Hereditary defect in the platelet release reaction caused by a deficiency in the storage pool of platelet adenine nucleotides.
TL;DR: The hypothesis that the patients' platelets contain a normal amount of metabolically active ADP, but are deficient in the storage pool is consistent with the hypothesis that they lack the storage, or non‐metabolic, pool of ADP.
Abstract: Summary A large family has recently been described in which impaired platelet aggregation was attributed to defective release of the ADP present, although in decreased amounts, in their platelets (Weiss et al, 1969). It was postulated that these patients might lack the storage, or non-metabolic, pool of ADP which is selectively released from specialized granules during the platelet release reaction and studies on three affected members of this family were undertaken to test this hypothesis. Citrated platelet-rich plasma (PRP) was incubated with [8-14C]adenine for 2 hr at 37°C and the specific activity of platelet nucleotides was determined. The release reaction was then induced by shaking the PRP with collagen fibres. The labelling patterns in the patients' platelets were distinctly abnormal. The specific activities of their platelet ADP following incubation with [14C]adenine were 4–6 times those of similarly treated normal platelets and were similar to those obtained in the normal platelets after they had been depleted of their non-metabolic (unlabelled) ADP by treatment with collagen. The findings are consistent with the hypothesis that the patients' platelets contain a normal amount of metabolically active ADP, but are deficient in the storage pool. Similar conclusions were reached for ATP. Incubation of the patients' platelets with collagen was accompanied by a normal disappearance of radioactive ATP and accumulation of radioactive IMP and hypoxanthine. Thus the abnormality in the platelet release reaction in these patients appears to be the result of a diminished storage pool of nucleotides rather than a block in the pathway which may provide the energy for this reaction.
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TL;DR: Results clearly demonstrate the presence of two distinct platelet ADP receptors in addition to the P2X receptor: one coupled to adenylyl cyclase and the other coupled to mobilization of calcium from intracellular stores through inositol trisphosphates.
467 citations
TL;DR: Under normal circumstances, platelets circulate in the blood for 10 days as smooth, disk-shaped cells that are nonadherent to each other and to normal vascular endothelium.
Abstract: (First of Two Parts) THE blood platelets, approximately 2 μm in diameter and numbering 200,000 to 400,000 per cubic millimeter, are produced in the megakaryocytes of the bone marrow by the coalescence of cytoplasmic membranes formed by invaginations of the megakaryocyte surface.1 Under normal circumstances, platelets circulate in the blood for 10 days as smooth, disk-shaped cells that are nonadherent to each other and to normal vascular endothelium. Their unique biologic properties are the changes that occur when the endothelium is broken or when disruption of the vessel allows the blood to come into contact with elements of the vessel . . .
448 citations
TL;DR: The present review summarizes the current knowledge about granule-bound platelet substances that are released extracellularly after platelet stimula tion and discusses the physiological significance of the secreted substances and their stability following release into the blood.
Abstract: Knowledge gained during the past two decades has greatly increased our understanding of the roles of platelets in hemostasis, thrombosis, and other biological processes (1-3). However, much remains to be learned. The present review summarizes our current knowledge about granule-bound platelet substances that are released extracellularly after platelet stimula tion. We briefly review the in vitro responses of platelets to various agonists, emphasizing the granule-bound substances and the mechanism(s) involved in their storage and release. These substances (some of which are also present in plasma, adsorbed on platelets, or present in nonsecretable platelet pools) comprise the secretable storage pool substances of the platelet. Where information is available, we discuss the physiological significance of the secreted substances and their stability following release into the blood. Finally we review congenital and acquired disorders of hemostasis in which the deficiencies of storage pool substances have been described.
293 citations
TL;DR: The biochemistry of platelets from two unrelated patients with the gray platelet syndrome, a deficiency of platelet alpha-granules, suggests that alpha- granules or their contents make a contribution to normal platelet aggregation.
Abstract: The biochemistry of platelets from two unrelated patients with the gray platelet syndrome, a deficiency of platelet alpha-granules, has been evaluated. Ultrastructural studies of their platelets revealed the number of alpha-granules to be less than 15% of normal, whereas the number of dense bodies was within normal limits. Platelets from both patients had severe deficiencies of platelet factor 4 and beta-thromboglobulin (less than 10% of normal). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a marked deficiency of thrombin-sensitive protein in both patients. Analysis of the platelet-derived growth factor in one patient showed it was also markedly reduced. Levels of lysosomal enzymes, adenine nucleotides, serotonin, and catalase, and conversion of arachidonic acid by the lipoxygenase and cyclo-oxygenase enzymes, were within normal limits. The results provide important evidence to define the contents of alpha-granules and to differentiate these contents from the contents of lysosomal granules, dense bodies, and peroxisomes. Functional studies of these platelets showed deficiencies in ADP, thrombin, and collagen aggregation. The results suggest that alpha-granules or their contents make a contribution to normal platelet aggregation.
