Exosomes refer to a group of extracellular vesicles naturally released from mammalian cells with a diameter of 30–150 nm. Exosomes contain a variety of biologically active molecules, such as cytoplasmic proteins, chemokines, cytokines, and microRNA (miRNA). They are widely involved in intercellular communication and regulate the behavior of recipient cells. Venous thrombosis is a pathological change caused by vascular endothelial cell damage, hemodynamic changes, and the hypercoagulable state of blood. Exosomes from different cell sources are involved in the process of venous thrombosis. Exosomes can also be used as therapeutic carriers for tissue regeneration and drug delivery. Therefore, the study of exosomes is crucial for the formation, diagnosis, and treatment of venous thrombosis. In this review, we summarize the biological characteristics of exosomes and their mechanism of action in venous thrombosis. In addition, we also focused on its potential clinical applications, including as a diagnostic marker and therapeutic carrier for venous thrombosis.
DeatherageBLCooksonBT.Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun. 2012;80:1948-57.
2.
DoyleLMWangMZ.Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8:727.
3.
KhazaeiFRezakhaniLAlizadehMMahdavianEKhazaeiM.Exosomes and exosome-loaded scaffolds: characterization and application in modern regenerative medicine. Tissue Cell. 2023;80:102007.
4.
YeSLLiWDLiWX, et al. The regulatory role of exosomes in venous thromboembolism. Front Cell Dev Biol. 2022;10:956880.
5.
BudnikIBrillA.Immune factors in deep vein thrombosis initiation. Trends Immunol. 2018;39:610-23.
RaskobGEAngchaisuksiriPBlancoAN, et al. Thrombosis: a major contributor to global disease burden. Thromb Res. 2014;134:931-8.
8.
ZifkosKDuboisCSchäferK.Extracellular vesicles and thrombosis: update on the clinical and experimental evidence. Int J Mol Sci. 2021;22:9317.
9.
WuPZhangBOcanseyDKWXuWQianH.Extracellular vesicles: a bright star of nanomedicine. Biomaterials. 2021;269:120467.
10.
KalluriRLeBleuVS.The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.
11.
van NielGD’AngeloGRaposoG. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213-28.
12.
ZhangYLiuYLiuHTangWH.Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.
13.
Kimiz-GebologluIOncelSS.Exosomes: large-scale production, isolation, drug loading efficiency, and biodistribution and uptake. J Control Release. 2022;347:533-43.
14.
ZhangYBiJHuangJTangYDuSLiP.Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine. 2020;15:6917-34.
15.
JiangZLiuGLiJ.Recent progress on the isolation and detection methods of exosomes. Chem Asian J. 2020;15:3973-82.
16.
ShiYShiHNomiALei-LeiZZhangBQianH.Mesenchymal stem cell-derived extracellular vesicles: a new impetus of promoting angiogenesis in tissue regeneration. Cytotherapy. 2019;21:497-508.
17.
PegtelDMGouldSJ.Exosomes. Annu Rev Biochem. 2019;88:487-514.
18.
IsaacRReisFCGYingWOlefskyJM.Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metab. 2021;33:1744-62.
19.
MondalJPillarisettiSJunnuthulaV, et al. Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications. J Control Release. 2023;353:1127-49.
20.
ValadiHEkströmKBossiosASjöstrandMLeeJJLötvallJO.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654-9.
21.
GurungSPerocheauDTouramanidouLBaruteauJ.The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. 2021;19:47.
22.
KimKAChoiSYKimR.Endovascular treatment for lower extremity deep vein thrombosis: an overview. Korean J Radiol. 2021;22:931-43.
23.
VerhammePHoylaertsMF.The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg. 2006;61:213-9.
24.
CyrARHuckabyLVShivaSSZuckerbraunBS.Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020;36:307-21.
25.
MosevollKAJohansenSWendelboØNepstadIBruserudØReikvamH.Cytokines, adhesion molecules, and matrix metalloproteases as predisposing, diagnostic, and prognostic factors in venous thrombosis. Front Med (Lausanne). 2018;5:147.
26.
SahaPBlackSBreenKPatelAModaraiBSmithA.Contemporary management of acute and chronic deep venous thrombosis. Br Med Bull. 2016;117:107-20.
27.
ChengXZhouHZhouYSongC.M2 macrophage-derived exosomes inhibit apoptosis of HUVEC cell through regulating miR-221-3p expression. Biomed Res Int. 2022;2022:1609244.
28.
YuMLiuWLiJ, et al. Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway. Stem Cell Res Ther. 2020;11:350.
29.
IncalzaMAD’OriaRNatalicchioAPerriniSLaviolaLGiorginoF.Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol. 2018;100:1-19.
30.
LibbyP.Inflammation in atherosclerosis. Nature. 2002;420:868-74.
31.
BonettiPOLermanLOLermanA.Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168-75.
32.
GambimMHdo Carmo AdeOMartiLVeríssimo-FilhoSLopesLRJaniszewskiM.Platelet-derived exosomes induce endothelial cell apoptosis through peroxynitrite generation: experimental evidence for a novel mechanism of septic vascular dysfunction. Crit Care. 2007;11:R107.
33.
