Signaling via P2Y12 may be critical for early stabilization of platelet aggregates.

P2Y(12) receptor antagonism inhibits platelet aggregation by preventing adenosine diphosphate (ADP)-mediated amplification of activation pathways downstream of primary agonists, such as thrombin and collagen. However, the role of ADP signaling in maintaining aggregate stability and the effects of P2Y(12) antagonists on preestablished aggregates in vitro and arterial thrombus in vivo are not well understood. This study evaluated the impact of P2Y(12) signaling on platelet aggregate stability and early thrombotic occlusion using a reversible P2Y(12) antagonist, ticagrelor. There were 2 study objectives: (1) to determine if there was a time-dependent factor on the capacity of a P2Y(12) antagonist to affect human platelet aggregate stability in vitro using light transmission aggregometry and (2) to evaluate the extent of arterial thrombus reversal in a preclinical model upon administration of ticagrelor in vivo. Platelet aggregates were exposed to ticagrelor after ADP or collagen activation, monitored for stability by aggregometry, and visualized by microscopy. Freshly formed ADP- and collagen-induced platelet aggregates were more rapidly dispersed by a P2Y(12) antagonist than drug carrier control at clinically relevant concentrations (P < 0.05). However, stable aggregates were not noticeably affected. A murine arterial thrombosis model was used to evaluate thrombus stability in an in vivo mouse model. Thrombotic occlusion was induced by FeCl(3), followed by a bolus intravenous administration of ticagrelor or vehicle control. Doppler blood flow was monitored before injury and 30 minutes after bolus administration. Arteries were retrieved for inspection for residual thrombus. Early arterial thrombotic occlusion in vivo was partially reversed by ticagrelor administration. Blood flow through the injured artery increased, and thrombus size within the artery decreased (P < 0.05, n = 3). In conclusion, P2Y(12) antagonism disrupts the stability of newly formed platelet aggregates, promoting disaggregation, and reverses thrombotic vascular occlusion. Thus, in addition to activating platelets, signaling via P2Y(12) seems to be required for stabilizing platelet thrombi.

Metal levels and glomerular filtration rate after unilateral Birmingham Hip Resurfacing.

Aims: The first aim of this study was to evaluate whether preoperative renal function is associated with postoperative changes in whole blood levels of metal ions in patients who have undergone a Birmingham Hip Resurfacing (BHR) arthroplasty with a metal-on-metal bearing. The second aim was to evaluate whether exposure to increased cobalt (Co) and chromium (Cr) levels for ten years adversely affected renal function. Methods: As part of a multicentre, prospective post-approval study, whole blood samples were sent to a single specialized laboratory to determine Co and Cr levels, and the estimated glomerular filtration rate (eGFR). The study included patients with 117 unrevised unilateral BHRs. There were 36 females (31%). The mean age of the patients at the time of surgery of 51.3 years (SD 6.5), and they all had preoperative one-, four-, five-, and ten-year laboratory data. The mean follow-up was 10.1 years (SD 0.2). Results: Median Co levels at one year postoperatively increased significantly compared with the preoperative values, by a factor of 9.7, from 0.13 to 1.26 ppb (p < 0.001), and the median Cr levels increased significantly by a factor of 2.5, from 0.60 to 1.50 ppb (p < 0.001). Lower preoperative eGFRs were associated with significantly larger increases in Co at one year compared with the preoperative levels (ρ = -0.26; p = 0.005), but there was no relationship between preoperative eGFRs and changes in Cr at one year (ρ = -0.13; p = 0.153). Metal levels remained relatively constant with the passage of time, with a median ten-year value of 1.12 ppb for Co and 1.29 ppb for Cr. There was no significant relationship between the Co and Cr levels at ten-year follow-up and the change in eGFR from the preoperative level to that at ten years (ρ = -0.02; p = 0.827 for Co; ρ = -0.008; p = 0.933 for Cr). Conclusion: Although patients with lower preoperative eGFRs tended to have larger increases in Co levels at one year, increased metal levels for patients who underwent unilateral BHR did not adversely affect renal function during the first ten postoperative years.

Results of the First U.S. FDA-Approved Hip Resurfacing Device at 10-Year Follow-up.

