s
Microparticles: mediators of cellular and environmental homeostasis
Böing, A.N.
Publication date
2011
Link to publication
Citation for published version (APA):
Böing, A. N. (2011). Microparticles: mediators of cellular and environmental homeostasis.
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Chapter 1
Background
Microparticles are small cell-derived vesicles, presumed to range in size between 100 nm and 1000 nm, and released from the cell (plasma) membrane. The presence of cell-derived microparticles in blood was first observed by Chargaff et al. in 19461. He showed that
‘plasma, freed from intact platelets, generates thrombin on recalcification and (that) the rate of this thrombin generation can be reduced by prior high-speed centrifugation of the plasma’. In 1967, Wolf et al. showed that high-speed centrifugation of platelet-free plasma resulted in a pellet, which triggered thrombin generation after recalcification of the plasma2.
Originally, Wolf called this coagulant material “platelet dust”, which name was changed into microparticles by Crawford et al. in 19713.
Especially since the 1990’s, the research on microparticles has increased tremendously. Nowadays, we know that probably all eukaryotic cell types, including blood cells such as platelets, monocytes, granulocytes, erythrocytes and endothelial cells, release microparticles. Furthermore, the occurrence of microparticles and other types of cell-derived vesicles is not limited to blood, but they are also present in other human body fluids, such as cerebrospinal fluid4, synovial fluid5, urine6;7 and mother milk8. In these body
fluids, microparticles coexist with cells in physiological and pathological conditions, but the numbers, cellular origin, composition and functions of the vesicles is different in health and disease. In this thesis the main focus is on the various functions of microparticles. Figure 1 gives an overview of the functions of microparticles.
Figure 1. The various functions of microparticles.
microparticles
angiogenesis (Chapter 5) coagulation (Chapters 7-9)
communication inflammation (Chapter 6) waste management (Chapters 2-4)
cell cell microparticles angiogenesis (Chapter 5) coagulation (Chapters 7-9) communication inflammation (Chapter 6) waste management (Chapters 2-4) cell
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Why do cells release microparticles?
To answer the question why cells release microparticles, we may learn from bacteria. Gram-negative bacteria release the so-called outer membrane vesicles, containing signalling molecules, into the environment to facilitate the communication between bacteria9 and between bacteria and eukaryotic cells10-12. Furthermore, these outer membrane
vesicles can contain bacterial virulence factors, e.g. cytolethal distending toxin, which can be delivered to (eukaryotic) host cells to kill these cells, thereby promoting bacterial survival10-12. Similarly, DNA-encoding virulence genes can be transferred to other
bacteria9. Thus, outer membrane vesicles facilitate communication and promote bacterial
survival.
Waste management
Cell-derived microparticles from eukaryotic cells, similar to the bacterial outer membrane vesicles, play a role in the protection against “stress” induced by either the environment (extracellular stress) or e.g. by accumulation of dangerous or redundant compounds within the cell (intracellular stress). For instance, platelets release C5b-9 complex-enriched microparticles upon incubation with the complement complex C5b-9, which can be considered as a form of extracellular stress, presumably to protect platelets from complement-induced lysis13. In addition, during incubation with cytostatic drugs cancer
cells release microparticles containing elevated concentrations of these drugs compared to the cancer cells themselves14;15. This release of microparticles can be considered as a form
of protection against intracellular stress. Furthermore, microparticles from healthy and viable endothelial cells contain caspase-3, which is one of the main executioner enzymes of programmed cell death (apoptosis)16. Since endothelial cells contain no detectable amounts
of caspase-3 but only the inactive proenzym, procaspase-3, we hypothesized that the potentially dangerous caspase-3 is continuously removed from the endothelial cells via the release of caspase-3 containing microparticles16. If so, then microparticles may indeed act
like “garbage cans”. Whether the release of caspase-3 containing microparticles contributes to cellular survival was investigated in Chapter 2 of this thesis.
