Publications by authors named "Lisa K Jennings"

77 Publications

Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study.

J Am Heart Assoc 2020 04 20;9(8):e015865. Epub 2020 Apr 20.

University of Florida College of Medicine-Jacksonville FL.

Background Vorapaxar as an adjunct to dual antiplatelet therapy (DAPT) reduces thrombotic events in patients with prior myocardial infarction at the expense of increased bleeding. Withdrawal of aspirin has emerged as a bleeding reduction strategy. The pharmacodynamic effects of vorapaxar with potent P2Y inhibitors as well as the impact of dropping aspirin is unexplored and represented the aim of the VORA-PRATIC (Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y Receptor Inhibitors Prasugrel and Ticagrelor) study. Methods and Results Post-myocardial infarction patients (n=130) on standard DAPT (aspirin+prasugrel or ticagrelor) were randomized to 1 of 3 arms: (1) triple therapy: aspirin+prasugrel/ticagrelor+vorapaxar; (2) dual therapy (drop aspirin): prasugrel/ticagrelor+vorapaxar; (3) DAPT: aspirin+prasugrel/ticagrelor. Pharmacodynamic assessments were performed at 3 time points (baseline and 7 and 30 days). Vorapaxar reduced CAT (collagen-ADP-TRAP)-induced platelet aggregation, a marker of platelet-mediated global thrombogenicity (triple therapy versus DAPT at 30 days: mean difference=-27; 95% CI,-35 to -19; <0.001; primary end point). This effect was attenuated but still significant in the absence of aspirin (dual therapy versus DAPT at 30 days: mean difference=-15; 95% CI,-23 to -7; <0.001; between-group comparisons, <0.05). Vorapaxar abolished TRAP-induced aggregation (<0.001), without affecting thrombin generation and clot strength. There were no differences in markers of P2Y reactivity. Markers sensitive to aspirin-induced effects increased (<0.001) in the dual-therapy arm. Conclusions In post-myocardial infarction patients treated with potent P2Y inhibitors, vorapaxar reduces platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y reactivity or clot kinetics. The clinical implications of these PD observations warrant future investigation. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02545933.
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http://dx.doi.org/10.1161/JAHA.120.015865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428520PMC
April 2020

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.

Thromb Haemost 2020 Apr 14;120(4):538-564. Epub 2020 Apr 14.

Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Haemostasis Research Unit, University College London, London, United Kingdom.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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http://dx.doi.org/10.1055/s-0040-1708035DOI Listing
April 2020

Pharmacodynamic Effects of Vorapaxar in Patients With and Without Diabetes Mellitus: Results of the OPTIMUS-5 Study.

JACC Basic Transl Sci 2019 Nov 1;4(7):763-775. Epub 2019 Sep 1.

Division of Cardiology, Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.

Vorapaxar reduces thrombotic cardiovascular events at the expense of increased bleeding. However, the differential pharmacodynamic (PD) effects of vorapaxar according to diabetes mellitus (DM) status are unknown. Moreover, although withdrawal of aspirin has emerged as a bleeding reduction strategy, the PD effects of stopping aspirin in patients treated with vorapaxar also are unknown. In this prospective PD investigation, vorapaxar was associated with reduced platelet-mediated thrombogenicity without affecting clot kinetics irrespective of DM status. However, platelet-mediated thrombogenicity increased after aspirin withdrawal, particularly among patients with DM. (Optimizing anti-Platelet Therapy In diabetes MellitUS-5 Study [OPTIMUS-5]; NCT02548650).
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http://dx.doi.org/10.1016/j.jacbts.2019.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978557PMC
November 2019

Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

N Engl J Med 2019 05 17;380(19):1825-1833. Epub 2019 Mar 17.

From the Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston (D.L.B.); the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia (C.V.P.); McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (J.I.W.); CirQuest Labs and the University of Tennessee Health Science Center, Memphis (L.K.J.); and PhaseBio Pharmaceuticals, Malvern, PA (S.X., S.E.A., B.R.U., M.C.M., J.S.L.).

Background: Ticagrelor is an oral P2Y inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful.

Methods: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay.

Results: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P<0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site.

Conclusions: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.).
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http://dx.doi.org/10.1056/NEJMoa1901778DOI Listing
May 2019

Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial.

Blood Cells Mol Dis 2018 09 21;72:37-43. Epub 2018 Jul 21.

Division of Hematology and Hematologic Malignancies in the Department of Internal Medicine and the Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA. Electronic address:

Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.
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http://dx.doi.org/10.1016/j.bcmd.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097632PMC
September 2018

Inhibitory mechanisms of very low-dose rivaroxaban in non-ST-elevation myocardial infarction.

