Factor VII polypeptides that are modified and uses thereof

• US 20090291890A1
• Filed: 04/10/2009
• Published: 11/26/2009
• Est. Priority Date: 04/11/2008
• Status: Active Grant

• Current Assignee: GC Biopharma Corporation
• Original Assignee: Catalyst Biosciences, Inc.
• Inventors: Madison, Edwin L., Thanos, Christopher
• Granted Patent: US 8,519,103 B2
• Time in Patent Office: Days
• US Class Current: 514/14.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 15/62 DNA sequences coding for fusion proteins
• CPC Class Codes: C12N 9/6437 Coagulation factor VIIa (3.4.21.21)
• CPC Class Codes: C12Y 304/21021 Coagulation factor VIIa (3.4.21.21)

Abstract

Modified factor VII polypeptides and uses thereof are provided. Such modified FVII polypeptides include Factor VIIa and other forms of Factor VII. Among modified FVII polypeptides provided are those that have altered activities, typically altered procoagulant activity, including increased procoagulant activities. Hence, such modified polypeptides are therapeutics.

Claims

1. A modified factor VII (FVII) polypeptide, comprising a modification in a FVII polypeptide, wherein

the modification is an amino acid replacement at a position corresponding to position 286 in a FVII polypeptide having the sequence of amino acids set forth in SEQ ID NO:

3 or in a corresponding residue in a FVII polypeptide, and

the modification is replacement at position 286 by a basic amino acid that results in a modified FVII polypeptide that exhibits increased coagulant activity compared to the FVII polypeptide that does not have the modification at position 286.

2. The modified FVII polypeptide of claim 1, wherein the basic amino acid is selected from among Arg (R), Lys (K) and His (H).

3. The modified FVII polypeptide of claim 1, wherein the modification is replacement of Gln (Q) with Arg (R).

4. The modified FVII polypeptide of claim 1, wherein the unmodified FVII polypeptide comprises a sequence of amino acids set forth in any of SEQ ID NOS:

1-3, 18-74, 98,158 or 343-353, or is an allelic or species variant thereof, or a variant having at least 60% sequence identity with the FVII of any of SEQ ID NOS;

1-3, 18-74, 98, 158 or 343-33, or is an active fragment of a FVII polypeptide that comprises a sequence of amino acids set forth in any of SEQ ID NOS;

1-3, 18-74, 98, 158 or 343-353.

5. The modified FVII polypeptide of claim 1, wherein the modified FVII polypeptide is an active fragment that contains a replacement at a position corresponding to position 286 in a FVII polypeptide.

6. The modified FVII polypeptide of claim 1 that has only the single modification at position 286.

7. The modified FVII polypeptide of claim 1, comprising one or more further modifications at another position in the FVII polypeptide.

8. The modified FVII polypeptide of claim 7 that has one or two modifications in addition to the modification at position 286.

9. The modified FVII polypeptide of claim 7, wherein a further modification is an amino acid replacement, insertion or deletion.

10. The modified FVII polypeptide of claim 7, wherein a further modification is an amino acid replacement at a position corresponding to a position selected from among 51, 52, 54, 60, 66, 68, 109, 119, 122, 124, 130, 132, 158, 161, 175, 196, 197, 199, 202, 216, 222, 237, 239, 257, 286, 287, 290 292, 294, 296, 298, 305, 314, 318, 321, 337, 341, 366, 373, 374, 394, 395 and 396.

11. The modified FVII polypeptide of claim 7, wherein a further amino acid modification is selected from among D196K, D196R, D196A, D196Y, D196F, D196W, D196L, D196I, K197Y, K197A, K197E, K197D, K197L, K197M, K197I, K197V, K197F, K197W, K199A, K199D, K199E, G237W, G237T, G237I, G237V, T239A, R290A, R290E, R290D, R290N, R290Q, R290K, R290M, R290V, K341E, K341R, K341Q, K341N, K341M, K341D, G237T238insA, G237T238insS, G237T238insV, G237T238insAS, G237T238insSA, D196K197insK, D196K197insR, D196K197insY, D196K197insW, D196K197insA, D196K197insM, K197I198insE, K197I198insY, K197I198insA, K197I198insS, T239S, T239N, T239Q, T239V, T239L, T239H, T239I, L287T, M298Q, P321K, P321E, P321Y, P321S, Q366D, Q366E, Q366N, Q366T, Q366S, Q366V, Q366I, Q366L, Q366M, H373D, H373E, H373S, H373L, H373I, H373F, H373A, K161S, K161A, K161V, H216S, H216A, H216K, H216R, S222A, S222K, S222V, S222N, S222E, S222D, H257A, H257S, Gla Swap FIX, {Gla Swap FIX/E40L}, {Gla Swap FIX/K43I}, {Gla Swap FIX/Q44S}, {Gla Swap FIX/M19K}, {Gla Swap FIX/M19K/E40L/K43I/Q44S}, Gla Swap FX, Gla Swap Prot C, Gla Swap Prot S, Gla Swap Thrombin, S52A, S60A, E394N, P395A, R396S, R202S, A292N, A294S, G318N, A175S, K109N, A122N, G124S, A51N, T130N, E132S, S52N, P54S, S119N, L121S, T128N, P129A, Q66N, Y68S, S103S111delinsQRLMEDICLPRWGCLWEDDF, H115S126delinsQRLMEDICLPRWGCLWEDDF, T128P134delinsQRLMEDICLPRWGCLWEDDF, S103S111delinsIEDICLPRWGCLWE, H115S126delinsIEDICLPRWGCLWE, T128P134delinsIEDICLPRWGCLWE, S103S111delinsDICLPRWGCLWED, H115S126delinsDICLPRWGCLWED, T128P134delinsDICLPRWGCLWED, P406insIEDICLPRWGCLW, P406insGGGSIEDICLPRWGCLW, P406insDICLPRWGCLWED, P406insGGGSDICLPRWGCLWED, S103S111delinsSFGRGDIRNV, H115S126delinsSFGRGDIRNV, T127P134delinsSFGRGDIRNV, P406insCSFGRGDIRNVC, P406insGGGSCSFGRGDIRNVC, V158T, V158D, L287T, E296V, M298K and M298Q.

