ABSTRACT
Tissue factor (TF) is a transmembrane protein that initiates coagulation following
contact with factor VII/VIIa. Recent experimental evidence, in particular from animal
models, suggests an important role for circulating TF in thrombosis. This has led
to a growing interest in the measurement of TF in whole blood and in cell-free plasma,
where functionally active TF is carried on cell-derived microparticles. In this review,
we address the range of assays for measuring circulating TF antigen and activity that
have been published. We comment on some of the crucial preanalytical and analytical
variables that influence the results and their interpretation.
KEYWORDS
Microparticle - tissue factor - thrombosis - whole blood - plasma
REFERENCES
- 1
Boulton F.
A hundred years of cascading— started by Paul Morawitz (1879–1936), a pioneer of haemostasis
and of transfusion.
Transfus Med.
2006;
16(1)
1-10
- 2
Nemerson Y.
Tissue factor and hemostasis.
Blood.
1988;
71(1)
1-8
- 3
Mackman N, Tilley R E, Key N S.
Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis.
Arterioscler Thromb Vasc Biol.
2007;
27(8)
1687-1693
- 4
Østerud B, Bjørklid E.
Sources of tissue factor.
Semin Thromb Hemost.
2006;
32(1)
11-23
- 5
Drake T A, Morrissey J H, Edgington T S.
Selective cellular expression of tissue factor in human tissues. Implications for
disorders of hemostasis and thrombosis.
Am J Pathol.
1989;
134(5)
1087-1097
- 6
Giesen P L, Rauch U, Bohrmann B et al.
Blood-borne tissue factor: another view of thrombosis.
Proc Natl Acad Sci U S A.
1999;
96(5)
2311-2315
- 7
Butenas S, Mann K G.
Active tissue factor in blood?.
Nat Med.
2004;
10(11)
1155-1156, correspondence
- 8
Bogdanov V Y, Hartcock J, Nemerson Y.
Active tissue factor in blood?.
Nat Med.
2004;
10(11)
1155-1156; author reply 1156
- 9
Egorina E M, Sovershaev M A, Bjørkøy G et al.
Intracellular and surface distribution of monocyte tissue factor: application to intersubject
variability.
Arterioscler Thromb Vasc Biol.
2005;
25(7)
1493-1498
- 10
Johnson G J, Leis L A, Bach R R.
Tissue factor activity of blood mononuclear cells is increased after total knee arthroplasty.
Thromb Haemost.
2009;
102(4)
728-734
- 11
Morel O, Toti F, Hugel B et al.
Procoagulant microparticles: disrupting the vascular homeostasis equation?.
Arterioscler Thromb Vasc Biol.
2006;
26(12)
2594-2604
- 12
Diamant M, Tushuizen M E, Sturk A, Nieuwland R.
Cellular microparticles: new players in the field of vascular disease?.
Eur J Clin Invest.
2004;
34(6)
392-401
- 13
Zillmann A, Luther T, Müller I et al.
Platelet-associated tissue factor contributes to the collagen-triggered activation
of blood coagulation.
Biochem Biophys Res Commun.
2001;
281(2)
603-609
- 14
Vandendries E R, Furie B C, Furie B.
Role of P-selectin and PSGL-1 in coagulation and thrombosis.
Thromb Haemost.
2004;
92(3)
459-466
- 15
Polgar J, Matuskova J, Wagner D D.
The P-selectin, tissue factor, coagulation triad.
J Thromb Haemost.
2005;
3(8)
1590-1596
- 16
Bauer K A, Kass B L, ten Cate H, Hawiger J J, Rosenberg R D.
Factor IX is activated in vivo by the tissue factor mechanism.
Blood.
1990;
76(4)
731-736
- 17
Østerud B, Rapaport S I.
Activation of factor IX by the reaction product of tissue factor and factor VII: additional
pathway for initiating blood coagulation.
Proc Natl Acad Sci U S A.
1977;
74(12)
5260-5264
- 18
Bauer K A, Mannucci P M, Gringeri A et al.
Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation
of the coagulation mechanism in vivo.
Blood.
1992;
79(8)
2039-2047
- 19
ten Cate H, Bauer K A, Levi M et al.
The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated
by tissue factor.
J Clin Invest.
1993;
92(3)
1207-1212
- 20
Mackman N.