Caspase-3 is known to promote membrane blebbing by cleavage of several kinases, including Rho-associated Coiled Coil Kinase 1 (ROCK1). Cleavage of ROCK1 results in
the formation of a constitutively active ROCK1, which in turn facilitates myosin light chain phosphorylation and thus membrane blebbing17. Whether caspase-3 contributes not only to
membrane blebbing but also to the subsequent release of microparticles was investigated in
Chapter 3 of this thesis. In Chapter 4 we investigated whether microparticles from
platelets, i.e. a-nucleated cells that per definition can not undergo full apoptosis including nuclear DNA fragmentation, contain caspase-3.
Exchange of genetic information
Recently, microvesicles (a term used to describe microparticles plus exosomes, particles in the presumed size range of 10 – 100 nm and released from the cell when their multivesicular bodies fuse with the outer cell membrane) were shown to contain mRNA and microRNA’s. Valadi et al. showed that mRNA in microvesicles from murine mast cells could be transferred to, and expressed by, human mast cells18. Also, murine embryonic
stem cells support self-renewal and expansion of adult stem cells by vesicle-mediated transfer of RNA19, and microvesicles from endothelial progenitor cells activate an
angiogenic program in endothelial cells by the transfer of mRNA20. Thus, similar to
vesicles from prokaryotes, the vesicles from eukaryotic cells are able to support the exchange of genetic information between cells. In the various studies, however, a clear distinction between the role of microparticles versus exosomes was not made, so it remains to be investigated which type of microvesicle actually performs those functions.
Microparticles and angiogenesis
Several studies have shown that microparticles promote or modulate angiogenesis. For instance, platelet microparticles containing important angiogenesis-promoting growth factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PGDF), induce angiogenesis in vitro and in vivo21;22. In contrast, endothelial microparticles impair angiogenesis at high
concentrations23, although the precise underlying mechanisms were not investigated in that
study.
As mentioned, one of the important growth factor in angiogenesis is VEGF. VEGF is produced by several organs and cells, and during pregnancies VEGF is also produced by
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the placenta. VEGF present in plasma can bind to VEGFR-1 (fms-like tyrosine kinase (Flt-1)) and VEGFR-2 on endothelial cells, thereby triggering angiogenesis. The VEGF receptor Flt-1 can be spliced alternatively, leading to the secretion of soluble (s) Flt-1. When sFlt-1 is present in plasma it will bind to VEGF, thereby lowering the concentration of plasma VEGF24. As a consequence, less VEGF will be available for the binding to VEGF receptors
on endothelial cells, thus resulting in suppression of angiogenesis. In preeclamptic patients, the plasma levels of sFlt-1 are known to be elevated compared to women with normal pregnancies25. In Chapter 5, we investigated whether the elevated concentrations of sFlt-1
are present as a truly “soluble” protein or whether sFlt-1 is also associated with microparticles in preeclamptic patients.
Microparticles and inflammation
Microparticles, generated in vitro and originating from various cell types, can stimulate the inflammatory process in several ways. They trigger the cellular production of a plethora of inflammatory mediators, such as interleukins, monocyt chemoattractant proteins (MCP) 1 and 2, tumor-necrosis factor (TNF), and matrix degrading enzymes, by transferring water-soluble second messengers26-29, and binding to specific adhesion receptors on cells30-33. The
ability of microparticles to affect inflammation was supported by a study of Berckmans et al. He showed that microparticles from synovial fluid of patients with rheumatic arthritis induce the release of inflammatory mediators from autologous synovial fibroblasts in vitro34.
Both inflammation and endothelial dysfunction play a role in development of preeclampsia, but the exact underlying mechanism behind the development of preeclampsia is unknown. Since microparticles of leukocytes are elevated in preeclamptic patients35, and
leukocyte-derived microparticles induce inflammation in vitro and ex vivo, we investigated whether microparticles of preeclamptic patients affect the mRNA expression of a set of inflammation genes in human umbilical vein endothelial cells in Chapter 6.
