Department of Pathology, Microbiology, and Immunology

 

 

   David Gailani, M.D.

 

 

Professor

Dept. of Pathology, Microbiology and Immunology 

Dept. of Medicine

 

  Contact Information

 

   Office Location:

538 PRB (6305)

Phone: (615) 936-1505

Fax: (615) 343-8420

Email:  dave.gailani@vanderbilt.edu

 

Campus Mail address:

Pathology, Microbiology and Immunology-3rd Fl

C-3321 MCN (2561)

 

US Mailing address: 

Dept of  Pathology, Microbiology and Immunology-3rd Fl

Vanderbilt University School of Medicine

C-3321 MCN

Nashville, TN 37232-2561

 

 

 

Education

 

 

M.D., U. Of Illinois, Chicago, IL
B.A., Cornell University, Ithaca, NY

 

 

Research Keywords

 

 

Biochemistry, Enzyme action, Gene regulation, Knockout, Mouse, Polymorphism, Protein structure

 

 

Research Description

 

 

A dynamic balance exists between the processes that form a blood clot at the site of blood vessel injury (coagulation) and the processes responsible for removing the clot once healing has occurred (fibrinolysis). This equilibrium, referred to as hemostasis, is required to prevent excessive blood loss from a wound (bleeding) while avoiding occlusion of normal blood vessels (thrombosis). My laboratory is involved in studying the contribution of certain plasma clotting factors to the formation of fibrin clots in normal and pathologic conditions. We are particularly interested in the plasma serine proteases factors IX and XI. These enzymes appear to be required for consolidating the hemostatic process after initial clot formation. Excessive activity of either protein has been linked to formation of pathologic blood vessel thrombosis. Utilizing a combination of site-directed mutagenesis, production of recombinant proteins in mammalian tissue culture, enzymology and classic coagulation assays we are investigation structure/function relationships as they relate to the activation, the activity, and binding interactions involving factors IX and XI. We are applying similar approaches to investigations of the proteases responsible for converting inactive factor XI to the active form factor XIa.

More recently, we have been investigating the contributions of factors IX and XI to hemostasis and thrombosis in vivo, using factor IX and factor XI deficient mice. These proteins appear to play important roles in the formation of abnormal occlusive thrombi in mouse models, and may be attractive targets for drugs to prevent or treat blood vessel thrombosis in human patients.

 

 

Publications

 

 

Wang, X, Cheng, Q, Xu, L, Feuerstein, GZ, Hsu, MY, Smith, PL, Seiffert, DA, Schumacher, WA, Ogletree, ML, Gailani, D. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J Thromb Haemost, 3(4), 695-702, 2005

Renn??, T, Pozgajov?!, M, Gr??ner, S, Schuh, K, Pauer, HU, Burfeind, P, Gailani, D, Nieswandt, B. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med, 2005

Ogawa, T, Verhamme, IM, Sun, MF, Bock, PE, Gailani, D. Exosite-mediated substrate recognition of factor IX by factor XIa. The factor XIa heavy chain is required for initial recognition of factor IX. J Biol Chem, 280(25), 23523-30, 2005

Kravtsov, DV, Monahan, PE, Gailani, D. A classification system for cross-reactive material-negative factor XI deficiency. Blood, 105(12), 4671-3, 2005

Cheng, Q, Zhao, Y, Lawson, WE, Polosukhin, VV, Johnson, JE, Blackwell, TS, Gailani, D. The effects of intrinsic pathway protease deficiencies on plasminogen deficient mice. Blood, 2005

Zivelin, A, Ogawa, T, Bulvik, S, Landau, M, Toomey, JR, Lane, J, Seligsohn, U, Gailani, D. Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation. J Thromb Haemost, 2(10), 1782-9, 2004

Schmidt, AE, Ogawa, T, Gailani, D, Bajaj, SP. Structural role of Gly(193) in serine proteases: investigations of a G555E (GLY193 in chymotrypsin) mutant of blood coagulation factor XI. J Biol Chem, 279(28), 29485-92, 2004

Baglia, FA, Gailani, D, Lopez, JA, Walsh, PN. Identification of a binding site for glycoprotein Ibalpha in the Apple 3 domain of factor XI. J Biol Chem, 279(44), 45470-6, 2004

