Dr. Michael Kalafatis

Blood Coagulation and Thrombosis. Thrombosis is the primary cause of death worldwide and one of two major focuses of my research.  My laboratory has a great deal of expertise in the biochemistry of coagulation and especially in the biochemistry of proteins composing prothrombinase. The coagulation system leans on a delicate balance between coagulant and anticoagulant factors. Any imbalance/defects in these systems can result in severe pathological conditions. The prothrombinase complex is the enzymatic complex responsible for timely thrombin formation at the place of vascular injury and is composed of the enzyme, factor Xa (fXa), the non-enzymatic cofactor factor Va (fVa), and the substrate prothrombin assembled on a lipid membrane in the presence of divalent metal ions.  fVa contributes to the activation of prothrombin mainly by stabilizing the enzymatic complex and altering the kinetic mechanism of fXa (increased k_cat). We have identified the molecular defect in factor V Leiden and we have delineated specific amino acid regions on the factor V/Va molecule that are crucial for their functions.  We have also recently identified specific amino acids on prothrombin that are responsible for its activity.  Data from my laboratory strongly suggest that amino acids Leu⁴⁸⁰ and Gln⁴⁸¹ from prothrombin are crucial for proper recognition of the fVa-dependent site(s) for fXa within prothrombinase, thus modulating the enzymatic activity of fXa within the prothrombinase complex. Overall, the data published from my laboratory the last 20 years underline the crucial physiological importance of fVa for thrombin generation and clot formation.

Cancer and Apoptosis. Another major part of the research work performed in my laboratory has to do with cancer and the understanding of the mechanism of apoptosis.  In addition, I am striving to establish a treatment for cancer that uses cytokines and natural non-toxic substances.  Cancer is the second cause of death worldwide.  The traditional way to treat cancer today is “cut, poison, and burn” which correlates to surgery, chemotherapy, and radiation respectively with the known devastating side effects. Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) is a cytokine that has the capability to induce both pathways of apoptosis (first extrinsic and then intrinsic) in cancer cells while it does not harm normal non-transformed cells.  However, one pitfall observed throughout the years in in vitro and in in a multitude of human trials in vivo, is the resistance of cancer cell lines to hTRAIL-induced apoptosis.  We have recently demonstrated convincingly in melanoma and triple negative breast cancer cell lines that recombinant (r) hTRAIL together with several natural compounds (Quercetin, Silibinin, Ursolic Acid) are efficient in inducing apoptosis in previously described TRAIL-resistant cancer cell lines.  Thus, by using natural non-harmful substances and rhTRAIL, under the conditions established, only cancer cells will undergo apoptosis while normal cells will not be affected.  I have proposed the application of “mother-nature”-derived compounds as sensitizing agents to deter rhTRAIL resistance.  The results from my laboratory suggest an efficacious way of treating cancer patients in the future.  Thus, using natural non-harmful substances and rhTRAIL, under the conditions established, only cancer cells will be specifically destroyed while normal cells will not be affected.

PUBLICATIONS IN REFEREED JOURNALS

1. Kalafatis, M. Identification des domaines fonctionnels du Facteur Willebrand humain l'aide d'anticorps monoclonaux.Thèse de Doctorat de l'Université Paris VI en Biochimie(Ph.D.University of Paris in Biochemistry) 1989.

2. Girma, J.P., Kalafatis, M., Pietu, G., Lavergne, J.M., Chopek, M.W., Edgington, T.S., and Meyer, D. Mapping of distinct von Willebrand Factor domains interacting with platelet GPIb and GPIIb/IIIa and with collagen using monoclonal antibodies.Blood, 1986, 67, 1356-1366

3. Kalafatis, M., Takahashi, Y., Girma, J.P., and Meyer, D. Localization of a collagen interactive domain of human von Willebrand Factor between amino acid residues Gly 911 and Glu 1365.Blood, 1987, 70, 1577-1583.

4. Takahashi, Y., Kalafatis, M., Girma, J.P., Sewerin, K., Andersson, L.O., and Meyer, D. Localization of a Factor VIII binding domain on a 34 kDa fragment of the N-terminal portion of von Willebrand Factor.Blood, 1987, 70, 1679-1682.

5. Takahashi, Y., Kalafatis, M., Girma, J.P., and Meyer, D. Abnormality of the N-terminal portion of von Willebrand Factor in type IIA and IIC von Willebrand disease.Thromb. Haemost., 1988, 60, 498-505.

