The anticoagulant function of coagulation factor V

Thomas J. Cramer; Andrew J. Gale

doi:10.1160/TH11-06-0431

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2012; 107(01): 15-21
DOI: 10.1160/TH11-06-0431

Review Article

Schattauer GmbH

The anticoagulant function of coagulation factor V

Thomas J. Cramer

¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

,

Andrew J. Gale

¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

› Institutsangaben

Abstract

Summary

Almost two decades ago an anticoagulant function of factor V (FV) was discovered, as an anticoagulant cofactor for activated protein C (APC). A natural mutant of FV in which the R506 inactivation site was mutated to Gln (FV_Leiden) was inactivated slower by APC, but also could not function as anticoagulant cofactor for APC in the inactivation of activated factor VIII (FVIIIa). This mutation is prevalent in populations of Caucasian descent, and increases the chance of thrombotic events in carriers. Characterisation of the FV anticoagulant effect has elucidated multiple properties of the anticoagulant function of FV: 1) Cleavage of FV at position 506 by APC is required for anticoagulant function. 2) The C-terminal part of the FV B domain is required and the B domain must have an intact connection with the A3 domain of FV. 3) FV must be bound to a negatively charged phospholipid membrane. 4) Protein S also needs to be present. 5) FV acts as a cofactor for inactivation of both FVa and FVIIIa. 6) The prothrombotic function of FV_Leiden is a function of both reduced APC cofactor activity and resistance of FVa to APC inactivation. However, detailed structural and mechanistic properties remain to be further explored.

Keywords

Activated protein C - anticoagulant - APC resistance - factor V - protein S

Volltext

Referenzen

References
1 Owren PA. Parahaemophilia; haemorrhagic diathesis due to absence of a previously unknown clotting factor. Lancet 1947; 01: 446-448.
2 Stormorken H. The discovery of factor V: a tricky clotting factor. J Thromb Haemost 2003; 01: 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 co-factor 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; 08: 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; 02: 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; 07: 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; 03: 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; 02: 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; 09: 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; 01: 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 APC-mediated 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 sub-unit 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; 03: 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; 03: 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.