12. The modified FVII polypeptide of claim 7, comprising modifications selected from among Q286R/M298Q, Q286R/Gla Swap FIX, Q286R/H257A, Q286R/S222A, Q286R/S222A/H257A, Q286R/S222A/Gla Swap FIX, Q286R/H257A/Gla Swap FIX, Q286R/S222A/H257A/Gla Swap FIX, Q286R/M298Q/K341Q, Q286R/M298Q/K199E, Q286R/M298Q/Gla Swap FIX, Q286R/Q366V, Q286R/A292N/A294S/Q366V, A175S/Q286R/Q366V, S222A/Q286R/Q366V, H257S/Q286R, H257S/Q286R/Q366V, S222A/H257A/Q286R/Q366V, Q286R/H373A, S222A/H257A/Q286R/M158Q, Q286R/K341D, Q286R/Q366D, Q286R/Q366N, Q286R/M298Q/Q366D, Q286R/M298Q/Q366N, Q286R/H373F, Q286R/M298Q/H373F, {Gla Swap FIX/E40L}/Q286R/M298Q, {Gla Swap FIX/K43I}/Q286R/M298Q, {Gla Swap FIX/Q44S}/Q286R/M298Q, {Gla Swap FIX/M19K}/Q286R/M298Q, {Gla Swap FIX/M19K/E40L/K43I/Q44S}/Q286R/M298Q, T128N/P129A/Q286R, T128N/P129A/Q286R/M298Q, T128N/P129A/Q286R/H373F, V158D/Q286R/E296V/M298Q, Gla Swap FIX/T128N/P129A/S222A/Q286R, Gla Swap FIX/T128N/P29A/Q286R/M298Q, T128N/P129A/S222A/H257A/Q286R/M298Q, T128N/P129A/Q286R/M298Q/H373F, S52A/S60A/Q286R, Gla Swap FIX/S52A/S60A/S222A/Q286R, S52A/S60A/Q286R/M298Q, Gla Swap FIX/S52A/S60A/Q286R/M298Q, S52A/S60A/S222A/H257A/Q286R/M298Q, S52A/S60A/Q286R/H373F/, S52A/S60A/Q286R/M298Q/H373F, T239V/Q286R, Gla Swap FIX/S222A/T239V/Q286R, T239V/Q286R/M298Q, S222A/T239V/H257A/Q286R/M298Q, Gla Swap FIX/T239V/Q286R/M298Q, T239V/Q286R/H373F, T239V/Q286R/M298Q/H373F, T2391/Q286R, Gla Swap FIX/S222A/T2391/Q286R, T239I/Q286R/M298Q, S222A/T2391/H257A/Q286R/M298Q, Gla Swap FIX/T239I/Q286R/M298Q, T239I/Q286R/H373F, T239I/Q286R/M298Q/H373F, Gla Swap FIX/S222A/Q286R/H373F, Gla Swap FIX/S222A/Q286R/M298Q, Gla Swap FIX/S222A/Q286R/M298Q/H373F, V158D/Q286R/E296V/M298Q/H373F, H257A/Q286R/M298Q, H257S/Q286R/M298Q, Gla Swap FIX/S222A/H257S/Q286R/, S222A/H257S/Q286R/M298Q, H257S/Q286R/M298Q/H373F, S222A/Q286R/M298Q/H373F, S222A/Q286R/M298Q, T128N/P129A/A175S/Q286R, A122N/G124S/A175S/Q286R, Gla Swap FIX/T128N/P129A/A175S/S222A/Q286R, Gla Swap FIX/A122N/G124S/A175S/S222A/Q286R, T128N/P129A/A175S/Q286R/M298Q, A122N/G124S/A175S/Q286R/M298Q, T128N/P129A/A175S/S222A/H257A/Q286R/M298Q, A122N/G124S/A175S/S222A/H257A/Q286R/M298Q, T128N/P129A/A175S/Q286R/M298Q/H373F, A122N/G124S/A175S/Q286R/M298Q/H373F, {Gla Swap FIX/K43I}/T128N/P129A/Q286R/M298Q, T128N/P129A/Q286R/M298Q/Q366N, {Gla Swap FIX/K43I}/Q286R/M298Q/Q366N, {Gla Swap FIX/K43I}/T128N/P129A/Q286R/M298Q/Q366N, V158D/Q286R/E296V/M298Q, T128N/P129A/Q286R/M298Q/Q366N/H373F, T239V/Q286R/M298Q/Q366N, T239I/Q286R/M298Q/Q366N, T128N/P129A/T239V/Q286R/M298Q, T128N/P129A/S222A/T239V/H257A/Q286R/M298Q, T128N/P129A/T239V/Q286R/M298Q/H373F, T128N/P129A/T239I/Q286R/M298Q and T128N/P129A/T239I/Q286R/M298Q/H373F.

13. The modified FVII polypeptide of claim 12, wherein the modification is Q286R/M298Q.

52. The modified FVII polypeptide of claim 7, comprising 2, 3, 4, 5, 6, 7, 8 or more modifications.

53. The modified FVII polypeptide of claim 7, comprising a heterologous Gla domain, or a sufficient portion thereof to effect phospholipid binding.

54. The modified FVII polypeptide of claim 53, wherein the heterologous Gla domain is selected from among a Gla domain in Factor IX (FIX), Factor X (FX), prothrombin, protein C, protein S, osteocalcin, matrix Gla protein, Growth-arrest-specific protein 6 (Gas6) and protein Z.

55. The modified FVII polypeptide of claim 53, wherein the heterologous Gla domain has a sequence of amino acids set forth in any of SEQ ID NOS:

83-91, 93 and 94, or a sufficient portion thereof to effect phospholipid binding.

56. The modified FVII polypeptide of claim 53, wherein all or a contiguous portion of the native FVII Gla domain is removed and is replaced with the heterologous Gla domain, or a sufficient portion thereof to effect phospholipid binding.

57. The modified FVII polypeptide of claim 56, wherein the native FVII Gla domain includes amino acids 1-45 in a FVII polypeptide having a sequence of amino acids set forth in SEQ ID NO:

3, or in corresponding residues in a FVII polypeptide.

58. The modified FVII polypeptide of claim 53, wherein the heterologous Gla domain contains a modification compared to the wild-type form of the heterologous Gla domain.

59. The modified FVII polypeptide of claim 58, wherein:

the heterologous Gla domain is a FIX Gla domain; and

the modification is an amino acid replacement at a position corresponding to a position selected from among positions 19, 40, 43 and 44 of the FIX Gla domain set forth in SEQ ID NO;

83.

60. The modified FVII polypeptide of claim 59, wherein the modification is selected from among M19K, E40L, K431 and Q44S.

61. The modified FVII polypeptide of claim 59, wherein the heterologous Gla domain contains a further modification.

62. The modified FVII polypeptide of claim 61, wherein:

the heterologous Gla domain is a FIX Gla domain; and

the further modification is an amino acid replacement at a position corresponding to a position selected from among positions 19, 40, 43 and 44 of the FIX Gla domain set forth in SEQ ID NO;

83.

63. The modified FVII polypeptide of claim 61, wherein the further modification is selected from among M19K, E40L, K431 and Q44S.

64. The modified FVII polypeptide of any of claim 63, wherein the modification is M19K/E40L/K43I/Q44S.

76. The modified FVII polypeptide of any of claims 53, exhibiting increased affinity for or binding to phospholipids compared with the unmodified FVII polypeptide.

77. The modified FVII polypeptide of claim 76, wherein the modified FVII polypeptide exhibits at least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more increased affinity for or binding to phospholipids.

