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DOI: 10.1055/s-0044-1789022
Role of Platelets and Their Interaction with Immune Cells in Venous Thromboembolism
Authors

Abstract
Venous thromboembolism (VTE) represents a significant global health challenge, ranking as the third leading cause of cardiovascular-related mortality. VTE pervades diverse clinical specialties, posing substantial risks to patient well-being and imposing considerable economic strains on health care systems. While platelets have long been recognized as pivotal players in hemostasis, emerging evidence underscores their multifaceted immune functions and their capacity to engage in crosstalk with other immune cells, such as neutrophils, thereby fostering immune-related thrombosis. Notably, investigations have elucidated the pivotal role of platelets in the pathogenesis of VTE. This review provides a comprehensive overview of platelet physiology, encompassing their activation, secretion dynamics, and implications in VTE. Moreover, it delineates the impact of platelet interactions with various immune cells on the initiation and progression of VTE, explores the correlation between platelet-related laboratory markers and VTE, and elucidates the role of platelets in thrombosis regression.
Keywords
platelets - immune cells - venous thromboembolism - hemostasis - immune thrombosis - thrombosis regression* Zhao Zhang, Xianghui Zhou, and Xin Zhou contributed equally to this article.
Publikationsverlauf
Artikel online veröffentlicht:
30. August 2024
© 2024. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
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References
- 1 Brass LF, Diamond SL, Stalker TJ. Platelets and hemostasis: a new perspective on an old subject. Blood Adv 2016; 1 (01) 5-9
- 2 Gremmel T, Frelinger III AL, Michelson AD. Platelet physiology. Semin Thromb Hemost 2016; 42 (03) 191-204
- 3 Patel P, Michael JV, Naik UP, McKenzie SE. Platelet FcγRIIA in immunity and thrombosis: adaptive immunothrombosis. J Thromb Haemost 2021; 19 (05) 1149-1160
- 4 Li Y, Feng G. TLR4 inhibitor alleviates sepsis-induced organ failure by inhibiting platelet mtROS production, autophagy, and GPIIb/IIIa expression. J Bioenerg Biomembr 2022; 54 (03) 155-162
- 5 van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol 2019; 16 (03) 166-179
- 6 Carestia A, Godin LC, Jenne CN. Step up to the platelet: Role of platelets in inflammation and infection. Thromb Res 2023; 231: 182-194
- 7 Shu L, Lin S, Zhou S, Yuan T. Glycan-lectin interactions between platelets and tumor cells drive hematogenous metastasis. Platelets 2024; 35 (01) 2315037
- 8 Nagy M, van der Meijden PEJ, Glunz J. et al. integrating mechanisms in thrombotic peripheral arterial disease. Pharmaceuticals (Basel) 2022; 15 (11) 15
- 9 Wei K, Huang H, Liu M, Shi D, Ma X. Platelet-derived exosomes and atherothrombosis. Front Cardiovasc Med 2022; 9: 886132
- 10 Kulkarni PP, Ekhlak M, Dash D. Non-canonical non-genomic morphogen signaling in anucleate platelets: a critical determinant of prothrombotic function in circulation. Cell Commun Signal 2024; 22 (01) 13
- 11 Panova-Noeva M, Wagner B, Nagler M. et al. Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies. EBioMedicine 2020; 60: 102978
- 12 Wolberg AS, Rosendaal FR, Weitz JI. et al. Venous thrombosis. Nat Rev Dis Primers 2015; 1: 15006
- 13 Delluc A, Lacut K, Rodger MA. Arterial and venous thrombosis: what's the link? A narrative review. Thromb Res 2020; 191: 97-102
