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Biomedical subjects

J F Mustard

Publications and source records attributed to J F Mustard.

At least 73 records · Page 4Linked to original sources
PubMed1986

Pathways responsible for platelet hypersensitivity in rats with diabetes. I. Streptozocin-induced diabetes.

Several pathways are activated when platelets aggregate and undergo the release reaction. We have examined the relative importance of these pathways in the responses to adenosine diphosphate (ADP), thrombin, or collagen of washed platelets from rats with diabetes induced by streptozocin. ADP-induced aggregation was enhanced without the release reaction with platelets from diabetic rats. Collagen-induced aggregation and release, and the adherence of platelets to collagen-coated glass were similar with platelets from diabetic and control rats. Thrombin (1 U/ml) induced more extensive loss of tritium from 3H-arachidonic acid-labeled platelets from diabetic rats than from control rats. Platelet aggregation and the release of 14C-serotonin from prelabeled platelets was greater in response to low concentrations of thrombin (0.04 U/ml). Creatine phosphate-creatine phosphokinase (CP/CPK) and aspirin completely blocked aggregation and partially blocked the release of granule contents from platelets from control and diabetic rats exposed to this low concentration of thrombin. Thus, the enhanced platelet aggregation in response to low concentrations of thrombin was likely mediated in part by released ADP and products formed from arachidonate. In contrast, with a higher concentration of thrombin (0.0625 U/ml), CP/CPK and aspirin did not inhibit the increased sensitivity of diabetic platelets to thrombin-induced aggregation and release; the concentrations of CP/CPK completely blocked aggregation induced by ADP (10 mumol/L), and the aspirin inhibited thromboxane B2 production in response to thrombin (1 U/ml) by 99%. Thus, a thrombin-induced pathway(s) of aggregation and release independent of released ADP and the products of arachidonate metabolism is enhanced in platelets from diabetic rats.

Adenosine Diphosphate↗
PubMed1986

Pathways responsible for platelet hypersensitivity in rats with diabetes. II. Spontaneous diabetes in BB Wistar rats.

The discovery of a group of spontaneously diabetic rats has made it possible to examine changes in diabetic animals in the absence of possible confounding toxic effects of diabetogenic agents. The responses of washed platelets to adenosine diphosphate (ADP), thrombin, or collagen have been compared with platelets from spontaneously diabetic rats (these rats were hyperglycemic), their nondiabetic littermates (normoglycemic), and control rats from the same colony. Platelets from the diabetic rats aggregated more extensively in response to ADP than did platelets from the nondiabetic littermates or control animals. In contrast, platelet aggregation and release of granule contents in response to a low thrombin concentration (0.05 U/ml) were greater with platelets from diabetic rats and nondiabetic littermates than with platelets from control rats. A similar effect of collagen on the release of platelet serotonin was observed. Except at low concentrations of thrombin, the enhanced sensitivity to thrombin-induced aggregation and release of granule contents from platelets from diabetic rats or their nondiabetic littermates could not be inhibited by creatine phosphate-creatine phosphokinase (CP/CPK) and aspirin (CP/CPK used at concentrations that inhibited aggregation induced by ADP [10 mumol/L] and aspirin at concentrations that inhibited thromboxane B2 production induced by thrombin [1 U/ml] by 99%). Loss of radioactivity from platelets labeled with 3H-arachidonic acid and the amount of thromboxane B2 formed in response to high concentrations of thrombin (1 U/ml) was greater from platelets from the diabetic rats or their nondiabetic littermates than from control animals. Thus the effect of diabetes on this aspect of arachidonate metabolism is not primarily determined by blood glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1986

The role of platelets in the development and complications of atherosclerosis.

