The anticoagulant function of coagulation factor V

Thrombosis and Haemostasis

Volumn 107, Issue 1, 2012, Pages 15-21

  Cramer, Thomas J ^a   Gale, Andrew J ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

Activated protein C; Anticoagulant; APC resistance; Factor V; Protein S

Indexed keywords

ACTIVATED PROTEIN C; BLOOD CLOTTING FACTOR 5; BLOOD CLOTTING FACTOR 5 LEIDEN; BLOOD CLOTTING FACTOR 5A; BLOOD CLOTTING FACTOR 7A; MUTANT PROTEIN; PROTEIN S;

AMINO ACID SUBSTITUTION; ANTICOAGULANT FUNCTION; ANTICOAGULATION; ARTICLE; CARBOXY TERMINAL SEQUENCE; CAUCASIAN; GENE MUTATION; HETEROZYGOTE; HUMAN; PHOSPHOLIPID MEMBRANE; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DOMAIN; PROTEIN FUNCTION; THROMBOSIS;

ANTICOAGULANTS; BLOOD COAGULATION; CATALYTIC DOMAIN; CELL MEMBRANE; FACTOR V; HAPLOTYPES; HUMANS; MODELS, BIOLOGICAL; MUTATION; PHOSPHOLIPIDS; PROTEIN C; PROTEIN STRUCTURE, TERTIARY;

EID: 84855307880     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/TH11-06-0431     Document Type: Article

References (110)

