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A Role for Prostaglandins and Thromboxanes in the Exposure of Platelet Fibrinogen Receptors

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A Role for Prostaglandins and Thromboxanes in the Exposure of Platelet Fibrinogen Receptors A role for prostaglandins and thromboxanes in the exposure of platelet fibrinogen receptors. J S Bennett, … , G Vilaire, J W Burch J Clin Invest. 1981;68(4):981-987. https://doi.org/10.1172/JCI110352. Research Article Exposure of fibrinogen receptors by a variety of agonists is a prerequisite for platelet aggregation. Because the synthesis of prostaglandins and thromboxane A2 also occurs during platelet aggregation we wondered whether these agents participate in the exposure of platelet fibrinogen receptors. Therefore, we measured the binding of human 125I-fibrinogen to gel-filtered normal human platelets after prostaglandin and thromboxane synthesis had been inhibited by aspirin or indomethacin. The fibrinogen binding assay was performed at 37 degrees C but without stirring to prevent the formation of platelet aggregates. Platelet secretion, measured with [14C]serotonin, did not occur during the procedure. Aspirin or indomethacin inhibited fibrinogen binding stimulated by 10 microM epinephrine by 53%, and inhibited fibrinogen binding stimulated by 1-2 microM ADP by 37.1%. However, ADP at concentrations greater than 2 microM returned fibrinogen binding toward control values. Scatchard analysis demonstrated that aspirin decreased the number but not the affinity of the exposed fibrinogen receptors. To determine whether prostaglandins are capable of directly exposing fibrinogen receptors, prostaglandin H2 was used to stimulate platelets in the fibrinogen binding assay. Prostaglandin H2 exposed approximately 54,000 fibrinogen receptors/platelet and corrected the deficit in receptor exposure induced by aspirin. These studies demonstrate that platelet prostaglandins or thromboxane A2 can play a direct role in the exposure of platelet fibrinogen receptors. In addition, they suggest that the synthesis […] Find the latest version: https://jci.me/110352/pdf A Role for Prostaglandins and Thromboxanes in the Exposure of Platelet Fibrinogen Receptors JOEL S. BENNETT, GASTON VILAIRE, and JOHN W. BURCH, Hematology-Oncology Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 A B S T R A C T Exposure of fibrinogen receptors by a INTRODUCTION variety of agonists is a prerequisite for platelet ag- Platelet aggregation, in vitro and in vivo, occurs in gregation. Because the synthesis of prostaglandins two phases: a primary phase due to direct stimula- and thromboxane A2 also occurs during platelet ag- tion by platelet agonists and a secondary phase due gregation we wondered whether these agents partici- to substances produced or released by stimulated pate in the exposure of platelet fibrinogen receptors. platelets (1). The importance of each of these phases Therefore, we measured the binding of human 125I- for platelet aggregation depends upon the nature of fibrinogen to gel-filtered normal human platelets after the platelet agonist. For example, the aggregation prostaglandin and thromboxane synthesis had been in- response to collagen is entirely dependent upon sub- hibited by aspirin or indomethacin. The fibrinogen stances produced or released by the platelet, whereas binding assay was performed at 370C but without the aggregation response to thrombin is not (2). The stirring to prevent the formation of platelet aggregates. platelet products that may be involved in secondary Platelet secretion, measured with [14C]serotonin, did platelet aggregation include ADP released from plate- not occur during the procedure. Aspirin or indometha- let-dense granules (1), the products of platelet arachi- cin inhibited fibrinogen binding stimulated by 10 ,M donic acid metabolism (prostaglandin endoperoxides epinephrine by 53%, and inhibited fibrinogen binding and thromboxane A2) (3), and the recently described stimulated by 1-2 ,uM ADP by 37.1%. However, ADP platelet activating factor (4). The relative contribution at concentrations >2 ,uM returned fibrinogen binding of these products to secondary platelet aggregation toward control values. Scatchard analysis demonstrated remains an area of controversy. For example, Charo that aspirin decreased the number but not the affinity et al. (2) suggested that secondary aggregation may be of the exposed fibrinogen receptors. To determine a direct response to platelet prostaglandins rather than whether prostaglandins are capable of directly ex- to secreted platelet ADP because they could demon- posing fibrinogen receptors, prostaglandin H2 was used strate that the onset of secondary platelet aggregation to stimulate platelets in the fibrinogen binding assay. was simultaneous with, and often preceded, the onset Prostaglandin H2 exposed -54,000 fibrinogen re- of