Although lipids have received most attention in relation to atherosclerosis, vessel injury also has a role in the development of atherosclerotic lesions. Thrombi that form at sites of injury can be incorporated into the wall, causing thickening, and platelets that adhere to damaged vessel walls release a growth factor (PDGF) that stimulates smooth muscle cell proliferation. The early lesions of atherosclerosis are focal and develop around vessel orifices and branches in relation to the patterns of blood flow and areas of increased permeability and endothelial cell damage. Platelets also contribute to the complications of advanced atherosclerosis caused by occlusive thrombi, thromboembolism, and spasm. The causes of vessel wall injury are not established, although there is evidence pointing to disturbed blood flow, hypertension, antigen--antibody complexes, complement, materials originating from platelets and white blood cells, bacteria, endotoxin, viruses, smoking, dietary lipids, homocystinemia, diabetes, other metabolic disorders, and stress. Platelets do not adhere to intact endothelium, but they adhere to the constituents of the subendothelium, release the contents of their granules (including PDGF), and form thromboxanes. If blood flow is disturbed, platelet--fibrin thrombi can form at sites of injury. Platelet adherence to a damaged wall does not require von Willebrand factor except under conditions of high wall shear. Repeated injury of a vessel wall leads to the development of lipid-rich atherosclerotic lesions, even in normocholesterolemic animals, but these lesions do not form if the experimental animals are made thrombocytopenic before injury is induced. Measurable changes in platelets that are associated with the clinical complications of atherosclerosis include shortened survival, release of granule contents (platelet factor 4, beta-thromboglobulin, thrombospondin), formation of thromboxanes, and decreased buoyant density. "Antiplatelet drugs" such as aspirin are proving to be beneficial in selected groups of patients, such as those with unstable angina. Thromboxane synthetase inhibitors and agents that block the thromboxane receptor on platelets are under investigation. Long term administration of "antiplatelet drugs" to affect the rate of development of atherosclerosis seems neither feasible nor desirable. Modification of dietary and smoking habits and control of hypertension are more likely to be beneficial for most individuals.

Animals↗
PubMed1986

Injury to cultured endothelial cells by thrombin-stimulated platelets.

In vivo, stimulated platelets may injure the endothelium. We have used cultured endothelial cells to assess endothelial cell damage caused by platelet stimulation with thrombin. Endothelial cells were cultured from umbilical veins and semiconfluent cultures were labeled with Na2 51CrO4. Twenty four hours later washed human platelets (final concentration 200,000 platelets/microliters) and thrombin (final concentration 4 units/ml) were added to the medium and the culture dish was shaken for 15 minutes. The percentage of cells detached from the culture dish and the percentage of 51Cr lost from the endothelial cells into the ambient fluid during the shaking were determined and used as indicators of cell injury. Increased percentages of loosened cells and 51Cr in the ambient fluid were observed with platelet suspension and thrombin compared to controls with neither platelet suspension nor thrombin and controls with either platelet suspension or thrombin. The platelet-free supernatant obtained after reaction of the platelets with thrombin also increased the percentage of loosened cells, but it did not increase the percentage of 51Cr in the ambient fluid to a significant degree. Thrombin alone caused a moderate loss of 51Cr, but no increased loosening of cells. Treatment of the platelets with acetylsalicylic acid prior to the experiment depressed the detachment effect of thrombin-stimulated platelets, but did not alter the effect on the release of 51Cr into the ambient fluid. Scanning and transmission electron microscopy of cultured endothelial cells exposed to thrombin-stimulated platelets confirmed the presence of loosening and injury to the endothelial cells. Thus, platelet stimulation with thrombin had at least two effects on the cultured endothelial cells: a loosening effect caused by material released from the platelets; an injury effect which, in order to reach its maximum, required the presence of stimulated platelets.

Aspirin↗
PubMed1985

Epinephrine-induced aggregation of rabbit platelets refractory to ADP.

The mechanisms involved in platelet aggregation induced by epinephrine are unclear. Although epinephrine does not aggregate washed rabbit platelets, platelets made refractory to ADP will aggregate in response to epinephrine in the presence of ADP. We have examined whether the mechanism(s) by which epinephrine induces aggregation of refractory platelets involves fibrinogen binding and Ca2+ association. With normal platelets, ADP causes aggregation, fibrinogen binding and Ca2+ association in a medium containing 0.2 mM 45Ca2+. After 3 min of incubation with ADP, fibrinogen dissociates from platelets, but 45Ca2+ does not. Epinephrine alone does not cause aggregation, fibrinogen binding or 45Ca2+ association. Platelets that are refractory to ADP do not aggregate and bind fibrinogen upon addition of ADP, but aggregate and bind fibrinogen in response to epinephrine, provided ADP is still present. These effects of epinephrine are mediated by the alpha-adrenergic receptor since they are blocked by phentolamine or verapamil and potentiated by propranolol. However, epinephrine-induced aggregation of platelets refractory to ADP does not involve further detectable increase in the amount of 45Ca2+ associated with the platelets.