BACKGROUND: The BIRMINGHAM HIP Resurfacing (BHR) system is a metal-on-metal hip implant system approved by the U.S. Food and Drug Administration in 2006. The approval required a multicenter, prospective, post-market-approval study. Our purpose is to report the current results at 10 years of follow-up. METHODS: Between October 2006 and December 2009, 280 primary BHR procedures were performed at 5 sites. Outcome measures included Kaplan-Meier survivorship, reasons for revision, radiographic component stability and osteolysis, Harris hip scores, and metal levels including cobalt and chromium. The mean age at the time of the procedure was 51.3 ± 7.1 years, 74% (206) of 280 BHRs were implanted in male patients, the mean body mass index was 27.8 ± 4.4 kg/m2, and 95% (265) of 280 hips had a primary diagnosis of osteoarthritis. The mean follow-up among all 280 hips was 9.0 ± 2.5 years. Prior to 10-year follow-up, 20 hips were revised and 5 patients representing 5 hips had died. Among the remaining 255 hips, 218 (85%) met the minimum follow-up of 10 years. RESULTS: The 10-year survival free from all-cause component revision was 92.9% (95% confidence interval [CI], 89.8% to 96.1%) for all hips and 96.0% (95% CI, 93.1% to 98.9%) among male patients <65 years old at the time of the procedure. Reasons for revision included femoral loosening (n = 5), femoral neck fracture (n = 3), pseudotumor (n = 3), osteolysis (n = 2), and acetabular loosening (n = 1), as well as 6 revisions for a combination of pain, noise, or metal levels. Among unrevised hips, the median Harris hip score improved from preoperatively (59) to 1 year postoperatively (99; p < 0.001) and remained stable through 10 years postoperatively (99; p = 0.08). Radiographically, 5% (10) of 218 unrevised hips had osteolysis with no component migration. Median metal levels had increased at 1 year postoperatively (cobalt: from 0.12 ppb preoperatively to 1.5 ppb at 1 year postoperatively, p < 0.001; chromium: from 0.6 ppb preoperatively to 1.7 ppb at 1 year postoperatively, p < 0.001), then remained stable through 5 years before slightly decreasing at 10 years postoperatively (cobalt: 1.3 ppb, p < 0.001; chromium: 1.4 ppb, p < 0.001). CONCLUSIONS: This prospective, multicenter, post-market-approval study demonstrated that the BHR implant system is safe and effective through 10 years of follow-up, particularly among young male patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Effects of annular contraction on anterior leaflet strain using an in vitro simulator with a dynamically contracting mitral annulus.

Using in vitro models, the mechanics as well as surgical techniques for mitral valves (MV) and MV devices can be studied in a more controlled environment with minimal monetary investment and risk. However, these current models rely on certain simplifications, one being that the MV has a static, rigid annulus. In order to study more complex issues of imaging diagnostics and implanted device function, it would be more advantageous to verify their use for a dynamic environment in a dynamic simulator. This study provides the novel design and development of a dynamically contracting annulus (DCA) within an in vitro simulator, and its subsequent use to study MV biomechanics. Experiments were performed to study the ability of the DCA to reproduce the MV leaflet mechanics in vitro, as seen in vivo, as well as investigate how rigid annuloplasties affect MV leaflet mechanics. Experiments used healthy, excised MVs and normal hemodynamics; contractile waveforms were derived from human in vivo data. Stereophotogrammetry and echocardiography were used to measure anterior leaflet strain and the change in MV geometry. In pursuit of the first in vitro MV simulator that more completely represents the dynamic motion of the full valvular apparatus, this study demonstrated the successful operation of a dynamically contracting mitral annulus. It was seen that the diseased contractile state increased anterior leaflet strain compared to the healthy contractile state. In addition, it was also shown in vitro that simulated rigid annuloplasty increased mitral anterior leaflet strain compared to a healthy contraction.

Platelet function recovery following exposure to triple anti-platelet inhibitors using an in vitro transfusion model.

INTRODUCTION: Dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 antagonist is standard of care to reduce risk of thrombosis, but does not directly target thrombin-dependent platelet activation. Therefore, PAR-1 antagonist addition to DAPT (i.e., triple anti-platelet therapy; TAPT) may improve the efficacy of treatment, though at the expense of an increase in bleeding risk. Using an in vitro transfusion model, we evaluated if platelet function loss associated with TAPT can be remedied by the addition of drug-naïve platelets. METHODS: To mimic TAPT, platelet-rich plasma (PRP) prepared from consented DAPT patients (DPRP) was incubated with a vorapaxar at therapeutic plasma levels (TPRP). To simulate platelet transfusions, TPRP was mixed with increasing proportions of drug-naïve PRP (NPRP). Platelet function recovery was assessed by light transmission aggregometry (LTA), aggregate morphology, and P-selectin expression. RESULTS: LTA results demonstrated that 20% NPRP was required to restore the ADP aggregation response in TPRP to the response observed in DPRP and 40% NPRP recovered aggregation to >65%. Higher NPRP fractions (60%) were required to restore the platelet reactivity using TRAP-6 (SFLLRN) or arachidonic acid (AA). PAR-4 aggregation was unaffected by platelet antagonists. A decrease in single, free platelets and incorporation of mepacrine-labeled naïve platelets into aggregates occurred with increasing NPRP portions. Upon agonist activation, the surface density and percent of P-selectin positive platelets increased linearly upon addition of NPRP. CONCLUSION: This in vitro model demonstrated that administration of drug-naïve platelets can be a useful strategy for reversing overall platelet inhibition observed with TAPT.