Microparticles and coagulation
Microparticles are best known for their coagulant properties. They can expose negatively charged phospholipids36;37, which are essential for the binding of coagulation factors,
thereby promoting the formation of the intrinsic Factor X (FX) converting tenase complex (IXa and VIIIa)- and the FII (prothrombin) converting prothrombinase complex (Xa and Va). Platelet-derived microparticles are enriched in binding sites for activated factor V (FVa), FVIIIa and FIXa, and provide a suitable membrane surface to promote thrombin generation13;38.
Apart from negatively charged phospholipids and thus binding sites for (activated) coagulation factors, microparticles can also expose tissue factor (TF). TF is a 45 kDa transmembrane protein, the main initiator of coagulation in vivo and is produced by various types of extravascular cells, including smooth muscle cells. Upon vascular damage, blood will contact the extravascular TF, resulting in (extrinsic) coagulation activation via activation of FX by the extrinsic tenase complex (TF, FVIIa). In plasma of healthy subjects, only very low amounts of TF (antigen) are detectable, and this TF can be present as a truly soluble (non-membrane bound) protein or associated with microparticles. Under pathological conditions, both endothelial cells, monocytes and possibly other leukocytes produce TF in response to endotoxin and other pro-inflammatory mediators, and this TF can be released from the cell surface on microparticles in vitro39-41.
Microparticles and in vivo coagulation
Previously, we demonstrated that pericardial (wound) blood from patients undergoing open heart surgery contains high numbers of microparticles exposing TF when compared to systemic blood samples from the same patients42. These pericardial microparticles triggered
TF-dependent thrombin generation in vitro42, and were prothrombogenic in a rat venous
stasis model in vivo43. In addition, we showed that high numbers of coagulant TF-exposing
microparticles were present in blood from a patient suffering from meningococcal septic shock and disseminated intravascular coagulation, whereas a patient with meningococcal septic shock without disseminated intravascular coagulation lacked such microparticles44,
suggesting that the presence of these TF-exposing microparticles is associated with (development of) disseminated intravascular coagulation in some patients. Furthermore, there is growing evidence that extrinsic coagulation activation and the development of venous thromboembolism in cancer patients is associated with the presence of TF-exposing microparticles that at least in part originate from the tumor45;46. Thus, TF-exposing
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microparticles can be present in human blood and these microparticles are capable of triggering TF-dependent coagulation in vitro and in vivo43;46;47.
The coagulant activity of TF is enhanced when negatively charged phospholipids such as phosphatidylserine (PS) or phosphatidylethanolamine (PE) are present48-52. Since nothing is known about the phospholipid composition of TF-exposing microparticles, and whether their phospholipid composition differs from non-TF-exposing microparticles, we investigated the phospholipid composition of TF-exposing microparticles from resting and activated endothelial cells, and their ability to trigger thrombus formation in vivo in
Chapter 7.
Indirect mechanisms of microparticle-induced coagulation
As mentioned above, microparticles can directly initiate and facilitate the coagulation process by exposure of PS and/or TF (Figure 2A). In addition, microparticles may also affect coagulation more indirectly. Microparticles from activated platelets expose P-selectin which can bind to P-selectin glycoprotein ligand-1 (PSGL-1) on monocytes. This interaction triggers de novo synthesis of TF by monocytes (Figure 2B), and this TF is released from the cell on TF-exposing microparticles (Figure 2B)53;54. Furie and coworkers
showed in a laser injury model that platelets adhere to the damaged vessel wall and then become activated. These activated platelets expose P-selectin, which in turn can capture circulating leukocyte-derived microparticles exposing PSGL-1 (from monocytes, but possibly also granulocytes) as well as TF. In this way, the circulating TF is thought to be delivered at the damaged vessel wall, where in turn this TF becomes coagulant and coagulation can be initiated (Figure 2C)55.
