Reduced Platelet Thromboxane Formation in Uremia. EVIDENCE FOR A FUNCTIONAL CYCLOOXYGENASE DEFECT

G. Remuzzi; A. Benigni; P. Dodesini; A. Schieppati; M. Livio; G. De Gaetano; J. S. Day; W. L. Smith; E. Pinca; P. Patrignani; C. Patrono

doi:10.1172/JCI110824

Reduced Platelet Thromboxane Formation in Uremia. EVIDENCE FOR A FUNCTIONAL CYCLOOXYGENASE DEFECT

G. Remuzzi,¹ A. Benigni,¹ P. Dodesini,¹ A. Schieppati,¹ M. Livio,¹ G. De Gaetano,¹ J. S. Day,² W. L. Smith,² E. Pinca,³ P. Patrignani,³ and C. Patrono³

Published March 1, 1983 - More info

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Abstract

A qualitative platelet abnormality and a bleeding tendency are frequently associated with renal failure and uremia. We demonstrated previously that uremic patients display an abnormal platelet aggregation to arachidonic acid and reduced malondialdehyde production in response to thrombin and arachidonic acid. The objectives of this investigation were: (a) to compare platelet prostaglandin (PG) and thromboxane (TX) production in whole blood and in platelet-rich plasma (PRP) of 21 uremic patients and 22 healthy subjects; (b) to evaluate the concentration and activity of platelet PG- and TX-forming enzymes; (c) to assess the functional responsiveness of the platelet TXA₂/PGH₂ receptor; (d) to explore the hemostatic consequences of partially reduced TXA₂ production.

Platelet immunoreactive TXB₂ production during whole blood clotting was significantly reduced, by ∼60%, in uremic patients as compared to age- and sex-matched controls. Exogenous thrombin (5-30 IU/ml) failed to restore normal TXB₂ production in uremic platelets. Uremic PRP produced comparable or slightly higher amounts of TXB₂ than normal PRP at arachidonate concentrations 0.25-1 mM. However, when exposed to substrate concentrations >2 mM, uremic PRP produced significantly less TXB₂ than normal PRP. To discriminate between reduced arachidonic acid oxygenation and altered endoperoxide metabolism, the time course of immunoreactive TXB₂ and PGE₂ production was measured during whole blood clotting. The synthesis and release of both cyclooxygenase-derived products was slower and significantly reduced, at all time intervals considered. Furthermore, PGI₂ production in whole blood, as reflected by serum immunoreactive 6-keto-PGF_1α concentrations, was significantly reduced in uremic patients as compared with healthy subjects. PGH synthase levels, as determined by an immunoradiometric assay, were not significantly different in platelets from uremic patients as compared to control platelets. A single 40-mg dose of aspirin given to five healthy volunteers reduced their serum TXB₂ to levels found in uremic patients. This was associated with a significant increase of threshold aggregating concentrations of ADP and arachidonic acid and prolongation of bleeding time. Substantially similar threshold concentrations of U46619, a TXA₂ agonist, induced aggregation of normal and uremic platelets. Prostacyclin induced a significant elevation of uremic platelet cyclic AMP, which was suppressed by U46619, further suggesting normal responsiveness of the TXA₂/PGH₂ receptor.

We conclude that: (a) an abnormality of platelet arachidonic acid metabolism exists in uremia, leading to a reduced TXA₂ production; (b) the characteristics of this abnormality are consistent with a functional cyclooxygenase defect; (c) reduced TXA₂ production may partially explain the previously described abnormality of platelet function in uremia.

Reduced Platelet Thromboxane Formation in Uremia. EVIDENCE FOR A FUNCTIONAL CYCLOOXYGENASE DEFECT

G. Remuzzi,¹ A. Benigni,¹ P. Dodesini,¹ A. Schieppati,¹ M. Livio,¹ G. De Gaetano,¹ J. S. Day,² W. L. Smith,² E. Pinca,³ P. Patrignani,³ and C. Patrono³

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Reduced Platelet Thromboxane Formation in Uremia. EVIDENCE FOR A FUNCTIONAL CYCLOOXYGENASE DEFECT

G. Remuzzi,1 A. Benigni,1 P. Dodesini,1 A. Schieppati,1 M. Livio,1 G. De Gaetano,1 J. S. Day,2 W. L. Smith,2 E. Pinca,3 P. Patrignani,3 and C. Patrono3

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G. Remuzzi,¹ A. Benigni,¹ P. Dodesini,¹ A. Schieppati,¹ M. Livio,¹ G. De Gaetano,¹ J. S. Day,² W. L. Smith,² E. Pinca,³ P. Patrignani,³ and C. Patrono³