Last Updated: 3/28/2010

Clinical Interests
My clinical interest is in thrombosis and hemostasis. I direct the T32 Training grant in hematology at UNC, which includes MD and PhD training slots in benitgn and malignant hematology.

Research Interests
My laboratory has been focused on understanding the role of circulating tissue factor - the 'trigger' for coagulation - in the pathogenesis of disorders of hemostasis and thrombosis. Better assays and clinical studies are needed in this area to ultimately determine whether the tissue factor pathway may be exploited in the treatment of bleeding disorders or as a target for anti-thrombotic agents. We currently are NIH-funded to explore the role of tissue factor-bearing microparticles in cancer-associated thrombosis.

Recent Accomplishments and Honors
1976 Harkness Bursary, University of St. Andrew's
1991 Watson Award, University of Minnesota Medical School
1999 Individual NRSA, NIH
1995-2000 NIH FIRST Award
1998 Teacher Of The Year Award, Dept of Medicine, University of Minnesota Medical School
1999 Elected Fellow, Royal College of Physicians (London)
2000 Outstanding Care Provider Award, Hemophilia Foundation of MN and Dakota
2002-2006 Best Doctors in America
2003 12th Annual Clinical Scholar Award, University of Minnesota Physicians
2003 Researcher of the Year Award, National Hemophilia Foundation
2004 Editorial Advisory Board, Journal of Thrombosis and Haemostasis
2005 Associate Editor, Thrombosis Research
2005 American Clinical and Climatological Association
2005 Harold R. Roberts Distinguished Professor, UNC
2005 Best Doctors, Minneapolis-St Paul Magazine

Training
University of Manchester 1978-1981
Manchester, England
M.B. Ch.B. 1981
University of St. Andrews 1975-1978
St. Andrews, Scotland
B. Sc. (Med. Sci.) 1978

