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Semin Thromb Hemost 2009; 35(1): 042-049
DOI: 10.1055/s-0029-1214147
© Thieme Medical Publishers

Pharmacogenetics in Hemostasis: Friend or Foe?

Kandelaria Rumilla1 , Dong Chen1 , Linnea M. Baudhuin1
  • 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Publication History

Publication Date:
23 March 2009 (online)

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ABSTRACT

Pharmacologic therapies are essential in the management of patients with hemostatic and thrombotic diseases because these therapies are able to modify components of the coagulation pathway and platelet response. Nevertheless, responses to different drugs vary significantly, and the best clinical outcome frequently involves a delicate risk/benefit balance. The recent exponential growth of pharmacogenomics has led to the emergence of individualized medicine that has revolutionized modern medical practice, allowing for a deeper understanding of pathophysiology, increased diagnostic specificity, and better markers for risk stratification and an enhanced potential for gene therapy. Management of drugs prescribed to treat thrombotic and hemostatic abnormalities may benefit from pharmacogenetics, and our focus in this review will be on the pharmacogenetics related to some of the more common drugs that fall into this category.

KEYWORDS

Pharmacogenetics - antiplatelet - anticoagulant - warfarin - clopidogrel - aspirin

REFERENCES

  • 1 CAPRIE Steering Committee . A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).  Lancet. 1996;  348 1329-1339
    CrossrefPubMedGoogle Scholar
  • 2 Diener H-C, Bogousslavsky J, Brass L M et al.. Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data.  Cerebrovasc Dis. 2004;  17 253-261
    CrossrefPubMedGoogle Scholar
  • 3 Fox K AA, Mehta S R, Peters R et al.. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.  Circulation. 2004;  110 1202-1208
    CrossrefPubMedGoogle Scholar
  • 4 Savi P, Herbert J-M. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis.  Semin Thromb Hemost. 2005;  31 174-183
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Angiolillo D J, Fernandez-Ortiz A, Bernardo E et al.. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.  J Am Coll Cardiol. 2007;  49 1505-1516
    CrossrefPubMedGoogle Scholar
  • 6 Gurbel P A, Bliden K P, Hiatt B L, O'Connor C M. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.  Circulation. 2003;  107 2908-2913
    CrossrefPubMedGoogle Scholar
  • 7 Michelson A D, Linden M D, Furman M I et al.. Evidence that pre-existent variability in platelet response to ADP accounts for 'clopidogrel resistance.'  J Thromb Haemost. 2007;  5 75-81
    CrossrefPubMedGoogle Scholar
  • 8 Lau W C, Gurbel P A, Watkins P B et al.. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance.  Circulation. 2004;  109 166-171
    CrossrefPubMedGoogle Scholar
  • 9 Lau W C, Waskell L A, Watkins P B et al.. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.  Circulation. 2003;  107 32-37
    CrossrefPubMedGoogle Scholar
  • 10 Umemura K, Furuta T, Kondo K. The common gene variants of CTP2C19 affect pharmacokinetics and pharmacodynmics in an active metabolite of clopidogrel in healthy subjects.  J Thromb Haemost. 2008;  6 1439-1441
    CrossrefPubMedGoogle Scholar
  • 11 Hulot J S, Bura A, Villard E et al.. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.  Blood. 2006;  108 2244-2247
    CrossrefPubMedGoogle Scholar