Gailani, D, Zivelin, A, Sinha, D, Walsh, PN. Do platelets synthesize factor XI. J Thromb Haemost, 2(10), 1709-12, 2004

Kravtsov, Dmitri V, Wu, Wenman, Meijers, Joost C, Sun, Mao-Fu, Blinder, Morey A, Dang, Thao P, Wang, Hongli, Gailani, David. Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain. Blood, 2004

Donahue, Brian S, Byrne, Daniel W, Gailani, David, George, Alfred L. Tissue factor and platelet glycoprotein Ib-alpha alleles are associated with age at first coronary bypass operation. Anesthesiology, 99(6), 1287-94, 2003

Tarumi, T, Kravtsov, DV, Moore, JH, Williams, SM, Gailani, D. Common single nucleotide polymorphisms in the promoter region of the human factor XI gene. J Thromb Haemost, 1(8), 1854-6, 2003

Aktimur, Aysar, Gabriel, Melanie A, Gailani, David, Toomey, John R. The factor IX gamma-carboxyglutamic acid (Gla) domain is involved in interactions between factor IX and factor XIa. J Biol Chem, 278(10), 7981-7, 2003

Cheng, Q, Sun, M-F, Kravtsov, D V, Aktimur, A, Gailani, D. Factor XI apple domains and protein dimerization. J Thromb Haemost, 1(11), 2340-7, 2003

Donahue, Brian S, Gailani, David, Higgins, Michael S, Drinkwater, Davis C, George, Alfred L. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation, 107(7), 1003-8, 2003

Tarumi, Takashi, Kravtsov, Dmitri V, Zhao, Mingming, Williams, Scott M, Gailani, David. Cloning and characterization of the human factor XI gene promoter: transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha ) is required for hepatocyte-specific expression of factor XI. J Biol Chem, 277(21), 18510-6, 2002

Sinha, D, Marcinkiewicz, M, Gailani, D, Walsh, PN. Molecular cloning and biochemical characterization of rabbit factor XI. Biochem J, 367(Pt 1), 49-56, 2002

Renn??, T, Gailani, D, Meijers, JC, M??ller-Esterl, W. Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein. J Biol Chem, 277(7), 4892-9, 2002

Renn??, T, Sugiyama, A, Gailani, D, Jahnen-Dechent, W, Walter, U, M??ller-Esterl, W. Fine mapping of the H-kininogen binding site in plasma prekallikrein apple domain 2. Int Immunopharmacol, 2(13-14), 1867-73, 2002

Rosen, ED, Gailani, D, Castellino, FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb Haemost, 87(4), 774-6, 2002

Sun, M F, Baglia, F A, Ho, D, Martincic, D, Ware, R E, Walsh, P N, Gailani, D. Defective binding of factor XI-N248 to activated human platelets. Blood, 98(1), 125-9, 2001

Gailani, D. Gene targeting in hemostasis. factor XI. Front Biosci, 6, D201-7, 2001

Gailani, D, Ho, D, Sun, M F, Cheng, Q, Walsh, P N. Model for a factor IX activation complex on blood platelets: dimeric conformation of factor XIa is essential. Blood, 97(10), 3117-22, 2001

Gailani D, Broze GJ. Factor XI and the contact system, in Metabolic and Molecular Basis of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, Eds. McGraw-Hill, NY, NY., 2001

Chan, JC, Ganopolsky, JG, Cornelissen, I, Suckow, MA, Sandoval-Cooper, MJ, Brown, EC, Noria, F, Gailani, D, Rosen, ED, Ploplis, VA, Castellino, FJ. The characterization of mice with a targeted combined deficiency of protein c and factor XI. Am J Pathol, 158(2), 469-79, 2001

Gailani, D. Activation of factor IX by factor XIa. Trends Cardiovasc Med, 10(5), 198-204, 2000

Tarumi, T, Martincic, D, Thomas, A, Janco, R, Hudson, M, Baxter, P, Gailani, D. Familial thrombophilia associated with fibrinogen paris V: Dusart syndrome. Blood, 96(3), 1191-3, 2000

Tarumi, T, Martincic, D, Whitlock, J A, Addy, J H, Williams, S M, Gailani, D. Conserved worldwide linkage disequilibrium in the human factor XI gene. Genomics, 70(2), 269-72, 2000

