Nigel S Key

University of North Carolina at Chapel Hill, North Carolina, United States

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Publications (162)805.63 Total impact

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    ABSTRACT: Background The role of immunosuppression in the management of patients with congenital hemophilia and inhibitors is uncertain. The use of rituximab has been limited to case reports and case series. In most reports, rituximab was used as second- or third-line treatment following failure of conventional immune tolerance induction (ITI) therapy, and more commonly in pediatric patients.Objectives The objective of this study is to describe our experience with rituximab for the eradication of factor VIII (FVIII) inhibitors in adult non-severe hemophilia A patients.PatientsWe retrospectively reviewed the medical records of adult non-severe hemophilia A patients with a diagnosis of FVIII inhibitor treated with rituximab (375 mg/m2 weekly x 4) as first-line treatment at our Hemophilia Center.ResultsWe identified 9 consecutive adult hemophilia A patients (moderate, n=5; mild, n=4) at our institution between 2000 and 2013, with a median age of 54 years (range: 24-77 years) at the time of inhibitor diagnosis. No patient received concomitant immune tolerance induction therapy. All 9 patients had successful eradication of FVIII inhibitors. The median time from first dose of rituximab to achieving a clinical response was 95 days (range: 12–278). Median follow-up was 56 months (range: 13-139). Following inhibitor eradication, 8 patients were re-challenged with FVIII concentrates. Two patients developed inhibitor recurrence associated with surgery.Conclusion This case series demonstrates that rituximab is a useful first-line treatment with sustained inhibitor eradication in adult non-severe hemophilia A patients.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2014; · 6.08 Impact Factor
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    ABSTRACT: Heparin, a commonly used anticoagulant drug, is a mixture of highly sulfated polysaccharides with various molecular weights. The unique sulfation pattern dictates the anticoagulant activity of heparin. Commercial heparins are categorized into three forms according to their average molecular weight (MW): unfractionated heparin (UFH, MWavg 14,000), low molecular weight heparin (LMWH, MWavg 3,500-6,500) and the synthetic pentasaccharide (fondaparinux, MW 1508.3). UFH is isolated from porcine intestine while LMWH is derived from UFH by various methods of depolymerization, which generate a wide range of oligosaccharide chain lengths. Different degradation methods result in structurally distinct LMWH products, displaying different pharmacological and pharmacokinetic properties. In this report, we utilized a chemoenzymatic method to synthesize LMWH with the emphasis on controlling the size distribution of the oligosaccharides. A tetrasaccharide primer and a controlled enzyme-based polymerization were employed to build a narrow size oligosaccharide backbone. The oligosaccharide backbones were further modified by a series of sulfation and epimerization steps in order to obtain a full anticoagulation activity. Determination of the anticoagulation activity in vitro and ex vivo indicated that the synthetic LMWH has higher potency than enoxaparin, a commercial LMWH drug in clinical usage.
    Glycobiology 03/2014; · 3.54 Impact Factor
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    ABSTRACT: Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs.
    Nature Chemical Biology 02/2014; · 12.95 Impact Factor
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    ABSTRACT: African Americans require higher doses of erythropoiesis-stimulating agents (ESAs) during dialysis to manage anemia, but the influence of sickle cell trait and other hemoglobinopathy traits on anemia in dialysis patients has not been adequately evaluated. We performed a cross-sectional study of a large cohort of adult African-American hemodialysis patients in the United States to determine the prevalence of hemoglobinopathy traits and quantify their influence on ESA dosing. Laboratory and clinical data were obtained over 6 months in 2011. Among 5319 African-American patients, 542 (10.2%) patients had sickle cell trait, and 129 (2.4%) patients had hemoglobin C trait; no other hemoglobinopathy traits were present. Sickle cell trait was more common in this cohort than the general African-American population (10.2% versus 6.5%-8.7%, respectively, P<0.05). Among 5002 patients (10.3% sickle cell trait and 2.4% hemoglobin C trait) receiving ESAs, demographic and clinical variables were similar across groups, with achieved hemoglobin levels being nearly identical. Patients with hemoglobinopathy traits received higher median doses of ESA than patients with normal hemoglobin (4737.4 versus 4364.1 units/treatment, respectively, P=0.02). In multivariable analyses, hemoglobinopathy traits associated with 13.2% more ESA per treatment (P=0.001). Within subgroups, sickle cell trait patients received 13.2% (P=0.003) higher dose and hemoglobin C trait patients exhibited a similar difference (12.9%, P=0.12). Sensitivity analyses using weight-based dosing definitions and separate logistic regression models showed comparable associations. Our findings suggest that the presence of sickle cell trait and hemoglobin C trait may explain, at least in part, prior observations of greater ESA doses administered to African-American dialysis patients relative to Caucasian patients.