- 14 Mwiza JMN, Lee RH, Paul DS. et al. Both G protein-coupled and immunoreceptor tyrosine-based activation motif receptors mediate venous thrombosis in mice. Blood 2022; 139 (21) 3194-3203
- 15 Bergmeier W, Stefanini L. Platelets at the vascular interface. Res Pract Thromb Haemost 2018; 2 (01) 27-33
- 16 Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest 2019; 129 (01) 12-23
- 17 Oishi S, Tsukiji N, Otake S. et al. Heme activates platelets and exacerbates rhabdomyolysis-induced acute kidney injury via CLEC-2 and GPVI/FcRγ. Blood Adv 2021; 5 (07) 2017-2026
- 18 Lee RH, Kawano T, Grover SP. et al. Genetic deletion of platelet PAR4 results in reduced thrombosis and impaired hemostatic plug stability. J Thromb Haemost 2022; 20 (02) 422-433
- 19 Han X, Nieman MT. PAR4 (protease-activated receptor 4): PARticularly important 4 antiplatelet therapy. Arterioscler Thromb Vasc Biol 2018; 38 (02) 287-289
- 20 Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413 (6851): 74-78
- 21 Gachet C, Hechler B. The platelet P2 receptors in thrombosis. Semin Thromb Hemost 2005; 31 (02) 162-167
- 22 Gachet C. Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol 2006; 46: 277-300
- 23 Bird JE, Wang X, Smith PL, Barbera F, Huang C, Schumacher WA. A platelet target for venous thrombosis? P2Y1 deletion or antagonism protects mice from vena cava thrombosis. J Thromb Thrombolysis 2012; 34 (02) 199-207
- 24 Payne H, Ponomaryov T, Watson SP, Brill A. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood 2017; 129 (14) 2013-2020
- 25 Meng D, Luo M, Liu B. The role of CLEC-2 and its ligands in thromboinflammation. Front Immunol 2021; 12: 688643
- 26 Hughes CE, Navarro-Núñez L, Finney BA, Mourão-Sá D, Pollitt AY, Watson SP. CLEC-2 is not required for platelet aggregation at arteriolar shear. J Thromb Haemost 2010; 8 (10) 2328-2332
- 27 Wang X, Liu B, Xu M. et al. Blocking podoplanin inhibits platelet activation and decreases cancer-associated venous thrombosis. Thromb Res 2021; 200: 72-80
- 28 Jandrot-Perrus M, Busfield S, Lagrue AH. et al. Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily. Blood 2000; 96 (05) 1798-1807
- 29 Jiang P, Jandrot-Perrus M. New advances in treating thrombotic diseases: GPVI as a platelet drug target. Drug Discov Today 2014; 19 (09) 1471-1475
- 30 Cosemans JM, Kuijpers MJ, Lecut C. et al. Contribution of platelet glycoprotein VI to the thrombogenic effect of collagens in fibrous atherosclerotic lesions. Atherosclerosis 2005; 181 (01) 19-27
- 31 Schulz C, Penz S, Hoffmann C. et al. Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo. Basic Res Cardiol 2008; 103 (04) 356-367
- 32 Lehmann M, Schoeman RM, Krohl PJ. et al. Platelets drive thrombus propagation in a hematocrit and glycoprotein VI-dependent manner in an in vitro venous thrombosis model. Arterioscler Thromb Vasc Biol 2018; 38 (05) 1052-1062
- 33 Slater A, Khattak S, Thomas MR. GPVI as an effective antithrombotic target. . Eur Heart J Cardiovasc Pharmacother 2024
- 34 Voors-Pette C, Lebozec K, Dogterom P. et al. Safety and tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol 2019; 39 (05) 956-964
- 35 Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity 2010; 32 (03) 305-315
- 36 Ebermeyer T, Cognasse F, Berthelot P, Mismetti P, Garraud O, Hamzeh-Cognasse H. Platelet innate immune receptors and TLRs: a double-edged sword. Int J Mol Sci 2021; 22 (15) 22
- 37 Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5 (04) 331-342
