Marie Hollenhorst, MD, PhD

All Publications

• Active surveillance of serious adverse events following transfusion of COVID-19 convalescent plasma. Transfusion Swenson, E., Wong, L. K., Jhaveri, P., Weng, Y., Kappagoda, S., Pandey, S., Pritchard, A., Rogers, A., Ruoss, S., Subramanian, A., Shan, H., Hollenhorst, M. 2021

  Abstract

  The reported incidence of adverse reactions following Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) transfusion has generally been lower than expected based on the incidence of transfusion reactions that have been observed in studies of conventional plasma transfusion. This raises the concern for under-reporting of adverse events in studies of CCP that rely on passive surveillance strategies.Our institution implemented a protocol to actively identify possible adverse reactions to CCP transfusion. In addition, we retrospectively reviewed the charts of inpatients who received CCP at Stanford Hospital between May 13, 2020 and January 31, 2021. We determined the incidence of adverse events following CCP transfusion.A total of 49 patients received CCP. Seven patients (14%) had an increased supplemental oxygen requirement within 4 h of transfusion completion, including one patient who was intubated during the transfusion. An additional 11 patients (total of 18, 37%) had increased oxygen requirements within 24 h of transfusion, including 3 patients who were intubated. Six patients (12%) fulfilled criteria for transfusion-associated circulatory overload (TACO).Using an active surveillance strategy, we commonly observed adverse events following the transfusion of CCP to hospitalized patients. It was not possible to definitively determine whether or not these adverse events are related to CCP transfusion. TACO was likely over-diagnosed given overlap with the manifestations of COVID-19. Nevertheless, these results suggest that the potential adverse effects of CCP transfusion may be underestimated by reports from passive surveillance studies.

  View details for DOI 10.1111/trf.16711

  View details for PubMedID 34677830

• Dr Judith Graham Pool and the development of cryoprecipitate. Transfusion Swenson, E. n., Hollenhorst, M. A. 2021

  View details for DOI 10.1111/trf.16412

  View details for PubMedID 33894065

• Bridging the Divide: Student Grand Rounds at the Interface of Basic Science and Clinical Medicine. Academic medicine : journal of the Association of American Medical Colleges Hollenhorst, M. A., Braun, D. A., Burtner, C. R., Cajigas, I., Cunningham-Bussel, A. C., Eser, P. O., Nabel, C. S., Tsai, F. D., Weeks, L. D., Michel, T., Yialamas, M. A. 2019

  Abstract

  PROBLEM: As biomedical research and clinical medicine become increasingly complex, physician-scientists and clinically oriented biomedical researchers play important roles in bridging the gap between disciplines. A lack of educational programming that addresses the unique needs of students preparing for careers at the interface of basic science and clinical medicine may contribute to trainee attrition.APPROACH: The MD-PhD/LHB Grand Rounds was introduced in 2008 as a trainee-driven collaborative effort of the Harvard/Massachusetts Institute of Technology MD-PhD program at Harvard Medical School (HMS MD-PhD program), Harvard's Leder Human Biology and Translational Medicine (LHB) program, and the Brigham and Women's Hospital (BWH) Internal Medicine Department. Each of the program's approximately 4 sessions per year begins with dinner, followed by a clinical case presentation led by a BWH MD-PhD resident with a master clinician faculty discussant, then a research presentation by an LHB PhD student or a MD-PhD student on a basic science topic related to the clinical case, and time for socialization.OUTCOMES: In a July 2017 survey of participating students and residents, respondents reported being highly satisfied with the program. Mean satisfaction ratings were 4.3 (SD 0.5) for 12 MD-PhD students, 4.2 (SD 0.7) for 31 LHB students, and 4.4 (SD 0.9) for 5 residents on a 5-point scale (5 = very satisfied). Free-text responses suggested MD-PhD students valued opportunities for active engagement with the resident presenter and faculty discussant. LHB students appreciated the absence of medical jargon in the clinical presentations. Residents' reported reasons for participating included enjoyment of teaching and interaction with students.NEXT STEPS: The Harvard MD-PhD/LHB Grand Rounds can serve as a template for developing similar programs at other institutions. Research is needed to determine whether such grand rounds programs can help fix the leaky pipeline in the training of future physician-scientists and clinically oriented biomedical researchers.

  View details for DOI 10.1097/ACM.0000000000003116

  View details for PubMedID 31833852

• Clinical decision support and improved blood use in patient blood management. Hematology. American Society of Hematology. Education Program Goodnough, L. T., Hollenhorst, M. A. 2019; 2019 (1): 577–82

  Abstract

  Despite many years of published medical society guidelines for red blood cell (RBC) transfusion therapy, along with clinical trials that provide Level 1 evidence that restrictive transfusion practices can be used safely and are equivalent to transfusions given more liberally, annualized blood transfusion activity did not begin to decline in the United States until 2010. Adoption of electronic medical records has subsequently allowed implementation of clinical decision support (CDS): best practice alerts that can be initiated to improve the use of blood components. We describe our own institutional experience using a targeted CDS to promote restrictive blood transfusion practice and to improve RBC use. A 42% reduction in RBC transfusions was demonstrated at our institution from a baseline in 2008 through 2015, and the rate remained stable through 2018. Although the data cannot be used to infer causality, this decreased RBC use was accompanied by improved clinical outcomes.

