Mark T Reding

University of Minnesota Duluth, Duluth, Minnesota, United States

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Publications (27)102.11 Total impact

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    ABSTRACT: Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in a large cohort (n=1321, 2003-2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III-IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.Bone Marrow Transplantation advance online publication, 13 July 2015; doi:10.1038/bmt.2015.162.
    No preview · Article · Jul 2015 · Bone marrow transplantation
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    ABSTRACT: This study investigated the relationship between anti-factor Xa (anti-FXa) and activated partial thromboplastin time (aPTT) for monitoring intravenous unfractionated heparin (IV-UFH) in patients with continuous-flow left ventricular assist devices (CF-LVADs). CF-LVADs have become mainstream therapy for patients with advanced heart failure. Thromboembolic events, device thrombosis, and bleeding continue to be a challenge with this technology. Adequate anticoagulation is required to prevent these adverse events. A prospective study of consecutive patients implanted with a CF-LVAD was conducted. Paired samples were considered concordant if aPTT values fell into expected ranges for subtherapeutic, therapeutic, and supratherapeutic anti-FXa levels. Heparin dosing was on the basis of anti-Xa levels. A total of 340 paired values from 38 patients were evaluated. Anti-FXa and aPTT were discordant in 253 samples (74.4%), with a high degree of variability in aPTT for any given anti-FXa level (r(2) = 0.57). Results were discordant in 104 samples (63.8%) from patients undergoing bridging therapy with warfarin and in 149 samples (84.2%) from patients with device obstruction and/or hemolysis (p < 0.001). The most common pattern of discordance was a supratherapeutic aPTT value despite a therapeutic anti-FXa level (49.1% for bridging vs. 75.8% for device obstruction and/or hemolysis; p < 0.001). Levels of aPTT were disproportionately prolonged relative to the corresponding anti-FXa levels in CF-LVAD patients, particularly those with device obstruction. Hemolysis and warfarin administration may falsely elevate aPTT, resulting in overestimation of heparin concentration and under-anticoagulation. Use of aPTT and anti-FXa to guide heparin therapy may lead to different estimates of heparin concentration in the same patient. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · JACC: Heart Failure
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    T E Coyle · M T Reding · J C Lin · LA Michaels · A Shah · J Powell
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    ABSTRACT: Background BAY94-9027 is a B-domain-deleted recombinant factorVIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. Objectives To assess the pharmacokinetics and safety of BAY94-9027 after single and repeated administration in subjects with severe hemophiliaA. Patients/Methods This 8-week, prospective, multicenter, open-label, phaseI trial was conducted in 14 subjects aged 21-58years with FVIII of <1%, >= 150days of exposure to FVIII, and no history of FVIII inhibitors. After a >= 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort1 [n=7], 25IUkg(-1); cohort2 [n=7], 50IUkg(-1)) for a 48-h pharmacokinetic (PK) study. After another >= 3-day washout, cohort1 received twice-weekly BAY94-9027 at 25IUkg(-1) (16 doses), and cohort2 received once-weekly BAY94-9027 at 60IUkg(-1) (nine doses). A 168-h PK study was performed after the first and last BAY94-9027 doses. Results BAY94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~19h (vs. ~13.0h for rFVIII-FS). BAY94-9027 was well tolerated, and no immunogenicity was observed. Conclusions This phaseI study demonstrates that BAY94-9027 has an extended half-life in subjects with hemophiliaA and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phaseIII study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.
    Preview · Article · Apr 2014 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: The international normalized ratio (INR) can be unreliable in patients with lupus anticoagulants (LACs) or other conditions affecting baseline testing. Alternative methods to assess anticoagulation on warfarin through measures of vitamin K-dependent factor activity by clot based or chromogenic assays may be necessary. In this patient population, the ideal method is unknown. Thirty-six patients stable on warfarin with LAC or unreliable INR testing had an INR, a prothrombin time-based clotting assay for factor II (FII) activity, and a chromogenic assay for factor X (CFX) activity were performed simultaneously. Eighty-nine sets of measurements were obtained of which 83 sets included all three assays. CFX and FII levels were well correlated (r = 0.92) in all patients and in 26 patients with a documented antiphospholipid antibody (r = 0.93). Parallel testing was seen in 99% of FII assays. Sixty-one percent of CFX and 57% of FII were within the therapeutic range. In 32 CFX and FII pairs wherein assessment of anticoagulation was discordant, 16 CFX agreed with INR and 13 FII agreed with INR (McNemar's, χ = 0.14, P = 0.7). The number of times tests were discrepant was not statistically different between CFX and FII (P = 0.36). CFX and FII activity are well correlated in patients that require alternative monitoring of warfarin. Either test can be used in this population.
    No preview · Article · Apr 2014 · Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis
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    Full-text · Article · Jan 2014 · Journal of Thrombosis and Haemostasis
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    Preview · Article · Sep 2013 · International Journal of Women's Health
  • Lisa M. Baumann Kreuziger · Mark T Reding