    Journal of the American Society of Nephrology 01/2014; · 8.99 Impact Factor
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    ABSTRACT: Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or PAR-2 on non-hematopoietic cells. FXa inhibition and PAR-2 deficiency on non-hematopoietic cells attenuated systemic inflammation, measured by plasma levels of IL-6. In contrast, neither thrombin inhibition nor PAR-1 deficiency on non-hematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by non-hematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of sVCAM-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa and thrombin differentially contribute to the vascular inflammation in a mouse model of SCD.
    Blood 01/2014; · 9.06 Impact Factor
  • M Y Lim, B Nielsen, A Ma, N S Key
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    ABSTRACT: Given the rarity of haemophilic pseudotumours, consensus on management is lacking. We describe the clinical features and management of haemophilic pseudotumours by retrospectively reviewing the medical records of haemophilia patients with a diagnosis of pseudotumour seen at our Hemophilia Center from 1981 to 2011. We recorded the following data: type and severity of haemophilia, documented aetiological antecedent, localization of the pseudotumour, presenting symptoms, management and outcome. We identified 12 pseudotumours in 11 patients over a 30-year period. Six patients had known inhibitors or a history of inhibitor. An aetiological antecedent leading to the development of pseudotumour was reported in nine cases. Localization of the pseudotumour was confined to soft tissue (n = 3) and bone (n = 8). Six of the 12 pseudotumours (50%) were not diagnosed at the time of initial presentation, with a delay ranging from 6 weeks to 6 years. In eight cases, surgical intervention (surgical drainage, n = 2; excision, n = 4; limb amputation, n = 2) was the initial treatment choice, with complete resolution in six cases. Conservative management with close monitoring occurred in three cases, with one case subsequently requiring surgical resection. We conclude that haemophilic pseudotumours still occur sporadically, and the diagnosis is frequently delayed. Surgical intervention is generally a safe and effective treatment, although conservative management may be appropriate in selected cases.
    Haemophilia 01/2014; 20(1):e58-62. · 3.17 Impact Factor
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    ABSTRACT: Objective The aim of the study is to examine the relationship between sickle cell trait (Hb AS) and other sickle hemoglobinopathies and the risk of thromboembolism during pregnancy or the puerperium. Study Design Retrospective cohort study of African American women receiving prenatal care from 1991 to 2006. Sickle cell status was ascertained by routine hemoglobin electrophoresis. Venous thromboembolism (VTE) was defined as one or more episodes of deep venous and/or pulmonary thromboembolism during pregnancy or the puerperium according to discharge diagnoses based on International Classification of Diseases, Ninth Revision codes. Results Among 22,140 women with hemoglobin (Hb) AA status, 20 women (0.09%) experienced pregnancy-related VTE compared with 3 women (0.15%) of 2,037 women with Hb AS; relative risk (RR) for the association with AS status = 1.6; 95% confidence interval (CI) 0.5 to 5.5. Of 103 women, 3 women (2.9%) with sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-thalassemia) experienced thromboembolism. Compared with women with Hb AA status, the RR = 32.2, 95% CI 9.7 to 107. Conclusion Sickle cell trait may be associated with a modest increase in VTE in the setting of pregnancy; sickle cell disease conditions are strongly associated with this rare but potentially fatal outcome.
