Nigel S Key

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

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Publications (179)889.32 Total impact

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    ABSTRACT: High-quality prospective trials of hemostatic "rescue" therapy to control massive bleeding in cardiac surgery are lacking. Wide variability in the care of patients with severe bleeding following cardiopulmonary bypass has precluded accurate comparison of treatment groups in previous studies. This study identified the use of a management protocol for early identification and uniform treatment of patients with massive bleeding for application in future trials of hemostatic rescue agents. A prospective, nonblinded, interventional feasibility study. A university teaching hospital. Forty-three adult patients undergoing complex cardiac surgery. Study participants undergoing high-risk cardiac surgery received standardized treatment in accordance with a bleeding management protocol. Twenty-seven patients (63%) had severe bleeding following heparin reversal and received conventional hemostatic resuscitation per protocol. Six patients had massive refractory bleeding. Compliance with protocol tasks was≥90% in 4 of 5 categories (anticoagulation, hemostasis scoring, recording blood loss, protocol transfusion) with the exception being submission of laboratory samples (76%). Measured bleeding rates (mL/h) following heparin reversal were clearly differentiated in those with hemostasis scores≥3 compared to those with scores≤2 (1,420±957 v 147±96; p<0.001). Adherence to a management protocol for massive bleeding is feasible and allows for homogenous treatment of patients before study arm randomization in future "rescue" therapy trials. The authors' protocol allowed for prompt and accurate identification of patients with severe bleeding refractory to conventional therapy. This review resolved several key barriers in the design of severe bleeding management trials. Copyright © 2014 Elsevier Inc. All rights reserved.
    Journal of Cardiothoracic and Vascular Anesthesia 12/2014; · 1.48 Impact Factor
  • Haemophilia 12/2014; · 2.47 Impact Factor
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    ABSTRACT: Coagulation factor V (FV) deficiency is a rare autosomal recessive bleeding disorder. We investigated a patient with severe FV deficiency (FV:C < 3%) and moderate bleeding symptoms. Thrombin generation experiments showed residual FV expression in the patient's plasma, which was quantified as 0.7 ± 0.3% by a sensitive prothrombinase-based assay. F5 gene sequencing identified a novel missense mutation in exon 4 (c.578G>C, p.Cys193Ser), predicting the abolition of a conserved disulphide bridge, and an apparently synonymous variant in exon 8 (c.1281C>G). The observation that half of the patient's F5 mRNA lacked the last 18 nucleotides of exon 8 prompted us to re-evaluate the c.1281C>G variant for its possible effects on splicing. Bioinformatics sequence analysis predicted that this transversion would activate a cryptic donor splice site and abolish an exonic splicing enhancer. Characterization in a F5 minigene model confirmed that the c.1281C>G variant was responsible for the patient's splicing defect, which could be partially corrected by a mutation-specific morpholino antisense oligonucleotide. The aberrantly spliced F5 mRNA, whose stability was similar to that of the normal mRNA, encoded a putative FV mutant lacking amino acids 427-432. Expression in COS-1 cells indicated that the mutant protein is poorly secreted and not functional. In conclusion, the c.1281C>G mutation, which was predicted to be translationally silent and hence neutral, causes FV deficiency by impairing pre-mRNA splicing. This finding underscores the importance of cDNA analysis for the correct assessment of exonic mutations. © 2014 John Wiley & Sons Ltd.
    Haemophilia 12/2014; · 2.47 Impact Factor
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    ABSTRACT: Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established.
    Journal of Thrombosis and Haemostasis 11/2014; · 6.08 Impact Factor
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    ABSTRACT: The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain.
    JAMA. 11/2014;
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    ABSTRACT: Numerous case reports describe stroke in individuals with sickle cell trait (SCT) in the absence of traditional risk factors for cerebrovascular disease. To date, no prospective epidemiological studies have investigated this association.
    Stroke 08/2014; 45(10). · 6.02 Impact Factor
