Biomedical subjects

J F Mustard

Publications and source records attributed to J F Mustard.

At least 199 records · Page 11Linked to original sources

PubMed1975

Platelets, thrombosis and drugs.

The development of thrombosis involves 4 main factors: the vessel wall, the formed elements of the blood, blood coagulation, and blood flow. In venous thrombosis, however, the major part in both the initiation and growth of thrombi is played by the platelets. In selecting drugs which inhibit platelet function it is helful to know which of the platelet reactions that contribute to thrombus formation can be inhibited by various agents. Platelets adhere to the damaged vessel wall, collagen being probably the most important constituent involved. They are then stimulated to release the contents of their storage granules. Release-inducing agents promote the discharge of adenosine diphosphate (ADP) which causes platelets in the vicinity to swell to a more spherical shape, extend pseudopods and adhere to each other. Platelet aggregation is reversible, and a number of drugs have been shown to be capable of inhibiting platelet function at various stages, both in vitro and in vivo. Adrenaline, noradrenaline, oestrogens and nicotine enhance aggregation. Drugs which inhibit platelet function include the non-steroidal anti-inflammatory drugs, the pyrimido-pyrimidines (e.g. dipyridamole), hydroxychloroquine, clofibrate, and dextran. In this review the effects of drugs which inhibit platelet function are outlined and the extent to which they can be used to influence the course of thromboembolic disease in man is discussed. It is suggested that combination of anti-platelet drugs with anticoagulants could prove clinically useful.

Blood Coagulation↗

PubMed1975

Conditions influencing platelet lysis.

When platelets take part in the formation of hemostatic plugs and thrombi in vivo, electron microscopic evidence indicates that some of the platelets not only release their granule contents but also undergo lysis. In the present study we have examined, in vitro, the relation between the release reaction of platelets and platelet lysis in response to the release-inducing agents thrombin and collagen. Release was measured by determining the amounts of 14C-serotonin and adenine nucleotides that appeared in the ambient fluid of prelabeled platelets. Lysis was measured by determining the amount of either lactate dehydrogenase or 14C-labeled cytoplasmic ATP from platelets incubated with -14C-adenosine. Washed platelets prepared from rabbit, pig, or human blood lost some lactate dehydrogenase and 14C-ATP upon exposure to thrombin, but the amounts of lactate dehydrogenase and 14C-ATP lost from rabbit platelets were much greater than from pig or human platelets. The reason for this species difference is not aparent. The platelet release reaction appeared to be necessary for lysis to occur. Reduction of the extent of the release reaction by preincubation of rabbit platelets with metabolic inhibitors to deplete metabolic ATP reduced the extent of lysis. In addition, it was apparent that the fall in platelet metabolic pool ATP caused by thrombin was not responsible for platelet lysis. Lack of calcium, addition of prostaglandin E(1), OR Increasing the albumin concentration of the suspending medium of rabbit platelets inhibited platelet lysis. These conditions may prevent the loss of material that causes lysis, inhibit the action of this lost material, or inhibit the lytic reaction. Release and lysis may occur together and release can occur without detectable lysis, but lysis in response to a release-inducing agent does not take place unless the release reaction occurs.

Adenosine↗

PubMed1975

Effects on platelet function of removal of platelet sialic acid by neuraminidase.

A number of investigators have implicated sialic acid on the surface of platelets in platelet function. In this study we have quantitated the amount of sialic acid removed by purified neuraminidase from the surface of washed platelets of man, rabbit, or pig and examined the effects of this removal. Purified neuraminidase did not induce the release of platelet granule contents. Platelets were pre-labeled with 14C-serotonin for measurement of the release reaction or with 51Cr for determination of adherence to a collagen-coated surface or damaged aortic surface, and for in vivo platelet survival studies. Washed, neuraminidase-treated platelets were resuspended in Tyrode's solution containing 0.35 per cent albumin or in citrated platelet-free plasma from the same species. Both resuspending fluids contained apyrase. Aggregating agents tested were ADP, acid-soluble collagen, thrombin, ristocetin (with human platelets), polylysine, and serotonin (with rabbit platelets). With all of these agents except polylysine, aggregation of neuraminidase-treated human or rabbit platelets was slightly enhanced compared with control platelets; aggregation of pig platelets was unchanged. When release-inducing agents were used, neuraminidase-treated platelets released more of their 14C-serotonin than control platelets. The extent to which rabbit platelets adhered to a collagen-coated surface or to the damaged surface of everted rabbit aorta was unchanged by pretreatment of platelets with neuraminidase. Therefore it seems unlikely that sialic acid is involved in platelet adherence to collagen. When more than 15 per cent of total sialic acid had been removed from rabbit platelets, they were completely cleared from the circulation within 1 hour of their injection into rabbits. When 8 to 10 per cent of total sialic acid had been removed, the platelets were not cleared immediately from the circulation but were cleared more quickly than control platelets. Thus, although removal of up to 65 per cent of platelet sialic acid has only a slightly enhancing effect on platelet aggregation and release in vitro, removal of as little as 8 to 10 per cent results in the recognition of platelets as "foreign" in vivo.

Adenosine Diphosphate↗

PubMed1975

Inhibition of platelet adherence to damaged surface of rabbit aorta.

A method has been developed for quantitative measurement of adherence of rabbit platelets to the damaged intimal surface of everted segments of rabbit thoracic aorta. Platelets were labeled with 51Cr, washed, and resuspended in Tyrode solution containing 0.35 per cent albumin and apyrase. This suspending medium contains physiologic concentrations of calcium and magnesium; apyrase degrades any ADP lost from the platelets or from the damaged wall. Everted aorta segments were rotated in the platelet suspensions. Neither platelet aggregation nor lysis occurred and the platelets adhered to the subendothelium either as individual platelets or as a single layer. Damage caused by scraping the everted segments with a scalpel blade increased adherence 50-fold. Acetylsalicylic acid (ASA) in vitro, or administered orally to the rabbits from which platelet suspensions were prepared, significantly reduced the number of platelets adherent to the damaged aorta wall. ASA affected only the platelets, and did not affect the damaged wall. Platelet adherence to the damaged wall was also reduced by the use of 4 per cent albumin in the suspending medium, or by the addition of citrate. Adherence of platelets resuspended in citrated plasma was low and further inhibition by ASA was not demonstrable. ASA may affect two aspects of thrombus formation: platelet adherence to subendothelial structures and the platelet release reaction induced by collagen (and possibly by other subendothelial structures). These studies show that ASA has a marked effect on adherence of platelets to subendothelium under conditions in which aggregation and thrombus formation are prevented.

Albumins↗

PubMed1975

The use and analysis of multiple responses in multicompartment cellular systems.

Within multicompartment cellular systems in the steady state the distrubution of tracer as a function of time is described by sums of exponentials. A design for data collection and analysis is set forward to deal with the problems of lumping and ill-conditioning inherent in such a mathematical description. This design requires the provision of multiple responses and can be analyzed by a Bayesian multivariate technique. Although only one response may be capable of completely characterizing the system, there is much to be gained from additional responses in terms of precision in parameter estimation. A time series is used to account for autocorrelated error in the responses. The design is compared to other least squares approaches and is demonstrated in an investigation of the transport and storage of serotonin in blood platelets. The kinetic parameters describing serotinin movement are estimated and their joint confidnece regions plotted.

Blood Platelets↗

PubMed1974