- 38 Stark K, Philippi V, Stockhausen S. et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016; 128 (20) 2435-2449
- 39 Théry C, Witwer KW, Aikawa E. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7 (01) 1535750
- 40 Boilard E, Duchez AC, Brisson A. The diversity of platelet microparticles. Curr Opin Hematol 2015; 22 (05) 437-444
- 41 Zhang J, Hu X, Wang T. et al. Extracellular vesicles in venous thromboembolism and pulmonary hypertension. J Nanobiotechnology 2023; 21 (01) 461
- 42 Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renné T, ten Cate H, Spronk HM. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10 (07) 1355-1362
- 43 Hérault JP, Perrin B, Jongbloet C, Pflieger AM, Bernat A, Herbert JM. Effect of factor Xa inhibitors on the platelet-derived microparticles procoagulant activity in vitro and in vivo in rats. Thromb Haemost 2000; 84 (04) 668-674
- 44 Ramacciotti E, Hawley AE, Farris DM. et al. Leukocyte- and platelet-derived microparticles correlate with thrombus weight and tissue factor activity in an experimental mouse model of venous thrombosis. Thromb Haemost 2009; 101 (04) 748-754
- 45 Snir O, Wilsgård L, Latysheva N. et al. Plasma levels of platelet-derived microvesicles are associated with risk of future venous thromboembolism. J Thromb Haemost 2022; 20 (04) 899-908
- 46 Guerreiro EM, Kruglik SG, Swamy S. et al. Extracellular vesicles from activated platelets possess a phospholipid-rich biomolecular profile and enhance prothrombinase activity. J Thromb Haemost 2024; 22 (05) 1463-1474
- 47 Wang J, Yu C, Zhuang J. et al. The role of phosphatidylserine on the membrane in immunity and blood coagulation. Biomark Res 2022; 10 (01) 4
- 48 Medfisch SM, Muehl EM, Morrissey JH, Bailey RC. Phosphatidylethanolamine-phosphatidylserine binding synergy of seven coagulation factors revealed using Nanodisc arrays on silicon photonic sensors. Sci Rep 2020; 10 (01) 17407
- 49 Rao NN, Gómez-García MR, Kornberg A. Inorganic polyphosphate: essential for growth and survival. Annu Rev Biochem 2009; 78: 605-647
- 50 Gajsiewicz JM, Smith SA, Morrissey JH. Polyphosphate and RNA differentially modulate the contact pathway of blood clotting. J Biol Chem 2017; 292 (05) 1808-1814
- 51 Verhoef JJ, Barendrecht AD, Nickel KF. et al. Polyphosphate nanoparticles on the platelet surface trigger contact system activation. Blood 2017; 129 (12) 1707-1717
- 52 Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost 2015; 13 (0 1, Suppl 1): S92-S97
- 53 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139 (06) 1143-1156
- 54 Labberton L, Kenne E, Long AT. et al. Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 2016; 7: 12616
- 55 Whyte CS, Chernysh IN, Domingues MM. et al. Polyphosphate delays fibrin polymerisation and alters the mechanical properties of the fibrin network. Thromb Haemost 2016; 116 (05) 897-903
- 56 Mathews R, Setthavongsack N, Le-Cook A. et al. Role of platelet count in a murine stasis model of deep vein thrombosis. Platelets 2024; 35 (01) 2290916
- 57 Yang J, Zhou X, Fan X. et al. mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation. Blood 2016; 128 (05) 615-624
- 58 Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 2014; 15 (03) 155-162
- 59 Gulcan M, Varol E, Etli M, Aksoy F, Kayan M. Mean platelet volume is increased in patients with deep vein thrombosis. Clin Appl Thromb Hemost 2012; 18 (04) 427-430
- 60 Díaz JM, Boietti BR, Vazquez FJ. et al. Mean platelet volume as a prognostic factor for venous thromboembolic disease. Rev Med Chil 2019; 147 (02) 145-152