    No preview · Article · Jul 2013 · Thrombosis Research
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    ABSTRACT: Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant haemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is not clear whether prophylaxis is necessary prior to delivery. The aim of this study was to define management, haemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using "factor VII deficiency" and "pregnancy" or "surgery." Overall 34 articles, four abstracts, and three institutional cases were reviewed. Literature from 1953 to 2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Haemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 caesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing caesarean section compared to vaginal delivery. Post-partum haemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum haemorrhage was seen in deliveries with and without prophylaxis. Therefore, we recommend that rfVIIa be available in the case of haemorrhage or surgical intervention, but not as mandatory prophylaxis.
    No preview · Article · Apr 2013 · Haemophilia
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    ABSTRACT: Background The benefits of routine prophylaxis vs. on-demand treatment with factorVIII products have not been evaluated in controlled clinical trials in older patients with hemophiliaA. Objectives To report results from a preplanned analysis of data from the first year of the 3-year SPINART study, which compares routine prophylaxis with on-demand treatment with sucrose-formulated recombinant FVIII (rFVIII-FS). Patients/MethodsSPINART is an open-label, randomized, controlled, parallel-group, multinational trial. Males aged 12-50years with severe hemophiliaA, 150 days of exposure to FVIII, no FVIII inhibitors, no prophylaxis for >12 consecutive months in the past 5years and 6-24 bleeding episodes in the preceding 6months were randomized 1:1 to rFVIII-FS prophylaxis (25IUkg(-1), three times weekly) or on-demand treatment. The primary efficacy endpoint, number of total bleeding episodes in the intent-to-treat population, was analyzed after the last patient had completed 1year of follow-up. A negative binomial model was used for the primary endpoint analysis; analysis of variance was used for confirmatory analysis of annualized bleeding rates. ResultsEighty-four patients were enrolled and analyzed (n=42 per group; mean age, 30.6years; median treatment duration, 1.7years). The median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-demand treatment (total, 0 vs. 54.5; total per year, 0 vs. 27.9; both P<0.0001). No treatment-related adverse events occurred, and no patients developed FVIII inhibitors. Conclusions Routine prophylaxis with rFVIII-FS leads to a significant reduction in bleeding as compared with on-demand treatment. Adverse events were consistent with the established rFVIII-FS safety profile.
    Full-text · Article · Mar 2013 · Journal of Thrombosis and Haemostasis
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    Mark T Reding · David L Cooper
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    ABSTRACT: Background: Bleeding symptoms commonly seen by multiple physician specialties may belie undiagnosed congenital or acquired bleeding disorders. Acquired hemophilia is a potentially life-threatening cause of unexplained acute bleeding manifested by an abnormal activated partial thromboplastin time (aPTT) that does not correct with 1:1 mixing with normal plasma. Methods: Practicing physicians (hematology/oncology, emergency medicine, geriatrics, internal medicine, rheumatology, obstetrics and gynecology, critical care medicine, and general surgery) completed an online survey based on a hypothetical case scenario. Results: Excluding surgeons and obstetrician/gynecologist respondents, 302 physicians (about 50 per specialty) were presented with an older adult woman complaining of recurrent epistaxis. Nearly 90% ordered a complete blood count and coagulation studies (aPTT, prothrombin time [PT]/international normalized ratio [INR]). Despite a prolonged aPTT of 42 seconds, <50% of nonhematologists would repeat the aPTT, and <45% would consult a hematologist; emergency medicine physicians were least likely (10%) and rheumatologists were most likely (43%) to consult. After presentation weeks later with bruising and abdominal/back pain, ≥90% of physicians within each specialty ordered a complete blood count or PT/INR/aPTT. Despite an aPTT of 63 seconds, the majority did not repeat the aPTT. At this point, approximately 75% of internal medicine and geriatric physicians indicated they would consult a hematologist, versus 47% in emergency medicine and 50% in critical care. All participants preferred abdominal computed tomography (80%–84%). After 12 hours of additional observation, 73% to 94% of respondents consulted a hematologist. Complete blood count revealed anemia and an aPTT twice the upper limit of normal; emergency medicine physicians remained least likely to request a consult. Conclusion: Determining the cause of an abnormal coagulation study result should carry equal weight as looking for the site of bleeding and could be facilitated by consultation with a hematologist. Insight from this survey highlights knowledge and practice gaps that could be the target of focused educational initiatives.