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    ABSTRACT: Canine immune thrombocytopenia (ITP) is analogous to human ITP, with similar platelet counts and heterogeneity in bleeding phenotype among affected individuals. With a goal of ultimately investigating this bleeding heterogeneity, a canine model of antibody-mediated ITP was developed. Infusion of healthy dogs with 2F9, a murine IgG2a monoclonal antibody to the canine platelet glycoprotein GPIIb (a common target of autoantibodies in ITP) resulted in profound, dose-dependent thrombocytopenia. Model dogs developed variable bleeding phenotypes, e.g. petechiae and haematuria, despite similar degrees of thrombocytopenia. 2F9 infusion was not associated with systemic inflammation, consumptive coagulopathy, or impairment of platelet function. Unexpectedly however, evaluation of cytokine profiles led to the identification of platelets as a potential source of serum interleukin-8 (IL8) in dogs. This finding was confirmed in humans with ITP, suggesting that platelet IL8 may be a previously unrecognized modulator of platelet-neutrophil crosstalk. The utility of this model will allow future study of bleeding phenotypic heterogeneity including the role of neutrophils and endothelial cells in ITP.
    British Journal of Haematology 07/2014; · 4.94 Impact Factor
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    ABSTRACT: For the documentation and comparison of outcomes of clinical care in hemophilia, especially with different treatment protocols, as well as in clinical trials of new clotting factor concentrates, it is necessary to have clear definitions of disease related variables as well as the response to therapeutic interventions that are offered to treat or prevent bleeding. In 2001, White et al provided definitions for the severity of hemophilia and the levels for low and high response inhibitors on behalf of the Factor VIII and IX Subcommittee of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) [1].This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 07/2014; · 6.08 Impact Factor
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    ABSTRACT: The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.
    Thrombosis and Haemostasis 06/2014; 112(3). · 5.76 Impact Factor
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    ABSTRACT: The prothrombotic nature of sickle cell disease (SCD) is evidenced by the chronically elevated levels of almost all coagulation activation biomarkers, and an increased incidence of certain thrombotic events, including venous thromboembolism. Numerous studies have attempted to define the extent and elucidate the mechanism of the observed increase in thrombin generation in SCD patients in vivo. In general, these studies were performed using thrombin generation assays in platelet poor or platelet rich plasma and showed little difference in endogenous thrombin potential between the SCD cohort and healthy matched controls. In SCD, erythrocytes and monocytes have been demonstrated to exhibit procoagulant characteristics. Thus, the absence of these cellular components in standard thrombin generation assays may fail to reflect global hypercoagulability in the whole blood of patients with SCD. We were therefore surprised to see no difference in net thrombin generation in tissue factor-initiated initiated clotting of whole blood from patients with SCD. However, we are continuing to reconcile these seemingly disparate observations by slight modifications of the whole blood model that include alternative coagulation triggers and a re-examination of the net thrombin generation when the protein/protein S system is simultaneously interrogated.
    Thrombosis Research 05/2014; 133 Suppl 1:S52-3. · 2.43 Impact Factor
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    ABSTRACT: Haemophilia therapy is experiencing an unprecedented expansion in the number and novelty of clotting factor concentrates. Every product must be licensed by regulatory authorities, primarily on the basis of its safety and efficacy profiles. The low prevalence of haemophilia, and other inherited bleeding disorders, presents a significant challenge to patient recruitment for preauthorization clinical trials, especially given the low frequency of inhibitory antibodies, the major adverse event related to clotting factor exposure. Other challenges include a lack of harmonization between the major regulatory authorities in certain key areas, the selection of laboratory monitoring methodologies and the difficulty in obtaining high-quality phase IV safety data following authorization. These aspects will be reviewed in this session, which will also highlight the roles played by the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis in the promotion of these discussions.
    Haemophilia 05/2014; 20(s4). · 2.47 Impact Factor
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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; · 3.75 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; · 9.47 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; · 9.78 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. · 2.47 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; · 2.43 Impact Factor

Publication Stats

4k Citations
889.32 Total Impact Points


  • 2007–2014
    • University of North Carolina at Chapel Hill
      • • Department of Medicine
      • • Department of Pathology and Laboratory 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
      • Servicio de Hemoterapia y Hemostasia
      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