80. The modified FVII polypeptide of claim 1 that exhibits increased resistance to antithrombin III compared with the unmodified FVII polypeptide.

81. The modified FVII polypeptide of claim 80, wherein the modified FVII polypeptide exhibits at least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more increased resistance to antithrombin III compared with the unmodified FVII polypeptide.

82. The modified FVII polypeptide of claim 1 that exhibits increased catalytic activity compared with the unmodified FVII polypeptide.

83. The modified FVII polypeptide of claim 80, wherein catalytic activity of the modified FVII polypeptide is at least about or is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more greater than the catalytic of an unmodified FVII polypeptide.

84. The modified FVII polypeptide of claim 1 that exhibits increased resistance to TFPI compared with the unmodified FVII polypeptide.

85. The modified FVII polypeptide of claim 1, wherein the modified FVII polypeptide exhibits at least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more greater resistance to TFPI compared to an unmodified FVII polypeptide.

86. The modified FVII polypeptide of claim 1, that exhibits increased resistance to the inhibitory effects of Zn²⁺ compared with the unmodified FVII polypeptide.

87. The modified FVII polypeptide of claim 86, wherein the modified FVII polypeptide exhibits at least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more greater resistance to the inhibitory effects of Zn²⁺ compared to an unmodified FVII polypeptide.

88. The modified FVII polypeptide of claim 7, comprising one or more modifications that introduces and/or eliminates one or more glycosylation sites compared to the unmodified FVII polypeptide.

89. The modified FVII polypeptide of claim 88, wherein 1, 2, 3, 4, 5, 6, or more glycosylation sites are introduced.

90. The modified FVII polypeptide of claim 88, wherein 1, 2, 3, 4, 5, 6, or more glycosylation sites are eliminated.

91. The modified FVII polypeptide of claim 88, wherein the glycosylation site is an N-glycosylation site.

92. The modified FVII polypeptide of claim 88, wherein the glycosylation site is an O-glycosylation site.

93. The modified FVII polypeptide of claim 1, comprising one or more further amino acid modification(s) that increases resistance to antithrombin-III, increases binding and/or affinity to phospholipids, increases affinity for tissue factor, increases intrinsic activity, increases TF-dependent activity, increases coagulant activity, alters the conformation of the polypeptide to alter zymogenicity, increases catalytic or coagulant activity by shifting the equilibrium between highly active and less active FVIIa conformations in favor of the highly active conformations, increases resistance to proteases, decreases glycosylation, increases glycosylation, reduces immunogenicity, increases stability, and/or facilitates chemical group linkage.

94. The modified FVII polypeptide of claim 93, wherein the altered zymogenicity confers a more zymogen-like shape or a less zymogen-like shape.

95. The modified FVII polypeptide of claim 1, comprising one or more further amino acid modification(s) selected from among S278C/V302C, L279C/N301C, V280C/V301C, S281C/V299C, insertion of a tyrosine at position 4, F4S, F4T, P10Q, P10E, P10D, P10N, Q21N, R28F, R28E, I30C, I30D, I30E, K32D, K32Q, K32E, K32G, K32H, K32T, K32C, K32A, K32S, D33C, D33F, D33E, D33K, A34C, A34E, A34D, A34I, A34L, A34M, A34V, A34F, A34W, A34Y, R36D, R36E, T37C, T37D, T37E, K38C, K38E, K38T, K38D, K38L, K38G, K38A, K38S, K38N, K38H, L39E, L39Q, L39H, W41N, W41C, W41E, W41D, 142R, I42N, I42S, I42A, I42Q, I42N, I42S, I42A, I42Q, I42K, S43Q, S43N, Y44K, Y44C, Y44D, Y44E, S45C, S45D, S45E, D46C, A51N, S53N, G58N, G59S, G59T, K62E, K62R, K62D, K62N, K62Q, K62T, L65Q, L65S, L65N, F71D, F71Y, F71E, F71Q, F71N, P74S, P74A, A75E, A75D, E77A, E82Q, E82N, E82S, E82T, T83K, N95S, N95T, G97S, G97T, Y101N, D104N, T106N, K109N, E116D, G117N, G124N, S126N, T128N, L141C, L141D, L141E, E142D, E142C, K143C, K143D, K143E, R144E, R144C, R144D, N145Y, N145G, N145F, N145M, N145S, N145I, N145L, N145T, N145V, N145P, N145K, N145H, N145Q, N145E, N145R, N145W, N145D, N145C, K157V, K157L, K157I, K157M, K157F, K157W, K157P, K157G, K157S, K157T, K157C, K157Y, K157N, K157E, K157R, K157H, K157D, K157Q, V158L, V158I, V158M, V158F, V158W, V158P, V158G, V158S, V158T, V158C, V158Y, V158N, V158E, V158R, V158K, V158H, V158D, V158Q, A175S, A175T, G179N, I186S, I186T, V188N, R202S, R202T, I205S, I205T, D212N, E220N, I230N, P231N, P236N, G237N, Q250C, V253N, E265N, T267N, E270N, A274M, A274L, A274K, A274R, A274D, A274V, A2741, A274F, A274W, A274P, A274G, A274T, A274C, A274Y, A274N, A274E, A274H, A274S, A274Q, F275H, R277N, F278S, F278A. F278N, F278Q, F278G, L280N, L288K, L288C, L288D, D289C, D289K, L288E, R290C, R290G, R290A, R290S, R290T, R290K, R290D, R290E, G291E, G291D, G291C, G291N, G291K, A292C, A292K, A292D, A292E, T293K, E296V, E296L, E2961, E296M, E296F, E296W, E296P, E296G, E296S, E296T, E296C, E296Y, E296N, E296K, E296R, E296H, E296D, E296Q, M298Q, M298V, M298L, M2981, M298F, M298W, M298P, M298G, M298S, M298T, M298C, M298Y, M298N, M298K, M298R, M298H, M298E, M298D, P303S, P303ST, R304Y, R304F, R304L, R304M, R304G, R304T, R304A, R304S, R304N, L305V, L305Y, L3051, L305F, L305A, L305M, L305W, L305P, L305G, L305S, L305T, L305C, L305N, L305E, L305K, L305R, L305H, L305D, L305Q, M306D, M306N, D309S, D309T, Q312N, Q313K, Q313D, Q313E, S314A, S314V, S314I, S314M, S314F, S314W, S314P, S314G, S314L, S314T, S314C, S314Y, S314N, S314E, S314K, S314R, S314H, S314D, S314Q, R315K, R315G, R315A, R315S, R315T, R315Q, R315C, R315D, R315E, K316D, K316C, K316E, V317C, V317K, V317D, V317E, G318N, N322Y, N322G, N322F, N322M, N322S, N322I, N322L, N322T, N322V, N322P, N322K, N322H, N322Q, N322E, N322R, N322W, N322C, G331N, Y332S, Y332A, Y332N, Y332Q, Y332G, D334G, D334E, D334A, D334V, D334I, D334M, D334F, D334W, D334P, D334L, D334T, D334C, D334Y, D334N, D334K, D334R, D334H, D334S, D334Q, S336G, S336E, S336A, S336V, S336I, S336M, S336F, S336W, S336P, S336L, S336T, S336C, S336Y, S336N, S336K, S336R, S336H, S336D, S336Q, K337L, K337V, K337I, K337M, K337F, K337W, K337P, K337G, K337S, K337T, K337C, K337Y, K337N, K337E, K337R, K337H, K337D, K337Q, K341E, K341Q, K341G, K341T, K341A, K341S, G342N, H348N, R353N, Y357N, I361N, F374P, F374A, F374V, F374I, F374L, F374M, F374W, F374G, F374S, F374T, F374C, F374Y, F374N, F374E, F374K, F374R, F374H, F374D, F374Q, V376N, R379N, L390C, L390K, L390D, L390E, M391D, M391C, M391K, M391N, M391E, R392C, R392D, R392E, S393D, S393C, S393K, S393E, E394K, P395K, E394C, P395D, P395C, P395E, R396K, R396C, R396D, R396E, P397D, P397K, P397C, P397E, G398K, G398C, G398D, G398E, V399C, V399D, V399K, V399E, L400K, L401K, L401C, L401D, L401E, R402D, R402C, R402K, R402E, A403K, A403C, A403D, A403E, P404E, P404D, P404C, P404K, F405K, P406C, K32N/A34S, K32N/A34T, F31N/D33S, F31N/D33T, 130N/K32S, I30N/K32T, A34N/R36S, A34N/R36T, K38N/F40S, K38N/F40T, T37N/L39S, T37N/L39T, R36N/K38S, R36N/K38T, L39N/W41S, L39N/W41T, F40N/I42S, F40N/I42T, I42N/Y44S, I42N/Y44T, Y44N/D46S, Y44N/D46T, D46N/D48S, D46N/D48T, G47N/Q49S, G47N/Q49T, K143N/N145S, K143N/N145T, E142N/R144S, E142N/R144T, L141N/K143S, L141N/K143T, I140N/E142S, I140N/E142T, R144N/A146S, R144N/A146T, A146N/K148S, A146N/K148T, S147N/P149S/, S147N/P149T, R290N/A292S, R290N/A292T, D289N/G291S, D289N/G291T, L288N/R290S, L288N/R290T, L287N/D289S, L287N/D289, A292N/A294S, A292N/A294T, T293N/L295S, T293N/L295T, R315N/V317S, R315N/V317T, S314N/K316S, S314N/K316T, Q313N/R315S, Q313N/R315T, K316N/G318S, K316N/G318T, V317N/D319S, V317N/D319T, K341N/D343S, K341N/D343T, S339N/K341S, S339N/K341T, D343N/G345S, D343N/G345T, R392N/E394S, R392N/E394T, L390N/R392S, L390N/R392T, K389N/M391S, K389N/M391T, S393N/P395S, S393N/P395T, E394N/R396S, E394N/R396T, P395N/P397S, P395N/P397T, R396N/G398S, R396N/G398T, P397N/V399S, P397N/V399T, G398N/L400S, G398N/L400T, V399N/L401S, V399N/L401T, L400N/R402S, L400N/R402T, L401N/A403S, L401N/A403T, R402N/P404S, R402N/P404T, A403N/F405S, A403N/F405T, P404N/P406S and P404N/P406T.