Adenosine Diphosphate↗
PubMed1985

Comparison of the interactions of fibrinogen and soluble fibrin with washed rabbit platelets stimulated with ADP.

Because fibrin, formed at a site of vessel wall injury, is involved in the formation and stabilization of a platelet aggregate or thrombus, we have studied reactions of fibrin with rabbit platelets. Gly-Pro-Arg-Pro, an inhibitor of fibrin polymerization, was used to prepare soluble fibrin. Fibrin alone did not cause aggregation of washed platelets, but addition of ADP caused aggregation and deaggregation identical to those observed in the presence of fibrinogen. Specific binding of 125I-fibrin to ADP-stimulated platelets was similar to that of 125I-fibrinogen, but 125I-fibrin did not dissociate, even in the presence of high concentrations of apyrase. High non-specific binding of 125I-fibrin was observed that was not associated with aggregation. EDTA, prostaglandin E1 (PGE1) and creatine phosphate/creatine phosphokinase prevented ADP-induced aggregation in the presence of fibrin and caused rapid deaggregation when added after ADP. They also inhibited 125I-fibrin binding when added before ADP, and EDTA or PGE1 caused partial dissociation of bound 125I-fibrin. In vivo, fibrin may bind to stimulated platelets, polymerize, form a gel, and interact with components of the plasma, the platelet aggregate, and the exposed subendothelium.

Adenosine Diphosphate↗
PubMed1985

Deaggregation of human platelets aggregated by thrombin.

Human platelets that have undergone the release reaction do not deaggregate readily. We examined conditions under which washed human platelets can be deaggregated after they have undergone an extensive release reaction induced by thrombin (1 or 5 U/ml). To make fibrinogen receptors unavailable, either CP/CPK (or apyrase) was used to remove released ADP, or PGE1 was used to increase cAMP. Chymotrypsin was used to digest proteins that might link platelets, and heparin to interact with released proteins and interfere with their binding to platelets and to each other. Individually, none of these caused deaggregation; heparin did not inhibit the effect of thrombin because no antithrombin III was present. Platelets exposed to thrombin (1 U/ml) which was neutralized at 90 sec by hirudin, could be deaggregated by combinations of CP/CPK (or apyrase) and chymotrypsin, or PGE1 and chymotrypsin. When a higher concentration of thrombin was used (5 U/ml) these combinations caused platelets to deaggregate only when heparin was added before thrombin induced the release reaction. Thus, when extensive release occurs three mechanisms may come into play to link human platelets: one that requires the fibrinogen receptor; a heparin-sensitive reaction that may involve the binding of released proteins; and a linkage that can be disrupted only by proteolysis, providing the other two mechanisms are also inhibited.

Blood Platelets↗
PubMed1985

Effects of plasmin on rabbit platelets.

The effects of plasmin have been examined because platelets may be exposed to plasmin in vivo and treatment of platelets with plasmin shortens platelet survival. Rabbit plasmin was prepared by urokinase activation of plasminogen immobilized on lysine-Sepharose. Plasmin caused rabbit platelets to aggregate and release the contents of their amine storage granules, but aggregation was slower than in response to ADP or thrombin. EDTA, prostaglandin E1, or creatine phosphate/creatine phosphokinase were inhibitory, but indomethacin was not. Deaggregation did not occur when platelets had been aggregated by a concentration of plasmin that caused extensive release of granule contents. EDTA or prostaglandin E1 caused deaggregation. Low concentrations of ADP and plasmin acted synergistically in causing platelet aggregation. Plasmin decreased the amounts of platelet membrane glycoproteins that stained with periodic acid-Schiff reagent; glycoprotein I was more susceptible than glycoprotein II and III. Concentrations of plasmin that induced the release of amine storage granule contents also released PAS-staining granule glycoproteins. Platelets incubated with plasmin, washed and resuspended, were not aggregated by ADP, but were aggregated strongly by the combination of fibrinogen and ADP, and bound 125I-fibrinogen to a greater extent than untreated platelets. Platelets preincubated with a high concentration of plasmin were unresponsive to thrombin, but were sometimes aggregated by fibrinogen. Plasmin decreased the buoyant density and increased the median size of platelets. Thus plasmin, as well as ADP and thrombin, may contribute to the density shift observed in platelets from rabbits in which thrombosis and continuous vessel injury have been induced.

