Добавил:

Sekretar kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.

Вуз:

Ростовский Государственный Медицинский Университет

Предмет:

Медицина общая

Файл:

Книга_3720_Библиотеки_им_академика_М_И_Перельмана

.pdf

Скачиваний:

Добавлен:

31.08.2026

Размер:

30 Мб

Скачать

☆

<<< < Предыдущая 1 2 3 4 5 6 78 / 508 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 > Следующая >>>

Fibrin Clot Structure and Function: A Novel Risk Factor for Arterial and Venous Thrombosis Chapter | 3 45

https://t.me/med1917

[46] Kostelansky MS, Betts L, Gorkun OV, Lord ST. 2.8 Å crystal structures of recombinant ﬁbrinogen fragment D with and without two peptide

ligands: GHRP binding to the “b” site disrupts its nearby calcium-binding site. Biochemistry 2002;41:12124e32. [47] Weisel JW, Stauffacher CV, Bullitt E, Cohen C. A model for ﬁbrinogen: domains and sequence. Science 1985;230:1388e91. [48] Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of ﬁbrinogen and ﬁbrin. Ann NY Acad Sci 2001;936:11e30. [49] Hantgan RR, Hermans J. Assembly of ﬁbrin: a light scattering study. J Biol Chem 1979;254:11272e81. [50] Mosesson MW, DiOrio JP, Siebenlist KR, Wall JS, Hainfeld JF. Evidence for a second type of ﬁbril branch point in ﬁbrin polymer networks, the

trimolecular junction. Blood 1993;82:1517e21. [51] Mosesson MW. Fibrinogen and ﬁbrin structure and functions. J Thromb Haemost 2005;3:1894e904. [52] Blombäck B, Carlsson K, Fatah K, Hessel B, Procyk R. Fibrin in human plasma: gel architectures governed by rate and nature of ﬁbrinogen

activation. Thromb Res 1994;75:521e38. [53] Weisel JW. Fibrin assembly. Lateral aggregation and the role of the two pairs of ﬁbrinopeptides. Biophys J 1986;50:1079e93. [54] Litvinov RI, Gorkun OV, Galanakis DK, Yakovlev S, Medved L, Shuman H, et al. Polymerization of ﬁbrin: direct observation and quantiﬁcation

of individual B:b knob-hole interactions. Blood 2007;109:130e8. [55] Wolberg AS, Monroe DM, Roberts HR, Hoffman M. Elevated prothrombin results in clots with an altered ﬁber structure: a possible mechanism of

the increased thrombotic risk. Blood 2003;101:3008e13. [56] Carr ME, Gabriel DA, McDonagh J. Inﬂuence of Ca

1986;239:513e6. [57] Muszbek L, Ariëns RAS, Ichinose A. Factor XIII: recommended terms and abbreviations. J Thromb Haemost 2007;5:181e3. [58] Muszbek L, Adany R, Mikkolla H. Novel aspects of blood coagulation factor XIII. 1. Structure, distribution, activation, and function. Crit Rev Clin

Lab Sci 1996;33:357e421. [59] Yorifuji H, Anderson K, Lynch GW, Van de Water L, McDonagh J. B protein of factor XIII: differentiation between free B and complexed B.

Blood 1988;72:1645e50. [60] Siebenlist KR, Mosesson MW. Evidence for intramolecular cross-linked A a/g chain heterodimers in plasma ﬁbrinogen. Biochemistry

1996;35:5817e21. [61] Janus TJ, Lewis SD, Lorand L, Shafer JA. Promotion of thrombin-catalyzed activation of factor XIII by ﬁbrinogen. Biochemistry

1983;22:6269e72. [62] Chen R, Doolittle RF. g-g Cross-linking sites in human and bovine ﬁbrin. Biochemistry 1979;10:4486e91. [63] Cottrell BA, Strong DD, Watt KW, Doolittle RF. Amino acid sequence studies on the alpha chain of human ﬁbrinogen: exact location of cross-

linking acceptor sites. Biochemistry 1979;18:5405e10. [64] McDonagh RP, McDonagh J, Blombäck M, Blombäck B. Crosslinking of human ﬁbrin: evidence for intermolecular crosslinking involving alpha-

chains. FEBS Lett 1971;14:33e6. [65] Duval C, Allan P, Connell SD, Ridger VC, Philippou H, Ariëns RAS. Roles of ﬁbrin a- and g-chain speciﬁc cross-linking by FXIIIa in ﬁbrin

structure and function. J Thromb Haemost 2014;111:842e50. [66] Valnickova Z, Enghild JJ. Human procarboxypeptidase U, or thrombin-activable ﬁbrinolysis inhibitor, is a substrate for transglutaminases: evi-

dence for transglutaminase-catalyzed cross-linking to ﬁbrin. J Biol Chem 1998;273:27220e4. [67] Mosher DF, Schad PE, Kleinman HK. Cross-linking of ﬁbronectin to collagen by blood coagulation factor XIIIa. J Clin Invest 1979;64:781e7. [68] Hada M, Kaminski M, Bockenstedt P, McDonagh J. Covalent crosslinking of von Willebrand to ﬁbrin. Blood 1986;68:95e101. [69] Barry ELR, Mosher DF. Factor XIIIa-mediated cross-linking of ﬁbronectin in ﬁbroblast cell layers: cross-linking of cellular and plasma ﬁbronectin

and of amino-terminal ﬁbronectin fragments. J Biol Chem 1989;264:4179e85. [70] Kurniawan NA, Grimbergen J, Koopman J, Koenderink GH. Factor XIII stiffens ﬁ

2014;12:1687e96. [71] Ariëns RAS, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of

factor XIII and affects cross-linked ﬁbrin structure. Blood 2000;96:988e95. [72] Lim BCB, Ariëns RAS, Carter AM, Weisel JW, Grant PJ. Genetic regulation of ﬁbrin structure and function: complex gene-environment

interactions may modulate vascular risk. Lancet 2003;361:1424e31. [73] Muszbek L, Katona É. Diagnosis and management of congenital and acquired FXIII deﬁciencies. Semin Thromb Hemost 2016;42:429e39. [74] Collen D. The plasminogen (ﬁbrinolytic ) system. Thromb Haemost 1999;82:259e70. [75] Cappelletti RM. Fibrinogen and ﬁbrin: structure and functional aspects. In: Stief T, editor. Thrombin: function and pathophysiology. Nova Science

Publishers, Inc.; 2012. p. 263e91. [76] Suenson E, Lutzen O, Thorsen S. Initial plasmin-degradation of ﬁbrin as the basis of a positive feed-back mechanism in ﬁbrinolysis. Eur J Biochem

1984;140:513e22. [77] Thorsen S. The mechanism of plasminogen activation and the variability of the ﬁbrin effector during tissue-type plasminogen activator-mediated

ﬁbrinolysis. Ann NY Acad Sci 1992;667:52e63. [78] Stump DC, Lijnen HR, Collen D. Puriﬁcation and characterization of single-chain urokinase-type plasminogen activator from human cell cultures.