96. The modified FVII polypeptide of claim 1, comprising substitution of positions 300-322, 305-322, 300-312, or 305-312 with the corresponding amino acids from trypsin, thrombin or FX, or substitution of positions 310-329, 311-322 or 233-329 with the corresponding amino acids from trypsin.

97. The modified FVII polypeptide of claim 1, wherein the unmodified FVII polypeptide has a sequence of amino acids set forth in SEQ ID NO:

3.

98. The modified FVII polypeptide of claim 97 having a sequence of amino acids set forth in any of SEQ ID NOS:

113-157 or 159-342.

99. The modified FVII polypeptide of claim 1, wherein the unmodified FVII polypeptide is an allelic or species variant of the polypeptide set forth in SEQ ID NO:

3.

100. The modified FVII polypeptide of claim 99, wherein the allelic or species variant has 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the polypeptide set forth in SEQ ID NO:

3, excluding the amino acid modification(s).

101. The modified FVII polypeptide of claim 1 that is a human polypeptide.

102. The modified FVII polypeptide of claim 1 that is a non-human polypeptide.

103. The modified FVII polypeptide of claim 1 that is a mature polypeptide.

104. The modified FVII polypeptide of claim 1, wherein only the primary sequence is modified.

105. The modified FVII polypeptide of claim 1, further comprising a chemical modification or a post-translational modification.

106. The modified FVII polypeptide of claim 1, wherein the FVII polypeptide is glycosylated, carboxylated, hydroxylated, sulfated, phosphorylated, albuminated, or conjugated to a polyethylene glycol (PEG) moiety.

107. The modified FVII polypeptide of claim 1 that is a single-chain polypeptide.

108. The modified FVII polypeptide of claim 1 that is a two-chain polypeptide.

109. The modified FVII polypeptide of claim 1 that is active or activated.

110. The modified FVII polypeptide of claim 109, wherein activation is effected by proteolytic cleavage by autoactivation, cleavage by Factor IX (FIXa), cleavage by Factor X (FXa), cleavage by Factor XII (FXIIa), or cleavage by thrombin.

111. The modified FVII polypeptide of claim 1 that retains one or more activities of the unmodified FVII polypeptide.

112. The modified FVII polypeptide of claim 1, comprising modifications at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 or 60 amino acid positions so long as the polypeptide retains at least one FVII activity of the unmodified FVII polypeptide.

113. The modified FVII polypeptide of claim 111, wherein the modified polypeptide retains at least about or 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500%, or more of an activity of the unmodified FVII polypeptide.

114. The modified FVII polypeptide of claim 111, wherein the one or more activities are selected from among tissue factor (TF) binding, factor X (FX) activation, Factor IX (FIX) activation and phospholipid binding.

115. The modified FVII polypeptide of claim 111, wherein the activities that are retained are increased compared to the unmodified FVII polypeptide.

116. The modified FVII polypeptide of claim 111, wherein the activities that are retained are decreased compared to the unmodified FVII polypeptide.

117. The modified FVII polypeptide of claim 1, wherein coagulation activity of the modified FVII polypeptide is at least about or is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more of the coagulation activity of the unmodified FVII polypeptide.