Adenosine Diphosphate↗
PubMed1985

Measurement of fibrinogen concentrations in suspensions of washed rabbit and human platelets by radioimmunoassays.

Although fibrinogen is a cofactor in platelet aggregation, washed rabbit platelets aggregate when stimulated with ADP even when no fibrinogen is added to the platelet suspension. Washed human platelets usually do not aggregate to a significant extent when stimulated with ADP unless fibrinogen is added. To study this phenomenon, radioimmunoassays for rabbit and human fibrinogens have been developed and used to measure fibrinogen concentrations in suspensions of washed platelets. The fibrinogen concentration in the suspending medium of rabbit platelets was 2.5 +/- 0.9 micrograms/10(9) platelets, and upon stimulation with 9 microM ADP it increased to 10.7 +/- 2.9 micrograms/10(9) platelets. The loss of fibrinogen from the platelets was significantly greater than the loss of 14C-serotonin (11% vs 2%). The presence of prostaglandin E1 reduced the fibrinogen concentration to approximately 1 micrograms/10(9) platelets and prevented aggregation and loss of fibrinogen when the platelets were stimulated with ADP. With human platelets, the extracellular concentrations of fibrinogen and beta-thromboglobulin, expressed as percentages of the amount in the platelets, were similar, and the increase in fibrinogen concentration upon ADP stimulation (approximately 2%) was much lower than with rabbit platelets. We conclude that rabbit platelets may release fibrinogen from their alpha-granules when stimulated with ADP, and that a portion of the released fibrinogen becomes available to support aggregation. Smaller amounts of fibrinogen would become available in the case of human platelets.

Adenosine Diphosphate↗
PubMed1985

Effect of ticlopidine on platelet aggregation, adherence to damaged vessels, thrombus formation and platelet survival.

Ticlopidine (100 mg/kg/day or 400 mg/kg/day) was administered to rats and rabbits for 48 hr before and during the experiments. Aggregation studies of twice-washed platelets resuspended in Tyrode solution containing apyrase and 0.35% albumin showed that inhibition by ticlopidine of aggregation induced by ADP, collagen, sodium arachidonate or thrombin persisted after resuspension, as did inhibition of the release of 14C-serotonin from prelabeled platelets. Thus the inhibitory effect of ticlopidine or its metabolite is not readily reversed. In both species, ticlopidine prolonged platelet survival when it had been shortened by the insertion of an indwelling aortic catheter, although only the higher dose was effective in rabbits. In this species, this dose also prolonged platelet survival in sham-operated animals. Ticlopidine did not have a significant effect on the clearance of rabbit platelets when their survival had been shortened by pretreatment with neuraminidase. Ticlopidine did not affect the number of 51Cr-labeled platelets that accumulated on the injured vessel wall in rats with indwelling aortic catheters or the amount of thrombus that formed around the catheters in the aortas of the rabbits. It also did not affect the accumulation of platelets in vivo on rabbit aortas de-endothelialized with a balloon catheter. Thus, although ticlopidine inhibited platelet aggregation and release and prolonged shortened platelet survival, it did not inhibit platelet adherence to the damaged wall or thrombosis caused by chronic arterial injury. It is evident that effects on platelet survival and thrombosis do not correlate. The reason for the prolongation of platelet survival is unknown.

Animals↗
PubMed1985

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP.

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.

Adenosine Diphosphate↗
PubMed1985

Platelets, endothelium, and vessel injury.