  View details for DOI 10.1182/hematology.2019000062

  View details for PubMedID 31808902

• Markers of autoimmunity in immune thrombocytopenia: prevalence and prognostic significance. Blood advances Hollenhorst, M. A., Al-Samkari, H. n., Kuter, D. J. 2019; 3 (22): 3515–21

  Abstract

  Prior studies have demonstrated an increased prevalence of autoimmune markers in patients with immune thrombocytopenia (ITP). Clinical experience has suggested that there may be an association between autoimmune markers and poor outcomes in ITP, but current guidelines do not encourage routine testing in these patients. We retrospectively assessed the prevalence of autoimmune markers in adult patients with ITP from our institutional database and used multiple logistic regression analyses to test for an association between autoimmune marker positivity and thrombotic events or clinical remission. We also assessed whether positivity for common autoimmune markers was associated with positivity for platelet autoantibodies. There was a high rate of autoimmune marker positivity in this population, with antinuclear antibody (65%), antithyroid peroxidase antibody (31%), and direct antiglobulin (29%) the most commonly found. Antithyroid peroxidase antibody positivity was associated with a lower probability of remission (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.09-0.79; P = .017). Lupus anticoagulant positivity was associated with a higher rate of thrombosis (OR, 8.92; 95% CI, 1.94-40.95; P = .005), and antinuclear antibody was strongly associated with thrombosis (P = .001). There was no relation between platelet autoantibody positivity and the presence of autoimmune markers. These results suggest that many patients with ITP have a state of immune dysregulation that extends beyond platelet autoantibodies and that certain autoimmune markers may be prognostically useful in this disorder.

  View details for DOI 10.1182/bloodadvances.2019000400

  View details for PubMedID 31730698

• Thrombosis, Hypercoagulable States, and Anticoagulants PRIMARY CARE Hollenhorst, M. A., Battinelli, E. M. 2016; 43 (4): 619-+

  Abstract

  Patients with derangements of secondary hemostasis resulting from inherited or acquired thrombophilias are at increased risk of venous thromboemboli (VTE). Evaluation of a patient with suspected VTE proceeds via evidence-based algorithms that involve computing a pretest probability based on the history and physical examination; this guides subsequent work-up, which can include D dimer and/or imaging. Testing for hypercoagulable disorders should be pursued only in patients with VTE with an increased risk for an underlying thrombophilia. Direct oral anticoagulants are first-line VTE therapies, but they should be avoided in patients who are pregnant, have active cancer, antiphospholipid antibody syndrome, severe renal insufficiency, or prosthetic heart valves.

  View details for DOI 10.1016/j.pop.2016.07.001

  View details for Web of Science ID 000389510000009

  View details for PubMedID 27866581

• A Head-to-Head Comparison of Eneamide and Epoxyamide Inhibitors of Glucosamine-6-Phosphate Synthase from the Dapdiamide Biosynthetic Pathway BIOCHEMISTRY Hollenhorst, M. A., Ntai, I., Badet, B., Kelleher, N. L., Walsh, C. T. 2011; 50 (19): 3859–61

  Abstract

  The dapdiamides make up a family of antibiotics that have been presumed to be cleaved in the target cell to enzyme-inhibitory N-acyl-2,3-diaminopropionate (DAP) warheads containing two alternative electrophilic moieties. Our prior biosynthetic studies revealed that an eneamide warhead is made first and converted to an epoxyamide via a three-enzyme branch pathway. Here we provide a rationale for this logic. We report that the R,R-epoxyamide warhead is a more efficient covalent inactivator of glucosamine-6-phosphate synthase by 1 order of magnitude versus the eneamide, and this difference correlates with a >10-fold difference in antibiotic activity for the corresponding acyl-DAP dipeptides.