- 61 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
- 62 Kapoor S, Opneja A, Nayak L. The role of neutrophils in thrombosis. Thromb Res 2018; 170: 87-96
- 63 Carminita E, Crescence L, Panicot-Dubois L, Dubois C. Role of neutrophils and NETs in animal models of thrombosis. Int J Mol Sci 2022; 23 (03) 23
- 64 von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
- 65 Wang Y, Gao H, Shi C. et al. Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat Commun 2017; 8: 15559
- 66 Page C, Pitchford S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int Immunopharmacol 2013; 17 (04) 1176-1184
- 67 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 9 (01) 61-67
- 68 Maugeri N, Rovere-Querini P, Evangelista V. et al. An intense and short-lasting burst of neutrophil activation differentiates early acute myocardial infarction from systemic inflammatory syndromes. PLoS One 2012; 7 (06) e39484
- 69 Zhou J, Xu E, Shao K. et al. Circulating platelet-neutrophil aggregates as risk factor for deep venous thrombosis. Clin Chem Lab Med 2019; 57 (05) 707-715
- 70 Kornerup KN, Salmon GP, Pitchford SC, Liu WL, Page CP. Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration. J Appl Physiol 2010; 109 (03) 758-767
- 71 Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32 (08) 1777-1783
- 72 Hidalgo A, Libby P, Soehnlein O, Aramburu IV, Papayannopoulos V, Silvestre-Roig C. Neutrophil extracellular traps: from physiology to pathology. Cardiovasc Res 2022; 118 (13) 2737-2753
- 73 Savchenko AS, Martinod K, Seidman MA. et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost 2014; 12 (06) 860-870
- 74 Pieterse E, Rother N, Garsen M. et al. Neutrophil extracellular traps drive endothelial-to-mesenchymal transition. Arterioscler Thromb Vasc Biol 2017; 37 (07) 1371-1379
- 75 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
- 76 Semeraro F, Ammollo CT, Morrissey JH. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118 (07) 1952-1961
- 77 Kumar R, Sonkar VK, Swamy J. et al. DNase 1 protects from increased thrombin generation and venous thrombosis during aging: cross-sectional study in mice and humans. J Am Heart Assoc 2022; 11 (02) e021188
- 78 Dyer MR, Chen Q, Haldeman S. et al. Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA. Sci Rep 2018; 8 (01) 2068
- 79 Carminita E, Crescence L, Brouilly N, Altié A, Panicot-Dubois L, Dubois C. DNAse-dependent, NET-independent pathway of thrombus formation in vivo. Proc Natl Acad Sci U S A 2021; 118 (28) 118
- 80 Martinod K, Demers M, Fuchs TA. et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 2013; 110 (21) 8674-8679
- 81 Speeckaert R, Lambert J, Grine L, Van Gele M, De Schepper S, van Geel N. The many faces of interleukin-17 in inflammatory skin diseases. Br J Dermatol 2016; 175 (05) 892-901
- 82 Yuan J, Ding PW, Yu M. et al. IL-17 Induces MPTP opening through ERK2 and P53 signaling pathway in human platelets. J Huazhong Univ Sci Technolog Med Sci 2015; 35 (05) 679-683
- 83 Yan M, Zhang X, Chen A. et al. Endothelial cell SHP-2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM-1-VE-cadherin interaction. FASEB J 2017; 31 (11) 4759-4769
- 84 Nhek S, Clancy R, Lee KA. et al. Activated platelets induce endothelial cell activation via an interleukin-1β pathway in systemic lupus erythematosus. Arterioscler Thromb Vasc Biol 2017; 37 (04) 707-716
- 85 Ding P, Zhang S, Yu M. et al. IL-17A promotes the formation of deep vein thrombosis in a mouse model. Int Immunopharmacol 2018; 57: 132-138