Injury to the endothelial lining of arteries is an important mechanism in both the early and late stages of the development of atherosclerosis. Platelets can contribute to the early lesions by releasing factors that cause smooth muscle cell migration and proliferation. In the later stages, the formation of large platelet-fibrin thrombi that become organized into the vessel wall contributes to the development of focal atherosclerotic narrowing of arteries. Injury to the vessel wall can also be a factor in causing spasm of coronary arteries, particularly at sites of stenosis. The spasm may cause ischemia, anginal pain, and, in some individuals, ventricular fibrillation and death. In other individuals, the spasm may not cause death but may persist long enough for an occlusive thrombus to form and cause myocardial infarction. The events leading to thrombosis involve not only the release of arachidonic acid and the formation of TXA2, but other pathways that are independent of the arachidonate pathway. In some circumstances thrombin (which causes platelet aggregation and release that are largely independent of the arachidonate pathway and TXA2 formation) is the primary stimulus causing the initiation and growth of the thrombus. The role of products of the arachidonate pathway in causing spasm is not understood. PGI2 produced by the vessel wall could be important in preventing or minimizing coronary artery spasm. The best way to prevent the development of atherosclerosis and its clinical complications is to prevent or minimize injury of the endothelium.

Animals↗
PubMed1984

Accumulation of the inositol phosphates in thrombin-stimulated, washed rabbit platelets in the presence of lithium.

Experiments with washed rabbit platelets demonstrate that stimulation with a low concentration of thrombin (0.1 unit/ml), that causes maximal aggregation and partial release of amine granule contents, also causes increased accumulation of [3H]inositol-labelled inositol trisphosphate (InsP3) in the presence of 20 mM-Li+. This concentration of Li+ was found to inhibit the degradation of inositol phosphates by phosphomonoesterases. This result indicates that phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] is degraded early after platelet stimulation with thrombin, although in a previous study we had found no decrease in amount. In the absence of Li+, the labelling of inositol bisphosphate (InsP2) increased more rapidly than that of InsP3, consistent with rapid degradation of InsP3 by phosphomonoesterase. After 30s the increase in InsP2 was augmented by Li+. This increase in InsP2 could have been due to increased degradation of phosphatidylinositol 4-phosphate or inhibition of breakdown of InsP2 to InsP with a lesser inhibition of breakdown of InsP3 to InsP2. The effect on InsP3 and InsP2 of stimulation of the platelets with 1.0 unit of thrombin/ml was comparable with the effect of the lower concentration of thrombin. Inositol phosphate (InsP) labelling did not increase in response to 0.1 unit of thrombin/ml, but increased when the platelets were stimulated with 1.0 unit of thrombin/ml. Whether the increase in InsP was due to increased degradation of phosphatidylinositol or a greater rate of breakdown of InsP2 to InsP than InsP to inositol cannot be determined in these experiments. These results indicate that degradation of PtdIns(4,5)P2 is an early event in platelet activation by thrombin and that formation of inositol phosphates and 1,2-diacylglycerol rather than a decrease in PtdIns(4,5)P2 may be the important change.

Animals↗
PubMed1984

Effect of amino sugars on platelet aggregation and on fibrinogen binding.

The amino sugars glucosamine, galactosamine and mannosamine (30 mM) inhibited aggregation of human or rabbit platelets induced by ADP, collagen, thrombin, PAF or high concentrations of sodium arachidonate. 125I-fibrinogen binding during ADP-induced aggregation, and release of amine storage granule contents were also inhibited. Increasing the calcium concentration of the suspending medium to 5 mM did not overcome the inhibitory effect on the release reaction. The amino sugars deaggregated rabbit platelets that had been aggregated by ADP, collagen or thrombin, but deaggregated human platelets readily only when ADP was used as the aggregating agent. Fibrinogen-induced aggregation of chymotrypsin-treated platelets was blocked by the amino sugars. They did not inhibit platelet adherence to a collagen-coated glass surface, nor affect release of granule contents from the adherent platelets. Aggregation and release induced by low concentrations of sodium arachidonate or the divalent cation ionophore A23187 were potentiated, indicating that the effects of the amino sugars on platelets are more complex than simple inhibition of the lectin-like activity that becomes available on the surface of platelets that have undergone the release reaction. One of the effects of the amino sugars, however, is interference with the binding of fibrinogen to platelets. The effects of the amino sugars are shared by other primary amines.