The role of tissue factor and factor VIIa in hemostasis.
Anesth Analg.
2009;
108(5)
1447-1452
- 21
Bach R R.
Tissue factor encryption.
Arterioscler Thromb Vasc Biol.
2006;
26(3)
456-461
- 22
Bach R R, Moldow C F.
Mechanism of tissue factor activation on HL-60 cells.
Blood.
1997;
89(9)
3270-3276
- 23
Chen V M, Ahamed J, Versteeg H H, Berndt M C, Ruf W, Hogg P J.
Evidence for activation of tissue factor by an allosteric disulfide bond.
Biochemistry.
2006;
45(39)
12020-12028
- 24
Ahamed J, Versteeg H H, Kerver M et al.
Disulfide isomerization switches tissue factor from coagulation to cell signaling.
Proc Natl Acad Sci U S A.
2006;
103(38)
13932-13937
- 25
Reinhardt C, von Brühl M L, Manukyan D et al.
Protein disulfide isomerase acts as an injury response signal that enhances fibrin
generation via tissue factor activation.
J Clin Invest.
2008;
118(3)
1110-1122
- 26
Cho J, Furie B C, Coughlin S R, Furie B.
A critical role for extracellular protein disulfide isomerase during thrombus formation
in mice.
J Clin Invest.
2008;
118(3)
1123-1131
- 27
Bach R R, Monroe D.
What is wrong with the allosteric disulfide bond hypothesis?.
Arterioscler Thromb Vasc Biol.
2009;
29(12)
1997-1998
- 28
Pendurthi U R, Ghosh S, Mandal S K, Rao L V.
Tissue factor activation: is disulfide bond switching a regulatory mechanism?.
Blood.
2007;
110(12)
3900-3908
- 29
Kothari H, Sen P, Pendurthi U R, Rao L V.
Bovine protein disulfide isomerase-enhanced tissue factor coagulant function: is phospholipid
contaminant in it the real culprit?.
Blood.
2008;
111(6)
3295-3296
- 30
Broze Jr G J.
Tissue factor pathway inhibitor.
Thromb Haemost.
1995;
74(1)
90-93
- 31
Santucci R A, Erlich J H, Labriola J et al.
Measurement of tissue factor activity in whole blood.
Thromb Haemost.
2000;
83(3)
445-454
- 32
Marsik C, Quehenberger P, Mackman N, Østerud B, Luther T, Jilma B.
Validation of a novel tissue factor assay in experimental human endotoxemia.
Thromb Res.
2003;
111(4–5)
311-315
- 33
Gregory S A, Edgington T S.
Tissue factor induction in human monocytes. Two distinct mechanisms displayed by different
alloantigen-responsive T cell clones.
J Clin Invest.
1985;
76(6)
2440-2445
- 34
Rivers R P, Hathaway W E, Weston W L.
The endotoxin-induced coagulant activity of human monocytes.
Br J Haematol.
1975;
30(3)
311-316
- 35
Østerud B, Flaegstad T.
Increased tissue thromboplastin activity in monocytes of patients with meningococcal
infection: related to an unfavourable prognosis.
Thromb Haemost.
1983;
49(1)
5-7
- 36
Nieuwland R, Berckmans R J, McGregor S et al.
Cellular origin and procoagulant properties of microparticles in meningococcal sepsis.
Blood.
2000;
95(3)
930-935
- 37
Key N S, Slungaard A, Dandelet L et al.
Whole blood tissue factor procoagulant activity is elevated in patients with sickle
cell disease.
Blood.
1998;
91(11)
4216-4223
- 38
Aras O, Shet A, Bach R R et al.
Induction of microparticle- and cell-associated intravascular tissue factor in human
endotoxemia.
Blood.
2004;
103(12)
4545-4553
- 39
Boden G, Vaidyula V R, Homko C, Cheung P, Rao A K.
Circulating tissue factor procoagulant activity and thrombin generation in patients
with type 2 diabetes: effects of insulin and glucose.
J Clin Endocrinol Metab.
2007;
92(11)
4352-4358
- 40
Boden G, Rao A K.
Effects of hyperglycemia and hyperinsulinemia on the tissue factor pathway of blood
coagulation.
Curr Diab Rep.
2007;
7(3)
223-227
- 41
Rao A K, Vaidyula V R, Bagga S et al.
Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating
tissue factor procoagulant activity in patients with peripheral arterial disease.
Thromb Haemost.
2006;
96(6)
738-743
- 42
Tutar E, Ozcan M, Kilickap M et al.
Elevated whole-blood tissue factor procoagulant activity as a marker of restenosis
after percutaneous transluminal coronary angioplasty and stent implantation.
Circulation.
2003;
108(13)
1581-1584
- 43
Vaidyula V R, Criner G J, Grabianowski C, Rao A K.
Circulating tissue factor procoagulant activity is elevated in stable moderate to
severe chronic obstructive pulmonary disease.
Thromb Res.
2009;
124(3)
259-261
- 44
Misumi K, Ogawa H, Yasue H et al.
Comparison of plasma tissue factor levels in unstable and stable angina pectoris.
Am J Cardiol.
1998;
81(1)
22-26
- 45
Parhami-Seren B, Butenas S, Krudysz-Amblo J, Mann K G.
Immunologic quantitation of tissue factors.
J Thromb Haemost.
2006;
4(8)
1747-1755
- 46
Albrecht S, Kotzsch M, Siegert G et al.
Detection of circulating tissue factor and factor VII in a normal population.
Thromb Haemost.
1996;
75(5)
772-777
- 47
Khorana A A, Francis C W, Menzies K E et al.
Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer.
J Thromb Haemost.
2008;
6(11)
1983-1985
- 48
Censarek P, Bobbe A, Grandoch M, Schrör K, Weber A A.
Alternatively spliced human tissue factor (asHTF) is not pro-coagulant.
Thromb Haemost.
2007;
97(1)
11-14
- 49
Sommeijer D W, Hansen H R, van Oerle R et al.
Soluble tissue factor is a candidate marker for progression of microvascular disease
in patients with type 2 diabetes.
J Thromb Haemost.
2006;
4(3)
574-580
- 50
Zumbach M, Hofmann M, Borcea V et al.
Tissue factor antigen is elevated in patients with microvascular complications of
diabetes mellitus.
Exp Clin Endocrinol Diabetes.
1997;
105(4)
206-212
- 51
Del Conde I, Bharwani L D, Dietzen D J, Pendurthi U, Thiagarajan P, López J A.
Microvesicle-associated tissue factor and Trousseau's syndrome.
J Thromb Haemost.
2007;
5(1)
70-74
- 52
Yu J L, May L, Lhotak V et al.
Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications
for tumor progression and angiogenesis.
Blood.
2005;
105(4)
1734-1741
- 53
Bom V J, Bertina R M.
The contributions of Ca2+, phospholipids and tissue-factor apoprotein to the activation
of human blood-coagulation factor X by activated factor VII.
Biochem J.
1990;
265(2)
327-336
- 54
Telgt D S, Macik B G, McCord D M, Monroe D M, Roberts H R.
Mechanism by which recombinant factor VIIa shortens the aPTT: activation of factor
X in the absence of tissue factor.
Thromb Res.
1989;
56(5)
603-609
- 55
Bogdanov V Y, Cimmino G, Tardos J G, Tunstead J R, Badimon J J.
Assessment of plasma tissue factor activity in patients presenting with coronary artery
disease: limitations of a commercial assay.
J Thromb Haemost.
2009;
7(5)
894-897
- 56
Van Dreden P, Rousseau A, Savoure A, Lenormand B, Fontaine S, Vasse M.
Plasma thrombomodulin activity, tissue factor activity and high levels of circulating
procoagulant phospholipid as prognostic factors for acute myocardial infarction.
Blood Coagul Fibrinolysis.
2009;
20(8)
635-641
- 57
Butenas S, Undas A, Gissel M T, Szuldrzynski K, Zmudka K, Mann K G.
Factor XIa and tissue factor activity in patients with coronary artery disease.
Thromb Haemost.
2008;
99(1)
142-149
- 58
Sambola A, Osende J, Hathcock J et al.
Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity.
Circulation.
2003;
107(7)
973-977
- 59
Ollivier V, Wang J, Manly D et al.
Detection of endogenous tissue factor levels in plasma using the calibrated automated
thrombogram assay.
Thromb Res.
2010;
125(1)
90-96
- 60
Haubold K, Rink M, Spath B et al.