118. The modified polypeptide of claim 111, wherein the activity is measured in vitro, ex vivo or in vivo.

119. A nucleic acid molecule, comprising a sequence of nucleotides encoding a modified FVII polypeptide of claim 1.

120. A vector, comprising the nucleic acid molecule of claim 119.

121. The vector of claim 120, wherein the vector is a prokaryotic vector, viral vector, or a eukaryotic vector.

122. The vector of claim 120, wherein the vector is a mammalian vector.

123. The vector of claim 121, wherein the viral vector is selected from among an adenovirus, an adeno-associated-virus, a retrovirus, a herpes virus, a lentivirus, a poxvirus, and a cytomegalovirus.

124. A cell, comprising the vector of claim 120.

125. The cell of claim 124, that is a eukaryotic cell.

126. The cell of claim 125, wherein the eukaryotic cell is a mammalian cell.

127. The cell of claim 126, wherein the mammalian cell is selected from among baby hamster kidney cells (BHK-21) or 293 cells or CHO cells.

128. The cell of claim 124, wherein the cell expresses the modified FVII polypeptide.

129. A modified FVII polypeptide that is produced by the cell of claim 124.

130. A pharmaceutical composition, comprising a therapeutically effective concentration or amount of a modified FVII polypeptide of claim 1, in a pharmaceutically acceptable vehicle.

131. The pharmaceutical composition of claim 130 that is formulated for local, systemic, or topical administration.

132. The pharmaceutical composition of claim 130 that is formulated for oral, nasal, pulmonary buccal, transdermal, subcutaneous, intraduodenal, enteral, parenteral, intravenous, or intramuscular administration.

133. The pharmaceutical composition of claim 130 that is formulated for controlled-release.

134. The pharmaceutical composition of claim 130 that is formulated for single-dosage administration.

135. A method, comprising treating a subject by administering the pharmaceutical composition of claim 130, wherein the subject has a disease or condition that is treated by administration of FVII or a procoagulant.

136. The method of claim 135, wherein the disease or condition is treated by administration of active FVII (FVIIa).

137. The method of claim 135, wherein treatment with the pharmaceutical composition ameliorates or alleviates the symptoms associated with the disease or condition.

138. The method of claim 135, further comprising monitoring the subject for changes in the symptoms associated with disease or condition that is treated by administration of FVII or a procoagulant.

139. The method of claim 135, wherein the disease or condition to be treated is selected from among blood coagulation disorders, hematologic disorders, hemorrhagic disorders, hemophilias, factor VII deficiency and bleeding disorders.

140. The method of claim 139, wherein the hemophilia is hemophilia A or hemophilia B or hemophilia C.

141. The method of claim 140, wherein the hemophilia is congenital.

142. The method of claim 140, wherein the hemophilia is acquired.

143. The method of claim 135, wherein the disease or condition is due to a bleeding complication due to surgery or trauma.

144. The method of claim 143, wherein the bleeding is manifested as acute haemarthroses, chronic haemophilic arthropathy, haematomas, haematuria, central nervous system bleedings, gastrointestinal bleedings, or cerebral haemorrhage.

145. The method of claim 143, wherein the bleeding is due to dental extraction.

146. The method of claim 143, wherein the surgery is heart surgery, angioplasty, lung surgery, abdominal surgery, spinal surgery, brain surgery, vascular surgery, dental surgery, or organ transplant surgery.

147. The method of claim 146, wherein the transplant surgery is selected from among transplantation of bone marrow, heart, lung, pancreas, and liver.

148. The method of claim 135, wherein the subject has autoantibodies to factor VIII or factor IX.

149. The method of claim 135, further comprising administering one or more additional coagulation factors.

150. The method of claim 149, wherein the one or more additional coagulation factors are selected from among plasma purified or recombinant coagulation factors, procoagulants, such as vitamin K, vitamin K derivative and protein C inhibitors, plasma, platelets, red blood cells and corticosteroids.

151. An article of manufacture, comprising packaging material and the pharmaceutical composition of claim 130 contained within the packaging material.

152. The article of manufacture of claim 151, wherein:

the modified FVII polypeptide is effective for treatment of a FVII-mediated disease or disorder, and the packaging material includes a label that indicates that the modified FVII polypeptide is used for treatment of a FVII-mediated disease or disorder.

153. A kit, comprising the pharmaceutical composition of claim 130, a device for administration of the composition and, optionally, instructions for administration.

14. A modified FVII polypeptide, comprising two or more modifications in a FVII polypeptide, allelic or species variant thereof or active fragment thereof, wherein:

one of the modifications is at a position corresponding to position Q286 in a FVII polypeptide having a sequence of amino acids set forth in SEQ ID NO;

3 or in corresponding residues in a FVII polypeptide;

the modification at position Q286, alone or in combination with any other modification, does not result in introduction of a new glycosylation site compared to the unmodified FVII polypeptide; and

the modified FVII polypeptide exhibits increased coagulant activity compared to the FVII polypeptide that does not have the modification at position 286.

15. The modified FVII polypeptide of claim 14, wherein the modifications are an amino acid replacement, insertion or deletion.

16. The modified FVII polypeptide of claim 15, wherein the modification is a replacement at a position corresponding to position Q286 in a FVII polypeptide having a sequence of amino acids set forth in SEQ ID NO:

3 or in corresponding residues in a FVII polypeptide is replacement by an amino acid selected from among Arg (R), Lys (K) His (H), Tyr (Y), Gly (G), Phe (F), Met (M), Ile (I), Leu (L), Val (V), Pro (P), Gle (E), Trp (W), Asp (D), and Cys (C).

17. The modified FVII polypeptide of claim 16, wherein the modification is Q286R.

18. The modified FVII polypeptide of claim 14, wherein one of the modifications is selected from among D196K, D196R, D196A, D196Y, D196F, D196W, D196L, D196I, K197Y, K197A, K197E, K197D, K197L, K197M, K197I, K197V, K197F, K197W, K199A, K199D, K199E, G237W, G237T, G237I, G237V, T239A, R290A, R290E, R290D, R290N, R290Q, R290K, R290M, R290V, K341E, K341R, K341Q, K341N, K341M, K341D, G237T238insA, G237T238insS, G237T238insV, G237T238insAS, G237T238insSA, D196K197insK, D196K197insR, D196K197insY, D196K197insW, D196K197insA, D196K197insM, K197I198insE, K197I198insY, K197I198insA, K197I198insS, T239S, T239N, T239Q, T239V, T239L, T239H, T239I, L287T, P321K, P321E, P321Y, P321S, Q366D, Q366E, Q366N, Q366T, Q366S, Q366V, Q366I, Q366L, Q366M, H373D, H373E, H373S, H373F, H373A, K161S, K161A, K161V, H216S, H216A, H216K, H216R, S222A, S222K, S222V, S222N, S222E, S222D, H257A, H257S, Gla Swap FIX, {Gla Swap FIX/E40L}, {Gla Swap FIX/K43I}, {Gla Swap FIX/Q44S}, {Gla Swap FIX/M19K}, {Gla Swap FIX/M19K/E40L/K431/Q44S}, Gla Swap FX, Gla Swap Prot C, Gla Swap Prot S, Gla Swap Thrombin, S52A, S60A, E394N, P395A, R396S, R202S, A292N, A294S, G318N, A175S, K109N, A122N, G124S, A51N, T130N, E132S, S52N, P54S, S119N, L121S, T128N, P129A, Q66N, Y68S, S103S111delinsQRLMEDICLPRWGCLWEDDF, H115S126delinsQRLMEDICLPRWGCLWEDDF, T128P134delinsQRLMEDICLPRWGCLWEDDF, S103S111delinsIEDICLPRWGCLWE, H115S126delinsIEDICLPRWGCLWE, T128P134delinsIEDICLPRWGCLWE, S103S111delinsDICLPRWGCLWED, H115S126delinsDICLPRWGCLWED, T128P134delinsDICLPRWGCLWED, P406insIEDICLPRWGCLW, P406insGGGSIEDICLPRWGCLW, P406insDICLPRWGCLWED, P406insGGGSDICLPRWGCLWED, S103S111delinsSFGRGDIRNV, H115S126delinsSFGRGDIRNV, T127P134delinsSFGRGDIRNV, P406insCSFGRGDIRNVC, P406insGGGSCSFGRGDIRNVC, V158T, V158D, L287T, E296V, M298K and M298Q.