J Biol Chem 1986;261:1274e8. [79] Francis CW, Marder VJ, Martin SE. Plasmic degradation of crosslinked ﬁbrin; structural analysis of the particulate clot and identiﬁcation of new

macromolecular-soluble complexes. Blood 1980;56:456e65. [80] Gaffney PJ, Brasher M. Subunit structure of the plasmin-induced degradation products of crosslinked ﬁbrin. BBA Protein Struct 1973;295:308e13.

2þ

on the structure of reptilase-derived and thrombin-derived ﬁbrin gels. Biochem J

brin clots by causing ﬁber compaction. J Thromb Haemost

46 Cardiovascular Thrombus

https://t.me/med1917

[81] Doolittle RF. Searching for differences between ﬁbrinogen and ﬁbrin that affect the initiation of ﬁbrinolysis. Cardiovasc Hematol Agents Med

Chem 2008;6:181e9.

[82] Marder VJ, Budzynski AZ, Barlow GH. Comparison of the physicochemical properties of fragment D derivatives of ﬁbrinogen and fragment D-D

of cross-linked ﬁbrin. BBA Protein Struct 1976;427:1e14.

[83] Pizzo SV, Taylor LM, Schwartz ML, Hill RL, McKee PA. Subunit structure of fragment D from ﬁbrinogen and cross-linked ﬁbrin. J Biol Chem

1973;248:4584e90.

[84] Collet JP, Park D, Lesty C, Soria J, Soria C, Montalescot G, et al. Inﬂuence of ﬁbrin network conformation and ﬁbrin ﬁber diameter on ﬁbrinolysis

speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000;20:1354e61.

[85] Sakata Y, Aoki N. Signiﬁcance of cross-linking of a

1982;69:536e42.

[86] Fraser SR, Booth NA, Mutch NJ. The antiﬁbrinolytic function of factor XIII is exclusively expressed through a

2011;117:6371e4.

[87] Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and ﬁbrinolytic cascades through the thrombin-

thrombomodulin complex. J Biol Chem 1996;271:16603e8.

[88] Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D. Platelets inhibit ﬁbrinolysis in vitro by both plasminogen activator inhibitor-1-

dependent and -independent mechanisms. Blood 1994;83:351e6.

[89] Astedt B, Lindoff C, Lecander I. Signiﬁcance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy. Semin Thromb Hemost

1998;24:431e5.

[90] Ferry JD. Structure and rheology of ﬁbrin networks. In: Kramer O, editor. Biological and synthetic polymer networks. Dordrecht: Springer

Netherlands; 1988. p. 41e55.

[91] Guthold M, Liu W, Sparks EA, Jawerth LM, Peng L, Falvo M, et al. A comparison of the mechanical and structural properties of ﬁbrin ﬁbers with

other protein ﬁbers. Cell Biochem Biophys 2007;49:165e81. [92] Brochu ABW, Craig SL, Reichert WM. Self-healing biomaterials. J Biomed Mater Res A 2011;96:492e506. [93] Kurniawan NA, Vos BE, Biebricher A, Wuite GJL, Peterman EJG, Koenderink GH. Fibrin networks support recurring mechanical loads by

adapting their structure across multiple scales. Biophys J 2016;111:1026e34. [94] Lim BBC, Lee EH, Sotomayor M, Schulten K. Molecular basis of ﬁbrin clot elasticity. Structure 2008;16:449e59. [95] Liu W, Carlisle CR, Sparks EA, Guthold M. The mechanical properties of single ﬁbrin ﬁbers. J Thromb Haemost 2010;8:1030e6. [96] Piechocka IK, Bacabac RG, Potters M, Mackintosh FC, Koenderink GH. Structural hierarchy governs ﬁbrin gel mechanics. Biophys J 2010;98:2281e9. [97] Kang H, Wen Q, Janmey PA, Tang JX, Conti E, MacKintosh FC. Nonlinear Elasticity of stiff ﬁlament networks: strain stiffening, negative normal

stress, and ﬁlament alignment in ﬁbrin gels. J Phys Chem B 2009;113:3799e805. [98] Carlisle CR, Sparks EA, Der Loughian C, Guthold M. Strength and failure of ﬁbrin ﬁber branchpoints. J Thromb Haemost 2010;8:1135e8. [99] Roska FJ, Ferry JD. Studies of ﬁbrin ﬁlm. I. Stress relaxation and birefringence. Biopolymers 1982;21:1811e32.

[100] Brown AEX, Litvinov RI, Discher DE, Purohit PK, Weisel JW. Multiscale mechanics of ﬁbrin polymer: gel stretching with protein unfolding and

loss of water. Science 2009;325:741e4.

[101] Domingues MM, Macrae FL, Duval C, McPherson HR, Bridge KI, Ajjan RA, et al. Thrombin and ﬁbrinogen gʹ impact clot structure by marked

effects on intraﬁbrillar structure and proto

ﬁbril packing. Blood 2016;127:487e95.

[102] Weisel JW, Veklich Y, Gorkun OV. The sequence of cleavage of ﬁbrinopeptides from ﬁbrinogen is important for protoﬁbril formation and

enhancement of lateral aggregation in ﬁbrin clots. J Mol Biol 1993;232:285e97.

[103] Bale MD, Muller MF, Ferry JD. Rheological studies of creep and creep recovery of unligated ﬁbrin clots: comparison of clots prepared with

thrombin and ancrod. Biopolymers 1985;24:461e82.

[104] Grieninger G, Lu X, Cao Y, Fu Y, Kudryk BJ, Galanakis DK, et al. Fib420, the novel ﬁbrinogen subclass: newborn levels are higher than adult.

Blood 1997;90:2609e14.

[105] Fu Y, Grieninger G. Fib420: a normal human variant of ﬁbrinogen with two extended alpha chains. Proc Natl Acad Sci USA 1994;91:2625e8. [106] Mosesson MW, Diorio JP, Hernandez I, Hainfeld JF, Wall JS, Grieninger G. The ultrastructure of ﬁbrinogen-420 and the ﬁbrin-420 clot. Biophys

Chem 2004;112:209e14.