Tissue factor procoagulant activity of plasma microparticles is increased in patients
with early-stage prostate cancer.
Thromb Haemost.
2009;
101(6)
1147-1155
- 61
Dvorak H F, Van DeWater L, Bitzer A M et al.
Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor
cells.
Cancer Res.
1983;
43(9)
4434-4442
- 62
Satta N, Toti F, Feugeas O et al.
Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated
procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide.
J Immunol.
1994;
153(7)
3245-3255
- 63
Himber J, Wohlgensinger C, Roux S et al.
Inhibition of tissue factor limits the growth of venous thrombus in the rabbit.
J Thromb Haemost.
2003;
1(5)
889-895
- 64
Chou J, Mackman N, Merrill-Skoloff G, Pedersen B, Furie B C, Furie B.
Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation
during thrombus propagation.
Blood.
2004;
104(10)
3190-3197
- 65
Hathcock J J, Nemerson Y.
Platelet deposition inhibits tissue factor activity: in vitro clots are impermeable
to factor Xa.
Blood.
2004;
104(1)
123-127
- 66
Hoffman M, Whinna H C, Monroe D M.
Circulating tissue factor accumulates in thrombi, but not in hemostatic plugs.
J Thromb Haemost.
2006;
4(9)
2092-2093
- 67
Hrachovinová I, Cambien B, Hafezi-Moghadam A et al.
Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis
in a mouse model of hemophilia A.
Nat Med.
2003;
9(8)
1020-1025
- 68
Day S M, Reeve J L, Pedersen B et al.
Macrovascular thrombosis is driven by tissue factor derived primarily from the blood
vessel wall.
Blood.
2005;
105(1)
192-198
- 69
Wang L, Miller C, Swarthout R F, Rao M, Mackman N, Taubman M B.
Vascular smooth muscle-derived tissue factor is critical for arterial thrombosis after
ferric chloride-induced injury.
Blood.
2009;
113(3)
705-713
- 70
Kretz C A, Vaezzadeh N, Gross P L.
Tissue factor and thrombosis models.
Arterioscler Thromb Vasc Biol.
2010;
30(5)
900-908
- 71
Biró E, Sturk-Maquelin K N, Vogel G M et al.
Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent
manner.
J Thromb Haemost.
2003;
1(12)
2561-2568
- 72
Davila M, Amirkhosravi A, Coll E et al.
Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation
activation.
J Thromb Haemost.
2008;
6(9)
1517-1524
- 73
Thomas G M, Panicot-Dubois L, Lacroix R, Dignat-George F, Lombardo D, Dubois C.
Cancer cell-derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate
thrombus formation in vivo.
J Exp Med.
2009;
206(9)
1913-1927
- 74
Diamant M, Nieuwland R, Pablo R F, Sturk A, Smit J W, Radder J K.
Elevated numbers of tissue-factor exposing microparticles correlate with components
of the metabolic syndrome in uncomplicated type 2 diabetes mellitus.
Circulation.
2002;
106(19)
2442-2447
- 75
Hron G, Kollars M, Weber H et al.
Tissue factor-positive microparticles: cellular origin and association with coagulation
activation in patients with colorectal cancer.
Thromb Haemost.
2007;
97(1)
119-123
- 76
Lechner D, Weltermann A.
Circulating tissue factor-exposing microparticles.
Thromb Res.
2008;
122(Suppl 1)
S47-S54
- 77
Jy W, Horstman L L, Jimenez J J et al.
Measuring circulating cell-derived microparticles.
J Thromb Haemost.
2004;
2(10)
1842-1851
- 78
Mobarrez F, Antovic J, Egberg N et al.
A multicolor flow cytometric assay for measurement of platelet-derived microparticles.
Thromb Res.
2010;
125(3)
e110-e116
- 79
Jy W, Horstman L L, Jimenez J J et al.
Measuring circulating cell-derived microparticles.
J Thromb Haemost.
2004;
2
1842-1851
- 80
Mallat Z, Benamer H, Hugel B et al.
Elevated levels of shed membrane microparticles with procoagulant potential in the
peripheral circulating blood of patients with acute coronary syndromes.
Circulation.
2000;
101(8)
841-843
- 81
Shet A S, Aras O, Gupta K et al.
Sickle blood contains tissue factor-positive microparticles derived from endothelial
cells and monocytes.