Blood Adv 2018 03;2(6):715-730

Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany.

Very low-dose (VLD) factor Xa (FXa) inhibition, in combination with acetylsalicylic acid (ASA) and clopidogrel, is associated with improved outcomes in patients with acute coronary syndrome (ACS) with a tolerable bleeding risk profile. To date, there are no data documenting platelet inhibition and the anticoagulatory effects of VLD FXa inhibition on top of guideline-adherent dual-antiplatelet therapy (DAPT) in patients with ACS. Patients with non-ST-elevation myocardial infarction (NSTEMI) receiving oral DAPT (ASA + clopidogrel, n = 20; or ASA + ticagrelor, n = 20) were prospectively enrolled in a nonrandomized study. Coagulation- and platelet-dependent thrombin generation (TG), measured by means of the calibrated automated thrombogram, were significantly decreased after in vitro and in vivo addition of rivaroxaban. As shown by a total thrombus-formation analysis approach, rivaroxaban treatment led to a significantly decreased coagulation-dependent (AR-chip) thrombus formation in patients treated with ASA plus P2Y inhibitor (clopidogrel/ticagrelor), whereas the pure platelet-dependent (PL-chip) thrombus formation was not affected at all. Adjunctive rivaroxaban therapy was not associated with significant differences in platelet aggregation assessed by light-transmission aggregometry (LTA). Nevertheless, according to fluorescence-activated cell sorter analysis, VLD rivaroxaban treatment resulted in a significantly reduced expression of platelet HMGB-1, whereas P-selectin exposure was not affected. Furthermore, an enhanced effect of rivaroxaban on total thrombus formation and TG was observed in particular in clopidogrel nonresponder patients defined as adenosine 5'-diphosphate-induced LTA ≥40%. VLD rivaroxaban reduces thrombus formation and platelet-dependent TG in patients with ACS receiving DAPT, which can be of potential ischemic benefit. This trial was registered at www.clinicaltrials.gov as #NCT01417884.
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http://dx.doi.org/10.1182/bloodadvances.2017013573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873232PMC
March 2018

Association of D-dimer Levels with Clinical Event Rates and the Efficacy of Betrixaban versus Enoxaparin in the APEX Trial.

TH Open 2018 Jan 8;2(1):e16-e24. Epub 2018 Jan 8.

Department of Medicine, Stanford University, Stanford, California, United States.

 Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial.  Hospitalized acutely medically ill subjects (  = 7,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement.  For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban (  < 0.001) and enoxaparin (  < 0.001) treatment arms. Among D-dimer-positive (≥ 2 × upper limit of normal; corresponding to ≥ 1.00 µg/mL) subjects, extended-duration betrixaban reduced the risk of experiencing the primary efficacy outcome (5.4% [  = 124] vs. 7.6% [  = 170]; odds ratio = 0.69; 95% confidence interval: 0.55-0.88; absolute risk reduction = 2.2%, number needed to treat = 46,  = 0.003). There was no interaction between D-dimer and the treatment effect (  = 0.53).  Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.
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http://dx.doi.org/10.1055/s-0037-1615288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524856PMC
January 2018

A prospective study of platelet function in trauma patients.

J Trauma Acute Care Surg 2016 May;80(5):726-32; discussion 732-3

From the Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee.

Background: Exsanguination associated with acute traumatic coagulopathy is a leading cause of death following injury. While platelets occupy a pivotal role in clot formation, clinical research has been scant because of complexities resulting from the need for rapid handling and complex testing of platelet functions. While the thrombin pathway has been proposed as a mediator of platelet dysfunction in trauma, it has not been systematically investigated. The purpose of this study was to evaluate the thrombin pathway in platelet dysfunction.

Methods: Forty trauma patients and 20 noninjured controls were enrolled in the study at a Level I trauma center. Platelet aggregation was tested by light transmission aggregometry with two agonists, adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP). Mean fluorescence intensity and percent positivity of CD62 on ADP-activated platelets were evaluated using flow cytometry. Enzyme-linked immunosorbent assays were performed to evaluate the concentrations of D-dimer, thrombin-antithrombin complex (TAT), and prothrombin fragment 1 + 2 (PF 1 + 2) in each sample.