- 86 Guidetti GF, Torti M, Canobbio I. Focal adhesion kinases in platelet function and thrombosis. Arterioscler Thromb Vasc Biol 2019; 39 (05) 857-868
- 87 Evangelista V, Pamuklar Z, Piccoli A. et al. Src family kinases mediate neutrophil adhesion to adherent platelets. Blood 2007; 109 (06) 2461-2469
- 88 Canino J, Guidetti GF, Galgano L. et al. The proline-rich tyrosine kinase Pyk2 modulates integrin-mediated neutrophil adhesion and reactive oxygen species generation. Biochim Biophys Acta Mol Cell Res 2020; 1867 (10) 118799
- 89 Momi S, Canino J, Vismara M. et al. Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis. Haematologica 2022; 107 (06) 1374-1383
- 90 Germain M, Chasman DI, de Haan H. et al; Cardiogenics Consortium. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet 2015; 96 (04) 532-542
- 91 Hinds DA, Buil A, Ziemek D. et al; METASTROKE Consortium, INVENT Consortium. Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. Hum Mol Genet 2016; 25 (09) 1867-1874
- 92 Kommareddi P, Nair T, Kakaraparthi BN. et al. Hair cell loss, spiral ganglion degeneration, and progressive sensorineural hearing loss in mice with targeted deletion of Slc44a2/Ctl2. J Assoc Res Otolaryngol 2015; 16 (06) 695-712
- 93 Bennett JA, Mastrangelo MA, Ture SK. et al. The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function. Nat Commun 2020; 11 (01) 3479
- 94 Rieckmann JC, Geiger R, Hornburg D. et al. Social network architecture of human immune cells unveiled by quantitative proteomics. Nat Immunol 2017; 18 (05) 583-593
- 95 Constantinescu-Bercu A, Grassi L, Frontini M, Salles-Crawley II, Woollard K, Crawley JT. Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2. eLife 2020; 9: 9
- 96 Tilburg J, Coenen DM, Zirka G. et al. SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis. J Thromb Haemost 2020; 18 (07) 1714-1727
- 97 Zirka G, Robert P, Tilburg J. et al. Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates. Blood 2021; 137 (16) 2256-2266
- 98 Altmann J, Sharma S, Lang IM. Advances in our understanding of mechanisms of venous thrombus resolution. Expert Rev Hematol 2016; 9 (01) 69-78
- 99 Modarai B, Burnand KG, Humphries J, Waltham M, Smith A. The role of neovascularisation in the resolution of venous thrombus. Thromb Haemost 2005; 93 (05) 801-809
- 100 Brogren H, Wallmark K, Deinum J, Karlsson L, Jern S. Platelets retain high levels of active plasminogen activator inhibitor 1. PLoS One 2011; 6 (11) e26762
- 101 Whyte CS, Mitchell JL, Mutch NJ. Platelet-mediated modulation of fibrinolysis. Semin Thromb Hemost 2017; 43 (02) 115-128
- 102 DeRoo E, Martinod K, Cherpokova D. et al. The role of platelets in thrombus fibrosis and vessel wall remodeling after venous thrombosis. J Thromb Haemost 2021; 19 (02) 387-399
- 103 Kisucka J, Butterfield CE, Duda DG. et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc Natl Acad Sci U S A 2006; 103 (04) 855-860
- 104 Xie Y, Muller WA. Molecular cloning and adhesive properties of murine platelet/endothelial cell adhesion molecule 1. Proc Natl Acad Sci U S A 1993; 90 (12) 5569-5573
- 105 Woodfin A, Voisin MB, Imhof BA, Dejana E, Engelhardt B, Nourshargh S. Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1. Blood 2009; 113 (24) 6246-6257
- 106 Saha P, Humphries J, Modarai B. et al. Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 2011; 31 (03) 506-512
- 107 Kellermair J, Redwan B, Alias S. et al. Platelet endothelial cell adhesion molecule 1 deficiency misguides venous thrombus resolution. Blood 2013; 122 (19) 3376-3384