Blood.
2003;
102(7)
2678-2683
- 82
Lacroix R, Robert S, Poncelet P, Dignat-George F.
Overcoming limitations of microparticle measurement by flow cytometry.
Semin Thromb Hemost.
2010;
36(8)
807-818
- 83
Zwaal R F, Schroit A J.
Pathophysiologic implications of membrane phospholipid asymmetry in blood cells.
Blood.
1997;
89(4)
1121-1132
- 84
Perez-Pujol S, Marker P H, Key N S.
Platelet microparticles are heterogeneous and highly dependent on the activation mechanism:
studies using a new digital flow cytometer.
Cytometry A.
2007;
71(1)
38-45
- 85
Amabile N, Guérin A P, Leroyer A et al.
Circulating endothelial microparticles are associated with vascular dysfunction in
patients with end-stage renal failure.
J Am Soc Nephrol.
2005;
16(11)
3381-3388
- 86
Nieuwland R.
Cellular origin of microparticles exposing tissue factor in cancer: a mixed double?.
J Thromb Haemost.
2008;
6(9)
1514-1516
- 87
Del Conde I, Shrimpton C N, Thiagarajan P, López J A.
Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated
platelets to initiate coagulation.
Blood.
2005;
106(5)
1604-1611
- 88
Zwicker J I, Liebman H A, Neuberg D et al.
Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic
events in malignancy.
Clin Cancer Res.
2009;
15(22)
6830-6840
- 89
Lawrie A S, Harrison P, Cardigan R A, Mackie I J.
The characterization and impact of microparticles on haemostasis within fresh-frozen
plasma.
Vox Sang.
2008;
95(3)
197-204
- 90
Gabriel D A, Giodano K.
Microparticle sizing and counting using light scattering methods.
Semin Thromb Hemost.
2010;
36(8)
824-832
- 91
Berckmans R J, Neiuwland R, Böing A N, Romijn F P, Hack C E, Sturk A.
Cell-derived microparticles circulate in healthy humans and support low grade thrombin
generation.
Thromb Haemost.
2001;
85(4)
639-646
- 92
Aupeix K, Hugel B, Martin T et al.
The significance of shed membrane particles during programmed cell death in vitro,
and in vivo, in HIV-1 infection.
J Clin Invest.
1997;
99(7)
1546-1554
- 93
Kushak R I, Nestoridi E, Lambert J, Selig M K, Ingelfinger J R, Grabowski E F.
Detached endothelial cells and microparticles as sources of tissue factor activity.
Thromb Res.
2005;
116(5)
409-419
- 94
Bajaj M S, Ghosh M, Bajaj S P.
Fibronectin-adherent monocytes express tissue factor and tissue factor pathway inhibitor
whereas endotoxin-stimulated monocytes primarily express tissue factor: physiologic
and pathologic implications.
J Thromb Haemost.
2007;
5(7)
1493-1499
- 95
Tesselaar M E, Romijn F P, Van Der Linden I K, Prins F A, Bertina R M, Osanto S.
Microparticle-associated tissue factor activity: a link between cancer and thrombosis?.
J Thromb Haemost.
2007;
5(3)
520-527
- 96
Bakouboula B, Morel O, Faure A et al.
Procoagulant membrane microparticles correlate with the severity of pulmonary arterial
hypertension.
Am J Respir Crit Care Med.
2008;
177(5)
536-543
- 97
Tilley R E, Holscher T, Belani R, Nieva J, Mackman N.
Tissue factor activity is increased in a combined platelet and microparticle sample
from cancer patients.
Thromb Res.
2008;
122(5)
604-609
- 98
Manly D A, Wang J, Glover S L et al.
Increased microparticle tissue factor activity in cancer patients with venous thromboembolism.
Thromb Res.
2010;
125(6)
511-512
- 99
Wang J G, Manly D, Kirchhofer D, Pawlinski R, Mackman N.
Levels of microparticle tissue factor activity correlate with coagulation activation
in endotoxemic mice.
J Thromb Haemost.
2009;
7(7)
1092-1098
Nigel S KeyM.D.
Harold R Roberts Distinguished Professor, Division of Hematology/Oncology, 932 Mary
Ellen Jones Building
CB #7035, Chapel Hill, NC 27599
Email: Nigel_key@med.unc.edu