Microparticles, TF and rafts
Previously, del Conde et al. showed that TF-exposing microparticles released from monocytic cells fuse with platelets, thereby directly delivering TF to the platelet surface. In this manner, TF as the initiator of coagulation and the coagulation factors to be activated are brought together (Figure 2D)56. He hypothesized that TF-exposing microparticles
originate from rafts, since they showed that the microparticles were enriched in raft-associated proteins compared to their releasing cells56. The presence of TF in rafts,
however, is still debated by several investigators57;58. Therefore, in Chapter 8, we
investigated whether TF is a raft associated protein in purified plasma membranes and whether TF-exposing microparticles contain rafts.
Figure 2 gives an overview of the currently known effects of microparticles on the activation of the coagulation cascade. Arbitrarily, we distinguish direct (A) and indirect (B-D) mechanisms. First, figure A shows that microparticles from platelets (PMP) directly stimulate coagulation by exposing phosphatidylserine (PS; ), which binds (activated) coagulation factors. In addition, microparticles from especially leukocytes and endothelial cells (LMP and EMP, respectively) can expose tissue factor (TF; ), the initiator of the coagulation cascade in vivo. Second, figure B shows that coagulation can be initiated indirectly by PMP from activated platelets by binding to monocytes. These microparticles expose not only PS, but also P-selectin ( ) and are thus capable of binding to monocytes via P-selectin glycoprotein ligand-1 (PSGL-1; ). This interaction upregulates the expression of TF in the monocyte (B). Subsequently, the TF-exposing monocytes release highly procoagulant TF-exposing microparticles (MMP; B). Third, another indirect mechanism of microparticle-induced coagulation has been proposed for thrombus formation in an endothelial injury model. Figure C shows that, upon endothelial injury, platelets adhere to the damaged vessel wall and become activated. Activated platelets expose PS and P-selectin. The latter can bind PSGL-1, which is exposed on circulating microparticles from monocytes. Since these microparticles also expose TF, TF becomes localized at the site of the thrombus to be formed, and coagulation can be initiated and propagated. Fourth, figure D shows that TF-exposing microparticles may fuse with the outer membranes from activated platelets, thereby delivering coagulant TF on the surface of the activated platelet. This delivery results in the ultimate co-localization of TF and coagulation factor complexes on the activated platelet surface, making platelets the mediator in the activation and propagation of the coagulation cascade.
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Figure 2. Mechanisms of microparticle-induced coagulation.
The coagulation cascade Microparticles and coagulation
LMP/EMP
A
B
C
D
monocyte platelet endothelial cell act. platelet act. platelet PMP MMP PMP X Xa Va prothrombin thrombin fibrinogen fibrinTF
VIIa PS PSXIIa XIa IXa VIIIa
PS
MMP
MMP
The coagulation cascade Microparticles and coagulation
LMP/EMP
A
B
C
D
monocyte platelet endothelial cell act. platelet act. platelet PMP MMP PMP X Xa Va prothrombin thrombin fibrinogen fibrinTF
VIIa PS PSXIIa XIa IXa VIIIa
PS
MMP
TF and PDI
TF can be present in two different conformational forms, a coagulant active form and a cell signalling active form, the latter lacking any coagulant activity. Protein disulfide isomerase (PDI) was shown to oxidize and reduce the disulfide bond between Cys186 and Cys209 in the extracellular domain of TF, thereby switching the function of TF from cell signalling to coagulation and vice versa59. Since then, the role of PDI in the regulation of the TF
coagulant activity has been strongly debated, since it is still unclear whether PDI can reach the cysteins deep inside the TF-VIIa complex60.
PDI is also present in microparticles. Microparticles from platelets contain PDI61.
Whether or not PDI in microparticles can influence the coagulant activity of TF present on microparticles or even cells, however, is unknown. We investigated in Chapter 8 to which extent PDI and TF are present in rafts from microparticles.