  • 12 Brandt J T, Close S L, Iturria S J et al.. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.  J Thromb Haemost. 2007;  5 2429-2436
    CrossrefPubMedGoogle Scholar
  • 13 Beitelshees A L, McLeod H L. Clopidogrel pharmacogenetics: promising steps towards patient care?.  Arterioscler Thromb Vasc Biol. 2006;  26 1681-1683
    CrossrefPubMedGoogle Scholar
  • 14 Conley P B, Delaney S M. Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis.  Curr Opin Hematol. 2003;  10 333-338
    CrossrefPubMedGoogle Scholar
  • 15 Hollopeter G, Jantzen H M, Vincent D et al.. Identification of the platelet ADP receptor targeted by antithrombotic drugs.  Nature. 2001;  409 202-207
    CrossrefPubMedGoogle Scholar
  • 16 von Beckerath N, von Beckerath O, Koch W et al.. P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose.  Blood Coagul Fibrinolysis. 2005;  16 199-204
    CrossrefPubMedGoogle Scholar
  • 17 Fontana P, Gaussem P, Aiach M et al.. P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study.  Circulation. 2003;  108 2971-2973
    CrossrefPubMedGoogle Scholar
  • 18 Bura A, Bachelot-Loza C, Ali F D, Aiach M, Gaussem P. Role of the P2Y12 gene polymorphism in platelet responsiveness to clopidogrel in healthy subjects.  J Thromb Haemost. 2006;  4 2096-2097
    CrossrefPubMedGoogle Scholar
  • 19 Fontana P, Dupont A, Gandrille S et al.. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects.  Circulation. 2003;  108 989-995
    CrossrefPubMedGoogle Scholar
  • 20 Lev E I, Patel R T, Guthikonda S et al.. Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel.  Thromb Res. 2007;  119 355-360
    CrossrefPubMedGoogle Scholar
  • 21 Angiolillo D J, Fernandez-Ortiz A, Bernardo E et al.. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease.  Thromb Res. 2005;  116 491-497
    CrossrefPubMedGoogle Scholar
  • 22 Angiolillo D J, Fernandez-Ortiz A, Bernardo E et al.. PlA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation.  Blood Coagul Fibrinolysis. 2004;  15 89-93
    CrossrefPubMedGoogle Scholar
  • 23 Cooke G E, Liu-Stratton Y, Ferketich A K et al.. Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination.  J Am Coll Cardiol. 2006;  47 541-546
    CrossrefPubMedGoogle Scholar
  • 24 Angiolillo D J, Fernandez-Ortiz A, Bernardo E et al.. 807 C/T Polymorphism of the glycoprotein Ia gene and pharmacogenetic modulation of platelet response to dual antiplatelet treatment.  Blood Coagul Fibrinolysis. 2004;  15 427-433
    CrossrefPubMedGoogle Scholar
  • 25 Awtry E H, Loscalzo J. Aspirin.  Circulation. 2000;  101 1206-1218
    CrossrefPubMedGoogle Scholar
  • 26 Lev E I, Patel R T, Maresh K J et al.. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance.  J Am Coll Cardiol. 2006;  47 27-33
    CrossrefPubMedGoogle Scholar
  • 27 Gum P A, Kottke-Marchant K, Welsh P A, White J, Topol E J. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.  , [Erratum in: J Am Coll Cardiol 2006;48:1918] J Am Coll Cardiol. 2003;  41 961-965
    CrossrefPubMedGoogle Scholar
  • 28 Gum P A, Kottke-Marchant K, Poggio E D et al.. Profile and prevalence of aspirin resistance in patients with cardiovascular disease.  Am J Cardiol. 2001;  88 230-235
    CrossrefPubMedGoogle Scholar
  • 29 Grotemeyer K H. Effects of acetylsalicylic acid in stroke patients. Evidence of nonresponders in a subpopulation of treated patients.  Thromb Res. 1991;  63 587-593
    CrossrefPubMedGoogle Scholar
  • 30 Buchanan M R, Brister S J. Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically.  Can J Cardiol. 1995;  11 221-227
    PubMedGoogle Scholar