6. Kalafatis, M., Jenny, R.J., Mann, and K.G. Identification and characterization of a phospholipid-binding site of bovine factor Va.J. Biol. Chem., 1990, 265, 21580-21589.

7. Kalafatis, M., Rand, M.D., Jenny, R.J., Ehrlich, Y.H., and Mann, K.G. Phosphorylation of factor Va and VIIIa by activated platelets.Blood, 1993, 81, 704-719.

8. Xue, J., Kalafatis, M., and Mann, K.G. Determination of the disulfide bridges in factor Va light chain.Biochemistry, 1993, 32, 5917-5923.

9. Kalafatis, M., and Mann, K.G. Role of the membrane in the inactivation of factor Va by activated protein C.J. Biol. Chem., 1993, 268, 27246-27257.

10. Kalafatis, M., Rand, M.D., and Mann, K.G. Factor Va-membrane interaction is mediated by two regions located on the light chain of the cofactor.Biochemistry, 1994, 33, 486-493.

11. Butenas, S., Lawson, J.H, Kalafatis M., and Mann, K.G. Cooperative interaction of divalent metal ions, substrate, and tissue factor with factor VIIa.Biochemistry, 1994 33, 3449-3456.

12. Rand, M.D., Kalafatis, M., and Mann, K.G. Platelet coagulation factor Va: The major secretory platelet phosphoprotein.Blood, 1994, 83, 2180-2190.

13. Kalafatis, M., Xue, J., Lawler, C.M., and Mann, K.G. Contribution of the heavy and light chains of factor Va to the interaction with factor Xa.Biochemistry, 1994, 33, 6538-6545.

14. Lu, D., Kalafatis, M., Mann, K. G., and Long, G. L. Loss of membrane-dependent factor Va cleavage: A mechanistic interpretation of the pathology of protein C_VERMONT.Blood,1994, 84, 687-690.

15. Lawson, J.H., Kalafatis, M., Stram, S., and Mann, K.G. A model for the tissue factor pathway to thrombin. 1. An empirical study.J. Biol. Chem., 1994, 269, 23357-23366.

16. Xue, J., Kalafatis, M., Silveira, J.R., Kung, C., and Mann, K.G. Determination of the disulfide bridges location in bovine factor Va heavy chain.Biochemistry, 1994 33, 13109-13116.

17. Kalafatis, M., Rand, M.D., and Mann, K.G. The mechanism of inactivation of human factor V and human factor Va by activated protein C.J. Biol. Chem., 1994, 269, 31869-31880.

18. Kalafatis, M., Bertina, R.M., Rand, M.D., and Mann, K.G. Characterization of the molecular defect in factor V^R506Q.J. Biol. Chem., 1995, 270, 4053-4057.

19. Kalafatis, M., and Mann, K.G. Factor V Leiden and Thrombophilia.N. Engl. J. Med., 1995, 332, 1382-1383.

20. Camire, R.M., Kalafatis, M., Cushman, M., Tracy, R.P., Mann, K.G., and Tracy, P.B. The mechanism of inactivation of platelet-derived factor Va from normal and APC-resistant individuals by activated protein C.J. Biol. Chem., 1995, 270, 20794-20800.

21. Kalafatis, M., Lu, D., Bertina, R.M., Long, G.L., and Mann, K.G. Biochemical prototype for familial thrombosis: A study combining a functional protein C mutation and factor V Leiden. Arterioscler. Thromb. Vasc. Biol., 1995, 15, 2181-2187.

22. Kalafatis, M., Haley, P.E., Lu, D., Bertina, R.M., Long, G.L., and Mann, K.G. Proteolytic events that regulate factor V activity in whole plasma from normal and activated protein C (APC)-resistant individuals during clotting: An insight into the APC-resistance assay.Blood, 1996, 87, 4695-4707.

23. Lu, D., Kalafatis, M., Mann, K.G., and Long, G.L. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V.Blood, 1996, 87, 4708-4717.

24. Simioni, P., Kalafatis, M., Millar D.S., Henderson, S.C., Luni, S., Cooper, D.N., and Girolami, A. Compound heterozygous protein C deficiency resulting in the presence of only thebform of protein C in plasma.Blood, 1996, 88, 2101-2108.

25. Bajzar, L., Kalafatis, M., Simioni, P., and Tracy, P.B. An antifibrinolytic mechanism describing the prothrombotic effect of factor V^Leiden.J. Biol. Chem., 1996, 271, 22949-22952.

26. Butenas, S., Kalafatis M., and Mann, K.G. Analysis of tissue plasminogen activator specificity using peptidyl fluorogenic substrates.Biochemistry,1997, 36, 2123-2131.