Alternatively spliced TF
In 2003, an alternatively spliced (as) form of TF was described, which lacks the transmembrane domain due to a deletion which results in a frameshift and thus a peptide sequence different from TF. This asTF is produced by several cell types and organs, and is present in blood of healthy human individuals62. Initially, asTF was claimed to possess
coagulant activity, which could not be confirmed in a more recent studie63. In Chapter 9,
we investigated whether asTF is associated with microparticles and whether such asTF has any coagulant activity.
Structure of the thesis
The main question in this thesis is to establish whether and how microparticles balance cellular and environmental homeostasis. In Chapter 2, the question whether the release of microparticles from human umbilical endothelial cells contributes to cellular survival is investigated. In Chapter 3, caspase-3 deficient cells were transfected with caspase-3 constructs to study the effects of these constructs on the release of microparticles and on the sorting of caspase-3 into these microparticles. To further investigate the presence of caspase-3 in microparticles, in Chapter 4 microparticles present in aging platelet concentrates were studied.
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In Chapter 5, 6 and 7, various functions of microparticles were investigated. In
Chapter 5 the extent of “soluble” VEGFR-1 (sFlt-1) association with microparticles in
plasma from pregnant women suffering from preeclampsia was studied. In Chapter 6, the expression levels of inflammation-related genes were investigated in human endothelial cells in response to microparticles from preeclamptic patients, and in Chapter 7 the phospholipid composition and in vivo coagulant properties of TF-exposing microparticles from endothelial cells were studied.
In Chapter 8, the presence of the coagulant and non-coagulant forms of TF in purified plasma membranes and microparticles was studied in detail, and their association with rafts and PDI. Finally, in Chapter 9 the question was addressed whether the alternatively spliced form of TF is associated with microparticles and whether this alternatively spliced form has any coagulant activity.
References
1. Chargaff E. West R. The biological significance of the thromboplastic protein of blood. J.Biol.Chem. 1946;166:189-197.
2. Wolf P. The nature and significance of platelet products in human plasma. Br.J.Haematol. 1967;13:269-288.
3. Crawford N. The presence of contractile proteins in platelet microparticles isolated from human and animal platelet-free plasma. Br.J.Haematol. 1971;21:53-69.
4. Morel N, Morel O, Petit L et al. Generation of procoagulant microparticles in cerebrospinal fluid and peripheral blood after traumatic brain injury. J.Trauma 2008;64:698-704.
5. Berckmans RJ, Nieuwland R, Tak PP et al. Cell-derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum. 2002;46:2857-2866.
6. Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc.Natl.Acad.Sci.U.S.A 2004;101:13368-13373.
7. Smalley DM, Sheman NE, Nelson K, Theodorescu D. Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. J.Proteome.Res. 2008;7:2088-2096. 8. Admyre C, Johansson SM, Qazi KR et al. Exosomes with immune modulatory features are
present in human breast milk. J.Immunol. 2007;179:1969-1978.
9. Mashburn LM, Whiteley M. Membrane vesicles traffic signals and facilitate group activities in a prokaryote. Nature 2005;437:422-425.
10. Furuta N, Tsuda K, Omori H et al. Porphyromonas gingivalis outer membrane vesicles enter human epithelial cells via an endocytic pathway and are sorted to lysosomal compartments. Infect.Immun. 2009;77:4187-4196.
11. Furuta N, Takeuchi H, Amano A. Entry of Porphyromonas gingivalis outer membrane vesicles into epithelial cells causes cellular functional impairment. Infect.Immun. 2009;77:4761-4770. 12. Kesty NC, Mason KM, Reedy M, Miller SE, Kuehn MJ. Enterotoxigenic Escherichia coli
vesicles target toxin delivery into mammalian cells. EMBO J. 2004;23:4538-4549.
13. Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for
coagulation factor Va and express prothrombinase activity. J.Biol.Chem. 1988;263:18205-18212.