  • 31 Wang T H, Bhatt D L, Topol E J. Aspirin and clopidogrel resistance: an emerging clinical entity.  Eur Heart J. 2006;  27 647-654
    CrossrefPubMedGoogle Scholar
  • 32 Eikelboom J W, Hirsh J, Weitz J I et al.. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.  Circulation. 2002;  105 1650-1655
    CrossrefPubMedGoogle Scholar
  • 33 Macchi L, Sorel N, Christiaens L. Aspirin resistance: definitions, mechanisms, prevalence, and clinical significance.  Curr Pharm Des. 2006;  12 251-258
    CrossrefPubMedGoogle Scholar
  • 34 Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive systematic review.  Br J Clin Pharmacol. 2008;  66 222-232
    CrossrefPubMedGoogle Scholar
  • 35 Gonzalez-Conejero R, Rivera J, Corral J et al.. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure?.  Stroke. 2005;  36 276-280
    CrossrefPubMedGoogle Scholar
  • 36 Catella-Lawson F, Reilly M P, Kapoor S C et al.. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.  N Engl J Med. 2001;  345 1809-1817
    CrossrefPubMedGoogle Scholar
  • 37 Maree A O, Curtin R J, Chubb A et al.. Cyclooxygenase-1 haplotype modulates platelet response to aspirin.  J Thromb Haemost. 2005;  3 2340-2345
    CrossrefPubMedGoogle Scholar
  • 38 Lepantalo A, Mikkelsson J, Resendiz J C et al.. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients.  Thromb Haemost. 2006;  95 253-259
    PubMedGoogle Scholar
  • 39 Hillarp A, Palmqvist B, Lethagen S, Villoutreix B O, Mattiasson I. Mutations within the cyclooxygenase-1 gene in aspirin non-responders with recurrence of stroke.  Thromb Res. 2003;  112 275-283
    CrossrefPubMedGoogle Scholar
  • 40 Papp E, Havasi V, Bene J et al.. Glycoprotein IIIA gene (PlA) polymorphism and aspirin resistance: is there any correlation?.  Ann Pharmacother. 2005;  39 1013-1018
    CrossrefPubMedGoogle Scholar
  • 41 Undas A, Brummel K, Musial J, Mann K G, Szczeklik A. Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury.  Circulation. 2001;  104 2666-2672
    CrossrefPubMedGoogle Scholar
  • 42 Szczeklik A, Undas A, Sanak M, Frolow M, Wegrzyn W. Relationship between bleeding time, aspirin and the PlA1/A2 polymorphism of platelet glycoprotein IIIa.  Br J Haematol. 2000;  110 965-967
    CrossrefPubMedGoogle Scholar
  • 43 Macchi L, Christiaens L, Brabant S et al.. Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T Kozak (GP Ibalpha) polymorphisms.  J Am Coll Cardiol. 2003;  42 1115-1119
    CrossrefPubMedGoogle Scholar
  • 44 Cooke G E, Bray P F, Hamlington J D, Pham D M, Goldschmidt-Clermont P J. PlA2 polymorphism and efficacy of aspirin.  Lancet. 1998;  351 1253
    CrossrefPubMedGoogle Scholar
  • 45 Cambria-Kiely J A, Gandhi P J. Aspirin resistance and genetic polymorphisms.  J Thromb Thrombolysis. 2002;  14 51-58
    CrossrefPubMedGoogle Scholar
  • 46 von Beckerath N, Koch W, Mehilli J et al.. Glycoprotein Ia gene C807T polymorphism and risk for major adverse cardiac events within the first 30 days after coronary artery stenting.  Blood. 2000;  95 3297-3301
    PubMedGoogle Scholar
  • 47 Budnitz D S, Shehab N, Kegler S R, Richards C L. Medication use leading to emergency department visits for adverse drug events in older adults.  Ann Intern Med. 2007;  147 755-765
    CrossrefPubMedGoogle Scholar
  • 48 Ray K K, Francis S, Crossman D C. A potential pharmacogenomic strategy for anticoagulant treatment in non-ST elevation acute coronary syndromes: the role of interleukin-1 receptor antagonist genotype.  J Thromb Haemost. 2005;  3 287-291