275 citations
TL;DR: In this paper, the storage pool deficiency (SPD) was identified in 18 patients with albinism and four miscellaneous unrelated patients by quantifying the number of α-granules, dense granules, and mitochondria in their platelets.
224 citations
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TL;DR: These studies lend further support to the hypothesis that ingestion of aspirin, in contrast to sodium salicylate, prolongs the bleeding time by inhibiting the release of platelet ADP, perhaps reflecting the findings in other cell systems which suggest that aspirin alters membrane permeability.
Abstract: Ingestion of 1.5 g of aspirin, but not of sodium salicylate, produced a significant prolongation of the bleeding time in six normal male subjects when compared with the effects of a placebo. Similar differences in the effect of the two drugs on platelets was also observed. Aspirin ingestion resulted in impaired platelet aggregation by connective tissue and was associated with a decreased release of platelet adenosine diphosphate (ADP); sodium salicylate had no effect on these values. In vitro, incubation of platelet-rich plasma with an optimum aspirin concentration of 0.50 mmole/liter (0.045 mg/ml) inhibited both the adhesion of platelets to connective tissue and the release of ADP as well as the secondary wave of platelet aggregation produced with ADP or epinephrine; sodium salicylate had no effect on these reactions, which were also normal in patients with von Willebrand's disease. The inhibitory effect produced by ingesting a single 1.8 g dose of aspirin was detectable for 4-7 days at which time salicylate was no longer detectable in the blood, which suggested an irreversible effect on the platelet. Aspirin also inhibited the release of platelet adenosine triphosphate (ATP), but had no effect on the platelet surface charge, available platelet ATP or ADP, or the destruction of ADP by plasma ADPase. These studies lend further support to the hypothesis that ingestion of aspirin, in contrast to sodium salicylate, prolongs the bleeding time by inhibiting the release of platelet ADP, perhaps reflecting the findings in other cell systems which suggest that aspirin alters membrane permeability.
524 citations
239 citations
TL;DR: A simple device for “dark” injection of firefly lantern extract into solutions is described, and the intensity of the initial light flash of the luciferin-luciferase reaction was found to be proportional to the concentration of ATP and of ADP, after conversion to ATP with the pyruvate-kinase system.
188 citations
TL;DR: Investigations of the haemostatic functions in three patients with the Wiskott‐Aldrich syndrome presented revealed abnormal morphology with reduced size and variations of shape, and a lack of the storage pool of adenine nucleotides.
Abstract: Summary. Investigations of the haemostatic functions in three patients with the Wiskott-Aldrich syndrome are presented. All patients had severe thrombocytopenia and prolonged bleeding times. The platelets had abnormal morphology with reduced size and variations of shape. Electron microscopy revealed ultrastructural abnormalities with a reduced number of organelles, and many of the platelets contained large numbers of tubules. Platelet electrophoretic mobility in citrated plasma was not reduced by collagen, and platelet aggregation by collagen and ADP was deficient. Biochemical studies revealed a lack of the storage pool of adenine nucleotides. Platelet adhesiveness in vitro in whole blood was reduced. Platelet factor-3 release by kaolin, ADP and freezing and thawing was normal in one and reduced in another of the patients.
Platelet survival studies showed a normal survival time of normal donor platelets in one patient, while autologous platelets had a markedly reduced survival time in two of the patients. The bone marrow contained normal numbers of megakaryocytes. By electron microscopy of the bone marrow, blood platelets were found to be phagocytosed by macrophages and reticulum cells. The main cause of the thrombocytopenia is most probably incrcased peripheral destruction of platelets. It is suggested that the qualitatively defective platelets are recognized in the reticulo-endothelial system as foreign particles and phagocytosed.
171 citations
TL;DR: The results can be explained by assuming 3 pools of ATP+ADP in platelets: one pool is stored in special granules, does not participate in metabolism and is directly extruded during the release reaction, and one pool consists presumably of ATP only, and is consumed intracellularly during release and converted to IMP.
151 citations