[107] Wolfenstein-Todel C, Mosesson MW. Carboxy-terminal amino acid sequence of a human ﬁbrinogen g-chain variant (gʹ). Biochemistry

1981;20:6146e9.

[108] Uitte de Willige S, Standeven KF, Philippou H, Ariëns RAS. The pleiotropic role of the ﬁbrinogen g

2009;114:3994e4001.

[109] Mosesson MW, Hernandez I, Raife TJ, Medved L, Yakovlev S, Simpson-Haidaris PJ, et al. Plasma ﬁbrinogen gʹ chain content in the thrombotic

microangiopathy syndrome. J Thromb Haemost 2007;5:62e9.

[110] Duval C, Ariëns RAS. Fibrinogen splice variation and cross-linking: effects on ﬁbrin structure/function and role of ﬁbrinogen gʹ as thrombo-

mobulin II. Matrix Biol 2017;60e61:8e15.

[111] Lovely RS, Boshkov LK, Marzec UM, Hanson SR, Farrell DH. Fibrinogen gʹ chain carboxy terminal peptide selectively inhibits the intrinsic

coagulation pathway. Br J Haematol 2007;139:494e503.

[112] Omarova F, Uitte De Willige S, Ariëns RAS, Rosing J, Bertina RM, Castoldi E. Inhibition of thrombin-mediated factor V activation contributes to

the anticoagulant activity of ﬁbrinogen gʹ. J Thromb Haemost 2013;11:1669e78.

[113] Gersh KC, Nagaswami C, Weisel JW, Lord ST. The presence of g

-plasmin inhibitor to ﬁbrin in inhibition of ﬁbrinolysis and in hemostasis. J Clin Invest

-antiplasmin cross-linking. Blood

chain in hemostasis. Blood

chain impairs ﬁbrin polymerization. Thromb Res 2009;124:356e63.

Fibrin Clot Structure and Function: A Novel Risk Factor for Arterial and Venous Thrombosis Chapter | 3 47

https://t.me/med1917

[114] Cooper AV, Standeven KF, Ariëns RAS. Fibrinogen gamma-chain splice variant g0alters ﬁbrin formation and structure. Blood 2003;102:535e40. [115] Allan P, Uitte de Willige S, Abou-Saleh RH, Connell SD, Ariëns RAS. Evidence that ﬁbrinogen gʹ directly interferes with protoﬁbril growth:

implications for ﬁbrin structure and clot stiffness. J Thromb Haemost 2012;10:1072e80.

[116] Kim PY, Vu TT, Leslie BA, Stafford AR, Fredenburgh JC, Weitz JI. Reduced plasminogen binding and delayed activation render gʹ-ﬁbrin more

resistant to lysis than gA-ﬁbrin. J Biol Chem 2014;289:27494e503.

[117] Fatah K, Silveira A, Tornvall P, Karpe F, Blombäck M, Hamsten A. Proneness to formation of tight and rigid ﬁbrin gel structures in men with

myocardial infarction at a young age. Thromb Haemost 1996;76:535e40.

[118] Fatah K, Hamsten A, Blomback B, Blomback M. Fibrin gel network characteristics and coronary heart disease: relations to plasma ﬁbrinogen

concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost 1992;68:130e5.

[119] Mills JD, Ariëns RAS, Mansﬁeld MW, Grant PJ. Altered ﬁbrin clot structure in the healthy relatives of patients with premature coronary artery

disease. Circulation 2002;106:1938e42.

[120] Dunn EJ, Ariëns RA, De Lange M, Snieder H, Turney JH, Spector TD, et al. Genetics of ﬁbrin clot structure: a twin study. Blood

2004;103:1735e40.

[121] Ariëns RAS, de Lange M, Snieder H, Boothby M, Spector TD, Grant PJ. Activation markers of coagulation and ﬁbrinolysis in twins: heritability of

the prethrombotic state. Lancet 2002;359:667e71.

[122] Ajjan R, Lim BCB, Standeven KF, Harrand R, Dolling S, Phoenix F, et al. Common variation in the C-terminal region of the ﬁbrinogen beta-chain:

effects on ﬁbrin structure, ﬁbrinolysis and clot rigidity. Blood 2008;111:643e50.

[123] Standeven KF, Grant PJ, Carter AM, Scheiner T, Weisel JW, Ariëns RAS. Functional analysis of the ﬁbrinogen Aalpha Thr312Ala polymorphism:

effects on ﬁbrin structure and function. Circulation 2003;107:2326e30.

[124] De Lange M, Andrew T, Snieder H, Ge D, Futers TS, Standeven K, et al. Joint linkage and association of six single-nucleotide polymorphisms in

the factor XIII-A subunit gene point to V34L as the main functional locus. Arterioscler Thromb Vasc Biol 2006;26:1914e9. [125] Borissoff JI, Spronk HMH, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011;364:1746e60. [126] Konings J, Govers-Riemslag JWP, Philippou H, Mutch NJ, Borissoff JI, Allan P, et al. Factor XIIa regulates the structure of the ﬁbrin clot

independently of thrombin generation through direct interaction with ﬁbrin. Blood 2011;118:3942e51. [127] Lepedda AJ, Cigliano A, Cherchi GM, Spirito R, Maggioni M, Carta F, et al. A proteomic approach to differentiate histologically classiﬁed stable

and unstable plaques from human carotid arteries. Atherosclerosis 2009;203:112e [128] Bini A, Fenoglio Jr JJ, Mesa-Tejada R, Kudryk B, Kaplan KL. Identiﬁcation and distribution of ﬁbrinogen, ﬁbrin, and ﬁbrin(ogen) degradation

products in atherosclerosis. Use of monoclonal antibodies. Arteriosclerosis 1989;9:109e21. [129] Harrison P, Cramer EM. Platelet alpha-granules. Blood Rev 1993;7:52e62. [130] Undas A, Zawilska K, Ciesla-Dul M, Lehmann-Kopydłowska A, Skubiszak A, Ciepłuch K, et al. Altered ﬁbrin clot structure/function in patients

with idiopathic venous thromboembolism and in their relatives. Blood 2009;114:4272e8. [131] Martinez MR, Cuker A, Mills AM, Crichlow A, Lightfoot RT, Chernysh IN, et al. Enhanced lysis and accelerated establishment of viscoelastic

properties of ﬁbrin clots are associated with pulmonary embolism. Am J Physiol Lung Cell Mol Physiol 2014;306:L397e404. [132] Tutwiler V, Litvinov RI, Lozhkin AP, Peshkova AD, Lebedeva T, Ataullakhanov FI, et al. Kinetics and mechanics of clot contraction are governed

by the molecular and cellular composition of the blood. Blood 2016;127:149e59. [133] Aleman MM, Byrnes JR, Wang JG, Tran R, Lam WA, Di Paola J, et al. Factor XIII activity mediates red blood cell retention in venous thrombi.

