, while patients were still on vincristine and prednisone. In contrast to the abnormal collagen response, platelet aggregation induced by epinephrine, arachidonic acid, adenosine diphosphate (ADP), and thrombin were normal both during and following therapy. In the one patient with a normal platelet count before therapy, aggregation induced by all agents was normal. This selective abnormality in collagen aggregation therefore appears to result from therapy, with the use of L-asparaginase in particular being implicated.

Arachidonic acid- or collagen-induced aggregation was accompanied by a progressive elevation in the level of cyclic GMP in washed human platelets with no significant alteration in the concentration of cyclic AMP. The extent of the increase in cyclic GMP was proportional to the concentration of arachidonic acid added. Enhanced accumulation of cyclic GMP produced by arachidonic or collagen was prevented by prior exposure of platelets to aspirin or indomethacin. Prostaglandin endoperoxide G2 caused platelet aggregation and an increase in cyclic GMP concentration; neither event was blocked by prostaglandin synthesis inhibitors. These results indicate that the generation of prostaglandin endoperoxides is a step in the sequence of events in platelet aggregation leading to the enhanced accumulation of cyclic GMP.

Serum complement studies were carried out in five children with acute lymphocytic leukemia. During therapy with L-asparaginase, prednisone and vincristine, hypocomplementemia developed in all patients, and disappeared within 2 weeks after the discontinuation of L-asparaginase. Complement breakdown products were not present in plasma. The changes of serum complement levels paralleled those of plasma fibrinogen. These findings suggest that the hypocomplementemia observed in these patients may be related to impaired protein synthesis induced by L-asparaginase.