    American Journal of Perinatology 12/2013; · 1.57 Impact Factor
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    ABSTRACT: Antiphospholipid syndrome (APS) is defined by the association of autoantibodies to certain phospholipid-binding proteins with arterial or venous thrombosis ('AT' or 'VT', respectively), and/or pregnancy-related morbidity (PM). Antiphospholipid antibodies (aPLA) promote activation of several cell types including monocytes, resulting in procoagulant tissue factor (TF) expression that may contribute to the vascular complications. Since TF synthesis by monocytes is frequently accompanied by release of TF-bearing microparticles, we hypothesized that plasma microparticle TF activity (MP-TF) may be elevated in APS patients and contribute to thrombosis and/or PM. Platelet-poor plasma specimens were obtained from 30 patients with definite APS and 72 patients with asymptomatic aPLA from the Antiphospholipid Syndrome Collaborative Registry (APSCORE). MP-TF was measured by an in-house factor Xa generation assay. The two groups were well matched for gender, age, ethnicity, proportions with underlying SLE, and aPLA profiles. MP-TF (median and (IQR)) in asymptomatic aPLA subjects was 0.09pg/mL (0.05-0.14) compared to 0.13pg/mL (0.10-0.17) in APS (p<0.001). No differences in MP-TF levels were observed between APS subjects with PM, thrombosis, or PM+thrombosis. Similarly, among subjects with either APS or asymptomatic aPLA, MP-TF did not differ in the presence or absence of underlying SLE. Prospective studies will be required to determine if plasma MP-TF activity is causally related to thrombotic or gestational complications in APS.
    Thrombosis Research 12/2013; · 3.13 Impact Factor
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    ABSTRACT: Homozygous sickle-cell disease (HbSS; SCD) is associated with vaso-occlusive manifestations of varying severity [1]. Pain crises are generally believed to result from obstruction of the microvasculature secondary to adhesion of red blood cells (RBCs) and other cellular elements, and decreased deformability of hypoxia-induced sickled RBCs, with ensuing activation of coagulation and inflammatory pathways [2, 3]. One of the proposed contributors to thrombosis in SCD is the loss of normal phospholipid asymmetry on sickled RBCs due to the repeated process of hypoxia-induced sickling and unsickling [4]. The exposure of anionic phosphatidylserine (PS) on the outer membrane supports the assembly of enzymatic clotting reactions, leading to a sub-population of RBCs with a prothrombotic phenotype [5, 6]. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 10/2013; · 6.08 Impact Factor
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    ABSTRACT: The contribution of platelet activation to the pathogenesis of sickle cell disease (SCD) remains uncertain. We evaluated the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the αIIbβ3 receptor, in SCD patients during acute painful episodes. In this single site, double-blind, placebo-controlled trial, eligible patients with SCD admitted for acute painful episodes were randomized to receive eptifibatide or placebo at a ratio of 2:1. Thirteen patients (SS - 10, Sβ(0) - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25years) or placebo (N=4; 3 females; median age - 31years). In the intent-to-treat analysis, there were no major bleeding episodes in either the eptifibatide or placebo arms (point estimate of difference: 0.00, 95% CI; -0.604, 0.372). There was one minor bleeding episode in the eptifibatide arm (point estimate of difference for any bleeding: 0.11, 95% CI: -0.502, 0.494). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference: 0.11, 95% CI: -0.587, 0.495). There were no differences in the median times to discharge, median times to crisis resolution or the median total opioid use. In this small study, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD. Clinicaltrials.gov Identifier: NCT00834899.