1. Owren PA. Parahaemophilia; haemorrhagic diathesis due to absence of a previously unknown clotting factor. Lancet 1947; 1: 446-448
2. Stormorken H. The discovery of factor V: a tricky clotting factor. J Thromb Haemost 2003; 1: 206-213
3. Dahlbäck B, et al. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
4. Bertina RM, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
5. Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A 1994; 91: 1396-1400
6. Kalafatis M, et al. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994; 269: 31869-31880
7. Fay PJ, et al. Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. Identification of cleavage sites and correlation of proteolysis with cofactor activity. J Biol Chem 1991; 266: 20139-20145
8. Nicolaes GA, et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 21158-21166
9. Fay PJ, et al. Human factor VIIIa subunit structure. Reconstruction of factor VIIIa from the isolated A1/A3-C1-C2 dimer and A2 subunit. J Biol Chem 1991; 266: 8957-8962
10. Fay PJ, Smudzin TM. Characterization of the interaction between the A2 subunit and A1/A3-C1-C2 dimer in human factor VIIIa. J Biol Chem 1992; 267: 13246-13250
11. Gale AJ, et al. Detailed mechanisms of the inactivation of factor VIIIa by activated protein C in the presence of its cofactors, protein S and factor V. J Biol Chem 2008; 283: 16355-16362
12. Norstrøm EA, et al. Importance of protein S and phospholipid for activated protein C-mediated cleavages in factor Va. J Biol Chem 2003; 278: 24904-24911
13. Rosing J, et al. Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 27852-27858
14. Yegneswaran S, et al. Protein S alters the active site location of activated protein C above the membrane surface. A fluorescence resonance energy transfer study of topography. J Biol Chem 1997; 272: 25013-25021
15. Yegneswaran S, et al. Relocating the active site of activated protein C eliminates the need for its protein S cofactor. A fluorescence resonance energy transfer study. J Biol Chem 1999; 274: 5462-5468
16. Tran S, Dahlbäck B. Novel APC-cleavage sites in FVa provide insights into mechanisms of action of APC and its cofactor protein S. J Thromb Haemost 2010; 8: 129-136
17. Cramer TJ, Gale AJ. Function of the activated protein C (APC) autolysis loop in activated FVIII inactivation. Br J Haematol 2011; 153: 644-654
18. O'Brien LM, et al. Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase. Blood 2000; 95: 1714-1720
19. Branson HE, et al. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 2: 1165-1168
20. Griffin JH, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
21. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746
22. Griffin JH, et al. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993
23. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
24. Koster T, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506
25. Cadroy Y, et al. Frequency of a defective response to activated protein C in patients with a history of venous thrombosis. Blood 1994; 83: 2008-2009
26. Sun X, et al. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood 1994; 83: 3120-3125
27. Zöller B, et al. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-2524
28. Heeb MJ, et al. Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V. Blood 1995; 85: 3405-3411
29. Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-18738
30. Rosendaal FR, et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-1508
31. Castoldi E, et al. 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
32. Greengard JS, et al. Pseudo-homozygous activated protein C resistance due to coinheritance of heterozygous factor V R506Q and type I factor V deficiency associated with thrombosis. Thromb Haemost 1995; 73: 1361 Abstract.
33. Guasch JF, et al. Molecular characterization of a type I quantitative factor V deficiency in a thrombosis patient that is ″pseudo homozygous″ for activated protein C resistance. Thromb Haemost 1997; 77: 252-257
34. Simioni P, et al. ″Pseudo homozygous″ activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. Thromb Haemost 1996; 75: 422-426
35. Zehnder JL, Jain M. Recurrent thrombosis due to compound heterozygosity for factor V Leiden and factor V deficiency. Blood Coagul Fibrinolysis 1996; 7: 361-362
36. Brugge JM, et al. Expression of the normal factor V allele modulates the APC resistance phenotype in heterozygous carriers of the factor V Leiden mutation. J Thromb Haemost 2005; 3: 2695-2702
37. Simioni P, et al. An underestimated combination of opposites resulting in enhanced thrombotic tendency. Blood 2005; 106: 2363-2365
38. Acharya SS, et al. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2004; 2: 248-256
39. Duckers C, et al. Factor V Leiden pseudo-homozygotes have a more pronounced hypercoagulable state than factor V Leiden homozygotes. J Thromb Haemost 2011; 9: 864-867
40. Castoldi E, et al. Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. Blood 2004; 103: 4173-4179
41. Zivelin A, et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood 2006; 107: 4666-4668
42. Chan WP, et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91: 1135-1139