Adenosine Diphosphate↗
PubMed1984

Effects of tris on responses of human and rabbit platelets to aggregating agents.

Despite reports that Tris [tris (hydroxymethyl)aminomethane] affects platelets, it is often used to buffer suspending media. Human or rabbit platelets were washed and resuspended in Tyrode solution containing apyrase and 0.35% albumin. Addition of 15 mM Tris partially inhibited primary aggregation induced by 10 microM ADP and inhibited aggregation and release of 14C-serotonin from prelabelled platelets stimulated with low concentrations of thrombin (0.05-0.2 U/mL), or collagen. Platelets resuspended in 15 mM Tris, 0.15 M NaCl, 0.35% albumin, pH 7.5, did not aggregate in response to 10 microM ADP whereas platelets in Tyrode-albumin aggregated extensively. Ca2+ (5 mM) did not overcome the inhibition of thrombin-induced aggregation. Tris (15 or 1.5 mM) potentiated aggregation and release induced by sodium arachidonate (20-50 microM) or the ionophore A23187 (0.6-1 microM). Pretreatment of platelets with aspirin did not prevent potentiation by A23187, indicating that it is not mediated through activation of the arachidonate pathway. The inhibitory and potentiating effects of Tris are similar to those of amino sugars, lysine, arginine and primary amines such as methylamine and cadaverine, and may represent general effects of amines on platelets. Potentiation of the effects of some aggregating agents and inhibition of others re-emphasizes the concept that there are several different mechanisms through which aggregation can occur. Tris-based buffers are unsuitable for platelet suspending media and their use as solvents for aggregating agents or inhibitors should be limited.

Adenosine Diphosphate↗
PubMed1984

Changes in the platelet phosphoinositides during the first minute after stimulation of washed rabbit platelets with thrombin.

Experiments with washed platelets from rabbits demonstrate that stimulation with a low concentration of thrombin (0.1 unit/ml) that causes maximal aggregation and partial release of granule contents does not significantly decrease the amount of phosphatidylinositol 4,5-bisphosphate [ PtdIns (4,5)P2] at 10s; this contrasts with ADP stimulation. The amount of PtdIns (4,5)P2 was significantly decreased by a higher concentration of thrombin (0.3 unit/ml). Increased turnover of the PtdIns (4,5)P2 at 60s was indicated by changes in labelling with [3H]glycerol in platelets stimulated with both concentrations of thrombin. An unexpected observation with the lower thrombin concentration was a significant increase in the amount of phosphatidylinositol ( PtdIns ) at 10s. This contrasts with data from other laboratories, which indicate that thrombin causes a significant decrease in PtdIns . At 60s, with the lower concentration of thrombin, PtdIns was significantly decreased. With the higher concentration of thrombin there was a significant decrease in the amount of PtdIns at 10s, in keeping with the data from other laboratories. The initial increase in PtdIns may not have been observed by other investigators because higher concentrations of thrombin were used. The reaction involved in this initial increase in the amount of PtdIns does not appear to be increased degradation of PtdIns4P or PtdIns (4,5)P2, since their total amount was unchanged at 10s. The magnitude of the increase in PtdIns is such that more than the existing pool of phosphatidic acid would have to be converted into PtdIns to account for the increase. It is suggested that synthesis of phosphatidic acid de novo from dihydroxyacetone phosphate and glycerol 3-phosphate might be the source of phosphatidic acid, which leads to increased PtdIns at 10s with the lower concentration of thrombin. Thus it appears that the initial response of platelets to thrombin does not require an early change in PtdIns (4,5)P2 and may involve stimulation of synthesis de novo of PtdIns via phosphatidic acid.

Animals↗
PubMed1984

Mechanisms in thrombosis.

A key factor in atherosclerosis, spasm and thrombosis is damage to the endothelium. Prevention of injury to the endothelium will reduce the extent of atherosclerosis, reduce the risk of spasm and prevent thrombosis. Future work in this field will obviously be centered primarily on the endothelium, mechanisms of injury and strategies for prevention of endothelial cell injury. At present, it is not known how useful drugs will be for the long term management of atherosclerosis and its complications. It may be that the more important approach in the future will be to modify risk factors such as smoking and diet since these might injure the endothelium.

Animals↗