  View details for PubMedID 21520904

• The Nonribosomal Peptide Synthetase Enzyme DdaD Tethers N beta-Fumaramoyi-L-2,3-diaminopropionate for Fe(II)/alpha-Ketoglutarate-Dependent Epoxidation by DdaC during Dapdiamide Antibiotic Biosynthesis JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hollenhorst, M. A., Bumpus, S. B., Matthews, M. L., Bollinger, J., Kelleher, N. L., Walsh, C. T. 2010; 132 (44): 15773–81

  Abstract

  The gene cluster from Pantoea agglomerans responsible for biosynthesis of the dapdiamide antibiotics encodes an adenylation-thiolation didomain protein, DdaD, and an Fe(II)/α-ketoglutarate-dependent dioxygenase homologue, DdaC. Here we show that DdaD, a nonribosomal peptide synthetase module, activates and sequesters N(β)-fumaramoyl-l-2,3-diaminopropionate as a covalently tethered thioester for subsequent oxidative modification of the fumaramoyl group. DdaC catalyzes Fe(II)- and α-ketoglutarate-dependent epoxidation of the covalently bound N(β)-fumaramoyl-l-2,3-diaminopropionyl-S-DdaD species to generate N(β)-epoxysuccinamoyl-DAP (DAP = 2,3-diaminopropionate) in thioester linkage to DdaD. After hydrolytic release, N(β)-epoxysuccinamoyl-DAP can be ligated to l-valine by the ATP-dependent ligase DdaF to form the natural antibiotic N(β)-epoxysuccinamoyl-DAP-Val.

  View details for PubMedID 20945916

• The ATP-Dependent Amide Ligases DdaG and DdaF Assemble the Fumaramoyl-Dipeptide Scaffold of the Dapdiamide Antibiotics BIOCHEMISTRY Hollenhorst, M. A., Clardy, J., Walsh, C. T. 2009; 48 (43): 10467–72

  Abstract

  The enzymes DdaG and DdaF, encoded in the Pantoea agglomerans dapdiamide antibiotic biosynthetic gene cluster, when expressed in Escherichia coli, form the tandem amide bonds of the dapdiamide scaffold at the expense of ATP cleavage. DdaG uses fumarate, 2,3-diaminopropionate (DAP), and ATP to make fumaroyl-AMP transiently on the way to the N(beta)-fumaroyl-DAP regioisomer. Then DdaF acts as a second ATP-dependent amide ligase, but this enzyme cleaves ATP to ADP and P(i) during amide bond formation. However, DdaF will not accept N(beta)-fumaroyl-DAP; the enzyme requires the fumaroyl moiety to be first converted to the fumaramoyl half-amide in N(beta)-fumaramoyl-DAP. DdaF adds Val, Ile, or Leu to the carboxylate of fumaramoyl-DAP to make dapdiamide A, B, or C, respectively. Thus, to build the dapdiamide antibiotic scaffold, amidation must occur on the fumaroyl-DAP scaffold, after DdaG action but before DdaF catalysis. This is an unusual instance of two ligases acting sequentially in untemplated amide bond formations using attack of substrate carboxylates at P(alpha) (AMP-forming) and then at P(gamma) (ADP-forming) of ATP cosubstrates.

  View details for PubMedID 19807062

• Localized expression of an anti-TNF single-chain antibody prevents development of collagen-induced arthritis GENE THERAPY Smith, R., Tarner, I. H., Hollenhorst, M., Lin, C., Levicnik, A. U., Fathman, C. G., Nolan, G. P. 2003; 10 (15): 1248-1257

  Abstract

  Although systemic administration of neutralizing anti-TNF antibodies has been used successfully in treating rheumatoid arthritis, there is a potential for side effects. We transduced a collagen reactive T-cell hybridoma with tissue-specific homing properties to assess therapeutic effects of local delivery to inflamed joints of anti-TNF single-chain antibodies (scFv) by adoptive cellular gene therapy. Cell culture medium conditioned with 1 x 10(6) scFv producer cells/ml had TNF neutralizing capacity in vitro equivalent to 50 ng/ml anti-TNF monoclonal antibody. Adding a kappa chain constant domain to the basic scFv (construct TN3-Ckappa) gave increased in vitro stability and in vivo therapeutic effect. TN3-Ckappa blocked development of collagen-induced arthritis in DBA/1LacJ mice for >60 days. Transgene expression was detected in the paws but not the spleen of treated animals for up to 55 days postinjection. No significant variations in cell proliferation or cytokine secretion were found in splenocytes or peripheral lymphocytes. IL-6 expression was blocked in the diseased paws of mice in the scFv treatment groups compared to controls. In conclusion, we have shown that local expression of an anti-inflammatory agent blocks disease development without causing demonstrable systemic immune function changes. This is encouraging for the potential development of safe adoptive cellular therapies to treat autoimmunity.

  View details for DOI 10.1038/sj.gt.3301980

  View details for Web of Science ID 000184207000007

  View details for PubMedID 12858190

• GRAIL: An E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4(+) T cells IMMUNITY Anandasabapathy, N., Ford, G. S., Bloom, D., Holness, C., Paragas, V., Seroogy, C., Skrenta, H., Hollenhorst, M., Fathman, C. G., Soares, L. 2003; 18 (4): 535-547

  Abstract

  T cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 costimulation. Induced expression of GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4(+) T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype.

  View details for Web of Science ID 000182353900009

  View details for PubMedID 12705856