    Thrombosis Research 08/2013; · 3.13 Impact Factor
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    ABSTRACT: Tissue factor (TF), the physiologic initiator of coagulation, is over-expressed in pancreatic cancer, and is associated with a pro-coagulant and pro-angiogenic state. We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival. Clinical data and plasma were obtained for consecutive patients with PBC seen at Roswell Park Cancer Institute from 2005-08. MP-TF activity levels were measured using a TF-dependent FXa generation assay. The study population comprised 117 patients, including pancreatic (n=80), biliary (n=34) or unknown primary histologically consistent with PBC (n=3). Of these, 52 patients (44.5%) experienced thromboembolism, including pulmonary embolism (n=15), deep venous thrombosis (n=21) and other arterial or venous events (n=32). Mean TF was 2.15 (range 0.17- 31.01) pg/mL. Median survival was 98.5days for MP-TF activity ≥2.5pg/mL versus 231days for MP-TF activity<2.5pg/mL (p<0.0001). In multivariate analysis, elevated MP-TF activity was associated with both VTE (OR 1.4, 95% CI 1.1-1.6) and mortality (HR 2.5, 95% CI 1.4-4.5). Elevated circulating MP-TF activity is associated with thrombosis and worsened survival in patients with PBC. MP-TF activity as a prognostic biomarker warrants further prospective evaluation.
    Thrombosis Research 07/2013; · 3.13 Impact Factor
  • Ming Y Lim, Kenneth I Ataga, Nigel S Key
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    ABSTRACT: Although it has long been recognized that sickle cell disease (SCD) and other hemoglobinopathies are associated with a state of chronic hyperactivation of coagulation, the study of the epidemiology of venous thromboembolic (VTE) complications in SCD is only now beginning to evolve. In parallel, mechanistic studies of the hypercoagulable state in humans and mouse models implicate an increasingly important causative role of hemolysis. The case for SCD as a thrombophilic state has been strengthened by the recent literature. In an attempt to better understand the underlying mechanism(s), global assays of coagulation (thromboelastography and thrombin generation assays) have been utilized by several groups, but thus far, the results have been inconsistent, probably because of the technical differences. However, global assays continue to support the case for an important role of peripheral blood cells and their derived microparticles in promoting coagulation activation. VTE is an underappreciated and potentially morbid complication of SCD. The mechanisms underlying this hypercoagulable state are complex. A greater understanding of these pathways may lead to the rational selection of therapies that not only prevent thrombosis, but also impact on many of the other vaso-occlusive complications of SCD.
    Current opinion in hematology 06/2013; · 5.19 Impact Factor
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    ABSTRACT: The pathophysiology and time course of coagulopathy after major burns are inadequately understood. Our study objectives were to determine whether acute traumatic coagulopathy (ATC) is seen in burn patients at admission and to determine the changes in international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelet count (PLT), and hemoglobin (Hgb) in the first 7 days after injury. We conducted a retrospective study of patients with burn injury of at least 15% total body surface area who presented to the University of North Carolina. Data on patient demographics, injury characteristics, and laboratory data (INR, aPTT, PLT, and Hgb) at admission and within the first 7 days after injury were recorded. We defined ATC as INR of 1.3 or greater, aPTT of 1.5 or greater times the mean normal limit, and normal PLT at admission. We studied the hematologic profile of 102 patients with burn injury of 15% to 100% total body surface area but did not identify a single patient with ATC at admission. The screening hematologic profile at admission was not influenced by burn severity. In the first 7 days after injury, the INR and aPTT were relatively preserved, while the PLT quickly recovered to baseline after an early decline and the Hgb remained stable at around 10 g/dL; all these changes occurred during the time when the burn patients had received large amounts of fluid resuscitation. The screening hematologic profile of burn patients at admission is normal, and the standard screening assays do not suggest the existence of ATC at admission. While this is a relatively small study, it provides evidence to suggest that ATC is unique to trauma patients. Prognostic study, level III.
    The journal of trauma and acute care surgery. 06/2013; 74(6):1474-9.
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    ABSTRACT: PURPOSETo provide recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. Prophylaxis in the outpatient, inpatient, and perioperative settings was considered, as were treatment and use of anticoagulation as a cancer-directed therapy. METHODSA systematic review of the literature published from December 2007 to December 2012 was completed in MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed evidence to determine which recommendations required revision.ResultsForty-two publications met eligibility criteria, including 16 systematic reviews and 24 randomized controlled trials.RecommendationsMost hospitalized patients with cancer require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for outpatients with cancer. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term (6 months) secondary prophylaxis. Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE. Anticoagulation should not be used for cancer treatment in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should provide patient education about the signs and symptoms of VTE.