Results: Compared with healthy controls, trauma patients had significantly decreased ADP- and TRAP-mediated platelet aggregation and ADP-mediated CD62 expression. In trauma patients, TRAP-mediated aggregation was inversely proportional to head Abbreviated Injury Scale (AIS) score. Glasgow Coma Scale (GCS) score was directly proportional to TRAP- and ADP-mediated aggregation. When compared with controls, significant differences of D-dimer, TAT, and PF 1 + 2 were found. Measures of shock, including admission blood pressure, pulse, base deficit, and lactate level, did not correlate with platelet dysfunction.

Conclusion: Trauma patients have significantly lower levels of platelet activation and aggregation compared with healthy controls. Severity of head injury was significantly correlated with platelet dysfunction in a stepwise fashion. Trauma patients also have significantly increased levels of D-dimer, TAT, and PF 1 + 2 when compared with healthy controls. Our data suggest that the thrombin receptor pathway plays an important role in platelet dysfunction in trauma.

Level Of Evidence: Prognostic and epidemiologic study, level III.
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http://dx.doi.org/10.1097/TA.0000000000001017DOI Listing
May 2016

The utility of tetraspanin CD9 as a biomarker for metastatic clear cell renal cell carcinoma.

Biochem Biophys Res Commun 2016 Feb 12;471(1):21-5. Epub 2016 Feb 12.

The University of Tennessee Health Science Center, Memphis, TN, USA; CirQuest Labs, LLC, Memphis, TN, USA.

The use of tetraspanin CD9 as a biomarker for renal cell carcinomas (RCC) has been explored with minor conclusions. Identification of a biomarker that not only distinguishes between the different types of renal cell carcinomas, but also predicts the metastatic potential of these tumors would significantly advance diagnosis and prognosis of kidney cancers. We utilized established cell lines to better understand the contribution of CD9 to the metastatic potential of clear cell renal cell carcinomas, and then applied our findings to the TCGA database and immunohistochemical analysis of human samples based on tumor grading to determine the utility of CD9 as a biomarker for RCC. Clear cell renal cell carcinoma (ccRCC) cell expression of tetraspanin CD9 was compared to normal kidney cells and found to be elevated. Upon knockdown of CD9, ccRCC cells obtained a more metastatic phenotype. We found E-cadherin expression to be repressed and the endothelial to mesenchymal transition markers Snail, Twist1, and Zeb1 to be elevated upon CD9 knockdown. Upon observing these gene expression changes in the TCGA database and in 10 cases, we found that CD9 and E-cadherin expression was lowered in higher grade ccRCC tumors. There was a significant correlation between CD9 and either E-cadherin, Snail, or Zeb1 in these tumors. Collectively, using tetraspanin CD9 in tandem with E-cadherin as a biomarker in renal cell carcinoma will help to not only distinguish between types, but also predict the metastatic potential of RCC.
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http://dx.doi.org/10.1016/j.bbrc.2016.02.008DOI Listing
February 2016

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

Thromb Res 2015 Dec 11;136(6):1216-23. Epub 2015 Sep 11.

CirQuest Labs, Memphis, TN, USA.; The University of Tennessee Health Science Center, Memphis, TN, USA.. Electronic address:

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.
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http://dx.doi.org/10.1016/j.thromres.2015.09.009DOI Listing
December 2015

Polydopamine Integrated Nanomaterials and Their Biomedical Applications.

Curr Pharm Des 2015 ;21(29):4262-75

20 South Dudley, Suite 900, Memphis, TN 38103.

In the past few decades, the applications of nanomaterials in biologic systems have become one of the most studied areas. Many novel syntheses and processing methods have been developed to generate nanomaterials to enhance biomedical applications. Among those methods, polydopamine (PDA) integrated nanomaterials have attracted considerable interest for various types of biomedical applications. This concise review outlines the basic chemistry and material science regarding PDA and discusses its successful applications in drug delivery, biosensing, antifouling and antimicrobial activities, as well as its interaction with cells.
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http://dx.doi.org/10.2174/1381612821666150901103418DOI Listing
August 2016

The spectrum of thrombin in acute coronary syndromes.

Thromb Res 2015 May 21;135(5):782-7. Epub 2015 Feb 21.