J Clin Invest 2014;124:3590e600. [134] Byrnes JR, Wang Y, Hansen CE, Ahn B, Mooberry MJ, Clark MA, et al. Factor XIIIa-dependent retention of red blood cells in clots is mediated by

ﬁbrin alpha-chain crosslinking. Blood 2015;126:1940e9. [135] Bouman AC, McPherson H, Cheung YW, Ten Wolde M, Ten Cate H, Ariëns RAS, et al. Clot structure and ﬁbrinolytic potential in patients with

post thrombotic syndrome. Thromb Res 2016;137:85e91. [136] Metassan S, Charlton AJ, Routledge MN, Scott DJA, Ariëns RAS. Alteration of ﬁbrin clot properties by ultraﬁne particulate matter. Thromb

Haemost 2010;103:103e13. [137] Metassan S, Routledge MN, Lucking AJ, Uitte de Willige S, Philippou H, Mills NL, et al. Fibrin clot structure remains unaffected in young, healthy

individuals after transient exposure to diesel exhaust. Part Fibre Toxicol 2010;7:1e4. [138] Pan X, Gong YY, Martinelli I, Angelici L, Favero C, Bertazzi PA, et al. Fibrin clot structure is affected by levels of particulate air pollution

exposure in patients with venous thrombosis. Environ Int 2016;92e93:70e6. [139] Barua RS, Sy F, Srikanth S, Huang G, Javed U, Buhari C, et al. Effects of cigarette smoke exposure on clot dynamics and ﬁbrin structure: an

ex vivo investigation. Arterioscler Thromb Vasc Biol 2010;30:75e9. [140] Alzahrani SH, Hess K, Price JF, Strachan M, Baxter PD, Cubbon R, et al. Gender-speciﬁc alterations in ﬁbrin structure function in type 2 diabetes:

associations with cardiometabolic and vascular markers. J Clin Endocrinol Metab 2012;97:2282e7. [141] Kovács A, Sótonyi P, Nagy AI, Tenekedjiev K, Wohner N, Komorowicz E, et al. Ultrastructure and composition of thrombi in coronary and

peripheral artery disease: correlations with clinical and laboratory ﬁndings. Thromb Res 2015;135:760e6. [142] Silvain J, Collet JP, Nagaswami C, Beygui F, Edmondson KE, Bellemain-Appaix A, et al. Composition of coronary thrombus in acute myocardial

infarction. J Am Coll Cardiol 2011;57:1359e67. [143] Jörneskog G, Egberg N, Fagrell B, Fatah K, Hessel B, Johnsson H, et al. Altered properties of the ﬁbrin gel structure in patients with IDDM.

Diabetologia 1996;39:1519e23.

48 Cardiovascular Thrombus

https://t.me/med1917

[144] Carr ME, Krishnaswami A, Martin EJ. Platelet contractile force (PCF) and clot elastic modulus (CEM) are elevated in diabetic patients with chest

pain. Diabet Med 2002;19:862e6. [145] Dunn EJ, Ariëns RAS, Grant PJ. The inﬂuence of type 2 diabetes on ﬁbrin structure and function. Diabetologia 2005;48:1198e206. [146] Dunn EJ, Philippou H, Ariëns RAS, Grant PJ. Molecular mechanisms involved in the resistance of ﬁbrin to clot lysis by plasmin in subjects with

type 2 diabetes mellitus. Diabetologia 2006;49:1071e80. [147] Pieters M, Covic N, Van Der Westhuizen FH, Nagaswami C, Baras Y, Loots DT, et al. Glycaemic control improves ﬁbrin network characteristics

in type 2 diabetes: a puriﬁed ﬁbrinogen model. Thromb Haemost 2008;99:691e700. [148] Walus-Miarka M, Wolkow P, Cyganek K, Mirkiewicz-Sieradzka B, Malecki MT, Undas A. Altered ﬁbrin-clot properties are associated with

retinopathy in type 2 diabetes mellitus. Diabetes Metab 2012;38:462e5. [149] Bochenek M, Zalewski J, Sadowski J, Undas A. Type 2 diabetes as a modiﬁer of ﬁbrin clot properties in patients with coronary artery disease.

J Thromb Thrombolysis 2013;35:264e70. [150] Neergaard-Petersen S, Hvas A-M, Kristensen SD, Grove EL, Larsen SB, Phoenix F, et al. The inﬂuence of type 2 diabetes on ﬁbrin clot properties

in patients with coronary artery disease. Thromb Haemost 2014;112:1142e50. [151] Undas A, Podolec P, Zawilska K, Pieculewicz M, Jedlinski I, Stgpien E, et al. Altered ﬁbrin clot structure/function in patients with cryptogenic

ischemic stroke. Stroke 2009;40:1499e501. [152] Undas A, Slowik A, Wolkow P, Szczudlik A, Tracz W. Fibrin clot properties in acute ischemic stroke: relation to neurological deﬁcit. Thromb Res

2010;125:357e61. [153] Stanford SN, Sabra A, D’Silva L, Lawrence M, Morris RH, Storton S, et al. The changes in clot microstructure in patients with ischaemic stroke

and the effects of therapeutic intervention: a prospective observational study. BMC Neurol 2015;15:35. [154] Bhasin N, Parry DJ, Scott DJA, Ariëns RAS, Grant PJ, West RM. Regarding “Altered ﬁbrin clot structure and function in individuals with

intermittent claudication”. J Vasc Surg 2009;49:1088e9. [155] Bhasin N, Ariëns RAS, West RM, Parry DJ, Grant PJ, Scott DJA. Altered ﬁbrin clot structure and function in the healthy ﬁrst-degree relatives of

subjects with intermittent claudication. J Vasc Surg 2008;48:1497e504. [156] Scott DJA, Prasad P, Philippou H, Rashid ST, Sohrabi S, Whalley D, et al. Clot architecture is altered in abdominal aortic aneurysms and correlates

with aneurysm size. Arterioscler Thromb Vasc Biol 2011;31:3004e10. [157] Fontaine V, Jacob M-P, Houard X, Rossignol P, Plissonnier D, Angles-Cano E, et al. Involvement of the mural thrombus as a site of protease

release and activation in human aortic aneurysms. Am J Pathol 2002;161:1701e10. [158] Lloyd GM, Newton JD, Norwood MGA, Franks SC, Bown MJ, Sayers RD. Patients with abdominal aortic aneurysm: are we missing the

opportunity for cardiovascular risk reduction? J Vasc Surg 2004;40:691e7. [159] Bailey MA, Grifﬁn KJ, Sohrabi S, Whalley DJ, Johnson AB, Baxter PD, et al. Plasma thrombin-antithrombin complex, prothrombin fragments 1

and 2, and D-dimer levels are elevated after endovascular but not open repair of infrarenal abdominal aortic aneurysm. J Vasc Surg

