David Gailani, M.D.

Professor

dave.gailani@vanderbilt.edu
Faculty Appointments
Professor of Pathology, Microbiology and Immunology Professor of Medicine
Education
M.D., Medicine, University of Illinois, College of Medicine, Chicago, IllinoisB.A., Biology, Cornell University, Ithaca, New York
Office Address
Hematology/Oncology Division
Vanderbilt University
777 Preston Research Building
2220 Pierce Ave. Nashville, TN 37232-6305
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.
Research Keywords
Biochemistry, Enzyme action, Gene regulation, Knockout, Mouse, Polymorphism, Protein structure
Publications
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 [print-electronic]. 2005 Nov 11/1/2005; 106(9): 3055-7. PMID: 15985536, PMCID: PMC1895339, PII: 2005-02-0577, DOI: 10.1182/blood-2005-02-0577, ISSN: 0006-4971.

Renné T, Pozgajová M, Grüner S, Schuh K, Pauer HU, Burfeind P, Gailani D, Nieswandt B. Defective thrombus formation in mice lacking coagulation factor XII. J. Exp. Med [print-electronic]. 2005 Jul 7/18/2005; 202(2): 271-81. PMID: 16009717, PMCID: PMC2213000, PII: jem.20050664, DOI: 10.1084/jem.20050664, ISSN: 0022-1007.

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 [print-electronic]. 2005 Jun 6/24/2005; 280(25): 23523-30. PMID: 15829482, PMCID: PMC2292466, PII: M500894200, DOI: 10.1074/jbc.M500894200, ISSN: 0021-9258.

Kravtsov DV, Monahan PE, Gailani D. A classification system for cross-reactive material-negative factor XI deficiency. Blood [print-electronic]. 2005 Jun 6/15/2005; 105(12): 4671-3. PMID: 15728123, PMCID: PMC1895004, PII: 2004-05-1864, DOI: 10.1182/blood-2004-05-1864, ISSN: 0006-4971.

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 [print-electronic]. 2005 Apr; 3(4): 695-702. PMID: 15733058, PII: JTH1236, DOI: 10.1111/j.1538-7836.2005.01236.x, ISSN: 1538-7933.

Baglia FA, Gailani D, López JA, Walsh PN. Identification of a binding site for glycoprotein Ibalpha in the Apple 3 domain of factor XI. J. Biol. Chem [print-electronic]. 2004 Oct 10/29/2004; 279(44): 45470-6. PMID: 15317813, PII: M406727200, DOI: 10.1074/jbc.M406727200, ISSN: 0021-9258.

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. 2004 Oct; 2(10): 1782-9. PMID: 15456490, PII: JTH882, DOI: 10.1111/j.1538-7836.2004.00882.x, ISSN: 1538-7933.

Gailani D, Zivelin A, Sinha D, Walsh PN. Do platelets synthesize factor XI?. J. Thromb. Haemost. 2004 Oct; 2(10): 1709-12. PMID: 15456479, PII: JTH935, DOI: 10.1111/j.1538-7836.2004.00935.x, ISSN: 1538-7933.

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 [print-electronic]. 2004 Jul 7/9/2004; 279(28): 29485-92. PMID: 15090552, PII: M402971200, DOI: 10.1074/jbc.M402971200, ISSN: 0021-9258.

Kravtsov DV, Wu W, Meijers JC, Sun MF, Blinder MA, Dang TP, Wang H, Gailani D. Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain. Blood [print-electronic]. 2004 Jul 7/1/2004; 104(1): 128-34. PMID: 15026311, PII: 2003-10-3530, DOI: 10.1182/blood-2003-10-3530, ISSN: 0006-4971.

Donahue BS, Byrne DW, Gailani D, George AL. Tissue factor and platelet glycoprotein Ib-alpha alleles are associated with age at first coronary bypass operation. Anesthesiology. 2003 Dec; 99(6): 1287-94. PMID: 14639140, PII: 00000542-200312000-00009, ISSN: 0003-3022.

Cheng Q, Sun MF, Kravtsov DV, Aktimur A, Gailani D. Factor XI apple domains and protein dimerization. J. Thromb. Haemost. 2003 Nov; 1(11): 2340-7. PMID: 14629467, PII: 418, ISSN: 1538-7933.

Tarumi T, Kravtsov DV, Moore JH, Williams SM, Gailani D. Common single nucleotide polymorphisms in the promoter region of the human factor XI gene [letter]. J. Thromb. Haemost. 2003 Aug; 1(8): 1854-6. PMID: 12911610, PII: 372j, ISSN: 1538-7933.

