Citrullinated Fibrinogen Renders Clots Mechanically Less Stable, but Lysis-Resistant

Name: Work Video:
Duration: 3 min 30 s
Imre Varjú; Nicoletta Sorvillo; Deya Cherpokova; A Farkas; Veronika J. Farkas; Erzsébet Komorowicz; Tímea Feller; Balázs Kiss; Miklós Kellermayer; László Szabó; András Wacha; Attila Bóta; Colin Longstaff; Denisa D. Wagner; Krasimir Kolev
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'underlying': [565], 'fibrin': [566, 732, 938, 1173, 1291, 1849], 'matrix': [567], 'its': [569, 2092], 'precursor': [570], 'fibrinogen.': [571, 1058], 'Citrullination': [572, 2190], 'a': [574, 656, 1147, 1252, 1304, 1437, 1466, 1579, 1756, 1767, 1997, 2099, 2192], 'posttranslational': [575], 'modification': [576], 'peptidyl-arginine': [578], 'by': [579, 897, 1110, 1127, 1161, 1310, 1350, 1663, 1736, 1758, 1766, 1970, 2395], 'PADs': [580], '(peptidyl-arginine-deiminases).1': [581], 'Both': [582], 'PAD2': [583], '4—proven': [585], 'catalyze': [587], 'fibrinogen': [588, 618, 672, 744, 832, 966, 988, 1087, 1112, 1130, 1194, 1332, 1379, 1435, 1444, 2233], 'citrullination—have': [589], 'been': [590], 'detected': [591, 1109], 'human': [593, 647, 660, 671, 1057, 1071, 1326, 1425, 1443, 1583], 'serum': [594], 'may': [596], 'be': [597, 2041, 2050, 2067, 2083], 'released': [598], 'from': [599, 762, 793, 1076, 1134, 1308, 1510, 1635, 1739], 'neutrophils': [600], 'during—or': [601], 'independently': [602], 'of—the': [603], 'formation': [604], 'highly': [607], 'procoagulant': [608], 'neutrophil': [609], 'extracellular': [610, 1824, 2149], 'traps.1': [611], 'However,': [612], '(1)': [613], 'effect': [615], 'citrullinated': [617, 805, 833, 1056, 1121, 1172, 1197, 1218, 1243, 1277, 1433], '(CitFg)': [619], 'on': [620, 869, 1299, 1445, 2076, 2387], 'clot': [621, 741, 1158, 1179, 1268, 1565, 1610], 'poorly': [624], 'understood': [625], '(2)': [627, 1575], 'no': [628, 1491, 2042], 'study': [629, 1632], 'has': [630], 'investigated': [631, 1320], 'CitFg': [632, 652, 665, 1391, 1519], 'intravascular': [634, 1561], 'thrombi.': [635, 1586], 'Here,': [636], 'we': [637, 669, 1319, 1394, 1430, 1451, 1547], 'provide': [638], 'evidence': [639], 'that': [640, 651, 1141, 1432, 1441, 1549, 1626, 2425], 'citrullination': [641, 1044, 1062, 1119, 1128, 1468, 1478, 1524, 2123], 'greatly': [642], 'impacts': [643], 'model': [648, 667, 1401], 'present': [654], 'murine': [657, 882, 1048, 1069, 1086, 1434, 1580], 'analogue': [658, 1581], 'thrombi.To': [663], 'incorporate': [664], 'thrombi,': [668, 1393], 'incubated': [670, 745], 'with': [673, 703, 746, 754, 817, 829, 834, 860, 965, 999, 1080, 1155, 1183, 1189, 1198, 1239, 1246, 1329, 1334, 1372, 1381, 1490, 1542, 1594, 1963, 1972, 2238, 2299], 'PAD4': [674, 699, 749, 837, 1024, 1337], '100': [676], 'mmol/L': [677, 680, 683], 'TRIS-HCl': [678], '10': [679, 755, 1190], 'CaCl2': [681], '1': [682, 919, 1330], 'DTT': [684], 'pH': [685], '7.5': [686], 'at': [687, 710, 918, 951, 1007, 1214, 1271, 1495, 1499, 1504], '37': [688], '°C': [689], '(concentrations': [690], 'incubation': [692], 'times': [693, 791, 826], 'were': [694, 977, 1125, 1459], 'adjusted': [695], 'different': [697], 'experiments).': [698], 'activity': [700], 'was': [701, 779, 801, 814, 895, 1011, 1174, 1261, 1348, 1480, 1520, 1526, 1661, 1734, 1764], 'halted': [702], '60': [704], 'mg/L': [705, 748, 836, 1200, 1336, 1383], 'Cl-amidine': [706], '(in': [707], 'controls': [708], 'immediately': [709], '0': [711, 849], 'hours).We': [712], 'studied': [713], 'properties': [716], 'clots': [718, 963, 1187, 1244, 1278, 1358, 1370, 1516, 1533, 1591, 1887, 1962, 2237], 'using': [719, 1013], 'atomic-force': [720], 'microscopy-based': [721], 'nano-thromboelastography2': [722], 'as': [723, 