Vanderbilt University School of
Gailani, David , M.D.
Professor of Pathology, Microbiology and Immunology
Professor of Medicine
Phone Number: (615) 936-1505
538 Preston Research Building
Hematology/Oncology Division Vanderbilt University 37232-6305
Biochemistry, Enzyme action, Gene regulation, Knockout,
Mouse, Polymorphism, Protein structure
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.
My clinical interests are in the areas of so-called "benign" hematology (Disorders of blood unrelated to malignancies). I am particualrly interested in abnormalities of hemostasis (bleeding disorders) and thrombotic disorders.
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. PMCID:1895339
Kravtsov, DV, Monahan, PE, Gailani, D. A classification system for cross-reactive material-negative factor XI deficiency. Blood, 105(12), 4671-3, 2005. PMCID:1895004
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. PMCID:2292466
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. PMCID:2213000
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.
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.
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.
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.
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, 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.
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, 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.
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.
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. PMCID:1222859
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.
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. PMCID:1850297
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.
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.
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.
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.
Gailani, D. Activation of factor IX by factor XIa. Trends Cardiovasc Med, 10(5), 198-204, 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.
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.
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, 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.
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, Lasky, N M, Broze, G J. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis, 8(2), 134-44, 1997.
Gailani, D, Sun, M F, Sun, Y. A comparison of murine and human factor XI. Blood, 90(3), 1055-64, 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.
Gailani, D. Advances and dilemmas in factor XI. Curr Opin Hematol, 1(5), 347-53, 1994.
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. PMCID:1137634
Broze, GJ, Gailani, D. The role of factor XI in coagulation. Thromb Haemost, 70(1), 72-4, 1993.
Gailani, D, Broze, GJ. Factor XI activation by thrombin and factor XIa. Semin Thromb Hemost, 19(4), 396-404, 1993.
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.
Gailani, D, Broze, GJ. Effects of glycosaminoglycans on factor XI activation by thrombin. Blood Coagul Fibrinolysis, 4(1), 15-20, 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.
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.
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, 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.