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

Abstract

A B S T R A C T 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 Portions of this work were presented at the Eastern Section

Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis.

“…Serum for studying platelet TxB2 production in response to endogenous thrombin was obtained by leaving multiple 1-ml aliquots of native blood, collected by intracardiac puncture from ether-anesthetized animals, at 370C for 30 min, after the method previously reported (11). The prepared sera were frozen and kept at -20'C until assayed.…”

“…In order to understand better the relationship between the increased Tx synthesis and proteinuria we studied two additional groups of animals injected with adriamycin (7.5 mg/kg); eight rats received three daily intraperitoneal injections of the Tx inhibitor, UK-38,485 (16), at doses of 20 mg/kg during the period of heavy proteinuria (days 14-18 after adriamycin), and eight rats received buffer alone for the same period. The dose of UK-38,485 used, when given to normal rats, caused 98% (from 142.8±76.7 to 2.45±1.27 ng/ml) inhibition of platelet Tx generation, as measured by the amount of Tx detected in serum after blood coagulation in vitro (11). All rats were killed on day 18, 4 h after the last UK-38,485 or buffer injection.…”

Antithrombotic Therapy in Patients With Chronic Kidney Disease

“…[27][28][29] Finally, several intrinsic platelet abnormalities have been described, including secretion defects related to impaired arachidonic acid release from platelet phospholipids and a storage pool defect, 30 lower mean content of adenosine diphosphate and ␤-thromboglobulin, 31,32 reduced sensitivity to platelet agonists, 33,34 and decreased thromboxane A 2 synthesis. 35 Overall, the normal platelet response to vessel wall injury with platelet activation, recruitment, adhesion, and aggregation (primary hemostasis) is defective, likely as a consequence of uremic toxins present in the circulating blood. 36 On the other hand, uremic platelets may also display some features of procoagulant activity such as increased thrombin generation, phosphatidylserine exposure, and higher concentrations of von Willebrand factor [11][12][13]37 and platelet-derived microparticles.…”

Lipid Composition of Platelets in Patients with Uremia

“…Platelets of patients with uremia are abnormal in many ways [1, 2, 3, 4, 5, 6]. Decreased adhesion to subendothelium [1, 2], impaired formation of thromboxane [3, 4] and abnormal aggregation response to agonists [2, 3, 4, 5, 6] have been well documented.…”

“…Decreased adhesion to subendothelium [1, 2], impaired formation of thromboxane [3, 4] and abnormal aggregation response to agonists [2, 3, 4, 5, 6] have been well documented. In addition, other structural defects, like a decrease in expression of membrane glycoproteins [7, 8, 9, 10] and dense granule content [4] have been described.…”