19. A modified FVII polypeptide, comprising modifications in a FVII polypeptide selected from among Q286R/Gla Swap FIX, Q286R/H257A, Q286R/S222A, Q286R/S222A/H257, Q286R/S222A/Gla Swap FIX, Q286R/H257A/Gla Swap FIX, Q286R/S222A/H257A/Gla Swap FIX, Q286R/M298Q, Q286R/M298Q/K341Q, Q286R/M298Q/K199E, Q286R/M298Q/Gla Swap FIX, Q286R/Q366V, Q286R/A292N/A294S/Q366V, A175S/Q286R/Q366V, S222A/Q286R/Q366V, H257S/Q286R, H257S/Q286R/Q366V, S222A/H257A/Q286R/Q366V, Q286R/H373A, S222A/H257A/Q286R/M298Q, V158D/E296V/M298Q, {Gla Swap FIX/E40L}/Q286R/M298Q, {Gla Swap FIX/K43I}/Q286R/M298Q, {Gla Swap FIX/Q44S}/Q286R/M298Q, {Gla Swap FIX/M19K}/Q286R/M298Q, {Gla Swap FIX/M19K/E40L/K43I/Q44S}/Q286R/M298Q, T128N/P129A/Q286R, T128N/P129A/Q286R/M298Q, T128N/P129A/Q286R/H373F, V158D/Q286R/E296V/M298Q, Gla Swap FIX/T128N/P129A/S222A/Q286R, Gla Swap FIX/T128N/P129A/Q286R/M298Q, T128N/P129A/S222A/H257A/Q286R/M298Q, T128N/P129A/Q286R/M298Q/H373F, S52A/S60A/Q286R, Gla Swap FIX/S52A/S60A/S222A/Q286R, S52A/S60A/Q286R/M298Q, Gla Swap FIX/S52A/S60A/Q286R/M298Q, S52A/S60A/S222A/H257A/Q286R/M298Q, S52A/S60A/Q286R/H373F/, S52A/S60A/Q286R/M298Q/H373F, T239V/Q286R, Gla Swap FIX/S222A/T239V/Q286R, T239V/Q286R/M298Q, S222A/T239V/H257A/Q286R/M298Q, Gla Swap FIX/T239V/Q286R/M298Q, T239V/Q286R/H373F, T239V/Q286R/M298Q/H373F, T239I/Q286R, Gla Swap FIX/S222A/T2391/Q286R, T239I/Q286R/M298Q, S222A/T239I/H257A/Q286R/M298Q, Gla Swap FIX/T2391/Q286R/M298Q, T239I/Q286R/H373F, T239I/Q286R/M298Q/H373F, Gla Swap FIX/S222A/Q286R/H373F, Gla Swap FIX/S222A/Q286R/M298Q, Gla Swap FIX/S222A/Q286R/M298Q/H373F, V158D/Q286R/E296V/M298Q/H373F, H257A/Q286R/M298Q, H257S/Q286R/M298Q, Gla Swap FIX/S222A/H257S/Q286R/, S222A/H257S/Q286R/M298Q, H257S/Q286R/M298Q/H373F, S222A/Q286R/M298Q/H373F, S222A/Q286R/M298Q, T128N/P129A/A175S/Q286R, A122N/G124S/A175S/Q286R, Gla Swap FIX/T128N/P129A/A175S/S222A/Q286R, Gla Swap FIX/A122N/G124S/A175S/S222A/Q286R, T128N/P129A/A175S/Q286R/M298Q, A122N/G124S/A175S/Q286R/M298Q, T128N/P129A/A175S/S222A/H257A/Q286R/M298Q, A122N/G124S/A175S/S222A/H257A/Q286R/M298Q, T128N/P129A/A175S/Q286R/M298Q/H373F, A122N/G124S/A175S/Q286R/M298Q/H373F, {Gla Swap FIX/K43I}/T128N/P129A/Q286R/M298Q, T128N/P129A/Q286R/M298Q/Q366N, {Gla Swap FIX/K43I}/Q286R/M298Q/Q366N, {Gla Swap FIX/K43I}/T128N/P129A/Q286R/M298Q/Q366N, V158D/Q286R/E296V/M298Q, T128N/P129A/Q286R/M298Q/Q366N/H373F, T239V/Q286R/M298Q/Q366N, T239I/Q286R/M298Q/Q366N, T128N/P129A/T239V/Q286R/M298Q, T128N/P129A/S222A/T239V/H257A/Q286R/M298Q, T128N/P129A/T239V/Q286R/M298Q/H373F, T128N/P129A/T239I/Q286R/M298Q and T128N/P129A/T239I/Q286R/M298Q/H373F.

20. The modified FVII polypeptide of claim 19, wherein the unmodified FVII polypeptide comprises a sequence of amino acids set forth in any of SEQ ID NOS:

1-3, 18-74, 98, 158 or 343-353, or is an allelic or species variant thereof, or a variant having at least 60% sequence identity with the FVII of any of SEQ ID NOS;

1-3, 18-74, 98, 158 or 343-33, or is an active fragment of a FVII polypeptide that comprises a sequence of amino acids set forth in any SEQ ID NOS;

1-3, 18-74, 98, 158 or 343-353.

21. A modified FVII polypeptide, comprising a modification in a FVII polypeptide, wherein the modification is at a position corresponding to a position selected from among 54, 66, 121, 122, 129 and 132 in a FVII polypeptide having a sequence of amino acids set forth in SEQ ID NO:

3 or in corresponding residues in a FVII polypeptide.