Department of Internal Medicine, The University of Tennessee Health Science Center, 956 Court Avenue, Coleman H300, Memphis, TN 38163, USA; Vascular Biology, The University of Tennessee Health Science Center, 956 Court Avenue, Coleman H300, Memphis, TN 38163, USA; Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, 956 Court Avenue, Coleman H300, Memphis, TN 38163, USA. Electronic address:

The role of thrombin in vascular physiology and pathophysiology continues to impact our understanding of many cellular processes and systems including the function of platelets, endothelial cells, smooth muscle cells, leukocytes and the regulation of the coagulation cascade. Recent acute coronary syndrome clinical trial results that have compared the use of parenteral or oral anticoagulants versus or in combination with anti-platelet agents have forced a reexamination of the importance of thrombin activity in influencing patient outcomes, particularly in the area of secondary prevention. The debate of the need to include oral anticoagulation as a concomitant or replacement therapy to an antiplatelet regimen as a means to improve patient outcomes requires further examination and larger prospective clinical trials.
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http://dx.doi.org/10.1016/j.thromres.2015.02.013DOI Listing
May 2015

Self-compassion and life satisfaction in gay men.

Psychol Rep 2014 Dec;115(3):888-95

1 California State University, Long Beach.

Studies have shown that gay men are at increased risk for anxiety and depression due to social oppression; research suggests that self-compassion is positively associated with life-satisfaction and emotional resilience. In a sample of 68 gay men (M age = 39.7 yr., SD = 16.3), the influence of self-compassion on satisfaction with life was examined while controlling for age, income, and openness about sexual orientation. Analysis of the data revealed that self-compassion was a significant predictor of satisfaction with life. Implications of this finding were discussed.
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http://dx.doi.org/10.2466/21.07.PR0.115c33z3DOI Listing
December 2014

Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: results from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial.

Am Heart J 2014 Dec 16;168(6):869-77.e1. Epub 2014 Sep 16.

Department of Medicine, Stanford University, Stanford, CA.

Background: Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time.

Methods: The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted.

Results: Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53).

Conclusions: We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.
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http://dx.doi.org/10.1016/j.ahj.2014.09.002DOI Listing
December 2014

Tetraspanin CD9 regulates cell contraction and actin arrangement via RhoA in human vascular smooth muscle cells.

PLoS One 2014 3;9(9):e106999. Epub 2014 Sep 3.

The Vascular Biology Center of Excellence and the Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Joint Program of Biomedical Engineering, University of Tennessee Health Science Center and the University of Memphis, Memphis, Tennessee, United States of America; CirQuest Labs, LLC, Memphis, Tennessee, United States of America.

The most prevalent cardiovascular diseases arise from alterations in vascular smooth muscle cell (VSMC) morphology and function. Tetraspanin CD9 has been previously implicated in regulating vascular pathologies; however, insight into how CD9 may regulate adverse VSMC phenotypes has not been provided. We utilized a human model of aortic smooth muscle cells to understand the consequences of CD9 deficiency on VSMC phenotypes. Upon knocking down CD9, the cells developed an abnormally small and rounded morphology. We determined that this morphological change was due to a lack of typical parallel actin arrangement. We also found similar total RhoA but decreased GTP-bound (active) RhoA levels in CD9 deficient cells. As a result, cells lacking a full complement of CD9 were less contractile than their control treated counterparts. Upon restoration of RhoA activity in the CD9 deficient cells, the phenotype was reversed and cell contraction was restored. Conversely, inhibition of RhoA activity in the control cells mimicked the CD9-deficient cell phenotype. Thus, alteration in CD9 expression was sufficient to profoundly disrupt cellular actin arrangement and endogenous cell contraction by interfering with RhoA signaling. This study provides insight into how CD9 may regulate previously described vascular smooth muscle cell pathophysiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106999PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153684PMC
November 2015

Benzimidazole analogs as potent hypoxia inducible factor inhibitors: synthesis, biological evaluation, and profiling drug-like properties.

Anticancer Res 2014 Aug;34(8):3891-904

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.

Aim: To develop potent HIF-1α inhibitors for potential treatment of cancer.

Materials And Methods: Chemical synthesis, HIF-luciferase assay, cytotoxic assay, platelet aggregation assay, western blot analysis, quantitative real-time PCR, aqueous solubility, protein binding, metabolic stability, and metabolic pathways.

Results: Thirteen novel benzimidazole analogs were synthesized. Compounds 3a and 3k showed the highest anti-HIF-1α activity. They are significantly more effective than YC-1 in the suppression of HIF-1α protein expression based on western blot assay. They show comparable potency in inhibition of cancer cell migration. They are less potent in the inhibition of platelet aggregation. 3k had the most favorable drug-like properties, including long half-life in human liver microsomes, medium protein binding level and reasonable aqueous solubility.

Conclusion: The potent anti-HIF-1α activity and favorable drug-like properties of compound 3k suggest that it may hold great potential as an adjuvant therapy for cancer treatment through repression of HIF-1α protein expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346463PMC
August 2014

PAR1 antagonists inhibit thrombin-induced platelet activation whilst leaving the PAR4-mediated response intact.

