Effects of meloxicam on platelet function in healthy adults: a randomized, double-blind, placebo-controlled trial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1), thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation, and COX-2, the enzyme that mediates inflammatory responses. Meloxicam is a relatively COX-2-selective anti-arthritis drug that shows significant TxA2 inhibition, albeit less than traditional NSAIDs. A randomized, double-blind, placebo-controlled trial was conducted in 79 healthy adults to compare the effects of once-daily therapeutic (7.5 mg, 15 mg) and supratherapeutic (30 mg) doses of meloxicam with extended-release indomethacin (Indo-ER 75 mg once daily) on bleeding time, TxA2 formation, and platelet aggregation. The authors measured platelet aggregation to COX-1-dependent (ADP arachidonate) and COX-1-independent (high-dose collagen) agonists, bleeding time, serum TxB2, and clotting times (aPTT and PT) after 8 days' administration and at 3 and 6 hours after steady-state dosing. Meloxicam significantly decreased TxB2 production compared with placebo in a dose-dependent fashion, reaching a peak of 77% inhibition 6 hours after 30 mg meloxicam; Indo-ER blocked TxB2 formation by 96% at the same time point. However, neither acute nor 8 days' administration of meloxicam at any dose caused a significant increase in bleeding time or inhibition of platelet aggregation to any agonist when compared with placebo. By contrast, Indo-ER significantly increased the bleeding time and inhibited platelet aggregation to COX-1-dependent agonists 6 hours after dosing. Clotting times were unaffected by any drug. It was concluded that unlike nonselective NSAIDs, meloxicam's blockade of TxA2 formation (even at supratherapeutic doses) does not reach levels that result in decreased in vivo platelet function, as measured by bleeding time and aggregometry. In this study of healthy subjects, meloxicam did not interfere with platelet-mediated hemostasis.

Antithrombin reduces monocyte and neutrophil CD11b up regulation in addition to blocking platelet activation during extracorporeal circulation.

BACKGROUND: Patients undergoing cardiac surgery requiring cardiopulmonary bypass develop a systemic inflammatory reaction. Antithrombin III (AT) has anticoagulant effects but also shows evidence of anti-inflammatory activity. The aim of this study was to examine whether exogenous AT could reduce white blood cell activation (CD11b up regulation or elastase release), in addition to inhibiting platelet (PLT) activation and fibrin generation, during simulated cardiopulmonary bypass (sCPB), undertaken in the absence of endothelium. STUDY DESIGN AND METHODS: sCPB was carried out with minimally heparinized (2 U/mL) human blood for 90 minutes in controls and with supplementation by low-dose (1 U/mL) and high-dose (5 U/mL) AT. RESULTS: High-dose AT blunted thrombin generation during sCPB (prothrombin fragment 1.2); both doses significantly inhibited thrombin activity (fibrinopeptide A). Complement activation (C3a and C5b-9) was unaffected by AT. High-dose AT inhibited PLT activation (P-selectin expression and P-selectin-dependent monocyte-PLT conjugate formation). AT supplementation at the higher dose significantly abrogated monocyte and neutrophil CD11b up regulation and neutrophil elastase release. CONCLUSION: In addition to anticoagulant and anti-PLT effects, pharmacologic AT doses significantly blunted monocyte and neutrophil CD11b up regulation and neutrophil elastase release during sCPB, independent of endothelial effects. These data provide evidence for the direct anti-inflammatory activity of AT that has clinical relevance for CPB complications.

Reversibility of severe metabolic stress in stored platelets after in vitro plasma rescue or in vivo transfusion: restoration of secretory function and maintenance of platelet survival.

BACKGROUND: Determining reversible aspects of the platelet storage lesion may result in improved function and survival of transfused platelets. STUDY DESIGN AND METHODS: Using a model of high-dose (apheresis-derived) platelet concentrates (PC), functional changes imposed by transient adverse metabolic conditions (pH < 6.0 for 1-2 hr) that could be reversed by autologous plasma rescue followed by standard platelet storage were investigated. Whole-blood-derived PCs were transfused into a small number of normal volunteers to determine platelet recovery and survival. RESULTS: Without rescue, high-dose PCs developed severe in vitro functional derangements at the time of the pH nadir including 1) loss of resting morphology; 2) complete abrogation of osmotic recovery and platelet aggregation and glycoprotein IIb/IIIa up-regulation to agonist; and 3) decreased alpha-granule release. By contrast, spontaneous and agonist-induced binding of annexin V were unaffected by adverse metabolic conditions. Plasma rescue to an optimal pH improved morphology scores, stabilized osmotic recovery, and completely restored platelet secretory responses, as measured by aggregation, glycoprotein IIb/IIIa up-regulation, and alpha-granule release. In a limited number of studies, plasma rescue was accompanied by preserved in vivo platelet recovery and survival after autologous transfusion after 5 days of storage. CONCLUSION: Transient derangement of platelet metabolism, which does not increase membrane phosphatidylserine exposure, causes in vitro functional abnormalities that are fully reversed or stabilized by metabolic rescue. Preliminary data suggest that such rescued platelets may have normal posttransfusion recovery and survival.