    Preview · Article · Oct 2012 · Journal of Multidisciplinary Healthcare
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    ABSTRACT: Thrombocytopenia has multiple etiologies, including hypoproliferation of bone marrow (BM) (e.g., aplastic anemia), reticuloendothelial sequestration (e.g., hepato- or splenomegaly), platelet destruction through interactions with altered von Willebrand factor (e.g., thrombotic thrombocytopenic purpura), or destruction of platelets by immune-mediated mechanisms. © 2012 John Wiley & Sons A/S.
    No preview · Article · Jul 2012 · European Journal Of Haematology
  • Julie E Adams · Mark T Reding
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    ABSTRACT: Hemophilia is a hereditary disease in which circulating levels of coagulation factors are lacking, resulting in a propensity toward bleeding. Intra-articular hemorrhages are a hallmark of hemophilia and may lead a cascade of cytokine elaboration and inflammatory-mediated changes, which ultimately result in cartilage loss and arthropathy. Diarthrodial joints, such as the knee, elbow, and ankle, are most commonly affected. This article highlights issues surrounding hemophilic arthropathy of the elbow and focuses on preventive measures, management strategies of the hemophilic elbow, and treatment options for established arthropathy.
    No preview · Article · May 2011 · Hand clinics
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    ABSTRACT: Liver sinusoidal endothelial cells are a major endogenous source of Factor VIII (FVIII), lack of which causes the human congenital bleeding disorder hemophilia A. Despite extensive efforts, gene therapy using viral vectors has shown little success in clinical hemophilia trials. Here we achieved cell type-specific gene targeting using hyaluronan- and asialoorosomucoid-coated nanocapsules, generated using dispersion atomization, to direct genes to liver sinusoidal endothelial cells and hepatocytes, respectively. To highlight the therapeutic potential of this approach, we encapsulated Sleeping Beauty transposon expressing the B domain-deleted canine FVIII in cis with Sleeping Beauty transposase in hyaluronan nanocapsules and injected them intravenously into hemophilia A mice. The treated mice exhibited activated partial thromboplastin times that were comparable to those of wild-type mice at 5 and 50 weeks and substantially shorter than those of untreated controls at the same time points. Further, plasma FVIII activity in the treated hemophilia A mice was nearly identical to that in wild-type mice through 50 weeks, while untreated hemophilia A mice exhibited no detectable FVIII activity. Thus, Sleeping Beauty transposon targeted to liver sinusoidal endothelial cells provided long-term expression of FVIII, without apparent antibody formation, and improved the phenotype of hemophilia A mice.
    Full-text · Article · Jul 2009 · The Journal of clinical investigation
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    J Astermark · S Lacroix-Desmazes · M T Reding
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    ABSTRACT: The immune response to factor VIII and the development of inhibitory antibodies is a complex multi-factorial process involving a variety of immune regulatory genes and cells, several of which have the potential to determine risk. A better understanding of the mechanisms involved will increase the likelihood of development of new therapeutic options for patients with hemophilia. This review summarizes genetic and non-genetic risk factors currently under evaluation, and the potential modulative effect of the von Willebrand factor on factor VIII immuno- and antigenicity. In addition, the role of T-regulatory cells in the pathogenicity of inhibitors will be discussed.
    Preview · Article · Jul 2008 · Haemophilia
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    ABSTRACT: Acquired red cell aplasia (RCA) is a rare disorder and can be either idiopathic or associated with certain diseases, pregnancy, or drugs. In exceptionally rare cases, it has been reported to co-exist with other autoimmune cytopenias. We report a high incidence of RCA and autoimmune hemolytic anemia (AIHA) in pancreas transplant recipients on alemtuzumab-based maintenance therapy. Between February 2003 and July 2005, 357 pancreas transplant recipients were treated with immunosuppressive regimens containing the lymphocyte-depleting antibody alemtuzumab, the T-cell activation inhibitor daclizumab, and the anti-metabolite mycophenolate mofetil (MMF). We retrospectively reviewed medical records, blood bank data and bone marrow biopsy specimens of patients with a Transplant Information Services database diagnosis of RCA and AIHA from February 2003 to November 2005. Severe RCA, AIHA, and idiopathic thrombocytopenic purpura (ITP) occurred independently or in combination, in 20 out of 357 (5.6%) pancreas transplant recipients, 12 to 24 months following the initiation of the aforementioned immunosuppressive regimens. Severe opportunistic infections developed late in 14/20 (70%) of these patients. Atypical morphologic features, including variable dysgranulopoiesis, variable megakaryocytic hyperplasia with normal or low peripheral platelet counts, and atypical lymphoid aggregates were found in bone marrow trephine sections of 11 patients in whom the diagnosis of RCA was made. We hypothesize that the combination of alemtuzumab, daclizumab and MMF can result in immune dysregulation thereby permitting autoantibody formation. Because the use of these three immune suppressants is becoming increasingly common, it is important to recognize the severe hematologic complications that can arise.