27. van ‘t Veer, C., Golden, N.J., Kalafatis, M., and Mann, K.G. Inhibitory mechanism of the protein C pathway on tissue factor induced thrombin generation. Synergistic effect in combination with tissue factor pathway inhibitor.J. Biol. Chem., 1997, 272, 7983-7994.

28. Mann, K.G., Hockin, M.F., Begin, K.J., and Kalafatis, M. Activated protein C cleavage of factor Va leads to dissociation of the A2 domain.J. Biol. Chem., 1997, 272, 20678-20683.

29. van ’t Veer, C., Kalafatis, M., Bertina, R.M., Simioni, P., and Mann, K.G. Increased tissue factor-initiated prothrombin activation as a result of the Arg⁵⁰⁶®Gln mutation in factor V^LEIDEN.J. Biol. Chem., 1997, 272, 20721-20729.

30. Egan, J.O., Kalafatis, M., and Mann, K.G. The effect of Arg³⁰⁶®Ala and Arg⁵⁰⁶®Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S.Protein Science,1997, 6, 2016-2027.

31. van ‘t Veer, C., Golden, N.J., Kalafatis, M., Simioni, P., Bertina R.M., and Mann, K.G. An in vitro analysis of the combination of factor V^Leidenand hemophilia A.Blood,1997, 90, 3067-3072.

32. Hockin, M.F., Kalafatis, M., Shatos, M.A., and Mann, K.G. Protein C activation and factor Va inactivation on human umbilical vein endothelial cells.Arterioscler. Thromb. Vasc. Biol.,1997, 17, 2765-2775.

33. Kalafatis, M. Identification and partial characterization of factor Va heavy chain-kinase from human platelets.J. Biol. Chem., 1998, 273, 8459-8466.

34. Camire, R.M., Kalafatis, M., Simioni, P., Girolami, A., and Tracy, P.B. Platelet-derived factor Va/Va^Leidencofactor activities are sustained on the surface of activated platelets despite the presence of activated protein C.Blood1998, 91, 2818-2829.

35. Long, G.L., Lu, D., Xie R., and Kalafatis, M. Human protein S cleavage and inactivation by coagulation factor Xa.J. Biol. Chem., 1998, 273, 11521-11526.

36. Camire, R.M., Kalafatis, M., and Tracy, P.B. Proteolysis of factor V by cathepsin G and elastase indicates that cleavage at Arg¹⁵⁴⁵optimizes cofactor function by facilitating factor Xa binding.Biochemistry,1998, 37, 11896-11906.

37. Castoldi, E., Kalafatis, M., Lunghi, B., Simioni, P., Ioannou, P.A., Petio, M., Girolami, A., Mann, K.G., and Bernardi, F. Molecular bases of pseudo-homozygous APC resistance: The compound heterozygosity for FV R506Q and a FV null mutation results in the exclusive presence of FV Leiden molecules in plasma.Thromb. Haemost.1998, 80, 403-406.

38. Simioni, P., Kalafatis, M., Manfrin, D., Tormene, D., and Girolami, A. Factor V variants, activated protein C resistance and venous thromboembolism.Blood Coagul.Fibrinolysis.1998, 9, 661-2.

39. Kalafatis, M., Bernardi, F., Simioni, P., Lunghi B., Girolami, A and Mann, K.G. Phenotype and genotype expression in pseudohomozygous factor V^LEIDEN. The need for phenotype analysis.Arterioscler. Thromb. Vasc. Biol.1999, 19, 336-342.

40. Hockin, M.F., Cawthern, K.M., Kalafatis, M., and Mann, K.G. A model describing the inactivation of factor Va by activated protein C (APC): Bond cleavage, fragment dissociation and product inhibition.Biochemistry1999, 38, 6918-6934.

41. Castoldi, E., Simioni, P., Kalafatis, M., Lunghi, B., Tormene, D., Girelli, D., Girolami, A., and Bernardi, F. Combinations of four mutations (FV R506Q, FVH1299R, FVY1702C, PT20210G/A) affecting the prothrombinase complex in a thrombophilic family.Blood2000, 96, 1443-1448.

42. Simioni, P., Vianello, F., Kalafatis, M., Barzon, L., Ladogana, S., Paolucci, P., Carotenuto, M., Dal Bello, F., Palù, P., and Girolami A. A dysfunctional factor X (Factor X San Giovanni Rotondo) Present at Homozygous and Double heterozygous level: Identification of a novel micro-deletion (delC556) and missense mutation (Lys⁴⁰⁸®Asn) in the factor X gene.A Study of an Italian Family.Thromb.Res.2001 101, 219-230.