Platelets 2015 21;26(3):236-42. Epub 2014 Apr 21.

Department of Cardiovascular Science, University of Sheffield , UK .

Thrombin-induced platelet activation is initiated by PAR1 and PAR4 receptors. Vorapaxar, a PAR1 antagonist, has been assessed in patients with acute coronary syndromes (ACS) and stable atherosclerotic disease in addition to standard-of-care treatment. In clinical trials, vorapaxar has been observed to reduce the frequency of ischaemic events in some subgroups though in others has increased the frequency of bleeding events. Among patients undergoing CABG surgery, which is associated with excess thrombin generation, bleeding was not increased. The aim of these studies was to investigate the effects of selective PAR1 antagonism on thrombin-induced platelet activation in patients receiving vorapaxar or placebo in the TRACER trial and to explore the roles of PAR1 and PAR4 in thrombin-induced platelet activation in healthy volunteers. ACS patients receiving vorapaxar or placebo in the TRACER trial were studied at baseline and 4 hours, 1 and 4 months during drug administration. Thrombin-induced calcium mobilisation in platelet-rich plasma was assessed by flow cytometry. In vitro studies were performed in healthy volunteers using the PAR1 antagonist SCH79797 or PAR4 receptor desensitisation. Vorapaxar treatment significantly inhibited thrombin-induced calcium mobilisation, leaving a residual, delayed response. These findings were consistent with calcium mobilisation mediated via the PAR4 receptor and were reproduced in vitro using SCH79797. PAR4 receptor desensitization, in combination with SCH79797, completely inhibited thrombin-induced calcium mobilisation confirming that the residual calcium mobilisation was mediated via PAR4. In conclusion vorapaxar selectively antagonises the PAR1-mediated component of thrombin-induced platelet activation, leaving the PAR4-mediated response intact, which may explain why vorapaxar is well tolerated in patients undergoing CABG surgery since higher thrombin levels in this setting may override the effects of PAR1 antagonism through PAR4 activation, thus preserving haemostasis. Further assessment may be warranted.
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http://dx.doi.org/10.3109/09537104.2014.902924DOI Listing
December 2015

Tetraspanin CD9 modulates human lymphoma cellular proliferation via histone deacetylase activity.

Biochem Biophys Res Commun 2014 May 18;447(4):616-20. Epub 2014 Apr 18.

Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Biology, Bioinformatics Program, University of Memphis, Memphis, TN 38152, United States. Electronic address:

Non-Hodgkin Lymphoma (NHL) is a type of hematological malignancy that affects two percent of the overall population in the United States. Tetraspanin CD9 is a cell surface protein that has been thoroughly demonstrated to be a molecular facilitator of cellular phenotype. CD9 expression varies in two human lymphoma cell lines, Raji and BJAB. In this report, we investigated the functional relationship between CD9 and cell proliferation regulated by histone deacetylase (HDAC) activity in these two cell lines. Introduction of CD9 expression in Raji cells resulted in significantly increased cell proliferation and HDAC activity compared to Mock transfected Raji cells. The increase in CD9-Raji cell proliferation was significantly inhibited by HDAC inhibitor (HDACi) treatment. Pretreatment of BJAB cells with HDAC inhibitors resulted in a significant decrease in endogenous CD9 mRNA and cell surface expression. BJAB cells also displayed decreased cell proliferation after HDACi treatment. These results suggest a significant relationship between CD9 expression and cell proliferation in human lymphoma cells that may be modulated by HDAC activity.
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http://dx.doi.org/10.1016/j.bbrc.2014.04.046DOI Listing
May 2014

The Utility of Platelet and Coagulation Testing of Antithrombotics: Fusing Science with Patient Care.

Drug Dev Res 2013 Dec 15;74(8):587-593. Epub 2013 Nov 15.

The University of Tennessee Health Science Center and CirQuest Labs Memphis, TN, USA.