    Full-text · Article · Sep 2007 · Haematologica
  • M T Reding
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    ABSTRACT: The development of inhibitor antibodies is perhaps the most serious complication of coagulation factor replacement therapy. A complex interaction of several variables leads to inhibitor formation in congenital haemophilia, while acquired haemophilia represents a failure of the immune tolerance mechanisms that regulate a normal immune response to factor VIII (FVIII). The immune response to FVIII is dependent upon the interaction of different CD4+ T-cell subsets (Th1, Th2 and Th3) specific for FVIII. Failure to activate regulatory CD4+ cells likely plays a crucial role in the development of FVIII inhibitors. Although the basic mechanisms of the immune response to FVIII in the setting of factor replacement therapy are being elucidated, a clear understanding of the relevance of these mechanisms in the context of successful immune tolerance therapy and ultimately gene therapy, awaits further study.
    No preview · Article · Jan 2007 · Haemophilia
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    ABSTRACT: Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enroll cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.
    Full-text · Article · Jan 2007 · Haemophilia
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    ABSTRACT: Molecular Therapy (2006) 13, S415|[ndash]|S415; doi: 10.1016/j.ymthe.2006.08.1182 1081. Targeted Nanocapsules for Liver Cell-Type Delivery of Plasmids In Vivo Betsy T. Kren1, Gretchen M. Unger2, Mark T. Reding1 and Clifford J. Steer11Department of Medicine, University of Minnesota, Minneapolis, MN2GeneSegues, Inc., Chaska, MN
    Full-text · Article · Apr 2006 · Molecular Therapy
  • AA Ashrani · M T Reding · A Shet · J Osip · A Humar · J R Lake · N S Key
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    ABSTRACT: We present the case of a 61-year-old man with severe haemophilia A and a high-titre factor VIII inhibitor who underwent successful orthotopic liver transplantation (OLT) for hepatocellular carcinoma. Postoperatively, a modest early anamnestic response to FVIII was followed by immunological tolerance to FVIII. This case illustrates the technical feasibility of OLT in some patients with high-titre inhibitors to FVIII, and suggests that immune tolerance may be induced by endogenously produced FVIII from the transplanted organ.
    No preview · Article · Dec 2004 · Haemophilia
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    ABSTRACT: Severe hemophilia A patients treated with factor (F)VIII may develop antibodies (Ab) that block FVIII function (inhibitors). Autoimmune inhibitors may develop in subjects without congenital hemophilia, and cause acquired hemophilia. Hemophiliacs without inhibitors and healthy subjects may also have small amounts of antiFVIII Ab. FVIII-specific CD4(+) T cells induce antiFVIII Ab synthesis. Here, we have examined their epitope repertoire in hemophilia patients and healthy subjects. We used overlapping synthetic peptides, spanning the sequence of the FVIII A3 domain, to challenge blood CD4(+) T cells in proliferation assays. The epitopes recognized in hemophilia A patients with or without inhibitors, acquired hemophilia patients, or healthy subjects overlapped, yet had characteristic differences. Most members of one or more study groups recognized the sequence regions 1691-1710, 1801-1820, 1831-1850, and 1941-60. In the proposed three-dimensional structure of the A3 domain, these sequences are largely exposed to the solvent and flanked by flexible sequence loops: these are structural features characteristic of 'universal' CD4(+) T epitopes. Hemophilia A patients with inhibitors recognized prominently only the sequence 1801-1820, which overlaps a known inhibitor binding site. This is consistent with the possibility that CD4(+) T cells recognizing epitopes within residues 1801-1820 have a role in inducing inhibitor synthesis. In contrast, CD4(+) T cells sensitized to sequences 1691-1710 and 1941-60, which are recognized by healthy subjects and hemophilia A patients without inhibitors, might curb inhibitor synthesis.
    Preview · Article · Sep 2004 · Journal of Thrombosis and Haemostasis

Publication Stats

696 Citations
102.11 Total Impact Points

Institutions

  • 1999-2015
    • University of Minnesota Duluth
      • • Medical School
      • • Department of Chemistry and Biochemistry
      Duluth, Minnesota, United States
  • 2013
    • Saint Mary's University of Minnesota
      Minneapolis, Minnesota, United States
  • 2004-2007
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 2001
    • Emory University
      • School of Medicine
      Atlanta, Georgia, United States
  • 2000
    • Saint Catherine University
      Minneapolis, Minnesota, United States