WangJChenSBihlJ.Exosome-mediated transfer of ACE2 (Angiotensin-Converting Enzyme 2) from endothelial progenitor cells promotes survival and function of endothelial cell. Oxid Med Cell Longev. 2020;2020:4213541.
34.
MukhopadhyaySJohnsonTADuruN, et al. Fibrinolysis and inflammation in venous thrombus resolution. Front Immunol. 2019;10:1348.
35.
LiJTanMXiangQZhouZYanH.Thrombin-activated platelet-derived exosomes regulate endothelial cell expression of ICAM-1 via microRNA-223 during the thrombosis-inflammation response. Thromb Res. 2017;154:96-105.
36.
NajemMYCouturaudFLemariéCA.Cytokine and chemokine regulation of venous thromboembolism. J Thromb Haemost. 2020;18:1009-19.
37.
FuchsTABrillADuerschmiedD, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880-5.
38.
LaridanEMartinodKDe MeyerSF.Neutrophil extracellular traps in arterial and venous thrombosis. Semin Thromb Hemost. 2019;45:86-93.
39.
ChenLHuLLiQMaJLiH.Exosome-encapsulated miR-505 from ox-LDL-treated vascular endothelial cells aggravates atherosclerosis by inducing NET formation. Acta Biochim Biophys Sin (Shanghai). 2019;51:1233-41.
40.
RossaintJKühneKSkupskiJ, et al. Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response. Nat Commun. 2016;7:13464.
41.
JiaoYLiWWangW, et al. Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock. Crit Care. 2020;24:380.
42.
StarkKPhilippiVStockhausenS, et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood. 2016;128:2435-49.
43.
FischerDBüssowJMeybohmP, et al. Microparticles from stored red blood cells enhance procoagulant and proinflammatory activity. Transfusion. 2017;57:2701-11.
44.
ErlWWeberCWardemannCWeberPC.Alpha-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-kappa B mobilization. Am J Physiol. 1997;273:H634-40.
45.
KoKWYooYIKimJY, et al. Attenuation of tumor necrosis factor-α Induced inflammation by umbilical cord-mesenchymal stem cell derived exosome-mimetic nanovesicles in endothelial cells. Tissue Eng Regen Med. 2020;17:155-63.
LacroixRSabatierFMialheA, et al. Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro. Blood. 2007;110:2432-9.
48.
LiLWangYYuX, et al. Bone marrow mesenchymal stem cell-derived exosomes promote plasminogen activator inhibitor 1 expression in vascular cells in the local microenvironment during rabbit osteonecrosis of the femoral head. Stem Cell Res Ther. 2020;11:480.
49.
VrijsenKRMaringJAChamuleauSA, et al. Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater. 2016;5:2555-65.
50.
ArdiVCKupriyanovaTADeryuginaEIQuigleyJP.Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A. 2007;104:20262-7.
51.
NosakaMIshidaYKimuraA, et al. Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice. J Clin Invest. 2011;121:2911-20.
52.
LozitoTPTuanRS.Endothelial cell microparticles act as centers of matrix metalloproteinsase-2 (MMP-2) activation and vascular matrix remodeling. J Cell Physiol. 2012;227:534-49.
53.
NosakaMIshidaYKimuraA, et al. Contribution of the TNF-α (Tumor Necrosis Factor-α)-TNF-Rp55 (Tumor Necrosis Factor Receptor p55) axis in the resolution of venous thrombus. Arterioscler Thromb Vasc Biol. 2018;38:2638-50.
54.
PalaretiGCosmiBLegnaniC, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-9.
55.
WojcikBMWrobleskiSKHawleyAEWakefieldTWMyersDDJrDiazJA.Interleukin-6: a potential target for post-thrombotic syndrome. Ann Vasc Surg. 2011;25:229-39.
56.
XiangEHanBZhangQ, et al. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis. Stem Cell Res Ther. 2020;11:336.
57.
KrugerPCEikelboomJWDouketisJDHankeyGJ.Deep vein thrombosis: update on diagnosis and management. Med J Aust. 2019;210:516-24.
58.
AuduCOGordonAEObiATWakefieldTWHenkePK.Inflammatory biomarkers in deep venous thrombosis organization, resolution, and post-thrombotic syndrome. J Vasc Surg Venous Lymphat Disord. 2020;8:299-305.
YeRYeCHuangYLiuLWangS.Circulating tissue factor positive microparticles in patients with acute recurrent deep venous thrombosis. Thromb Res. 2012;130:253-8.
63.
KahnSRShrierIJulianJA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.
64.
WatsonLBroderickCArmonMP.Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2016;11:Cd002783.
65.
MoustafaAAlimHMChowdhuryMAEltahawyEA.Postthrombotic syndrome: long-term sequela of deep venous thrombosis. Am J Med Sci. 2018;356:152-8.
66.
PanZChenQDingHLiH.MicroRNA-342-3p loaded by human umbilical cord mesenchymal stem cells-derived exosomes attenuates deep vein thrombosis by downregulating EDNRA. J Thromb Thrombolysis. 2022;54:411-9.
67.
HouYCLiJAZhuSJ, et al. Tailoring of cardiovascular stent material surface by immobilizing exosomes for better pro-endothelialization function. Colloids Surf B Biointerfaces. 2020;189:110831.