Publications
1. \Key NS, Vercellotti GM, Winkelmann JC, Moldow CF, Goodman JL, Esmon NL, Esmon CT, Jacob HS: Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. Proc. Natl. Acad. Sci. (USA) 87:7095-7099, 1990
2. Key NS, Platt JL, Vercellotti GM: Vascular endothelial cell proteoglycans are susceptible to cleavage by neutrophils. Arteriosclerosis & Thromb 12:836-842, 1992
3. Watson KV, Key NS: Vascular complications of essential thrombocythemia: a link to cardiovascular risk factors. Br J Haem 83:198-203, 1993
4. Slungaard A, Vercellotti GM, Tran T, Gleich GJ, Key NS. Eosinophil cationic granule proteins impair thrombomodulin function: a potential mechanism for thromboembolism in hypereosinophilic heart disease. J Clin Invest 91:1721-1730, 1993
5. Key NS, Bach RR, Vercellotti GM, Moldow CF: Herpes simplex virus type 1 does not require productive infection to induce tissue factor in human umbilical vein endothelial cells Lab Invest 68:645-651, 1993
6. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM: Induction of tissue factor expression on peripheral blood monocytes by C-reactive protein. Blood 82:513-520, 1993
7. Slungaard A, Key NS: Platelet factor four amplifies thrombomodulin-mediated activation of Protein C. Critical role of thrombomodulin glycosaminoglycan domain and -carboxyglutamic acid domain of protein C. J Biol Chem 269:25549-25556, 1994
8. Dudek AZ, Pennell CA, Decker TD, Young TA, Key NS, Slungaard A: Platelet factor 4 binds to glycanated forms of thrombomodulin and to protein C: a potential mechanism for enhancing generation of activated protein C. J Biol Chem 272(50):31785-92, 1997.
9. Key NS, Slungaard A, Dandelet L, Nelson SC, Moertel C, Styles LA, Kuypers FA, Bach RR. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 91:4216-4223, 1998
10. Solovey A, Gui L, Key N, Hebbel R: Tissue factor expression by endothelial cells in sickle cell anemia. J Clin Invest 101:1899-1904, 1998
11. Key NS, Aledort LM, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb & Haemost. 80:912-918, 1998
12. Behl R, Klein MB, Dandelet L, Bach RR, Goodman JL, Key NS: Induction of tissue factor procoagulant activity in myelomonocytic cells inoculated by agent of human granulocytic ehrlichiosis. Thromb & Haemost 83:114-8, 2000
13. Ozcan M, Morton CT, Solovey A, Dandelet L, Bach RR, Hebbel RP, Slungaard A, Key NS. Whole blood tissue factor procoagulant activity remains detectable during severe bone marrow aplasia following bone marrow transplantation. Thromb Haemost 2001; 85:250-5.
14. Reding MT, Wu H, Krampf M, Okita D, Diethelm-Okita BM, Key NS, Conti-Fine BM. CD4+ T cells specific for factor VIII as a target for specific suppression of inhibitor production. Adv Exp Med Biol; 2001489:119-34,
15. Key NS, Christie B, Henderson N, Nelsestuen GL. Possible synergy between recombinant factor VIIa and prothrombin complex concentrate in hemophilia therapy: Thromb Haemost 2002;88(1):60-65
16. Tutar E, Ozcan M, Kilicap M, Gulec S, Aras O, Pamir G, Oral D, Dandelet L, Key NS. Elevated whole blood tissue factor procoagulant activity as a marker of restenosis after percutaneous transluminal coronary angioplasty and stent implantation. Circulation 2003;108:1581-1584
17. Slungaard A, Fernandez JA, Griffin JH, Key NS, Long JR, Piegors DJ, Lentz SR. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo. Blood 2003;102:146-151
18. Xiong G, Aras O, Shet A, Key NS, Arriaga EA. Analysis of individual platelet-derived microparticles, comparing flow cytometry and capillary electrophoresis with laser-induced fluorescence detection. Analyst 2003;128:581-588
19. Shet AS, Aras O, Gupta K, Hass M, Rausch DJ, Saba N, Koopmeiners L, Key NS, Hebbel RP. Sickle blood contains tissue factor positive microparticles derived from endothelial cells and monocytes. Blood 2003;102:2678-2683
20. Aras O, Shet A, Bach RR, Hysjulien JL, Slungaard A, Hebbel RP, Escolar G, Jilma B, Key NS. Induction of microparticle and cell-associated intravascular tissue factor in human endotoxemia. Blood 2004;103:4545-4553
21. Key NS. Inhibitors in congenital coagulation disorders. British Journal of Haematology 2004;127:379-391
22. Xia Y-F, Ye B-Q, Li Y-D, Wang J-G, He X-J, Lin X, Ma D, Slungaard A, Hebbel RP, Key NS, Geng J-G. Andrographolide attenuates inflammation by inhibition of NF-B activation through covalent modification of reduced cys62 of p50. J Immunol 2004:173;4207-4217
23. Koreth R, Weinert C, Weisdorf D, Key NS. Measurement of bleeding severity: a critical review. Transfusion 2004;44(4):605-617
24. Ohlfest JR, Frandsen JR, Fritz S, Lobitz P, Perkinson S, Clark K, Key NS, McIvor RS, Hackett P, Largaespada DA. Phenotypic correction and long-term factor VIII expression in hemophilia A mice by immunotolerization and non-viral gene transfer using the sleeping beauty transposon. Blood 2005;105:2691-2698
25. Nelsestuen GL, Zhang Y, Martinez MB, Key NS, Jilma B, Verneris M, Sinaiko A, Kasthuri RS. Plasma protein profiling: unique and stable features of individuals. Proteomics 2005 Aug 30 [Epub ahead of print]
26. Key NS. More on: 'Intensity of warfarin anticoagulation in antiphospholipid syndrome.' (letter). J Thromb Haemost 2005:3(10);2368-2369
27. White JG, Key NS, King RA, Vercellotti GM. A "touch" of the White Platelet Syndrome. Platelets 2005:16(6);346-361.
28. Ohlfest JR, Frandsen JL, Fritz S, Lobitz PD, Perkinson SG, Clark KJ, Nelsestuen G, Key NS, McIvor RS, Hackett PB, Largaespada DA. Phenotypic correction and long-term factor VIII expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system. Blood 2005;105:2691-2698