2013;57:1512e8. [160] Macrae FL, Evans HL, Bridge KI, Johnson A, Scott DJA, Ariëns RAS. Common FXIII and ﬁbrinogen polymorphisms in abdominal aortic

aneurysms. PLoS One 2014;9:1e7. [161] Zhou H, Yan H, Bertram P, Hu Y, Springer LE, Thompson RW, et al. Fibrinogen-speciﬁc antibody induces abdominal aortic aneurysm in mice

through complement lectin pathway activation. Proc Natl Acad Sci USA 2013;110:E4335e44. [162] Zhou H, Yan H, Stover C, Montes Fernandez T, Rodriguez De Cordoba S, Song W, et al. Antibody directs properdin-dependent activation of the

complement alternative pathway in a mouse model of abdominal aortic aneurysm. Proc Natl Acad Sci USA 2012;109:E415e22. [163] Hinterseher I, Erdman R, Donoso LA, Vrabec TR, Schworer CM, Lillvis JH, et al. Role of complement cascade in abdominal aortic aneurysms.

Arterioscler Thromb Vasc Biol 2011;31:1653e60. [164] Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013;121:4985e96. [165] Galanakis DK, Ghebrehiwet BA. Unique property of a plasma proteoglycan, the Clq Inhibitor: an anticoagulant state resulting from its binding to

ﬁbrinogen. J Clin Invest 1994;93:303e10. [166] Hess K, Alzahrani SH, Mathai M, Schroeder V, Carter AM, Howell G, et al. A novel mechanism for hypoﬁbrinolysis in diabetes: the role of

complement C3. Diabetologia 2012;55:1103e13. [167] Howes JM, Richardson VR, Smith KA, Schroeder V, Somani R, Shore A, et al. Complement C3 is a novel plasma clot component with anti-

ﬁbrinolytic properties. Diabetes Vasc Dis Res 2012;9:216e25. [168] Richardson VR, Schroeder V, Grant PJ, Standeven KF, Carter AM. Complement C3 is a substrate for activated factor XIII that is cross-linked to

ﬁbrin during clot formation. Br J Haematol 2013;160:116e9. [169] Hess K, Ajjan R, Phoenix F, Dobó J, Gál P, Schroeder V. Effects of MASP-1 of the complement system on activation of coagulation factors and

plasma clot formation. PLoS One 2012;7:1e12. [170] Weisel JW, Nagaswami C. Computer modeling of ﬁbrin polymerization kinetics correlated with electron microscope and turbidity observations:

clot structure and assembly are kinetically controlled. Biophys J 1992;63:111e28. [171] Ząbczyk M, Blombäck M, Majewski J, Karkowski G, Wallen HN, Undas A, et al. Assays of ﬁbrin network properties altered by VKAs in atrial

ﬁbrillation e importance of using an appropriate coagulation trigger. Thromb Haemost 2015;113:851e61. [172] Nenci GG, Parise P, Morini M, Rossini A, Agnelli G. Fibrin clots obtained from plasma containing heparin show a higher sensitivity to

t-PA-induced lysis. Blood Coagul Fibrinolysis 1992;3:279e85.

Fibrin Clot Structure and Function: A Novel Risk Factor for Arterial and Venous Thrombosis Chapter | 3 49

https://t.me/med1917

[173] Parise P, Morini M, Agnelli G, Ascani A, Nenci GG. Effects of low molecular weight heparins on ﬁbrin polymerization and clot sensitivity to

t-PA-induced lysis. Blood Coagul Fibrinolysis 1993;4:721e7.

[174] Carr ME, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufﬁcient to reverse

heparin anti-platelet effects. Thromb Res 1994;75:617e30.

[175] He S, Blombäck M, Bark N, Johnsson H, Wallen NH. The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect

Xa-inhibitor (danaparoid) increase ﬁbrin network porosity and thus facilitate ﬁbrinolysis. Thromb Haemost 2010;103:1076e84.

[176] Ammollo CT, Semeraro F, Incampo F, Semeraro N, Colucci M. Dabigatran enhances clot susceptibility to ﬁbrinolysis by mechanisms dependent

on and independent of thrombin-activatable ﬁbrinolysis inhibitor. J Thromb Haemost 2010;8:790e8.

[177] Carr ME, Angchaisuksiri P, Carr SL, Martin EJ. Effect of non-heparin thrombin antagonists on thrombin generation, platelet function, and clot

structure in whole blood. Cell Biochem Biophys 2003;39:89e100.

[178] Varin R, Mirshahi S, Mirshahi P, Klein C, Jamshedov J, Chidiac J, et al. Whole blood clots are more resistant to lysis than plasma clots: greater

efﬁcacy of rivaroxaban. Thromb Res 2013;131:e100e9.

[179] Williams S, Fatah K, Ivert T, Blombäck M. The effect of acetylsalicylic acid on ﬁbrin gel lysis by tissue plasminogen activator. Blood Coagul

Fibrinolysis 1995;6:718e25.

[180] Williams S, Fatah K, Hjemdahl P, Blombäck M. Better increase in ﬁbrin gel porosity by low dose than intermediate dose acetylsalicylic acid.

Eur Heart J 1998;19:1666e72.

[181] He S, Bark N, Wang H, Svensson J, Blomba M. Effects of acetylsalicylic acid on increase of ﬁbrin network porosity and the consequent

upregulation of ﬁbrinolysis. J Cardiovasc Pharmacol 2009;53:24e9.

[182] Ajjan RA, Standeven KF, Khanbhai M, Phoenix F, Gersh KC, Weisel JW, et al. Effects of aspirin on clot structure and ﬁbrinolysis using a novel

in vitro cellular system. Arterioscler Thromb Vasc Biol 2009;29:712e7.