43. Kalafatis, M. and Mann, K.G. The role of the membrane in the inactivation of factor Va by plasmin.Amino acid region 307-348 of factor V plays a critical role for factor Va cofactor function.J. Biol. Chem.2001, 276, 18614-18623.

44. Kalafatis, M., Simioni, P., and Bernardi, F. Phenotype and genotype expression in pseudohomozygous R2 factor V.Blood2001, 98, 1988-1989.

45. Simioni, P., Kalafatis M., Tormene D., Luni, S., Zerbinati, P., Barzon, L., Palù, G., and Girolami A. Abnormal propeptide processing resulting in the presence of two abnormal species of protein C in plasma. Characterization of the dysfunctional protein C Padua₃(Protein C_{R-1L/propeptide}).Thromb. Haemost.2001, 86, 1017-1022.

46. Silveira, J.R., Kalafatis, M., and Tracy, P.B. Carbohydrate moieties on factor V, but not the derived cofactor, factor Va, regulate its inactivation by activated protein C. Biochemistry2002, 41, 1672-1680.

47. Hung, K., Sun, X., Ding, H., Kalafatis, M., Simioni P., and Guo B. A MALDI-TOF based mini sequencing method for screening of the G¹⁶⁹¹®A mutation in the factor V gene.Blood Coagul. Fibrinolysis.2002, 13, 117-122.

48. Kalafatis, M., Simioni, P., Tormene, D., Beck, D.O., Luni, S., and Girolami, A. Isolation and characterization of an anti-factor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations.Blood 2002, 99, 3985-3992.

49. Singh, L.S. and Kalafatis, M. Sequencing of full length cDNA encoding theaandbsubunits of human casein kinase II from human platelets and megakaryocytic cells.Expression of casein kinase IIaintronless gene in a megakaryocytic cell line.Biochemistry2002, 41, 8935-8940.

50. Kalafatis, M. and Beck, D.O. Identification of a binding site for blood coagulation factor Xa on the heavy chain of factor Va.Amino acid residues 323-331 of factor V contain an interactive site for activated factor X.Biochemistry. 2002, 41, 12715-12728.

51. Singh, L.S., Bukys, M.A., Beck, D.O., and Kalafatis, M. Amino acids Glu³²³, Tyr³²⁴, Glu³³⁰, and Val³³¹of factor Va heavy chain are essential for expression of cofactor activity.J. Biol. Chem. 2003, 278, 28335-28345.

52. Kalafatis, M., Beck, D.O., and Mann, K.G. Structural requirements for expression of factor Va activity.J. Biol. Chem. 2003, 278, 33550-33561.

53. Beck, D.O., Bukys, M.A., Singh, L.S., Szabo, K.A. and Kalafatis, M. The contribution of amino acid region Asp⁶⁹⁵-Tyr⁶⁹⁸of factor V to procofactor activation and factor Va function.J. Biol. Chem.2004, 279, 3084-3095.

54. Gould, W.R., Simioni, P., Silveira, J.R., Luni S., Kalafatis M., and Tracy P.B. Megakaryocytes endocytose and subsequently modify human plasma-derived factor Vin vivoto form the platelet-derived pool.J. Thromb. Haemost.2005, 3, 450-456.

55. Bukys, M.A., Blum, M.A., Young, P.Y, Bruffato, N., Nesheim, M.E., and Kalafatis, M. Incorporation of Factor Va into Prothrombinase is required for coordinated cleavage of Prothrombin by Factor Xa.J. Biol. Chem.2005, 280, 27393-27401.

56. Orban, T., Kalafatis, M., and Gogonea, V. Completed Three-Dimensional Model of Human Coagulation Factor Va. Molecular Dynamics Simulations and Structural Analyses.Biochemistry2005, 44, 13082-13090.

57. Bukys, M.A., Orban, T., Kim, P.Y., Beck, D.O., Nesheim, M.E., and Kalafatis, M. The structural integrity of anion binding exosite I of thrombin is required and sufficient for timely activation of factor V and factor VIII.J. Biol. Chem.2006, 281, 18569-18580.

58. Butenas, S., Orfeo, T., Kalafatis, M., and Mann K.G.Peptidomimetic inhibitors for activated protein C: Implications for hemophilia management.J. Thromb. Haemost.2006, 4, 2411-2416.