29. Ashrani AA, Gabriel DA, Gajewski JL, Weisdorf DJ, Key NS. Pilot study to test the efficacy and safety of recombinant factor VIIa in the treatment of hemorrhagic cystitis following high dose chemotherapy. Bone Marrow Transplantation 2006;38:825-828
30. Reich LM, Folsom AR, Key NS, Boland LL, Heckbert SR, Rosamond WD, Cushman M. Prospective study of subclinical atherosclerosis and venous thromboembolism. J Thromb Haemost 2006:4;1909-1913
31. Wang JG, Mahmud SA, Thompson JA, Geng JG, Key NS, Slungaard A. The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states. Blood 2006:107(2);558-65
32. Marsik C, Halama T, Schlifke I, Mustafa S, Endler G, Hysjulien JL, Key NS, Jilma B. Tissue factor -1208 D/I polymorphism affects basal but not LPS-induced TF-mRNA levels or coagulation during experimental endotoxemia in humans. J Thromb Haemost 2006: 4;745-749
33.Ataga KI, Key NS. Hypercoagulability in sickle cell disease: new approaches to an old problem. Hematology Am Soc Hematol Educ Program 2007;91-96
34. Key NS, Negrier C. Coagulation Factor Concentrates: Past, Present, and Future. Lancet 2007;370(9585):439-448
35. Elimelakh M, Dayton V, Park KC, Griessner AC, Sutherland D, Bland B, Howe RB, van Burik J-A, Ashrani AA, Reding MT, Eastlund T, Singleton TP, Gruessner RW, Key NS. Red cell aplasia and autoimmune hemolytic anemia following immunosuppression with Alemtuzumab, Mycophenolate, and Daclizumab in pancreas transplant recipients. Haematologica 2007;92:1029-1036
36. Mackman N, Tilley RE, Key NS. Role of the tissue factor and factor VII in hemostasis and thrombosis. Arterioscl Thromb Vasc Biol 2007;27(8):1687-1693
37. Teitel J, Berntorp E, Collins P, d'Oiron R, Ewenstein B, Gomperts E, Goudemand J, Gringeri A, Key N, Leissinger C, Monahan P, Young G. A systematic approach to controlling problem bleeds in patients with severe haemophilia A and high-titre inhibitors. Haemophilia 2007; 13:256-263
38. Kasthuri RS, Wroblewski M, Jilma B, Key NS, Nelsestuen GL. Biomarkers of an exaggerated response to endotoxemia. Biomarkers 2007;12(3):287-302
39. Hu G, Guo D, Key NS, Conti-Fine BM. Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and hemophilia A patients. Thromb Haemost 2007;97:788-794
40. Kren BT, Yin W, Key NS, Hebbel RP, Steer CJ. Blood outgrowth endothelial cells as a vehicle for transgene delivery of hepatocyte secreted proteins via Sleeping Beauty. Endothelium 2007:14;97-104
41. Austin H, Key NS, Benson JM, Lally C, Dowling NF, Whitsett C, Hooper WC. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007;110:908-912
42. Monroe DM, Key NS. The tissue factor-factor VIIa complex: procoagulant activity, regulation, and multitasking. J Thromb Haemost 2007;5:1097-1105
43. Crow SS, Sullivan VV, Aysola AE, Key NS, Harker-Murray P, Foker JE, Steiner ME. Postoperative coagulopathy in a pediatric patient after exposure to bovine topical thrombin. Ann Thorac Surg 2007;83:1547-1549
44. Adrogue HE, Matas AJ, McGlennon RC, Key NS, Gruessner A, Gruessner RW, Humar A, Sutherland DER, Kandaswamy R. Do inherited hypercoagulable states play a role in thrombotic events affecting kidney/pancreas transplant recipients? Clin Transplant 2007;21:32-37
45. Perez-Pujol S, Marker P, Key NS. Platelet microparticles are heterogenous and highly dependent on the activation mechanism: studies using a new digital flow cytometer. Cytometry A 2007;71(1):38-45
46. Tolar J, Orchard PJ, Key NS, Blazar BR. Circulating anticoagulant glycosaminoglycans in Mucopolysaccharidosis type 1. J. Thromb. Haemost. 2008;6(5):893-895
47. Li YD, Ye BQ, Zheng SX, Wang JT, Wang JG, Chen M, Liu JG, Pei XH, Wang LJ, Lin ZX, Gupta K, Mackman N, Slungaard A, Key NS, Geng JG. NF-kB Transcription factor P50 critically regulates tissue factor expression in deep vein thrombosis. J Biol Chem 2009:284(7);4473-83
48. Adam SS, Key NS, Greenberg CS. Clinical utility of D-dimer antigen measurements in hematologic disorders. Blood 2009:113;2878-2887
49. Yi X, Kim K, Yuan W, Xu L, Kim H-S, Homeister JW, Key NS, Maeda N. Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury. J. Leuk. Biol. 2009;85(1):146-153
50. Key NS, Kasthuri RS. Current treatment of venous thromboembolism. Arterioscl Thromb Vasc Biol 2010:30;372-375
51. Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010:8;221-227
52. Manly DA, Wang J, Glover SL, Kasthuri R, Liebman HA, Key NS, Mackman N. Increased microparticle tissue factor activity in cancer patients with venous thromboembolism. Thromb Res 2009 Oct 23 [E Pub]
53. Key NS, Kasthuri RS. Current treatment of venous thromboembolism. Arterioscl Thromb Vasc Biol 2010:30;372-375
54. Derebail VK, Nachman PN, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High prevalence of sickle trait and other hemoglobinopathies in African-American patients with end stage renal disease. J Am Soc Nephrol 2010;21:413-417 [Editorial same issue]
55. Uaprasert N, Voorhees PM, Mackman, Key N.S. Venous Thromboembolism in multiple myeloma: current perspectives in pathogenesis. Eur J Cancer (In Press)
56. Key NS, Chantrathammacart P, Moody PW, Chang J-Y. Membrane microparticles in VTE and cancer. Thromb Res (In Press)
57. Amin C, Mackman N, Key NS. Microparticles and Cancer. Pathophysiology of Haemostasis and Thrombosis. 2008;36(3-4):177-83

E-mail: nkey@email.unc.edu
Telephone: 919-966-3311
FAX: 919-966-7639
Address: 932 Mary Ellen Jones Bldg. CB#7035 Chapel Hill, NC 27599

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