    Journal of Clinical Oncology 05/2013; · 18.04 Impact Factor
  • PLoS ONE 05/2013; 8(5):61120-. · 3.73 Impact Factor
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    ABSTRACT: Microparticles (MP) are sub-micron sized vesicles released by activated or apoptotic cells. They are generally defined as 0.1 to 1 μm membrane particles that expose the anionic phospholipid phosphatidylserine (PS) and membrane antigens representative of their cellular origin [1]. It is now well recognized that MP behave as vectors of bioactive molecules, playing a role in blood coagulation, inflammation, cell activation and cancer metastasis. In clinical practice, circulating MP originating from blood and vascular cells are elevated in a variety of prothrombotic and inflammatory disorders, cardiovascular diseases, autoimmune conditions, infectious diseases and cancer [1-3]. © 2013 International Society on Thrombosis and Haemostasis.
    Journal of Thrombosis and Haemostasis 04/2013; · 6.08 Impact Factor
  • Journal of Thrombosis and Haemostasis 04/2013; 11:1190-93. · 6.08 Impact Factor
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    ABSTRACT: Activation of coagulation pathways may contribute to risk for non-AIDS related conditions among HIV positive patients. We measured tissue factor-dependent procoagulant activity on circulating microparticles (MP-TF) in the plasma of 163 HIV positive participants, both untreated and treated, with viral suppression. MP-TF activity was 39% lower among treated versus untreated participants (p<0.001), which persisted in adjusted models (-36%; p=0.03). Among treated participants, MP-TF activity correlated modestly with D-dimer (r=0.24; p=0.01), vWF (r=0.36; p<0.001), and IL-6 (r=0.20; p=0.04) levels. Future research should focus on mechanisms driving residual functional TF activity and whether these alterations have clinical consequences for non-AIDS defining complications.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 03/2013; · 4.65 Impact Factor
  • Nigel S Key
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    ABSTRACT: There has been a resurgent interest in the molecular and cellular mechanisms of thrombogenesis in venous thromboembolism (VTE). Improved animal models of VTE, combined with high-resolution microscopy techniques, have helped to uncover novel roles for blood cells including platelets and innate immune cells, particularly neutrophils. These insights are likely to result in novel disease biomarkers and perhaps even adjunctive anti-thrombotic therapies.
    Journal of Thrombosis and Thrombolysis 02/2013; · 1.99 Impact Factor

Publication Stats

3k Citations
805.63 Total Impact Points

Institutions

  • 2007–2014
    • University of North Carolina at Chapel Hill
      • • Department of Pathology and Laboratory Medicine
      • • Department of Medicine
      North Carolina, United States
    • The Scripps Research Institute
      La Jolla, California, United States
  • 2013
    • Children's Hospital Los Angeles
      Los Angeles, California, United States
    • University of Vermont
      Burlington, Vermont, United States
  • 2012
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 2011
    • Cincinnati Children's Hospital Medical Center
      Cincinnati, Ohio, United States
  • 2010
    • Centers for Disease Control and Prevention
      • Division of Blood Disorders
      Druid Hills, GA, United States
  • 2009
    • Emory University
      Atlanta, Georgia, United States
  • 1990–2009
    • University of Minnesota Twin Cities
      • • Division of Hematology, Oncology and Transplantation
      • • Department of Medicine
      • • Department of Laboratory Medicine and Pathology
      Minneapolis, MN, United States
  • 1992–2007
    • University of Minnesota Duluth
      • • Medical School
      • • Department of Chemistry and Biochemistry
      Duluth, Minnesota, United States
  • 2006
    • Malmö University
      Malmö, Skåne, Sweden
  • 2005
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2004
    • University of Miami Miller School of Medicine
      • Division of Hospital Medicine
      Miami, FL, United States
  • 2003
    • Ankara University
      • Department of Cardiology
      Ankara, Ankara, Turkey
  • 2001
    • Sina Hospital
      Mashad, Razavi Khorasan, Iran