    CrossrefPubMedGoogle Scholar
  • 49 Wysowski D K, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action.  Arch Intern Med. 2007;  167 1414-1419
    CrossrefPubMedGoogle Scholar
  • 50 Gage B F, Eby C, Johnson J A et al.. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.  , [Erratum in: Clin Pharmacol Ther 2008;84:430] Clin Pharmacol Ther. 2008;  84 326-331
    CrossrefPubMedGoogle Scholar
  • 51 Flockhart D A, O'Kane D, Williams M S et al.. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin.  Genet Med. 2008;  10 139-150
    CrossrefPubMedGoogle Scholar
  • 52 Aithal G P, Day C P, Kesteven P J, Daly A K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.  Lancet. 1999;  353 717-719
    CrossrefPubMedGoogle Scholar
  • 53 Linder M W, Looney S, Adams III J E et al.. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.  J Thromb Thrombolysis. 2002;  14 227-232
    CrossrefPubMedGoogle Scholar
  • 54 Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis.  Genet Med. 2005;  7 97-104
    PubMedGoogle Scholar
  • 55 Voora D, Eby C, Linder M W et al.. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.  Thromb Haemost. 2005;  93 700-705
    PubMedGoogle Scholar
  • 56 Joffe H V, Xu R, Johnson F B et al.. Warfarin dosing and cytochrome P450 2C9 polymorphisms.  Thromb Haemost. 2004;  91 1123-1128
    PubMedGoogle Scholar
  • 57 Furuya H, Fernandez-Salguero P, Gregory W et al.. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy.  Pharmacogenetics. 1995;  5 389-392
    CrossrefPubMedGoogle Scholar
  • 58 Higashi M K, Veenstra D L, Kondo L M et al.. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.  JAMA. 2002;  287 1690-1698
    CrossrefPubMedGoogle Scholar
  • 59 Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study.  Clin Pharmacol Ther. 2008;  83 460-470
    CrossrefPubMedGoogle Scholar
  • 60 Rieder M J, Reiner A P, Gage B F et al.. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.  N Engl J Med. 2005;  352 2285-2293
    CrossrefPubMedGoogle Scholar
  • 61 Harrington D J, Gorska R, Wheeler R et al.. Pharmaocynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1.  J Thromb Haemost. 2008;  6 1663
    CrossrefPubMedGoogle Scholar
  • 62 Loebstein R, Dvoskin I, Halkin H et al.. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance.  Blood. 2007;  109 2477-2480
    CrossrefPubMedGoogle Scholar
  • 63 Osman A, Enstrom C, Arbring K, Soderkvist P, Lindahl T L. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records.  J Thromb Haemost. 2006;  4 1723-1729
    CrossrefPubMedGoogle Scholar
  • 64 Rost S, Fregin A, Ivaskevicius V et al.. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.  Nature. 2004;  427 537-541
    CrossrefPubMedGoogle Scholar
  • 65 Harrington D J, Underwood S, Morse C et al.. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1.  Thromb Haemost. 2005;  93 23-26
    PubMedGoogle Scholar
  • 66 Chen L Y, Eriksson N, Gwilliam R et al.. Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing.  Blood. 2005;  106 3673-3674
    CrossrefPubMedGoogle Scholar
  • 67 Shikata E, Ieiri I, Ishiguro S et al.. Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity.  Blood. 2004;  103 2630-2635
    CrossrefPubMedGoogle Scholar
  • 68 Caldwell M D, Awad T, Johnson J A et al.. CYP4F2 genetic variant alters required warfarin dose.  Blood. 2008;  111 4106-4112
    CrossrefPubMedGoogle Scholar
  • 69 Sconce E A, Daly A K, Khan T I, Wynne H A, Kamali F. APOE genotype makes a small contribution to warfarin dose requirements.  Pharmacogenet Genomics. 2006;  16 609-611
