Aspirin prolongs bleeding time in uremia by a mechanism distinct from platelet cyclooxygenase inhibition.

Abstract

We reported that aspirin (ASA) abnormally prolongs bleeding time (BT) in uremia. The present study was designed to investigate whether (a) the abnormally prolonged post-ASA BT in uremia is due to different ASA pharmacokinetics and bioavailability that might be a consequence of uremic condition, (b) platelet cyclooxygenase is peculiarly sensitive to ASA in uremia, and (c) ASA affects primary hemostasis in uremia by a mechanism independent of cyclooxygenase inhibition. Our results showed that in patients with uremia, but not in normal subjects, ASA markedly prolongs the BT. This effect is transient and depends on the presence of ASA in the blood. The observed differences in ASA kinetic parameters are not an explanation of the exaggerated effect of ASA on primary hemostasis in uremia. The sensitivity of platelet cyclooxygenase to ASA inhibition is comparable in uremics and in normal subjects. The temporal dissociation between ASA-induced prolongation of BT and the effect on platelet thromboxane A2 generation suggests that ASA inhibits platelet function in uremia by a mechanism distinct from cyclooxygenase blocking. This possibility is strengthened by the observation that ibuprofen at a dose that fully inhibits platelet cyclooxygenase activity does not significantly prolong BT.

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

“…Although this novel anti-platelet mechanism of aspirin can be observed in vivo in the mouse, it is unlikely that receptor shedding occurs in healthy humans, because after intake of aspirin plasma levels of about 2 mM are reached and shedding takes place in our experiments at concentrations of 20 mM. However, in some patients with impaired renal clearance (16) or patients that display massive bleeding after aspirin intake (hyper responders (44)) shedding may occur at concentrations of aspirin lower than 20 mM. Although we do not have evidence for this, these data might suggest that effective compensatory mechanism may exist to prevent shedding under therapeutically relevant conditions in humans.…”

“…Aspirin treatment causes an increased bleeding tendency in uremic patients compared with healthy volunteers, although COX was completely inhibited in all subjects tested (16). In addition, ibuprofen, a member of the NSAID family, at a dose that fully inhibits COX-1 activity did not significantly prolong bleeding time in these patients indicating a second anti-platelet mechanism of aspirin distinct from COX-1 inhibition (16). This is supported by in vivo findings demonstrating an increase in bleeding time of high dose aspirintreated rabbits, which was not related to COX-1 blockage (17).…”

“…However, not all clinical observations can be explained by this mechanism. Aspirin treatment causes an increased bleeding tendency in uremic patients compared with healthy volunteers, although COX was completely inhibited in all subjects tested (16). In addition, ibuprofen, a member of the NSAID family, at a dose that fully inhibits COX-1 activity did not significantly prolong bleeding time in these patients indicating a second anti-platelet mechanism of aspirin distinct from COX-1 inhibition (16).…”

Prognostic Implications of Chronic Kidney Disease on Patients Presenting with ST-Segment Elevation Myocardial Infarction with versus without Stent Thrombosis

“…These observations are contrary to a previous report [17] and may have some important clinical implications. CKD patients comprise a high-risk group among PCI-treated patients with a greater tendency for both bleeding [25] and thrombosis [9,10,11,12,13]. Thus, among patients who survived an ST event, those with CKD, despite a higher risk for bleeding [25], may still require more intense long-term clinical follow-up, possibly in conjugation with platelet function testing.…”

Medikamentöse Therapie zur Prognoseverbesserung nach akutem Myokardinfarkt

“…Es gibt jedoch Hinweise, dar3 niedrige Dosierungen von 20 bis 40 mg/d ASS eher die thrombozyt~ire Bildung von Thromboxan A2 als die Prostacyclinsynthese in Endothelzellen hemmen [6]. Offenbar ist jedoch nicht die gesamte antithrombotische Wirkung des ASS allein ª die Hemmung der Thromboxan-A2-Bildung zu erklfiren, so das weitere, cyclooxygenaseunabh~ingige Wirkprinzipien des ASS vermutet wurden [7,10].…”