22. The modified FVII polypeptide of claim 21, wherein the modification is selected from among P54S, Q66N, L121S, A122N, P129A and E132S.

23. The modified FVII polypeptide of any of claim 21, comprising one or more further modifications at another position in the FVII polypeptide.

24. The modified FVII polypeptide of claim 23, wherein the further modification is an amino acid replacement, insertion or deletion.

25. The modified FVII polypeptide of claim 23, wherein one of the further modifications is selected from among P54S, S52N, Y58S, S119N, G124S, T128N, T130N, V158D, A175S, S222A, G241S, E296V, M298Q, E394N, P395A, R396S, G318N and Q366V.

26. The modified FVII polypeptide of claim 25, comprising modifications selected from among S119N/L121S, T128N/P129A, A122N/G124S, A122N/G124S/A175S, A122N/G124S/E394N/P395A/R396S, A122N/G124S/E394N/P395A/R396S/G318N, A122N/G124S/E394N/P395A/R396S, S52N/P54S/A122N/G124S/E394N/P395A/R396S, S52N/P54S, S119N/L121S/A175S, T128N/P129A/A175S, T130N/E132S, Q66N/Y68S, T128N/P129A/V158D/E296V/M298Q, T128N/P129A/S222A, T128N/P129A/A175S/Q366V, A122N/G124S/A175S/Q366V, T128N/P129A/A175S/S222A, A122N/G124S/A175S/S222A, T128N/P129A/M298Q and T128N/P129A/M298Q/H373F.

27. A modified FVII polypeptide, comprising a modification in a FVII polypeptide, wherein the modification corresponds to a modification selected from among T239S, T239Q, T239V, T239L, T239H, T239I, P321K, P321E, P321Y, P321S, Q366D, Q366N, Q366V, Q366I, Q366L, Q366M, H373D, H373E, H373S, H373F, H373A, K161S, K161V, H216S, H216K, H216R, S222A, S222K, S222V, S222D, S222N, S222E and H247S in a FVII polypeptide having a sequence of amino acids set forth in SEQ ID NO:

3 or in corresponding residues in a FVII polypeptide.

28. The modified FVII polypeptide of claim 27, comprising one or more further modifications at another position in the FVII polypeptide.

29. The modified FVII polypeptide of claim 28, wherein one of the further modifications is an amino acid replacement at a position corresponding to a position selected from among 51, 52, 54, 60, 66, 68, 109, 119, 122, 124, 130, 132, 158, 161, 175, 196, 197, 199, 202, 216, 222, 237, 239, 257, 286, 287, 290 292, 294, 296, 298, 305, 314, 318, 321, 337, 341, 366, 373, 374, 394, 395 and 396.

30. The modified FVII polypeptide of claim 28, wherein one of the further amino acid modifications is selected from among Q286N, Q286E, Q286D, Q286S, Q286T, Q286R, Q286K, Q286A, Q286V, Q286M, Q286L, Q286Y, D196K, D196R, D196A, D196Y, D196F, D196W, D196L, D196I, K197Y, K197A, K197E, K197D, K197L, K197M, K197I, K197V, K197F, K197W, K199A, K199D, K199E, G237W, G237T, G237I, G237V, T239A, R290A, R290E, R290D, R290N, R290Q, R290K, R290M, R290V, K341E, K341R, K341Q, K341N, K341M, K341D, G237T238insA, G237T238insS, G237T238insV, G237T238insAS, G237T238insSA, D196K197insK, D196K197insR, D196K197insY, D196K197insW, D196K197insA, D196K197insM, K197I198insE, K197I198insY, K197I198insA, K197I198insS, T239S, T239N, T239Q, T239V, T239L, T239H, T239I, L287T, P321K, P321E, P321Y, P321S, Q366D, Q366E, Q366N, Q366T, Q366S, Q366V, Q366I, Q366L, Q366M, H373D, H373E, H373S, H373F, H373A, K161S, K161A, K161V, H216S, H216A, H216K, H216R, S222A, S222K, S222V, S222N, S222E, S222D, H257A, H257S, Gla swap FIX, Gla swap FX, Gla Swap Prot C, Gla Swap Prot S, Gla swap Thrombin, Gla Swap FIX, {Gla Swap FIX/E40L}, {Gla Swap FIX/K43I}, {Gla Swap FIX/Q44S}, {Gla Swap FIX/M19K}, {Gla Swap FIX/M19K/E40L/K43I/Q44S}, S52A, S60A, E394N, P395A, R396S, R202S, A292N, A294S, G318N, A175S, K109N, A122N, G124S, A51N, T130N, E132S, S52N, P54S, S119N, L121S, T128N, P129A, Q66N, Y68S, S103S111delinsQRLMEDICLPRWGCLWEDDF, H115S126delinsQRLMEDICLPRWGCLWEDDF, T128P134delinsQRLMEDICLPRWGCLWEDDF, S103S111delinsIEDICLPRWGCLWE, H115S126delinsIEDICLPRWGCLWE, T128P134delinsIEDICLPRWGCLWE, S103S111delinsDICLPRWGCLWED, H115S126delinsDICLPRWGCLWED, T128P134delinsDICLPRWGCLWED, P406insIEDICLPRWGCLW, P406insGGGSIEDICLPRWGCLW, P406insDICLPRWGCLWED, P406insGGGSDICLPRWGCLWED, S103S111delinsSFGRGDIRNV, H115S126delinsSFGRGDIRNV, T127P134delinsSFGRGDIRNV, P406insCSFGRGDIRNVC, P406insGGGSCSFGRGDIRNVC, V158T, V158D, L287T, M298K and M298Q.

31. The modified FVII polypeptide of claim 30, comprising modifications selected from among Q366D/H373E, Q366V/H373V, Q366V/H373L, Q366V/H3731, S222K/H257A, H216A/S222A, S222S/Gla Swap FIX, S222A/H257A/Gla Swap FIX, S222A/M298Q, S222A/H257A/M298Q, S222A/A292N/A294S/Q366V, A175S/S222A/Q366V, S222A/Q366V, H257S/Q366V, S222A/H373A, M298Q/H373F, S52A/S60A/S222A, S222A/T239V, VI 58D/T239V/E296V/M298Q, S222A/T239I, V158D/E296V/M298Q/H373F, Gla Swap FIX/Q366V, M298Q/Q366N/H373F, T239V/M298Q/H373F and T239I/M298Q/H373F.

32. A modified FVII polypeptide, comprising two or more modifications in a FVII polypeptide, allelic or species variant thereof or active fragments thereof, wherein:

the two or more amino acid modifications are selected from among amino acid modifications corresponding to H216A, H257A, E394N, P395A, R396S, K109N, A292N, A175S, H257A and Gla Swap FIX.

33. The modified FVII polypeptide of claim 32, comprising modifications selected from among H216A/H257A, E394N/P395A/R396S and K109N/A175S.