[Table: see text] There is an increasing need for the standardization of platelet function and coagulation testing for the assessment of antithrombotic therapies. Investigators continue to strive to identify ideal laboratory testing and monitoring procedures for acquired and inherited platelet function defects as well as for evaluating patient status when treated with existing or emerging antithrombotics. These therapies are used primarily in the treatment of ischemic complications. In patients receiving antithrombotic therapy, the balance between hemostasis and thrombosis is a challenge as there is an ongoing risk for bleeding when patients are receiving antiplatelet agents or anticoagulants to lessen their risk for secondary thrombotic events. There are several diverse tests for monitoring anticoagulant therapy; however, as new agents are developed, more specific tests will be required to directly assess these agents in relationship to overall coagulation status. Research in the platelet biology field is ongoing to provide point-of-care methodologies for the assessment of platelet reactivity in terms of both bleeding and thrombosis risk. Currently there are no instruments that reliably assess the risk of bleeding. The challenges that routinely faced are the complexity of physiology, the need for standardization of platelet testing methodology, and the necessity for appropriate interpretation of the test results.
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http://dx.doi.org/10.1002/ddr.21119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902984PMC
December 2013

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

J Cardiovasc Pharmacol 2014 Jun;63(6):520-7

*Vascular Biology Center, The University of Tennessee Health Science Center, Memphis, TN; †Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, TN; ‡CirQuest Labs, LLC, Memphis, TN; and §AstraZeneca, Research and Development, Mölndal, Sweden.

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.
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http://dx.doi.org/10.1097/FJC.0000000000000076DOI Listing
June 2014

Association of aspirin dose and vorapaxar safety and efficacy in patients with non-ST-segment elevation acute coronary syndrome (from the TRACER Trial).

Am J Cardiol 2014 Mar 25;113(6):936-44. Epub 2013 Dec 25.

Department of Medicine, Stanford University, Stanford, California.

Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.
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http://dx.doi.org/10.1016/j.amjcard.2013.11.052DOI Listing
March 2014

Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy.

Thromb Haemost 2014 May 9;111(5):883-91. Epub 2014 Jan 9.

Lisa K. Jennings, PhD, 20 S. Dudley, Suite 900, Memphis, TN 38103, USA, Tel.: +1 901 866 1700, Fax: +1 901 866 1702, E-mail:

Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.
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http://dx.doi.org/10.1160/TH13-07-0624DOI Listing
May 2014

Pro-MMP-9 upregulation in HT1080 cells expressing CD9 is regulated by epidermal growth factor receptor.

Biochem Biophys Res Commun 2013 Dec 16;442(1-2):99-104. Epub 2013 Nov 16.

The Vascular Biology Center of Excellence, Department of Internal Medicine, USA; Department of Microbiology, Immunology, and Biochemistry, USA.

Degradation of the surrounding extracellular matrix (ECM) by matrix metalloproteinases (MMPs) drives invasion and metastasis of cancer cells. We previously demonstrated that tetraspanin CD9 expression upregulates pro-MMP-9 expression and release and promotes cellular invasion in a human fibrosarcoma cell line (HT1080). These events were dependent upon the highly functional second extracellular loop of CD9. We report here that the epidermal growth factor receptor (EGFR) tyrosine kinase expression and activity are involved in the CD9-mediated increase in pro-MMP-9 release and cellular invasion. Pro-MMP-9 expression was significantly decreased in a dose-dependent manner using first a broad spectrum receptor tyrosine kinase inhibitor and multiple specific EGFR inhibitors in CD9-HT1080 cells. Furthermore, gefitinib treatment of CD9-HT1080 cells reduced invasion through matrigel. EGFR knockdown using short interfering RNA resulted in decreased pro-MMP-9 expression and release into the media and subsequent cellular invasion without affecting CD9 expression or localization. Conclusively, this study points to EGFR as a key mediator between CD9-mediated pro-MMP-9 release and cellular invasion of HT1080 cells.
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http://dx.doi.org/10.1016/j.bbrc.2013.11.021DOI Listing
December 2013

Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9.

PLoS One 2013 28;8(6):e67766. Epub 2013 Jun 28.

The Vascular Biology Center of Excellence and the Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP) production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor. Tetraspanins, a family of cell surface organizers, play a major role in cell signaling events and have been implicated in regulating metastasis in numerous cancer cell lines. We stably expressed tetraspanin CD9 in an invasive and metastatic human fibrosarcoma cell line (CD9-HT1080) to investigate its role in regulating tumor cell invasiveness. CD9-HT1080 cells displayed a highly invasive phenotype as demonstrated by matrigel invasion assays. Statistically significant increases in MMP-9 production and activity were attributed to CD9 expression and were not due to any changes in other key tetraspanin complex members or MMP regulators. Increased invasion of CD9-HT1080 cells was reversed upon silencing of MMP-9 using a MMP-9 specific siRNA. Furthermore, we determined that the second extracellular loop of CD9 was responsible for the upregulation of MMP-9 production and subsequent cell invasion. We demonstrated for the first time that tetraspanin CD9 controls HT1080 cell invasion via upregulation of an integral member of the MMP family, MMP-9. Collectively, our studies provide mounting evidence that altered expression of CD9 may be a novel approach to regulate tumor cell progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067766PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696041PMC
April 2014

Elevating local concentrations of GPIIb-IIIa antagonists counteracts platelet thrombus stability.