Aktimur A, Gabriel MA, Gailani D, Toomey JR. The factor IX gamma-carboxyglutamic acid (Gla) domain is involved in interactions between factor IX and factor XIa. J. Biol. Chem [print-electronic]. 2003 Mar 3/7/2003; 278(10): 7981-7. PMID: 12496253, PII: M212748200, DOI: 10.1074/jbc.M212748200, ISSN: 0021-9258.

Donahue BS, Gailani D, Higgins MS, Drinkwater DC, George AL. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation. 2003 Feb 2/25/2003; 107(7): 1003-8. PMID: 12600914, ISSN: 1524-4539.

Renné T, Sugiyama A, Gailani D, Jahnen-Dechent W, Walter U, Müller-Esterl W. Fine mapping of the H-kininogen binding site in plasma prekallikrein apple domain 2. Int. Immunopharmacol. 2002 Dec; 2(13-14): 1867-73. PMID: 12489801, PII: S1567-5769(02)00170-4, ISSN: 1567-5769.

Sinha D, Marcinkiewicz M, Gailani D, Walsh PN. Molecular cloning and biochemical characterization of rabbit factor XI. Biochem. J. 2002 Oct 10/1/2002; 367(Pt 1): 49-56. PMID: 12084014, PMCID: PMC1222859, PII: BJ20020232, DOI: 10.1042/BJ20020232, ISSN: 0264-6021.

Tarumi T, Kravtsov DV, Zhao M, Williams SM, Gailani D. 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 [print-electronic]. 2002 May 5/24/2002; 277(21): 18510-6. PMID: 11891231, PII: M201886200, DOI: 10.1074/jbc.M201886200, ISSN: 0021-9258.

Rosen ED, Gailani D, Castellino FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse [letter]. Thromb. Haemost. 2002 Apr; 87(4): 774-6. PMID: 12008966, ISSN: 0340-6245.

Renné T, Gailani D, Meijers JC, Müller-Esterl W. Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein. J. Biol. Chem [print-electronic]. 2002 Feb 2/15/2002; 277(7): 4892-9. PMID: 11733491, PII: M105221200, DOI: 10.1074/jbc.M105221200, ISSN: 0021-9258.

Sun MF, Baglia FA, Ho D, Martincic D, Ware RE, Walsh PN, Gailani D. Defective binding of factor XI-N248 to activated human platelets. Blood. 2001 Jul 7/1/2001; 98(1): 125-9. PMID: 11418471, ISSN: 0006-4971.

Gailani D, Ho D, Sun MF, Cheng Q, Walsh PN. Model for a factor IX activation complex on blood platelets: dimeric conformation of factor XIa is essential. Blood. 2001 May 5/15/2001; 97(10): 3117-22. PMID: 11342438, ISSN: 0006-4971.

Gailani D. Gene targeting in hemostasis. factor XI. Front. Biosci. 2001 Feb 2/1/2001; 6: D201-7. PMID: 11171549, ISSN: 1093-9946.

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. 2001 Feb; 158(2): 469-79. PMID: 11159184, PMCID: PMC1850297, PII: S0002-9440(10)63989-2, DOI: 10.1016/S0002-9440(10)63989-2, ISSN: 0002-9440.

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.

Tarumi T, Martincic D, Whitlock JA, Addy JH, Williams SM, Gailani D. Conserved worldwide linkage disequilibrium in the human factor XI gene. Genomics. 2000 Dec 12/1/2000; 70(2): 269-72. PMID: 11112356, PII: S0888-7543(00)96393-6, DOI: 10.1006/geno.2000.6393, ISSN: 0888-7543.

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. 2000 Aug 8/18/2000; 275(33): 25139-45. PMID: 10823824, PII: M001890200, DOI: 10.1074/jbc.M001890200, ISSN: 0021-9258.

Tarumi T, Martincic D, Thomas A, Janco R, Hudson M, Baxter P, Gailani D. Familial thrombophilia associated with fibrinogen paris V: Dusart syndrome. Blood. 2000 Aug 8/1/2000; 96(3): 1191-3. PMID: 10910944, ISSN: 0006-4971.

Gailani D. Activation of factor IX by factor XIa. Trends Cardiovasc. Med. 2000 Jul; 10(5): 198-204. PMID: 11282295, PII: S1050-1738(00)00070-0, ISSN: 1050-1738.

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. 2000 Jan 1/15/2000; 95(2): 564-8. PMID: 10627463, ISSN: 0006-4971.