[183] Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenoﬁbrate, and quinapril increase clot permeability and enhance ﬁbrinolysis

in patients with coronary artery disease. J Tissue Eng Regen Med 2010;4:1029e36.

[184] Yakovlev S, Makogonenko E, Kurochkina N, Nieuwenhuizen W, Ingham K, Medved L. Conversion of ﬁbrinogen to ﬁbrin: mechanism of

exposure of tPA- and plasminogen-binding sites. Biochemistry 2000;39:15730e41.

[185] Tsurupa G, Medved L. Identiﬁcation and characterization of novel tPA- and plasminogen-binding sites within ﬁbrin(ogen) aC-domains.

Biochemistry 2001;40:801e8.

[186] Schielen JG, Adams HPHM, van Leuven K, Voskuilen M, Tesser GI, Nieuwenhuizen W. The sequence g-(312-324) is a ﬁbrin-speciﬁc epitope.

Blood 1991;77:2169e73.

[187] Henschen A, Mcdonagh J. Fibrinogen,

Publishers B.V.; 1986. p. 171e241.

ﬁbrin and factor XIII. In: Zwaal RFA, Hemker HC, editors. Blood coagulation, vol. 13. Elsevier Science

Chapter 4

https://t.me/med1917

The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications

Kerry Layne, Gabriella Passacquale and Albert Ferro

King’s College London, London, United Kingdom

PLATELETS

Platelets, otherwise known as thrombocytes, are approximately 2.5-mm anuclear, disc-shaped cytoplasmic fragments whose primary physiological function is to contribute to hemostasis [1], although they play further roles in inﬂammatory processes. Their ultrastructure is depicted in Fig. 4.1. Platelets are derived from megakaryocyte precursor cells, which are present within the bone marrow. Thrombopoietin, a glycoprotein growth factor, is the primary regulator of megakaryocyte production and development, alongside numerous cytokines and hormones. As megakaryocytes mature, they enlarge to allow high concentrations of ribosomes to accumulate, from which platelet-speciﬁc proteins will eventually be formed

[2]. Although this process has not been fully elucidated, in vitro data suggest that pseudopodial elongations, termed

proplatelets, emerge from the mature megakaryocyte, and platelets are budded off from the ends of these processes [3]. Each megakaryocyte can release thousands of platelets, which enter the systemic circulation or are reserved within the spleen [2]. Circulating platelets have a life span of 8e10 days, and are typically present at a concentration of 150e400  10

The platelet stru cture is maintained by a complex actin cytoskeleton structure, while the cell surface is covered by invaginations of the plasma membrane, forming a network of tubes, termed the open canalicular system [5]. This allows substances to be transported from the surface to within the platelet, while additionally providing a mechanism of secreting storage granules [6]. The open canalicular system, along with the surface membranes of platelet storage granules, allows a two- to fourfold increase in platelet surface area [7].

per liter of blood [4].

Electron dense granule: nucleotides (ADP),

, serotonin

Specific α-granule: fibrinogen, factor V, vWF, fibronectin, β-thromboglobulin, heparin antagonist (PF 4), thrombospondin

FIGURE 4.1 Diagrammatic representation of platelet ultrastructure. ADP, adenosine diphosphate; PF 4, platelet factor 4; vWF, von Willebrand factor.

Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00004-1

Glycogen Glycocalyx

Mitochondrion

Lysosome

Plasma membrane

Platelet phospholipid

Open canalicular system

Submembranous filaments (platelet contractile protein)

Dense tubular system

52 Cardiovascular Thrombus

https://t.me/med1917

There are three main classes of storage granules within platelets. The most abundant, and most thoroughly

characterized, are the alpha granules, which contain hundreds of soluble proteins, including:

1. hemostatic proteins, such as ﬁbrinogen and von Willebrand factor;

2. coagulation factors, including factors V, XI, and XIII;

3. cellular adhesion molecules, including P-selectin and CD63;

4. cytokines, including platelet factor 4 and chemokine (CeC motif) ligand 5;

5. growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, and insulin-like

growth factor [7].

In addition, there are dense (als o known as delta) granules, which contain platelet activation factors, such as ADP, ATP, serotonin, histamine, and ionized calcium [8]. Lysosomal granules contain hydrolytic enzymes, which are released upon platelet activation [9].

PLATELET ACTIVATION AND FUNCTION

The classically described function of platelets is to prevent hemorrhage. In the presence of an intact, healthy endothelium, circulating platelets remain in a resting state. Platelets move into an activated state in response to several factors that signal vascular trauma, whereby they adhere to damaged endothelium and locally mediate both thrombotic and inﬂammatory events via the secretion of cytokines and interaction with leukocytes. This results in chemotaxis and the development of an inﬂammatory milieu within the arterial wall.

When endothelial damage has occurred, the extracellular matrix is exposed and collagens are released. Collagens stimulate a change in the conformation of platelets, which change from a discoid shape to a spherical one, and develop dendritic pseudopodia, as shown in Fig. 4.2 [10]. The collagens bind to von Willebrand factor, which interacts with glycoprotein Ib/V/IX, a transmembrane protein complex on the surface of platelets that mediates the tethering of activated platelets to the site of vascular injury [11e14]. The collagen receptor, glycoprotein VI, is also expressed on the platelet surface, and binds to collagen to induce the release of secondary platelet agonists, incl uding thromboxane A ADP, thrombin, and adrenaline, which serve to stimulate further autocrine and paracrine platelet activation [13].

Platelet agonists act on G-protein-coupled receptors, including those linked to the G

, and Giproteins, to activate

q,G13

the platelet integrin glycoprotein IIb/IIIa [15]. This receptor mediates platelet adhesion via binding to ﬁbrinogen, which leads to the formation of bridges between platelets. A hemostatic platelet plug subsequently develops, which increases in size as further platelet activation is propagated (Fig. 4.3).

(TXA2),

Thrombin

Thrombin forms a key part of the initiation of the coagulation cascade, and is produced upon cleavage of prothrombin by activated factor Xa. Thrombin acts as a serine protease to convert ﬁbrinogen to ﬁbrin, which subsequently polymerizes into

FIGURE 4.2 Platelet structural changes in response to activation. Platelet activation is one of the earliest stages in the development of an arterial

thrombus. At the site of endothelial damage, platelets can become activated by binding to molecules such as exposed collagen within the vessel wall, thrombin generated from the coagulation cascade, or other activators, such as ADP released from red cells. The ﬁrst visible sign of platelet activation is a shape change characterized by the appearance of numerous pseudopodia, as is seen by comparing these two scanning electron micrographs. ADP, adenosine diphosphate.