J Thromb Thrombolysis 2013 Jul;36(1):31-41

Department of Internal Medicine, Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, 956 Court Avenue Coleman H300, Memphis, TN 38163, USA.

Glycoprotein IIb-IIIa (GPIIb-IIIa) antagonists have the capacity to destabilize coronary thrombi and restore vessel patency. Antagonist concentration and residence time, which can be increased by local intracoronary (LIC) administration, and thrombus age may be key factors that influence thrombus stability. Light transmission aggregometry was used to examine the effects of exposing human platelet aggregates to extremely high local levels of GPIIb-IIIa antagonists versus conventional therapeutic levels in vitro. Freshly-formed or aged platelet aggregates were subjected to GPIIb-IIIa antagonists (abciximab, eptifibatide) or direct thrombin inhibitor bivalirudin at concentrations simulating either conventional intravenous (IV) or LIC administration. The degree of antagonist-induced disaggregation was significantly higher using elevated (LIC) doses versus conventional (IV) doses (60.1 % vs. 7.4 % for abciximab, 41.6 % or 45.3 % vs. 17.6 % for eptifibatide, p < 0.01). Bivalirudin did not promote disaggregation. Microscopy confirmed noticeably smaller, more dispersed aggregates for antagonist LIC treatments. Dosing at LIC levels also induced more disaggregation than IV levels when aggregates were aged for 30 min prior to exposure. An in vitro perfusion model was used to simulate the fluid dynamics of IV or LIC administration of abciximab using a microporous local drug delivery balloon catheter such as the Atrium ClearWay™ RX. The perfusion model resulted in more rapid thrombus clearance with LIC dosing levels compared to IV. In summary, boosting the concentration of GPIIb-IIIa antagonists enhances dispersal of human platelet aggregates in vitro. These data provide a foundation for investigating increased local concentrations of GPIIb-IIIa antagonists in patients, as with LIC administration.
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http://dx.doi.org/10.1007/s11239-012-0814-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682094PMC
July 2013

Initiation of rivaroxaban following low molecular weight heparin for thromboprophylaxis after total joint replacement: the Safe, Simple Transitions (SST) study.

Thromb Res 2012 Nov 2;130(5):709-15. Epub 2012 Aug 2.

Janssen Research and Development, LLC, Raritan, NJ 08869-1420, USA.

Introduction: No data are available regarding appropriate strategies for the transition of patients undergoing total hip or knee replacement (THR/TKR) surgery from subcutaneous low molecular weight heparin (LMWH) to rivaroxaban. This study determined the pharmacodynamic effects of rivaroxaban on the first day of administration compared with serial administration in patients who had transitioned to rivaroxaban 22-28 hours after the last once-daily LMWH dose (or 12-18 hours after the last twice-daily LMWH dose).

Methods: Patients undergoing THR or TKR surgery who had received at least one post-operative LMWH dose were included in this open-label, single-arm, multicentre study. Measurements of anti-Factor Xa activity and prothrombin time were made on the first and third days of daily rivaroxaban administration. The effects of age and renal function on these parameters, and safety and tolerability, were assessed.

Results: Fifty-six patients were enrolled in the Safe, Simple Transitions (SST) study; 52 patients comprised the intention-to-treat population. Mean anti-Factor Xa activity increased slightly but significantly from day 1 to day 3, whereas the area under the concentration-time curve (AUC) was similar on days 1 and 3. Mean prothrombin time was slightly prolonged on day 1 compared with day 3; the AUC was significantly increased (p<0.0001). The pharmacodynamic effects of rivaroxaban were slightly increased in older patients and those with reduced renal function. There were no cases of venous thromboembolism or bleeding and no unexpected adverse events.

Conclusion: Initiating rivaroxaban approximately 12 or 24 hours after the last LMWH dose (as appropriate) provides a simple, well-tolerated transition strategy for thromboprophylaxis in patients undergoing THR/TKR surgery.
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http://dx.doi.org/10.1016/j.thromres.2012.07.014DOI Listing
November 2012

Pharmacokinetic and pharmacodynamic effects of elinogrel: results of the platelet function substudy from the intravenous and oral administration of elinogrel to evaluate tolerability and efficacy in nonurgent percutaneous coronary intervention patients (INNOVATE-PCI) trial.