Sun MF, Zhao M, Gailani D. Identification of amino acids in the factor XI apple 3 domain required for activation of factor IX. J. Biol. Chem. 1999 Dec 12/17/1999; 274(51): 36373-8. PMID: 10593931, ISSN: 0021-9258.

Martincic D, Kravtsov V, Gailani D. Factor XI messenger RNA in human platelets. Blood. 1999 Nov 11/15/1999; 94(10): 3397-404. PMID: 10552949, ISSN: 0006-4971.

Gailani D, Reese EP. Anticoagulant-induced skin necrosis in a patient with hereditary deficiency of protein S. Am. J. Hematol. 1999 Mar; 60(3): 231-6. PMID: 10072117, PII: 10.1002/(SICI)1096-8652(199903)60:3<231::AID-AJH12>3.0.CO;2-N, ISSN: 0361-8609.

Zhao M, Abdel-Razek T, Sun MF, Gailani D. Characterization of a heparin binding site on the heavy chain of factor XI. J. Biol. Chem. 1998 Nov 11/20/1998; 273(47): 31153-9. PMID: 9813019, ISSN: 0021-9258.

Martincic D, Zimmerman SA, Ware RE, Sun MF, Whitlock JA, Gailani D. Identification of mutations and polymorphisms in the factor XI genes of an African American family by dideoxyfingerprinting. Blood. 1998 Nov 11/1/1998; 92(9): 3309-17. PMID: 9787168, ISSN: 0006-4971.

Gailani D, Sun MF, Sun Y. A comparison of murine and human factor XI. Blood. 1997 Aug 8/1/1997; 90(3): 1055-64. PMID: 9242536, ISSN: 0006-4971.

Gailani D, Lasky NM, Broze GJ. A murine model of factor XI deficiency. Blood Coagul. Fibrinolysis. 1997 Mar; 8(2): 134-44. PMID: 9518045, ISSN: 0957-5235.

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. 1997; 1-17.

Sun Y, Gailani D. Identification of a factor IX binding site on the third apple domain of activated factor XI. J. Biol. Chem. 1996 Nov 11/15/1996; 271(46): 29023-8. PMID: 8910554, ISSN: 0021-9258.

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. 1994 Nov 11/1/1994; 303 ( Pt 3): 923-8. PMID: 7980463, PMCID: PMC1137634, ISSN: 0264-6021.

Gailani D. Advances and dilemmas in factor XI. Curr. Opin. Hematol. 1994 Sep; 1(5): 347-53. PMID: 9371304, ISSN: 1065-6251.

Gailani D, Broze GJ. Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. Blood. 1993 Aug 8/1/1993; 82(3): 813-9. PMID: 8338946, ISSN: 0006-4971.

Broze GJ, Gailani D. The role of factor XI in coagulation. Thromb. Haemost. 1993 Jul 7/1/1993; 70(1): 72-4. PMID: 8236118, ISSN: 0340-6245.

Gailani D, Broze GJ. Effects of glycosaminoglycans on factor XI activation by thrombin. Blood Coagul. Fibrinolysis. 1993 Feb; 4(1): 15-20. PMID: 8457645, ISSN: 0957-5235.

Gailani D, Broze GJ. Factor XI activation by thrombin and factor XIa. Semin. Thromb. Hemost. 1993; 19(4): 396-404. PMID: 8140432, DOI: 10.1055/s-2007-993291, ISSN: 0094-6176.

Gailani D. An IgG inhibitor against coagulation factor XIII: resolution of bleeding after plasma immunoadsorption with staphylococcal protein A. Am. J. Med. 1992 Jan; 92(1): 110-2. PMID: 1731502, ISSN: 0002-9343.

Gailani D, Broze GJ. Factor XI activation in a revised model of blood coagulation. Science. 1991 Aug 8/23/1991; 253(5022): 909-12. PMID: 1652157, ISSN: 0036-8075.

Macfarlane DE, Gailani D. Identification of phosphoprotein NP33 as a nucleus-associated ribosomal S6 protein and its phosphorylation in hematopoietic cells. Cancer Res. 1990 May 5/15/1990; 50(10): 2895-900. PMID: 2334893, ISSN: 0008-5472.

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. 1990 Feb; 74(2): 192-202. PMID: 2317454, ISSN: 0007-1048.

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. 1989 Oct 10/1/1989; 49(19): 5329-33. PMID: 2670202, ISSN: 0008-5472.

Macfarlane DE, Gailani D, Vann K. A phorbol ester tolerant (PET) variant of HL-60 promyelocytes. Br. J. Haematol. 1988 Mar; 68(3): 291-302. PMID: 3162684, ISSN: 0007-1048.