43. Williamson D, et al. Factor V Cambridge: A new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-1144
44. Liang R, et al. Clinical significance of Arg306 mutations of factor V gene. Blood 1998; 92: 2599-2600
45. van der Neut Kolfschoten M, et al. The activated protein C (APC)-resistant phenotype of APC cleavage site mutants of recombinant factor V in a reconstituted plasma model. Blood Coagul Fibrinolysis 2002; 13: 207-215
46. Norstrøm E, et al. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 2002; 100: 524-530
47. Cai H, et al. A novel mutation (g2172-->c) in the factor v gene in a chinese family with hereditary activated protein C resistance. Thromb Res 2010; 125: 545-548
48. Mumford AD, et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123: 496-501
49. Dahlbäck B. The discovery of activated protein C resistance. J Thromb Haemost 2003; 1: 3-9
50. Lu D, et al. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Blood 1996; 87: 4708-4717
51. Váradi K, et al. Factor V enhances the cofactor function of protein S in the APCmediated inactivation of factor VIII: influence of the factor VR506Q mutation. Thromb Haemost 1996; 76: 208-214
52. Thorelli E, et al. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood 1999; 93: 2552-2558
53. Cramer TJ, et al. Factor V is an anticoagulant cofactor for activated protein C during inactivation of factor Va. Pathophysiol Haemost Thromb 2010; 37: 17-23
54. Pipe SW, et al. Mild hemophilia A caused by increased rate of factor VIII A2 subunit dissociation: evidence for nonproteolytic inactivation of factor VIIIa in vivo. Blood 1999; 93: 176-183
55. Kalafatis M, et al. Characterization of the molecular defect in factor VR506Q. J Biol Chem 1995; 270: 4053-4057
56. Thorelli E, et al. The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V. J Biol Chem 1998; 273: 16140-16145
57. Jenny RJ, et al. Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci USA 1987; 84: 4846-4850
58. Kane WH, Davie EW. Cloning of a cDNA coding for human factor V, a blood coagulation factor homologous to factor VIII and ceruloplasmin. Proc Natl Acad Sci USA 1986; 83: 6800-6804
59. Gershagen S, et al. A cDNA coding for human sex hormone binding globulin. Homology to vitamin K-dependent protein S. FEBS Lett 1987; 220: 129-135
60. Lundwall A, et al. Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. Proc Natl Acad Sci USA 1986; 83: 6716-6720
61. Harmon S, et al. Dissociation of activated protein C functions by elimination of protein S cofactor enhancement. J Biol Chem 2008; 283: 30531-30539
62. Preston RJ, et al. Multifunctional specificity of the protein C/activated protein C Gla domain. J Biol Chem 2006; 281: 28850-28857
63. Smirnov MD, et al. A chimeric protein C containing the prothrombin Gla domain exhibits increased anticoagulant activity and altered phospholipid specificity. J Biol Chem 1998; 273: 9031-9040
64. Andersson HM, et al. Activated protein C cofactor function of protein S: a critical role for Asp95 in the EGF1-like domain. Blood 2010; 115: 4878-4885
65. Saller F, et al. The gamma-carboxyglutamic acid domain of anticoagulant protein S is involved in activated protein C cofactor activity, independently of phospholipid binding. Blood 2005; 105: 122-130
66. He X, et al. Amino acid residues in thrombin-sensitive region and first epidermal growth factor domain of vitamin K-dependent protein S determining specificity of the activated protein C cofactor function. J Biol Chem 1998; 273: 27449-27458
67. Chang GT, et al. Construction and characterization of thrombin-resistant variants of recombinant human protein S. Thromb Haemost 1994; 72: 693-697
68. Dahlbäck B, et al. Characterization of functionally important domains in human vitamin K-dependent protein S using monoclonal antibodies. J Biol Chem 1990; 265: 8127-8135
69. Long GL, et al. Human protein S cleavage and inactivation by coagulation factor Xa. J Biol Chem 1998; 273: 11521-11526
70. Hackeng TM, et al. Conformational changes in activated protein C caused by binding of the first epidermal growth factor-like module of protein S. Biochem J 2000; 349: 757-764
71. Mille-Baker B, et al. Deletion or replacement of the second EGF-like domain of protein S results in loss of APC cofactor activity. Blood 2003; 101: 1416-1418
72. Stenberg Y, et al. Characterization of recombinant epidermal growth factor (EGF)-like modules from vitamin-K-dependent protein S expressed in Spodoptera cells--the cofactor activity depends on the N-terminal EGF module in human protein S. Eur J Biochem 1998; 251: 558-564
73. Dahlbäck B, et al. High affinity interaction between C4b-binding protein and vitamin K-dependent protein S in the presence of calcium. Suggestion of a third component in blood regulating the interaction. J Biol Chem 1990; 265: 16082-16087
74. Hillarp A, Dahlbäck B. Novel subunit in C4b-binding protein required for protein S binding. J Biol Chem 1988; 263: 12759-12764
75. Schwalbe R, et al. Assembly of protein S and C4b-binding protein on membranes. J Biol Chem 1990; 265: 16074-16081