The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 53

https://t.me/med1917

FIGURE 4.3 Platelet aggregation. Once activated, platelets release the contents of their alpha granules, which are particularly rich in ADP, and also

produce thromboxane A activating additional platelets. Alongside these processes, platelet activation causes the exposure of thousands of speciﬁc surface receptorsdthe glycoprotein IIb/IIIa receptorsdwhich bind to ﬁbrinogen. Each ﬁbrinogen molecule is able to bind to the glycoprotein IIb/IIIa receptors on two adjacent platelets, thereby binding them close together. This electron micrograph shows an evolving platelet thrombus in which a number of platelets have become activated and have bound tightly together. ADP, adenosine diphosphate.

(TXA2), which is released into the surrounding area. Both ADP and TXA2act to amplify the platelet reaction by recruiting and

multimeric strands to create a mesh that, along with platelets, forms the hemostatic plug [16]. Thrombin additionally converts factor XIII to XIIIa, which induces the formation of covalent cross-links between the ﬁbrin strands, thus further stabilizing and strengthening the clot [17].

Thrombin binds to protease-activated receptors on endothelial cells, activating the cells and thus promoting platelet adhesion and cytokine release and triggering endothelial cell production of platelet-activating factor [18]. Thrombin can additionally modify vascular tone by direct and indirect effects on vascular smooth muscle cells and postcapillary vessels

[19e21], partially via the promotion of Ca

2þ

release from intracellular stores and Ca2þinﬂux across the plasma membrane

[22]. This is of particular clinical relevance in the context of subarachnoid hemorrhage, in which thrombin accumulates at

the site of the bleed and ampliﬁes cerebral vasospasm; the contractile response to thrombin is then typically augmented by the upregulation of protease-activated receptor-1 [23].

Adenosine Diphosphate

ADP is a platelet agonist that interacts with platelet purinergic P2 receptors, including P2Y1,P2Y12, and P2X1[24]. Upon binding to ADP, platelets undergo a conformational change, developing a spiculated, spherical shape, enabling the release of granular contents (containing additional ADP) and thus further augmenting platelet aggregation [25,26]. As with thrombin, ADP enhances intracellular stored Ca via the plasma membrane [24]. The P2Y calcium, and stimulates the phospholipase C and inositol phosphate signaling pathways. P2Y receptor that blocks adenylyl cyclase signaling and reduces intracellular cyclic adenosine monophosphate (cAMP) levels. The fall in cAMP inhibits phosphorylation of vasodilator-stimulated phosphoprotein, which subsequently induces activation of the glycoprotein IIb/IIIa receptor and platelet aggregation [27].P2X allowing rapid calcium inﬂux upon binding of ADP [26]. Patients with abnormal storage and release of ADP from dense granules typically present wi th prolonged bleeding times due to impaired platelet aggregation [28].

Thromboxane A

Binding of ADP to P2Y12stimulates phospholipase A2-induced release of arachidonic acid (AA) from phospholipid. AA is converted to prostaglandin (PG) G subsequently converted to TXA

via TXA2synthase [24,25]. The thromboxane/PGH2receptor is present on platelets, as

well as monocytes, erythrocytes, and endothelial cells. TXA main isoforms: the G

-coupled TPa and the Gi-coupled TPb receptors. These two receptors differ in their C-terminal

cytoplasmic domains [29], with the TPa isoform primarily bring expressed on platelets [30]. TXA receptor leads to activation of both G

and Giproteins, with consequent activation of both phospholipase C and adenylyl

2þ

release through inositol phosphate production and rapid calcium inﬂux

-protein-coupled receptor mediates the platelet structural changes, mobilizes

1Gq

is a Gi-protein-coupled

functions as a ligand-gated ion channel,

by cyclooxygenase-1, which is then reduced by a peroxidase to PGH2and

binds to the thromboxane/PGH2receptor, which has two

binding to the TPa

54 Cardiovascular Thrombus

https://t.me/med1917

cyclase, while its binding to TPb results in Giactivation and consequent inhibition of adenylyl cyclase, the net result in platelets being their activation leading to the aforementioned conformational changes and aggregation [31].

Aside from platelet activation, TXA and is a potent vasoconstrictor [34]. TXA adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and plays complex roles in endothelial cell migration [33]. Mutations in the TP receptors result in a varied clinical picture, ranging from impaired hemostasis when reduced receptor activity is present to predisposition to thrombosis and infarction [35,36]. Due to the short half-life of TXA

, its metabolite 11-dehydro TXB2is commonly used when measured in urine as an indirect measure of TXA2[37].

plays roles in atherogenesis, vascular remodeling, and immunog enicity [32,33]

increases the expression of endothelial adhesion molecules, such as intercellular

PLATELETS AS MODULATORS OF INFLAMMATION: RELEVANCE TO ATHEROSCLEROSIS

Although the classical role of platelets is in hemostasis, in recent years it has become increasingly apparent that they play a critical role in promoting inﬂammation also, through their interactions with leukocytes, and this is especially relevant in the pathophysiology of atherosclerosis, which is now generally considered to be an inﬂammatory disease. We will here explore further the role of platelets in atherosclerosis, and in doing so will focus on their ability to modulate the trafﬁcking of inﬂammatory cells, mainly myeloid cell types, within the arterial wall. We will then proceed to address the role of platelets in modulating inﬂammation, with particular reference to atherosclerosis, and examine the evidence that antiplatelet therapy may modify expression of the aforementioned biomarkers. In the ﬁnal part of this chapter, based on these considerations, we will explore the possibility that antiplatelet therapy may be a useful novel approach to inhibiting atherogenesis.

THE ROLE OF INFLAMMATION IN ATHEROSCLEROSIS

The “Justiﬁcation for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin” (JUPITER) study identiﬁed that elevated levels of high-sensitivity C-reactive protein (hs-CRP), a hepatically synthesized biomarker of inﬂammation produced in response to macrophage-derived interleukin-6 (IL-6), were associated with cardiovascular events, including myocardial infarction and stroke in patients with no previously known cardiac disease [38,39]. hs-CRP was found to be a stronger predictor of cardiovascular disease than the traditionally used low-density lipoprotein (LDL) cholesterol levels, demonstrating the importance of underlying inﬂammation in the development of cardiovascular disease. However, hs-CRP is a nonspec iﬁc acute-phase response protein, and rises in most pathologies where an inﬂammatory response is generated, including malignancy, autoimmune disease, late-stage pregnancy, and bacterial infection. hs-CRP has yet to be causally related to coronary heart disease, and a reduction in baseline levels of hs-CRP has not been shown to improve prognosis [40,41].