    CrossrefPubMedGoogle Scholar
  • 70 Wadelius M, Sorlin K, Wallerman O et al.. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors.  Pharmacogenomics J. 2004;  4 40-48
    CrossrefPubMedGoogle Scholar
  • 71 Vecsler M, Loebstein R, Almog S et al.. Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin.  Thromb Haemost. 2006;  95 205-211
    PubMedGoogle Scholar
  • 72 Krynetskiy E, McDonnell P. Building individualized medicine: prevention of adverse reactions to warfarin therapy.  J Pharmacol Exp Ther. 2007;  322 427-434
    CrossrefPubMedGoogle Scholar
  • 73 Lippi G, Franchini M, Montagnana M, Guidi G C. Genomics and proteomics in venous thromboembolism: building a bridge toward a rational personalized medicine framework.  Semin Thromb Hemost. 2007;  33 759-770
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Wadelius M, Chen L Y, Downes K et al.. Common VKORC1 and GGCX polymorphisms associated with warfarin dose.  Pharmacogenomics J. 2005;  5 262-270
    CrossrefPubMedGoogle Scholar
  • 75 Coumadin Medication Guide .New York, NY; Bristol-Myers Squibb Company 2007
  • 76 McClain M R, Palomaki G E, Piper M, Haddow J E. A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding.  Genet Med. 2008;  10 89-98
    CrossrefPubMedGoogle Scholar
  • 77 Anderson J L, Horne B D, Stevens S M et al.. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation.  Circulation. 2007;  116 2563-2570
    CrossrefPubMedGoogle Scholar
  • 78 Toriello M, Meccariello P, Mazzaccara C et al.. Comparison of the TaqMan and LightCycler systems in pharmacogenetic testing: evaluation of CYP2C9*2/*3 polymorphisms.  Clin Chem Lab Med. 2006;  44 285-287
    CrossrefPubMedGoogle Scholar
  • 79 King C R, Porche-Sorbet R M, Gage B F et al.. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose.  Am J Clin Pathol. 2008;  129 876-883
    CrossrefPubMedGoogle Scholar
  • 80 McWilliam A, Lutter R, Nardinelli C. Health Care Savings from Personalizing Medicine Using Genetic Testing: The Case of Warfarin. Washington, DC; AEI-Brookings Joint Center for Regulatory Studies Working Paper 06–23 2006
    Google Scholar
  • 81 You J H, Chan F W, Wong R S, Cheng G. The potential clinical and economic outcomes of pharmacogenetics-oriented management of warfarin therapy - a decision analysis.  Thromb Haemost. 2004;  92 590-597
    PubMedGoogle Scholar
  • 82 President's Council of Advisors on Science and Technology. Priorities for Personalized Medicine .Available at: http://www.ostp.gov/galleries/PCAST/pcast_report_v2.pdf Accessed September 2008
  • 83 Reynolds K K, Valdes Jr R, Hartung B R, Linder M W. Individualizing warfarin therapy.  Personalized Medicine. 2007;  4 11-31
    CrossrefPubMedGoogle Scholar
  • 84 Michelson A D, Furman M I, Goldschmidt-Clermont P et al.. Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists.  Circulation. 2000;  101 1013-1018
    PubMedGoogle Scholar
  • 85 Chen Y, Kuehl G E, Bigler J et al.. UGT1A6 polymorphism and salicylic acid glucuronidation following aspirin.  Pharmacogenet Genomics. 2007;  17 571-579
    CrossrefPubMedGoogle Scholar
  • 86 Angiolillo D J, Fernandez-Ortiz A, Bernardo E et al.. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel.  Arterioscler Thromb Vasc Biol. 2006;  26 1895-1900
    CrossrefPubMedGoogle Scholar

Linnea M BaudhuinPh.D. 

Assistant Professor of Laboratory Medicine and Pathology, Department of Laboratory Medicine and Pathology

Mayo Clinic, 200 First St. SW, Rochester, MN 55905

Email: baudhuin.linnea@mayo.edu