Arachidonic acid induces human platelet-fibrin retraction: The role of platelet cyclic endoperoxides

Minno, G. Di; Bertelè, Vittorio; Cerletti, Chiara; Gaetano, Giovanni de; Silver, Melvin J.

doi:10.1016/0049-3848(82)90230-4

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…It is known that prostacyclin either administered in vivo or added in vitro may inhibit the first wave of aggregation in response to ADP (35,55), the clot retraction (43), and the exposure of fibrinogen and vWF receptors on platelets (56,57). However, at variance with ticlopidine, prostacyclin cannot be said to induce a thrombasthenic-like state in normal platelets, since these effects are associated with increases in intraplatelet cAMP able to inhibit platelet activation (16,58).…”

Section: Discussionmentioning

confidence: 99%

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Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Minno¹,

Cerbone²,

Mattioli³

et al. 1985

J. Clin. Invest.

201

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To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets obtained from eight healthy volunteers before and 1 wk after daily administration of 500 mg of ticlopidine. We found the following: ticlopidine significantly (P < 0.001) prolonged the skin bleeding time and impaired the binding of radiolabeled fibrinogen and von Willebrand Factor, the clot retraction and the aggregation of platelets in response to ADP, epinephrine, thrombin, ionophore A23187, collagen, or arachidonic acid. In contrast, the administration of this drug did not affect intraplatelet levels of cAMP, agglutination and binding of von Willebrand Factor in response to ristocetin, shape change in response to ADP, collagen, thrombin, or arachidonic acid, or binding of prostaglandin El to resting platelets. Secretion of ATP in response to ADP or epinephrine was completely inhibited, whereas secretion as well as thromboxane synthesis in response to high concentrations of collagen, arachidonic acid, calcium ionophore A23187, or thrombin was unaffected. Studies with monoclonal antibodies showed that the glycoprotein IIb-IIIa complex (the putative receptor for fibrinogen and von Willebrand Factor on the surface of platelets exposed to naturally occurring aggregating agents) was quantitatively unaffected by ticlopidine. This observation was further confirmed by densitometric scannings of Periodic Acid-Schiff-stained gels of platelet suspensions. The onset, as well as the cessation of the inhibitory effect of ticlopidine on platelets was very slow, and reached a maximum after a 3-5-d administration. In addition, ticlopidine appeared to be a much more potent inhibitor when administered to subjects than when added in vitro to platelets. Finally, abnormalities comparable to those found in volunteers taking ticlopidine were observed when platelets from untreated subjects were incubated in the plasma of ticlopidine-treated subjects.We conclude that ticlopidine induces a thrombasthenic state in normal platelets without affecting the glycoprotein IlbIIIa complex quantitatively. Furthermore, our data suggest that one or more active metabolites rather than the native drug Portions of this work were presented at a symposium ("Ticlopidine: Quo vadis?") in Montpellier, France, 1983, and were published in abstract form in the proceedings of that symposium.Address reprint requests to Dr. Di Minno.

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Section: Discussionmentioning

confidence: 99%

“…The platelet-fibrin clot retraction was measured on PRP as described elsewhere (43). Briefly, a series of samples, each containing 0.5 ml of unstirred PRP, were incubated at 370C with 1-10 Ml of each retracting agent or vehicle.…”

Section: Introductionmentioning

confidence: 99%

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Minno¹,

Cerbone²,

Mattioli³

et al. 1985

J. Clin. Invest.

201

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Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclooxygenase products

Bertelè

Falanga

Tomasiak

et al. 1984

Blood

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Dazoxiben , an imidazole-derived selective inhibitor of thromboxane A2 (TxA2) synthetase, prevented TxB2 synthesis in vitro in platelet-rich plasma from 16 normal subjects. Inhibition of TxB2 synthesis was accompanied by increased generation of PGE2, PGF2 alpha, and PGD2, as shown by radioimmunoassay, thin-layer radiochromatography, and high- resolution gas chromatography-mass spectrometry. Even at dazoxiben concentrations (40–80 microM) above those inhibiting TxB2 synthesis, platelet aggregation induced by threshold concentrations of arachidonic acid was inhibited in only 4 of 16 subjects, referred to as responders. The remaining 12 individuals were defined as nonresponders. The aggregating effect of arachidonic acid and of the prostaglandin- endoperoxide analog U-46619 was potentiated by PGE2 and prevented by PGD2 at concentrations within the range of those detected in dazoxiben - treated platelet-rich plasma. The antiaggregating effect of dazoxiben was counteracted by PGE2 (in responders) and was potentiated by PGD2 (in nonresponders). Platelets from responders and nonresponders did not differ in the amount of immunoreactive PGE2 material or in their sensitivity to U-46619 or PGD2. It is concluded that inhibition of thromboxane synthetase does not per se prevent platelet aggregation. The functional result of thromboxane suppression appears to be modulated by an interplay of the prostaglandin-endoperoxides, PGE2 and PGD2, which are formed in excess.

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Changes in Phosphoinositides in Rabbit Platelets during Clot Formation. Comparison of Platelets Stimulated by ADP or by Thrombin in the Presence of Polymerising Fibrin

et al. 1990

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Platelet phosphoinositide metabolism was examined during platelet-fibrin clot formation stimulated by ADP (10 μM) plus reptilase, or by thrombin (1 U/ml), for 120 s in the presence of fibrinogen, to determine which changes are specifically associated with this process. Stirring at 200 rpm was used to minimise the contribution of aggregation to the platelet changes. Under these conditions, thrombin caused extensive release of the contents of platelet granules; ADP plus reptilase did not. The presence of fibrinogen decreased the amount of extractable phosphatidylinositol 4,5-bisphosphate (PIP(2)) by 46.4±5.5% when thrombin was the stimulus, and by 47.4±5.5% when the platelets were stimulated by ADP plus reptilase. Fibrinogen did not decrease the extraction of other phospholipids. The amount of phosphatidylinositol 4-phosphate (PIP) increased when platelets were stimulated in either the presence or absence of fibrinogen. These increases were greater in the presence of fibrinogen and the thrombin-induced increase was smaller than the increase induced by ADP plus reptilase; with ADP plus reptilase, the increase in PIP more than accounted for the loss of extractable PIP(2). In platelets prelabelled with [(3)H]inositol, the decrease in PIP(2) labelling induced by fibrinogen with ADP plus reptilase as the stimulus was accounted for by the increase in PIP labelling; the decrease induced by fibrinogen with thrombin as the stimulus was not. With thrombin, 46.5% of the decrease in PIP(2) labelling, caused by fibrinogen, was accounted for by label that remained with the interfacial protein after lipid extraction; with ADP plus reptilase, the amount of label with this protein was the same with or without fibrinogen. Only thrombin increased the amount of label in inositol trisphosphate (IP(3)) and the amount of phosphatidic acid (PA); these changes were not increased by fibrinogen. Thus, the results with ADP plus reptilase indicate that clot formation is not dependent on release of granule contents, formation of detectable IP(3) or PA (and hence does not require activation of phospholipase C) or association of [(3)H]inositol-labelled compounds with protein. Clot formation is associated with a shift in the PIP(2)-PIP equilibrium toward PIP.

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Arachidonic acid induces human platelet-fibrin retraction: The role of platelet cyclic endoperoxides

Cited by 3 publications

References 10 publications

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclooxygenase products

Changes in Phosphoinositides in Rabbit Platelets during Clot Formation. Comparison of Platelets Stimulated by ADP or by Thrombin in the Presence of Polymerising Fibrin

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