Factors Influencing the Deaggregation of Human and Rabbit Platelets

Kinlough-Rathbone, R L; Mustard, J. F.; Perry, David S.; Dejana, Elisabetta; Cazenave, J. P.; Packham, Marian A.; Harfenist, EJ

doi:10.1055/s-0038-1657353

Cited by 61 publications

(36 citation statements)

References 29 publications

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“…Disaggregation of platelets has been considered by some investigators (47)(48)(49)(50)(51) as an important in vitro measure of the efficacy of antiplatelet agents. The mechanism by which agents that disaggregate platelets act depends upon the specific disaggregant and the agonist used.…”

Section: Resultsmentioning

confidence: 99%

Tissue plasminogen activator promotes platelet disaggregation in plasma.

1987

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We studied the disaggregation of human platelets by tissue-type plasminogen activator (t-PA). When added to a suspension of human platelets induced to aggregate in plasma with adenosine 5'-diphosphate, t-PA promoted disaggregation of platelets over several minutes. Addition of fresh plasma or purified human fibrinogen to disaggregated platelets facilitated (reversible) aggregation and subsequent disaggregation. Aspirin treatment of platelets markedly potentiated the ability of t-PA to induce disaggregation. Disaggregation was inhibited by alpha-2-antiplasmin. Comparative analysis of the rate of proteolysis of plateletbound fibrinogen with that of ambient plasma fibrinogen suggested that fibrinogenolysis of cohesive fibrinogen occurred more rapidly than fibrinogenolysis of ambient fibrinogen. These data demonstrate that t-PA facilitates platelet disaggregation in plasma through kinetically selective proteolysis of cohesive fibrinogen by plasmin, and suggest that thrombolytic mechanisms may serve both to remove platelets from platelet-fibrin thrombi and to disperse circulating platelet aggregates.

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Section: Resultsmentioning

confidence: 99%

Tissue plasminogen activator promotes platelet disaggregation in plasma.

1987

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“…41 Among other a-granulesecreted gh/coproteins, TSP has been shown to contribute to the stabilization of platelet aggregation by promoting formation of large aggregates of thrombinstimulated platelets. 7 -8 In this study, we used recombinant proteins encompassing amino acid residues 1 to 174 (TSP18) and 1 to 242 (TSP28) of human TSP.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Legrand

Morandi

Mendelovitz

et al. 1994

Arterioscler Thromb

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Thrombospondin (TSP) is a platelet a-granule adhesive protein that plays a critical role in the stabilization of thrombus by promoting the formation of platelet macroaggregates. We have recently shown that a monoclonal antibody (mAb) to the NH 2 -terminal heparin-binding domain of TSP, MAE, inhibits platelet aggregation induced by thrombin in a dose-dependent manner. In this study, we have expressed in Escherichia coli two recombinant proteins comprising residues 1 to 174 (TSP18) and 1 to 242 (TSP28) of TSP. After purification, both proteins reacted equally well with mAb MAII, whereas the reactivity of TSP18 for heparin was lower than that of TSP28 or native TSP. At micromolar concentrations, TSP18 and TSP28 inhibited the second wave of platelet aggregation and the concomitant release of [

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“…78 Other bonds, so far poorly understood, may also bind the platelets together. 79 As a result, aggregation associated with secretion is not readily reversed.…”

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confidence: 99%

Platelet activation.

Zucker¹,

Nachmias²

1985

Arteriosclerosis

201

101

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Platelets are discoidal cytoplasmic particles that respond to a variety of stimuli by developing filopodia and rounding up (shape change), developing the ability to bind fibrinogen from the medium, and, with strong stimuli such as thrombin and PAF-acether, secreting the contents of several types of granules. Arachidonic acid is cleaved from phospholipids by phospholipase A2 and converted by the platelets to endoperoxides, and then to thromboxane A2. The bound dimeric fibrinogen molecules probably cause aggregation by forming bridges between platelets. Aggregation is reinforced by secreted fibrinogen and thrombospondin, which binds the platelets, and by thromboxane A2 and endoperoxides, as well as secreted ADP, which cause additional receptor-mediated activation. The responses to these stimuli are initiated when the agonists bind to specific receptors on the plasma membrane. Subsequent steps resemble those in other types of responsive cells: breakdown of phosphatidylinositol bisphosphate into diacylglycerol, a stimulator of protein kinase C, and inositol-1,4,5-trisphosphate, recently shown to be a potent calcium ionophore. The response of shape change results from increased cytoplasmic Ca2+ which permits phosphorylation of one of the light chains of myosin by a calcium-calmodulin-dependent kinase, with resulting enhanced actin-myosin interaction. Secretion is associated with phosphorylation of a 40,000 to 47,000 dalton protein by the diacylglycerol-activated protein kinase C. These recent findings have increased our understanding of the mechanisms of platelet activation, but much remains to be learned. How do agonist-receptor complexes influence PIP2 breakdown? Is this indeed the first step in activation? What mediates adhesion of platelets to the injured blood vessel wall? Does transduction of this stimulus occur by the same mechanism as transduction of commonly used soluble stimuli? What is the role of the phosphorylated 40-47 K protein in secretion? What change in GP IIb-IIIa promotes their ability to bind fibrinogen? What is the role of calcium-activated protease? Of the phosphorylation of actin-binding protein? Progress is being made rapidly, and these questions may be answered within a few years.

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Factors Influencing the Deaggregation of Human and Rabbit Platelets

Cited by 61 publications

References 29 publications

Tissue plasminogen activator promotes platelet disaggregation in plasma.

Tissue plasminogen activator promotes platelet disaggregation in plasma.

Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Platelet activation.

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