59. Bukys, M.A., Kim, P.Y., Nesheim, M. E., and Kalafatis, M. A control switch for prothrombinase.A hirudin-like peptide from the COOH-terminus of factor Va heavy chain regulates the rate and pathway for the activation of prothrombin by prothrombinase.J. Biol. Chem.2006, 281, 39194-39204.

60. Erdogan, E., Bukys, M.A., Orfeo T., Mann, K.G., and Kalafatis, M. Identification of an inactivating cleavage site for thrombin on the heavy chain of factor Va.Thromb. Haemost.2007, 98, 998-1006.

61. Erdogan, E., Bukys, M.A., and Kalafatis, M. The contribution of amino acids 1508-1515 of factor V to light chain formation.J. Thromb. Haemost.2008, 6, 118-124

62. Bukys, M.A. Orban, T., Kim. P.Y., Nesheim, M. E., and Kalafatis, M. The interaction of fragment 1of prothrombin with the membrane surface is a prerequisite for optimum expression of factor Va cofactor activity within prothrombinase.Thromb. Haemost., 2008, 99, 511-522.

63. Barhoover, M.A., Orban, T., Beck, D.O., Bukys, M.A., and Kalafatis, M. The contribution of amino acid region 334-335 from factor Va heavy chain to the catalytic efficiency of prothrombinase.Biochemistry, 2008, 47, 6840-6850.

64. Hirbawi, J., Bukys, M.A., Barhoover, M.A., Erdogan, E., and Kalafatis M. Role of the acidic hirudin-like COOH-terminal amino acid region of factor Va heavy chain in the enhanced function of prothrombinase.Biochemistry,2008, 47, 7963-7974.

65. Barhoover, M.A., Orban, T. Bukys, M.A., and Kalafatis M. Cooperative regulation of the activity of factor Xa within prothrombinase by discrete amino acid regions from factor Va heavy chain.Biochemistry, 2008, 47, 12835-12843.

1. Hirbawi, J., Vaughn, J.L., Bukys, M.A., Vos, H., and Kalafatis M.The contribution of amino acid region 659-663 of factor Va heavy chain to the activity of factor Xa within prothrombinase.Biochemistry, 2010, 49, 8520-8534.

67. Barhoover, M.A. and Kalafatis M. Cleavage at both Arg³⁰⁶and Arg⁵⁰⁶is required and sufficient for timely and efficient inactivation of factor Va by activated protein C.Blood Coag Fibrinolysis, 2011, 22, 317-324.

68. Wiencek J.R., Na M., Hirbawi J., and Kalafatis, M. Amino Acid region 1000-1008 of factor V is a dynamic regulator for the emergence of procoagulant activity.J. Biol. Chem., 2013, 288, 37026-37038.

69. Wiencek J.R., Hirbawi J., Yee, V.C., and Kalafatis, M. The dual regulatory role of amino acids Leu480 and Gln481 of prothrombin.J. Biol. Chem., 2016, 291, 1565-1581.

70. Turner K.A., Lindner D.J., and Kalafatis, M. Recombinant human Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand selectively induces apoptosis in malignant melanoma.Int J Cancer Oncol2017, 4(1), 1-8.

71. Turner K.A. and Kalafatis, M. The Case Back on the TRAIL: The case back on the trail. Death Receptors as Markers for rhTRAIL-Sensitivity.The Journal of Applied Laboratory Medicine (JALM)2017, 2(2) 176-185.

72. Hirbawi J. and Kalafatis M:The spellbinding effects of the acidic COOH-Terminus of factor Va heavy chain on prothrombinase activity and function.ACS Omega2017, 2, 5529-5537.

73. Manouchehri, J.M. and Kalafatis, M. Sensitization of rhTRAIL-Resistant Triple Negative Breast Carcinoma Through Silibinin Co-Treatment.Anticancer Research2017,37(12), 6593-6599.

74. Manouchehri, J.M., Turner, K.A., and Kalafatis, M. TRAIL-induced apoptosis in TRAIL-resistant breast carcinoma through Quercetin co-treatment.Breast Cancer: Basic and Clinical Research2018, 12, 1-12.

75. Turner, K.A., Manouchehri, J.M., and Kalafatis, M.Sensitization of recombinant human tumor necrosis factor-related apoptosis-inducing ligand-resistant malignant melanomas by quercetinMelanoma Research, 2018, 28(4), 277-285.

76. Manouchehri, J.M. and Kalafatis, M. Ursolic acid promotes the sensitization of rhTRAIL-resistant triple-negative breast cancer.Anticancer Research2018,38(12), 6789-6795.