Patients with chronic inﬂammatory diseases, such as inﬂammatory bowel disease and rheumatoid arthritis, carry an increased risk of developing cardiovascular disease in later life, suggesting a possible link between inﬂammatory processes and atherogenesis [42].Proinﬂammatory biomarkers have been shown to have signiﬁcant prognostic value in myocardial infarction [43], and a 2015 clinical trial has also identiﬁed potential beneﬁts arising from administration of an antiinﬂammatory therapy (colchicine) in the management of acute ST-segment elevation myocardial infarction (STEMI) [44].

MONOCYTES

Monocytes are mononuclear white blood cells that play a pivotal role in the human adaptive immune response. Monocytes comprise approximately 1%e8% of circulating leukocytes and have a half-life of around 1e3 days, after which they move into tissues and differentiate into macrophages or dendritic cells [45]. Monocytes migrate to sites of local inﬂammation where their roles include phagocytosis and pro- or antiinﬂammatory cytokine production.

The Role of Monocytes in Atherosclerosis

Monocytes play a pivotal role in the development of atherosclerosis via formation and deposition of lipid-laden foam cells within the arterial tunica intima, which contribute to plaque instability [46]. Monocytes are further implicated in the development of atherosclerosis and plaque rupture due to their involvement in plaque neovascularization. As plaque size increases, impaired oxygen diffusion develops, and the proximal cells of the tunica intima become hypoxic [47]. Cellular

The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 55

https://t.me/med1917

oxygen levels become depleted and hypoxia-inducible factor 1 production is upregulated, which induces expression of angiogenic signaling molecules, including VEGF and endothelial nitric oxide synthase, which serve to enhance the development of adventitial vasa vasorum and intraplaque microvessels [47]. Monocytes strongly express receptors to VCAM-1, which is produced by intraplaq ue microvessels [48e50]. The chronic inﬂammation present in atherosclerosis triggers increased expression of endothelial markers of activation, including VCAM-1, ICAM-1 (also known as CD54), and P-selectin (CD62P). There is additional upregulation of monocyte chemoattractant protein-1 (MCP-1), one of the primary chemokines involved in regulating migration and inﬁltration of monocytes, and its monocytic receptor, CeC chemokine receptor type 2 (CCR2) [51,52].

Evidence suggests that circulating monocytes may also serve as endothelial progenitor cells, further amplifying angiogenesis [48,53]. The newly formed microvessels are fragile and prone to hemorrhaging. As erythrocytes extravasate from bleeding neovessels, their lipid-rich cellular contents contribute to further evolut ion of the atheromatous lesion, while the free hemoglobin potentiates reactive oxygen species (ROS) generation and proinﬂammatory cytokine generation [54]. Intraplaque hemorrhage is one of the principal determinants of plaque rupture [55].

Monocyte Phenotypes and Their Differential Contribution to Atherosclerosis

Until recently, human monocytes were divided into two major subsets based on their surface expression of CD14 and CD16: the CD14 “classical” group, which is involved in phagocytosis and proinﬂammatory cytokine production [52,56]. The

CD14

CD16þsubgroup has since been subdivided into the CD14

low

CD14

CD16þor “nonclassical” monocyte group. The CD14 which enhances vascular monocyte recruitment and their subsequent transendothelial migration [52]. CD14 monocytes are highly proinﬂammatory [57], while the CD14 rearrangement and demonstrates high motility and patrolling behavior [58]. Table 4.1 gives further details regarding monocyte subsets. There are additional, smaller, poorly characterized subsets of monocytes, including the CD56 which may be associated with certain autoimmune diseases [59].

Prior to the subdivision of the CD16

producer of serum tumor necrosis factor a in response to inﬂammatory challenges [57]. It was subsequently found that

CD16

monocytes were expressed at relatively low levels in healthy individuals but showed ampliﬁed expression in the presence of coronary atherosclerosis, suggestive of a possible role for CD16 correlation between intima media thickness and CD14

CD16and the CD14þCD16þgroups. Around 85%e90% of monocytes comprise the CD14þCD16or

high

CD16þgroup expresses the MCP-1 receptor CCR2,

low

CD16þgroup expresses genes involved in cytoskeletal

monocyte group, it was well recognized that the CD16þsubset was a major

high

CD16þcell counts has been observed [61].

CD16þor “intermediate” group and the

high

CD16

group,

monocytes in atherogenesis [60].A

TABLE 4.1 Monocyte Subset Characteristics

Monocyte Subsets Classical Intermediate Nonclassical

CD14 expression þþ þþ þ

CD16 expression þ þþ

CCR2 expression þþ 

Primary functions Phagocytosis [137]

Cytokine response

Inﬂammatory effects

Tissue repair [138] Immune response [138, 139]

Response to cell-surface TLRs

[140]

Weakly proinﬂammatory (IL-6

[141],

IL-1b [140], TNF-a correlation)

Angiogenesis [139] Phagocytosis [138]

Response to cell-surface TLRs [140] Response to viruses via

1. Highly proinﬂammatory

(IL-6 [141], IL-1b [140], TNF-a correlation)

2. Antiinﬂammatory

(IL-10 correlation [141])

Cytoskeleton rearrangement

[138]

TLR7eTLR8eMyD88eMEK pathway [140]

Weakly proinﬂammatory (TNF-a correlation [138])

CCR2,CeC chemokine receptor type 2; IL, interleukin; TLR, Toll-like receptor; TNF-a, tumor necrosis factor a; MyD88, Myeloid differentiation primary response 88: MEK, Mitogen-activated protein kinase kinase.

<<< < Предыдущая 1 2 3 4 5 6 78 / 508 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 > Следующая >>>

Соседние файлы в папке Библиотека им академика М.И. Перельмана

#
31.08.202631 Мб0Книга_3715_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202631 Мб0Книга_3716_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202631 Мб0Книга_3717_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202631 Мб0Книга_3718_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202631 Мб0Книга_3719_Библиотеки_им_академика_М_И_Перельмана.djvu
#
31.08.202630 Мб0Книга_3720_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202630 Мб0Книга_3721_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202630 Мб0Книга_3722_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202630 Мб0Книга_3723_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202629 Мб0Книга_3726_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202629 Мб0Книга_3727_Библиотеки_им_академика_М_И_Перельмана.pdf