Ho, DH, Badellino, K, Baglia, FA, Sun, MF, Zhao, MM, Gailani, D, Walsh, PN. The role of high molecular weight kininogen and prothrombin as cofactors in the binding of factor XI A3 domain to the platelet surface. J Biol Chem, 275(33), 25139-45, 2000

Barrow, RT, Healey, JF, Gailani, D, Scandella, D, Lollar, P. Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules. Blood, 95(2), 564-8, 2000

Martincic, D, Kravtsov, V, Gailani, D. Factor XI messenger RNA in human platelets. Blood, 94(10), 3397-404, 1999

Sun, M F, Zhao, M, Gailani, D. Identification of amino acids in the factor XI apple 3 domain required for activation of factor IX. J Biol Chem, 274(51), 36373-8, 1999

Gailani, D, Reese, E P. Anticoagulant-induced skin necrosis in a patient with hereditary deficiency of protein S. Am J Hematol, 60(3), 231-6, 1999

Martincic, D, Zimmerman, S A, Ware, R E, Sun, M F, Whitlock, J A, Gailani, D. Identification of mutations and polymorphisms in the factor XI genes of an African American family by dideoxyfingerprinting. Blood, 92(9), 3309-17, 1998

Zhao, M, Abdel-Razek, T, Sun, M F, Gailani, D. Characterization of a heparin binding site on the heavy chain of factor XI. J Biol Chem, 273(47), 31153-9, 1998

Gailani D, Broze GJ. Regulation of coagulation by tissue factor pathway inhibitor, in Recent Advances in Blood Coagulation 7, Poller L, Ludlum CA, Eds. Churchill Livingstone, Edinburgh,., 1-17, 1997

Gailani, D, Sun, M F, Sun, Y. A comparison of murine and human factor XI. Blood, 90(3), 1055-64, 1997

Gailani, D, Lasky, N M, Broze, G J. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis, 8(2), 134-44, 1997

Sun, Y, Gailani, D. Identification of a factor IX binding site on the third apple domain of activated factor XI. J Biol Chem, 271(46), 29023-8, 1996

Girard, TJ, Gailani, D, Broze, GJ. Complementary DNA sequencing of canine tissue factor pathway inhibitor reveals a unique nanomeric repetitive sequence between the second and third Kunitz domains. Biochem J, 303 ( Pt 3), 923-8, 1994

Gailani, D. Advances and dilemmas in factor XI. Curr Opin Hematol, 1(5), 347-53, 1994

Gailani, D, Broze, GJ. Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. Blood, 82(3), 813-9, 1993

Broze, GJ, Gailani, D. The role of factor XI in coagulation. Thromb Haemost, 70(1), 72-4, 1993

Gailani, D, Broze, GJ. Effects of glycosaminoglycans on factor XI activation by thrombin. Blood Coagul Fibrinolysis, 4(1), 15-20, 1993

Gailani, D, Broze, GJ. Factor XI activation by thrombin and factor XIa. Semin Thromb Hemost, 19(4), 396-404, 1993

Gailani, D. An IgG inhibitor against coagulation factor XIII: resolution of bleeding after plasma immunoadsorption with staphylococcal protein A. Am J Med, 92(1), 110-2, 1992

Gailani, D, Broze, GJ. Factor XI activation in a revised model of blood coagulation. Science, 253(5022), 909-12, 1991

Macfarlane, DE, Gailani, D. Identification of phosphoprotein NP33 as a nucleus-associated ribosomal S6 protein and its phosphorylation in hematopoietic cells. Cancer Res, 50(10), 2895-900, 1990

Gailani, D, Fisher, TC, Mills, DC, Macfarlane, DE. P47 phosphoprotein of blood platelets (pleckstrin) is a major target for phorbol ester-induced protein phosphorylation in intact platelets, granulocytes, lymphocytes, monocytes and cultured leukaemic cells: absence of P47 in non-haematopoietic cells. Br J Haematol, 74(2), 192-202, 1990

Gailani, D, Cadwell, FJ, O'Donnell, PS, Hromas, RA, Macfarlane, DE. Absence of phorbol ester-induced down-regulation of myc protein in the phorbol ester-tolerant mutant of HL-60 promyelocytes. Cancer Res, 49(19), 5329-33, 1989

Macfarlane, DE, Gailani, D, Vann, K. A phorbol ester tolerant (PET) variant of HL-60 promyelocytes. Br J Haematol, 68(3), 291-302, 1988