34. The modified FVII polypeptide of claim 32, further comprising a modification corresponding to M298Q or A294S.

35. The modified FVII polypeptide of claim 34, comprising modifications selected from among H257A/M298Q, and K109N/A292N/A294S.

36. A modified FVII polypeptide, comprising modifications in a FVII polypeptide, allelic and species variant thereof or active fragments thereof corresponding to S52A/S60A/V158D/E296V/M298Q or V158D/T239I/E296V/M298.

37. A modified FVII polypeptide, comprising a serum albumin binding sequence in a FVII polypeptide, allelic and species variant thereof or active fragments thereof.

38. The modified FVII polypeptide of claim 37, wherein the serum albumin binding sequence has a sequence of amino acids set forth in any of SEQ ID NOS:

103-109, or a sufficient portion thereof to effect serum albumin binding.

39. The modified FVII polypeptide of claim 37, wherein the serum albumin binding sequence replaces a contiguous sequence of amino acid residues of the unmodified FVII polypeptide.

40. The modified FVII polypeptide of claim 37, comprising a modification selected from among S103S111 delinsQRLMEDICLPRWGCLWEDDF, H115S126delinsQRLMEDICLPRWGCLWEDDF, T128P134delinsQRLMEDICLPRWGCLWEDDF, S103S111delinsIEDICLPRWGCLWE, H115S126delinsIEDICLPRWGCLWE, T128P134delinsIEDICLPRWGCLWE, S103S111delinsDICLPRWGCLWED, H115S126delinsDICLPRWGCLWED, T128P134delinsDICLPRWGCLWED, P406insIEDICLPRWGCLW, P406insGGGSIEDICLPRWGCLW, P406insDICLPRWGCLWED and P406insGGGSDICLPRWGCLWED.

41. The modified FVII polypeptide of claim 37, exhibiting increased affinity for or binding to serum albumin binding compared with the unmodified FVII polypeptide.

42. The modified FVII polypeptide of claim 41, wherein the modified FVII polypeptide exhibits at least about or 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more increased affinity for or binding to serum albumin binding.

49. The modified polypeptide of claim 37, comprising one or more further modifications at another position in the FVII polypeptide.

50. The modified FVII polypeptide of claim 49, wherein the further modification is an amino acid replacement at a position corresponding to a position G237V.

51. The modified FVII polypeptide of claim 50, comprising a modification selected from among S103S111delinsIEDICLPRWGCLWE/G237V, S103S111delinsDICLPRWGCLWED/G237V, H115S126delinsQRLMEDICLPRWGCLWEDDF/G237V, H115S126delinsIEDICLPRWGCLWE/G237V, H115S126delinsDICLPRWGCLWED/G237V, T128P134delinsQRLMEDICLPRWGCLWEDDF/G237V, T128P134delinsIEDICLPRWGCLWE/G237V, S103S111delinsQRLMEDICLPRWGCLWEDDF/G237V and T128P134delinsDICLPRWGCLWED/G237V.

43. A modified FVII polypeptide, comprising a platelet integrin α

IIbβ

3 binding sequence in a FVII polypeptide, allelic and species variant thereof or active fragments thereof.

44. The modified FVII polypeptide of claim 43, wherein the serum albumin binding sequence has a sequence of amino acids set forth in any of SEQ ID NOS:

110-112, or a sufficient portion thereof to effect platelet integrin α

IIbβ

3 binding.

45. The modified FVII polypeptide of claim 43, wherein the serum albumin binding sequence replaces a contiguous sequence of amino acid residues of the unmodified FVII polypeptide.

46. The modified FVII polypeptide of claim 43, comprising a modification selected from among S103S111 delinsSFGRGDIRNV, H115S126delinsSFGRGDIRNV, T127P134delinsSFGRGDIRNV, P406insCSFGRGDIRNVC and P406insGGGSCSFGRGDIRNVC.

47. The modified FVII polypeptide of claim 43, exhibiting increased affinity for or binding to platelet integrin α

IIbβ

3 compared with the unmodified FVII polypeptide.

48. The modified FVII polypeptide of claim 47, wherein the modified FVII polypeptide exhibits at least about or 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500% or more increased affinity for or binding to platelet integrin α

IIbβ

3 binding.

65. A modified FVII polypeptide, comprising a heterologous Gla domain or a sufficient portion thereof to effect phospholipid binding, wherein the heterologous Gla domain comprises a modification, whereby

binding to or affinity for platelets is increased compared to a FVII polypeptide with an unmodified heterologous Gla domain, or

the heterologous Gla domain contains one or modifications compared to the corresponding wild-type form of the heterologous Gla domain.

66. The modified FVII polypeptide of claim 65, wherein the heterologous Gla domain is selected from among a Gla domain in Factor IX (FIX), Factor X (FX), prothrombin, protein C, protein S, osteocalcin, matrix Gla protein, Growth-arrest-specific protein 6 (Gas6) and protein Z.

67. The modified FVII polypeptide of claim 65, wherein the unmodified or wild-type heterologous Gla domain has a sequence of amino acids set forth in any of SEQ ID NOS:

83-91, 93 and 94, or a sufficient portion thereof to effect phospholipid binding.

68. The modified FVII polypeptide of claim 65, wherein all or a contiguous portion of the native FVII Gla domain is removed and is replaced with the heterologous Gla domain, or a sufficient portion thereof to effect phospholipid binding.

69. The modified FVII polypeptide of claim 68, wherein the native FVII Gla domain includes amino acids 1-45 in a FVII polypeptide having a sequence of amino acids set forth in SEQ ID NO:

3, or in corresponding residues in a FVII polypeptide.

70. The modified FVII polypeptide of claim 65, wherein:

the heterologous Gla domain is a FIX Gla domain; and

the modification is an amino acid replacement at a position corresponding to a position selected from among positions 19, 40, 43 and 44 of the FIX Gla domain set forth in SEQ ID NO;

83.

71. The modified FVII polypeptide of claim 70, wherein the modification is selected from among M19K, E40L, K431 and Q44S.

72. The modified FVII polypeptide of claim 65, wherein the heterologous Gla domain contains a further modification.

73. The modified FVII polypeptide of claim 72, wherein:

the heterologous Gla domain is a FIX Gla domain, and the further modification is an amino acid replacement at a position corresponding to a position selected from among positions 19, 40, 43 and 44 of the FIX Gla domain set forth in SEQ ID NO;

83.

74. The modified FVII polypeptide of claim 73, wherein the further modification is selected from among M19K, E40L, K431 and Q44S.

75. The modified FVII polypeptide of claims 73, wherein the modification is M19K/E40L/K431/Q44S.

78. The modified FVII polypeptide of claims 65, exhibiting increased affinity for or binding to phospholipids compared with the unmodified FVII polypeptide.

79. The modified FVII polypeptide of claim 78, wherein the modified FVII polypeptide exhibits at least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%,