Carol M. Ingerman

Arachidonic acid-induced human platelet aggregation and prostaglandin formation☆

Abstract Arachidonic acid and several of its salts caused aggregation of platelets in platelet-rich plasma. Other fatty acids did not cause aggregation when tested under similar conditions. Platelet aggregation induced by arachidonic acid was inhibited by adenosine, β naphthol, non-steroidal anti-inflammatory agents, unsaturated fatty acids and albumin. At concentrations too low to cause aggregation, arachidonic acid enhanced aggregation induced by collagen, ADP or epinephrine. Arachidonic acid caused platelets to form PGE 2 and PGF 2α . However, it failed to induce prostaglandin synthesis or platelet aggregation in plateletrich plasma obtained one hour after the ingestion of a therapeutic dose of aspirin. This effect of aspirin persisted for several days. The significance of these findings in relation to hemostasis and thrombosis is discussed.

Arachidonic Acid Causes Sudden Death in Rabbits

Injection of sodium arachidonate (1.4 milligrams per kilogram) into the marginal ear veins of rabbits caused death within 3 minutes. Histological examination showed platelet thrombi in the microvasculature of the lungs. Rabbits were protected from the lethal effects of arachidonic acid by pretreatment with aspirin. Fatty acids closely related to arachidonic acid did not cause death.

Prostaglandin D2 inhibits the aggregation of human platelets.

Abstract Prostaglandin D2, heretofore considered to be biologically inactive, was found to be more than twice as potent as prostaglandin E1 as an inhibitor of aggregation in human citrated platelet-rich plasma. It was much less potent than prostaglandin E1 in rabbit or rat platelet-rich plasma. This prostaglandin, or a derivative of it, may prove to be of greater value than prostaglandin E1 in maintaining the viability of stored platelets and as an antithrombotic agent.

Duration of inhibition of platelet prostaglandin formation and aggregation by ingested aspirin or indomethacin.

Abstract Platelet prostaglandin production was abolished in platelet-rich plasma taken from 4 adult subjects one and 6 hours after ingestion of aspirin or indomethacin. The second wave of epinephrine-induced platelet aggregation was also abolished. Sodium salicylate did not produce these effects. While the effects of aspirin persisted for as long as 2 to 3 days those of indomethacin lasted less than 24 hours.

Prostaglandin endoperoxides and thromboxane A2 can induce platelet aggregation in the absence of secretion

PLATELET aggregation and secretion are widely studied not only because they are believed to reflect the major in vivo platelet function, formation of the primary haemostatic plug, but also because they involve fundamental cellular regulatory mechanisms. The synthesis of biologically active prostaglandin (PG) intermediates (endoperoxides and thromboxanes) seems to be an important step in the regulation of platelet function1,2, but the physiological roles and mechanism(s) of these compounds are unknown. It is claimed by Malmsten et al.3 and Samuelsson et. al.4 that PG endoperoxides and thromboxane A2 cause platelet aggregation only by inducing platelets to secrete ADP that in turn causes aggregation. In view of observations that platelets deficient in releasable ADP (storage pool-deficient platelets or platelets depleted of storage granules) still aggregate in response to arachidonic acid5–7, the precursor of the intermediates, the validity of this claim has been open to question. We have investigated platelet stimulation by PG endoperoxides (PGG2 and PGH2), an endoperoxide analogue ((15S)-hydroxy-11α, 9α-(epoxymethano) prosta-5Z, 13E-dienoic acid; U-46619), thromboxane A2-like material and arachidonic acid, using a new instrument that simultaneously monitors aggregation and secretion in the same platelet suspension8, permitting careful analysis of the relationships between aggregation and secretion. We report here that although high concentrations of the endoperoxide analogue, the natural endoperoxides and thromboxane A2 induce both platelet aggregation and secretion, low concentrations cause aggregation without detectable secretion.

Human blood prostaglandins: formation during clotting.

Abstract 1. Normal human plasma contains only trace amounts of E or F types of prostaglandins. 2. Prostaglandins E 2 and F 2α are formed in platelet-rich plasma in response to thrombin. 3. Serum, obtained by allowing whole blood to clot at 37°, contains relatively large amounts of prostaglandins E 2 and F 2α . 4. The significance of the above findings is discussed and it is suggested that prostaglandins are formed by platelets during hemostasis and thrombosis.

DIRECT MEASUREMENT OF PLATELET SECRETION IN WHOLE BLOOD

Abstract Platelet secretion is usually measured using platelet-rich plasma (PRP) or washed platelets resuspended in buffered saline. We report here measurements of the release of adenosine triphosphate (ATP) from platelets in citrated whole blood in response to thrombin and collagen. The amount of ATP released correlates with the platelet content of the whole blood and is partially dependent on prostaglandin synthesis when release is induced by collagen. Further, the release of ATP does not occur in blood from a patient with storage-pool deficient platelets.

Blood platelets and the inflammatory process

There appears to be an encouraging body of evidence supporting a relationship between hemostasis and inflammation with the platelet being the main link between the two. These processes are both triggered by damage to blood vessels and a response which occurs within seconds of this damage is the adhesion of platelets to the injured tissue and to each other. During the hemostatic process inflammatory agents are released from platelets.Some anti-inflammatory agents such as aspirin also have anti-hemostatic properties and this seems to be because they act on platelets. During platelet aggregation, platelets synthesize the potent inflammatory agent prostaglandin E2 and its formation is prevented by aspirin. Only a few years ago in a discussion on ‘The source of the prostaglandins in inflammation’ [49], platelets were not even mentioned. The evidence summarized in this paper now makes it apparent that the platelet can no longer be neglected as a potential source of inflammatory agents.

Ophthalmic manifestations of the Hermansky-Pudlak syndrome (oculocutaneous albinism and hemorrhagic diathesis).

We report the association of oculocutaneous albinism and defective platelet function, the Hermansky-Pudlak syndrome, in two young Puerto Rican patients, a 17-year-old boy and a 9-year-old girl. Wide variation in pigmentation may obscure the diagnosis of albinism. Puerto Rican albinos are at increased risk of inheriting this autosomal recessive syndrome. Although usually mild, bleeding in affected patients can be life-threatening, especially after aspirin administration. Albino patients should be questioned about a history of bleeding and referred for hematologic consultation.

Uptake and inactivation of a-type prostaglandins by human red cells***

Incubation of A type prostaglandins with whole blood or washed red cells at 37 degrees C converted them to more polar products with negligible vasodepressor and smooth muscle-contracting activities. This conversion did not occur in platelet-rich plasma. Uptake of the prostaglandins by red cells was demonstrated at both 4 degrees C and 37 degrees C. The data suggest 1) that if PGA is released from tissues into the blood stream or is administered for therapeutic purposes, its biological activity would be diminished by human red cells, and 2) that development of an assay for PGA in blood should take into account its uptake and metabolism by human red cells.