14. Safaei R, Larson BJ, Cheng TC et al. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol.Cancer Ther. 2005;4:1595-1604.
15. Shedden K, Xie XT, Chandaroy P, Chang YT, Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res. 2003;63:4331-4337.
16. Abid Hussein MN, Nieuwland R, Hau CM et al. Cell-derived microparticles contain caspase-3 in vitro and in vivo. J.Thromb.Haemost. 2005;3:888-896.
17. Sebbagh M, Renvoize C, Hamelin J et al. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat.Cell Biol. 2001;3:346-352. 18. Valadi H, Ekstrom K, Bossios A et al. Exosome-mediated transfer of mRNAs and microRNAs
is a novel mechanism of genetic exchange between cells. Nat.Cell Biol. 2007;9:654-659. 19. Ratajczak J, Miekus K, Kucia M et al. Embryonic stem cell-derived microvesicles reprogram
hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006;20:847-856.
20. Deregibus MC, Cantaluppi V, Calogero R et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 2007;110:2440-2448.
21. Brill A, Dashevsky O, Rivo J, Gozal Y, Varon D. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc.Res. 2005;67:30-38. 22. Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparticles induce angiogenesis in
vitro. Br.J.Haematol. 2004;124:376-384.
23. Mezentsev A, Merks RM, O'Riordan E et al. Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress. Am.J.Physiol Heart Circ.Physiol 2005;289:H1106-H1114. 24. Maynard SE, Min JY, Merchan J et al. Excess placental soluble fms-like tyrosine kinase 1
(sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J.Clin.Invest 2003;111:649-658.
25. Levine RJ, Lam C, Qian C et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N.Engl.J.Med. 2006;355:992-1005.
26. Barry OP, Pratico D, Lawson JA, FitzGerald GA. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J.Clin.Invest 1997;99:2118-2127. 27. Barry OP, Pratico D, Savani RC, FitzGerald GA. Modulation of monocyte-endothelial cell
interactions by platelet microparticles. J.Clin.Invest 1998;102:136-144.
28. Barry OP, Kazanietz MG, Pratico D, FitzGerald GA. Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway. J.Biol.Chem. 1999;274:7545-7556.
29. Mause SF, von HP, Zernecke A, Koenen RR, Weber C. Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler.Thromb.Vasc.Biol. 2005;25:1512-1518.
30. Distler JH, Huber LC, Hueber AJ et al. The release of microparticles by apoptotic cells and their effects on macrophages. Apoptosis. 2005;10:731-741.
31. Forlow SB, McEver RP, Nollert MU. Leukocyte-leukocyte interactions mediated by platelet microparticles under flow. Blood 2000;95:1317-1323.
32. Mesri M, Altieri DC. Endothelial cell activation by leukocyte microparticles. J.Immunol. 1998;161:4382-4387.
33. Nomura S, Tandon NN, Nakamura T et al. High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. Atherosclerosis 2001;158:277-287.
1
34. Berckmans RJ, Nieuwland R, Kraan MC et al. Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res.Ther. 2005;7:R536-R544.
35. Van Wijk MJ, Nieuwland R, Boer K et al. Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction? Am.J.Obstet.Gynecol. 2002;187:450-456.
36. Thiagarajan P, Tait JF. Collagen-induced exposure of anionic phospholipid in platelets and platelet-derived microparticles. J.Biol.Chem. 1991;266:24302-24307.
37. Zwaal RF, Comfurius P, Bevers EM. Platelet procoagulant activity and microvesicle formation. Its putative role in hemostasis and thrombosis. Biochim.Biophys.Acta 1992;1180:1-8.
38. Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J.Biol.Chem. 1989;264:17049-17057.
39. Abid Hussein MN, Meesters EW, Osmanovic N et al. Antigenic characterization of endothelial cell-derived microparticles and their detection ex vivo. J.Thromb.Haemost. 2003;1:2434-2443. 40. Kagawa H, Komiyama Y, Nakamura S et al. Expression of functional tissue factor on small
vesicles of lipopolysaccharide-stimulated human vascular endothelial cells. Thromb.Res. 1998;91:297-304.