77. Kalafatis, M.COVID-19: A serious vascular disease with primary symptoms of a respiratory ailment. The Journal of Applied Laboratory Medicine (JALM)2021, 6(5), 1099-1104.

INVITED REVIEWS

78. Kalafatis, M., Girma, J.P., and Meyer, D. Identification des domaines fonctionnels du facteur Willebrand humain.Innov. Tech. Biol. Med.(ITBM),1988, 9, 682-690.

79. Kalafatis, M., Swords, N.A., Rand, M.D., and Mann, K.G. Membrane-dependent reactions in blood coagulation. Role of the vitamin K-dependent enzyme complexes.Molecular Basis of Disease.Biochim. Biophys. Acta, 1994, 1227, 113-129.

80. Mann, K.G, and Kalafatis, M. The coagulation explosion.Cerebrovascular Diseases,1995, 5, 93-97.

81. Kalafatis, M., Egan, J.O., van’t Veer, C., and Mann, K.G. Regulation and regulatory role ofg-carboxyglutamic acid containing clotting factors.Critical Reviews in Eukaryotic Gene Expression, 1996, 6, 87-101.

82. Kalafatis, M. The molecular basis for activated protein C-resistance.American Heart Association Newsletter, (Thrombosis Council) Fall 1996, pp. 7-9.

83. Kalafatis, M., and Mann, K.G. Factor V^Leidenand Thrombophilia. Arterioscler. Thromb. Vasc. Biol., 1997, 17, 620-627.

84. Kalafatis, M., Egan, J.O., van’t Veer, C., Cawthern, K.M., and Mann, K.G. The Regulation of clotting factors.Critical Reviews in Eukaryotic Gene Expression, 1997, 7, 241-280.

85. Mann, K.G. and Kalafatis, M. Factor V: A Combination of Dr. Jeckyll and Mr. Hyde.Blood, 2003, 101, 20-30.(Figure 2 of the manuscript is the cover picture of volume 101, number 1, of January 1 2003 edition of Blood).

86. Kalafatis, M. Factor V: A plethora of potent anticoagulant molecules.Current Opinion in Hematology, 2005, 12, 141-148

BOOK CHAPTERS

87. Girma, J.P., Kalafatis, M., and Meyer, D. Mapping of von Willebrand Factor functional domains with monoclonal antibodies. In:Factor VIII/von Willebrand factor. Biological and clinical advances.Eds. N.L. Ciavarella, Z.R. Ruggeri, T.S. Zimmerman; 1986 pp. 137-148. Wichtig Editore, Italy.

88. Girma, J.P., Kalafatis, M., Takahashi, Y., and Meyer, D. Recognition of three distinct functional domains of human von Willebrand factor using monoclonal antibodies. In:Utilisation of monoclonal antibodies for the understanding and detection of platelet activity. Ed. J. McGregor; 1986, pp. 219-225. Elsevier Science publishers B.V., The Netherlands.

89. Kalafatis, M., Krishnaswamy, S., Rand, M.D., and Mann, K.G. Factor V. In:Proteolytic Enzymes in Coagulation, Fibrinolysis, and Complement Activation.Methods Enzymology, 1993, 222, 224-236.

90. Kalafatis, M., Egan, J.O., and Mann, K.G. Coagulation Factors. In:Endothelium in Clinical Practice., Eds. Rubanyi/Dzau 1996 pp 245-264. Marcel Dekker, Inc., publisher, New York, NY USA.

91. Kalafatis, M., van ’t Veer, C., and Mann, K.G. Coagulation Factors. In:Encyclopedic Reference of Vascular Biology and Pathology. Ed. A. Bikfalvi; 2000, pp 49-64. Springer-Verlag Berlin Heidelberg, Germany.

92.Kalafatis, M.,and Mann K.G.Factor V: D_rJeckyl and M_rHyde. In: Proceedings of the hemophilia care in the new millennium. Eds. D.M. Monroe, U. Hedner, M.R. Hoffman, C. Negrier, G.F. Savidge, and G.C. White; 2001, pp 31-43. Kluwer Academic/Plenum Publishers, New York, NY, USA.

93.Kalafatis, M., Negrescu, E., Byzova, T., and Plow, E.F. Platelets and prothrombin. In:Platelet Function: Assessment, Diagnosis, and Function. Eds. M. Quinn and D. Fitzgerald; 2005, pp 279-296. Humana Press Inc., Totowa, NJ, USA.