76. Fernández JA, et al. Identification of residues 413-433 of plasma protein S as essential for binding to C4b-binding protein. J Biol Chem 1993; 268: 16788-16794
77. Fernández JA, et al. Involvement of amino acid residues 423-429 of human protein S in binding to C4b-binding protein. Blood Cells Mol Dis 1998; 24: 101-112
78. Linse S, et al. A region of vitamin K-dependent protein S that binds to C4b binding protein (C4BP) identified using bacteriophage peptide display libraries. J Biol Chem 1997; 272: 14658-14665
79. Maurissen LF, et al. Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation. Blood 2008; 111: 3034-3041
80. Van de Poel RH, et al. C4b-binding protein inhibits the factor V-dependent but not the factor V-independent cofactor activity of protein S in the activated protein C-mediated inactivation of factor VIIIa. Thromb Haemost 2001; 85: 761-765
81. Van Wijnen M, et al. Characterization of mini-protein S, a recombinant variant of protein S that lacks the sex hormone binding globulin-like domain. Biochem J 1998; 330 (Pt 1): 389-396
82. Nyberg P, et al. The SHBG-like region of protein S is crucial for factor V-dependent APC-cofactor function. FEBS Lett 1998; 433: 28-32
83. Kane WH, et al. Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats. Biochemistry 1987; 26: 6508-6514
84. Fernández JA, et al. The carbohydrate moiety of factor V modulates inactivation by activated protein C. Blood 1997; 89: 4348-4354
85. Silveira JR, et al. Carbohydrate moieties on the procofactor factor V, but not the derived cofactor factor Va, regulate its inactivation by activated protein C. Biochemistry 2002; 41: 1672-1680
86. Hoekema L, et al. Human factor Va1 and factor Va2: properties in the procoagulant and anticoagulant pathways. Biochemistry 1997; 36: 3331-3335
87. Rosing J, et al. Characterization of two forms of human factor Va with different cofactor activities. J Biol Chem 1993; 268: 21130-21136
88. Kim SW, et al. Partial glycosylation at asparagine-2181 of the second C-type domain of human factor V modulates assembly of the prothrombinase complex. Biochemistry 1999; 38: 11448-11454
89. Nicolaes GAF, et al. Partial glycosylation of Asn2181 in human factor V as a cause of molecular and functional heterogeneity. Modulation of glycosylation efficiency by mutagenesis of the consensus sequence for N-linked glycosylation. Biochemistry 1999; 38: 13584-13591
90. Steen M, et al. Functional characterization of Factor V-Ile359Thr, a novel mutation associated with thrombosis. Blood 2004; 103: 3381-3387
91. Autin L, et al. Proposed structural models of the prothrombinase (FXa-FVa) complex. Proteins 2006; 63: 440-450
92. Castoldi E, et al. Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma. Thromb Haemost 2000; 83: 362-365
93. Lunghi B, et al. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-48
94. Bayston TA, et al. A polymorphism in the human coagulation factor V gene. Hum Mol Genet 1994; 3: 2085.
95. De Visser MC, et al. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost 2000; 83: 577-582
96. Yamazaki T, et al. Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype. Blood 2002; 100: 2515-2521
97. Castaman G, et al. Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for Arg506Gln (factor V Leiden) and His1299Arg substitutions in factor V. Br J Haematol 1997; 99: 257-261
98. Bernardi F, et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90: 1552-1557
99. Hoekema L, et al. Functional properties of factor V and factor Va encoded by the R2-gene. Thromb Haemost 2001; 85: 75-81
100. Castaman G, et al. Heterogeneity of activated protein C resistance phenotype in subjects with compound heterozygosity for HR2 haplotype and FV Leiden mutation (R506Q) in factor V gene. Thromb Haemost 2000; 84: 357-358
101. Luddington R, et al. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost 2000; 83: 204-208
102. Faioni EM, et al. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden). Blood 1999; 94: 3062-3066
103. Castaman G, et al. The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis. Haematologica 2003; 88: 1182-1189
104. Yamazaki T, et al. The D2194G mutation is responsible for increased levels of FV1 in carriers of the factor V R2 haplotype. Thromb Haemost 2010; 104: 860-861
105. Govers-Riemslag JW, et al. Reduced factor V concentration and altered FV1/FV2 ratio do not fully explain R2-associated APC-resistance. Thromb Haemost 2002; 88: 444-449
106. Tracy PB, et al. Radioimmunoassay of factor V in human plasma and platelets. Blood 1982; 60: 59-63
107. Gould WR, et al. Unique in vivo modifications of coagulation factor V produce a physically and functionally distinct platelet-derived cofactor: characterization of purified platelet-derived factor V/Va. J Biol Chem 2004; 279: 2383-2393
108. Gould WR, et al. Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor. J Thromb Haemost 2005; 3: 450-456
109. Camire RM, et al. Secretable human platelet-derived factor V originates from the plasma pool. Blood 1998; 92: 3035-3041
110. Østerud B, et al. Factor V activity of platelets: evidence for an activated factor V molecule and for a platelet activator. Blood 1977; 49: 819-834.