platelet secretion and both could be prevented by ceptors/platelet and corrected the deficit in receptor inhibition of prostaglandin synthesis. On the other exposure induced by aspirin. These studies demon- hand, Malmsten et al. (5) have suggested that the ag- strate that platelet prostaglandins or thromboxane A2 gregation of platelets produced by prostaglandins is can play a direct role in the exposure of platelet fi- mediated by the prostaglandin-stimulated secretion of brinogen receptors. In addition, they suggest that the platelet ADP. synthesis of prostaglandins and thromboxane A2 by Stimulation of platelets by a variety of agonists ex- stimulated platelets may be all that is required for poses a limited number of fibrinogen receptors on the optimal secondary platelet aggregation. platelet surface (6-8). Exposure of these receptors is a direct consequence of platelet stimulation and ap- pears to be required for platelet aggregation (6, 9). A preliminary report of this work was presented at the 38th Moreover, it is unrelated to platelet shape change (10) Annual Meeting of the American Federation for Clinical Research, San Francisco, Calif., 27 April 1981. and is independent of platelet secretion (6, 7). There- Received for publication 30 March 1981 and in revised fore, investigation of the factors involved in fibrinogen form 22 June 1981. receptor exposure permits an examination of the events J. Clin. Invest. © The American Society for Clinical Investigation, Inc. - 0021-9738/81/10/0981/07 $1.00 981 Volume 68 October 1981 981 -987 leading to platelet aggregation, isolated from other Preparation and isolation of prostaglandin H2. Prosta- aspects of platelet function. In this study we have in- glandin H2 (PGH2)1 was prepared by modification of the methods of Nugteren and Hazelhof (14) and Hamberg et al. vestigated the contribution of prostaglandins to the (15). A microsomal pellet prepared from homogenized sheep exposure of fibrinogen receptors on normal human seminal vesicles was resuspended in 15 ml of Tris buffer platelets. We have demonstrated that the prosta- containing 1 mM phenol and 3 mM p-hydroxymercuri- glandins or thromboxane A2 synthesized by ADP- or benzoate. Arachidonic acid (2.5 gmol) containing a tracer participate directly quantity of [14C]arachidonic acid was added and the mixture epinephrine-stimulated platelets was shaken vigorously for 2 min. The suspension was then in the exposure of fibrinogen receptors. Thus, these acidified with 0.2 M citric acid and extracted twice with studies provide further evidence for a direct role of diethyl ether. The ether layers were combined, washed with platelet prostaglandins in normal platelet aggregation. water, dried with anhydrous MgSO4, and evaporated on ice under nitrogen. The residue was redissolved in diethyl ether, and the prostaglandins were separated by thin-layer chro- METHODS matography (Silica Gel 60 F-254 precoated thin-layer chromatography plates, Merck AG, Darmstadt, West Ger- Materials. Lyophilized human fibrinogen was purchased many) at -20°C with a solvent system containing ethyl from Kabi (AB), Kabi Blood Products Div., Stockholm, acetate:2,2,4-trimethylpentane:acetic acid (50:50:0.5, vol/vol/ Sweden. Sepharose 2B and 4B were obtained from Pharmacia vol). Prostaglandin B, (Rf = 0.18) was used as a reference Fine Chemicals, Div. of Pharmacia Inc., Piscataway, N. J. compound and was located with 254 nm light. The Rf of PGH2 Sigma Chemical Co., St. Louis, Mo., supplied the ADP, ATP, was 0.24. The area of the developed chromatogram corre- epinephrine bitartrate, human albumin-fraction V, indometha- sponding to PGH2 was scraped and the removed silica gel cin, imipramine, and p-hydroxymercuribenzoate. Acetyl- was extracted with acetone. salicylic acid was purchased from the Aldrich Chemical Co., When the ability of PGH2 to stimulate fibrinogen binding Inc., Milwaukee, Wis. William F. Nye, Inc., Fairhaven, was measured, an aliquot of the acetone extract was added Mass., supplied methyl silicone oil (DC 200) and hi-phenyl to a polypropylene tube (Falcon Labware, Div. of Becton- silicone oil (DC550). Carrier-free '25I-sodium iodine, ['4C]5- Dickinson & Co., Oxnard, Calif.), the acetone was evaporated hydroxytryptamine binoxalate, [14C]arachidonic acid, Econo- under nitrogen, and a platelet suspension was immediately fluor, and Protosol were obtained from New England Nuclear, added. The remainder of the fibrinogen binding assay was Boston, Mass. Arachidonic acid (>99% pure) was purchased performed as described in the previous section. from Nu Chek Prep, Inc., Elysian, Minn. Prostaglandin B1 Studies of platelet aggregation and secretion. Platelet was a gift of Dr. John E. Pike, Upjohn Co., Kalamazoo, aggregation was studied by the method of Born (16) with a Mich. All other chemicals were of reagent grade. Chrono-Log single-channel
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