41. 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;153:3245-3255.
42. Sturk-Maquelin KN, Nieuwland R, Romijn FP et al. Pro- and non-coagulant forms of non-cell-bound tissue factor in vivo. J.Thromb.Haemost. 2003;1:1920-1926.
43. Biro E, Sturk-Maquelin KN, Vogel GM et al. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J.Thromb.Haemost. 2003;1:2561-2568.
44. Nieuwland R, Berckmans RJ, McGregor S et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000;95:930-935.
45. Tesselaar ME, Romijn FP, van dL, I et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J.Thromb.Haemost. 2007;5:520-527.
46. Zwicker JI, Liebman HA, Neuberg D et al. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin.Cancer Res. 2009;15:6830-6840.
47. Dvorak HF, Van DL, Bitzer AM et al. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res. 1983;43:4434-4442.
48. Bach R, Rifkin DB. Expression of tissue factor procoagulant activity: regulation by cytosolic calcium. Proc.Natl.Acad.Sci.U.S.A 1990;87:6995-6999.
49. Greeno EW, Bach RR, Moldow CF. Apoptosis is associated with increased cell surface tissue factor procoagulant activity. Lab Invest 1996;75:281-289.
50. Le DT, Rapaport SI, Rao LV. Relations between factor VIIa binding and expression of factor VIIa/tissue factor catalytic activity on cell surfaces. J.Biol.Chem. 1992;267:15447-15454. 51. Le DT, Rapaport SI, Rao LV. Studies of the mechanism for enhanced cell surface factor
VIIa/tissue factor activation of factor X on fibroblast monolayers after their exposure to N-ethylmaleimide. Thromb.Haemost. 1994;72:848-855.
52. Wolberg AS, Monroe DM, Roberts HR, Hoffman MR. Tissue factor de-encryption: ionophore treatment induces changes in tissue factor activity by phosphatidylserinedependent and -independent mechanisms. Blood Coagul.Fibrinolysis 1999;10:201-210.
53. Celi A, Pellegrini G, Lorenzet R et al. P-selectin induces the expression of tissue factor on monocytes. Proc.Natl.Acad.Sci.U.S.A 1994;91:8767-8771.
54. Furie B, Furie BC. P-selectin induction of tissue factor biosynthesis and expression. Haemostasis 1996;26 Suppl 1:60-65.
55. Falati S, Liu Q, Gross P et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J.Exp.Med. 2003;197:1585-1598.
56. Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005;106:1604-1611.
57. Dietzen DJ, Page KL, Tetzloff TA. Lipid rafts are necessary for tonic inhibition of cellular tissue factor procoagulant activity. Blood 2004;103:3038-3044.
58. Mandal SK, Pendurthi UR, Rao LV. Cellular localization and trafficking of tissue factor. Blood 2006;107:4746-4753.
59. Ahamed J, Versteeg HH, Kerver M et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc.Natl.Acad.Sci.U.S.A 2006;103:13932-13937.
60. Bach RR, Monroe D. What is wrong with the allosteric disulfide bond hypothesis? Arterioscler.Thromb.Vasc.Biol. 2009;29:1997-1998.
61. Raturi A, Miersch S, Hudson JW, Mutus B. Platelet microparticle-associated protein disulfide isomerase promotes platelet aggregation and inactivates insulin. Biochim.Biophys.Acta 2008;1778:2790-2796.
62. Bogdanov VY, Balasubramanian V, Hathcock J et al. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat.Med. 2003;9:458-462.
63. Censarek P, Bobbe A, Grandoch M, Schror K, Weber AA. Alternatively spliced human tissue factor (asHTF) is not pro-coagulant. Thromb.Haemost. 2007;97:11-14.