Circ Cardiovasc Interv 2012 Jun 22;5(3):347-56. Epub 2012 May 22.

University of Florida-Shands Jacksonville, Jacksonville, FL 32209, USA.

Background: Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations.

Methods And Results: This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens.

Conclusions: Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.111.965608DOI Listing
June 2012

Hematoma-inspired alginate/platelet releasate/CaPO4 composite: initiation of the inflammatory-mediated response associated with fracture repair in vitro and ex vivo injection delivery.

J Mater Sci Mater Med 2012 Aug 16;23(8):1971-81. Epub 2012 May 16.

Biomedical Engineering Department, Herff College of Engineering, The University of Memphis, Memphis, TN 38152, USA.

A clinical need continues for consistent bone remodeling within problematic sites such as those of fracture nonunion, avascular necrosis, or irregular bone formations. In attempt to address such needs, a biomaterial system is proposed to induce early inflammatory responses after implantation and to provide later osteoconductive scaffolding for bone regeneration. Biomaterial-induced inflammation would parallel the early stage of hematoma-induced fracture repair and allow scaffold-promoted remodeling of osseous tissue to a healthy state. Initiation of the wound healing cascade by two human concentrated platelet releasate-containing alginate/β-tricalcium phosphate biocomposites has been studied in vitro using the TIB-71™ RAW264.7 mouse monocyte cell line. Inflammatory responses inherent to the base material were found and could be modulated through incorporation of platelet releasate. Differences in hydrogel wt% (2 vs. 8 %) and/or calcium phosphate granule vol.% (20 vs. 10 %) allowed for tuning the response associated with platelet releasate-associated growth factor elution. Tunability from completely suppressing the inflammatory response to augmenting the response was observed through varied elution profiles of both releasate-derived bioagents and impurities inherent to alginate. A 2.5-fold upregulation of inducible-nitric oxide synthase gene expression followed by a tenfold increase in nitrite media levels was induced by inclusion of releasate within the 8 wt%/10 vol.% formulation and was comparable to an endotoxin positive control. Whereas, near complete elimination of inflammation was seen when releasate was included within the 2 wt%/20 vol.% formulation. These in vitro results suggested tunable interactions between the multiple platelet releasate-derived bioagents and the biocomposites for enhancing hematoma-like fracture repair. Additionally, minimally invasive delivery for in situ curing of the implant system via injection was demonstrated in rat tail vertebrae using microcomputed tomography.
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http://dx.doi.org/10.1007/s10856-012-4672-9DOI Listing
August 2012

Induction of the early inflammatory-mediated cellular responses of fracture healing in vitro using platelet releasate-containing alginate/CaPO4 biomaterials for early osteoarthritis prevention.

J Biomed Mater Res A 2012 May 15;100(5):1107-14. Epub 2012 Feb 15.

Biomedical Engineering Department, Herff College of Engineering, The University of Memphis, Memphis, Tennessee 38152-3210, USA.

A significant gap exists in our understanding of subchondral and cancellous bone changes that may regulate osteoarthritis progression. Herein, we complement our prior osteochondrogenesis work with growth factor elution and monocyte and endothelial cell activation using two biomaterial formulations. The design of these biomaterials was inspired by the roles of a fracture hematoma, more specifically, the potential of significant cross-talk among cells and cellular factors that affect bone remodeling. Biomaterials, referred to herein as F1+ and F2+, are human concentrated platelet releasate-containing alginate/beta-tricalcium phosphate composites. F1+ has a higher calcium phosphate volume percentage and lower alginate polymer weight percent hydrogel versus F2+. The majority of releasate-derived platelet-derived growth factor eluted over 24 h for F1+ and 48 h for F2+, suggesting sustained release with an increase in alginate weight percentage. Simple monocyte and endothelial cell migration studies demonstrated 650% and 900% increases with F1+ eluate over medium alone, respectively. Induction of endothelial cell invasion over supplemented medium positive control was also shown for F2+ eluate (p = 0.03) with F1+ eluate being similar to the control. Monocyte transendothelial migration was increased over 300% and 400% for F1+ and F2+ eluates compared with medium alone, respectively. In addition, F1+ and F2+ eluates induced spontaneous endothelial tube formations similar to supplemented medium, demonstrating a well-formed network of capillary-like structures. This work demonstrated our biomaterial formulations ability to induce characteristics in vitro that parallel the in vivo behavior of fracture hematomas and potential to induce bone remodeling for the early treatment of osteoarthritic joints.
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http://dx.doi.org/10.1002/jbm.a.34038DOI Listing
May 2012
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