725, 765, 1016, 1146, 1257, 1748, 1750, 2071], 'well': [724, 1749], 'oscillation': [726], 'rheometry.3': [727], 'In': [728, 1411, 1508, 2096], 'nano-thromboelastography,': [729], 'forming': [731], 'deflects': [733], 'vertically': [735], 'traveling': [736], 'cantilever': [737, 776, 1144], 'immersed': [738], 'into': [739, 1613, 2119], '(6': [742], 'µmol/L': [743, 831, 1196, 1331, 1378], '0.25': [747], '0/3': [751], 'hours,': [752, 840, 850], 'clotted': [753, 1324], 'nmol/L': [756, 822, 1191, 1374], 'thrombin).': [757, 1081], 'Fibrin': [758, 910], 'strength': [759, 911], 'calculated': [761], 'deflection': [764], 'force': [767], 'difference': [768], '(ΔF)': [769], 'between': [770, 2289], 'onset': [772], 'end': [774, 1204], 'pulls.': [777], 'ΔF': [778, 1152, 1168], 'markedly': [780, 1247, 1563], 'decreased': [781, 1221, 1235, 1284, 2239], 'throughout': [782], 'clotting': [784, 810, 825, 925], 'CitFg,': [786], 'ratio': [789, 1165], 'elapsed': [792], 'start': [794], 'until': [795, 1004], 'maximal': [797, 1151, 1157, 1167], 'slope': [798], 'force-curves': [800], '3.10±0.68': [802], '(3/0': [803], 'hours': [804, 1171, 1276], 'fibrin,': [806, 1889], 'n=3),': [807], 'indicating': [808, 1177, 1220, 1283], 'delayed': [809], '(Figure': [811, 1263, 1361, 1448, 1473], '[A]).': [812], 'This': [813, 2102, 2400], 'line': [816, 1182], 'electromechanical': [818], 'coagulometry': [819], 'results:': [820], '17': [821], 'thrombin': [823, 1192, 1375], 'yielded': [824], '37.6±2.6/77.8±6.9*/87.4±6.0**': [827], 's': [828], '4': [830], '0.4': [835], '0/3/4': [839, 1339], 'respectively': [841], '(n=7,': [842], 'Kruskal-Wallis': [843], 'test': [844, 1387, 1536, 1603], 'P=0.0002,': [845], '*P=0.0152,': [846], '**P=0.0017': [847], 'versus': [848], 'Dunn-test;': [851], 'mean±SE': [852], 'mean': [854, 889], 'shown': [855, 1054], 'throughout,': [856], 'statistical': [857], 'analyses': [858], 'performed': [859, 1395], 'GraphPad': [861], 'Prism': [862], '9.00).Download': [863], 'figureDownload': [864], 'PowerPointFigure.': [865], 'Citrullinated': [866, 1106, 2232], 'fibrin(ogen):': [867], 'effects': [868], '(A': [871], 'B)': [873], '(C': [876], 'D)': [878], 'presence': [880, 1389], 'samples': [883], '(E': [884], 'F).': [886], 'Mean±SE': [887], 'shown.': [890], 'Red/green:': [891], 'control/citrullinated.': [892], 'Animal': [893, 900, 2441], 'work': [894, 1660, 2428], 'approved': [896], 'Institutional': [899, 1667], 'Care': [901], 'Use': [903], 'Committee': [904, 2090], '(No.': [905], '17-01-3308R).': [906], 'A,': [907, 1872, 1874, 1906, 1914, 1916, 1954, 2174, 2223, 2225, 2256], 'Nano-thromboelastography': [908], '(nanoTEG).': [909], 'during': [912, 1850], 'clotting.2B,': [913], 'Microrheology.': [914], '0.015': [915], 'oscillatory': [916], 'strain': [917, 1255], 'Hz': [920], 'imposed': [921], '2': [922, 2374], 'min': [923, 935, 976], 'after': [924, 933, 974, 1352], 'initiation.3': [926], 'G′,': [927], 'G″:': [928], 'storage': [929, 1207], 'loss': [931, 1209, 1229], 'moduli': [932, 1210], '15': [934, 1373], 'clotting.': [936], 'Curves:': [937], 'viscosity': [939, 1250], '(η)': [940], 'vs': [941, 1070], 'increasing': [942, 1258], 'shear': [943, 1259, 1287], '(τ)': [945], 'postclotting.3': [946], 'Factor': [947], 'XIIIa-inhibitor': [948], 'ZED1301': [949], 'added': [950], '20': [952], 'µmol/L.': [953], 'C,': [954, 1862, 1952, 2180], 'Photoscanning.': [955], 'tPA': [956, 1314, 1354], '(tissue-type': [957], 'plasminogen': [958, 1309, 1311, 1316, 1622], 'activator)-induced': [959], 'lysis': [960, 1322, 1571], 'plasma': [962, 1072, 1078, 1102, 1327, 1509, 1532, 1852], 'spiked': [964, 1328], '(citrullinated': [967], 'indicated': [969], 'time).': [970], 'Lysis-front': [971], 'run': [972], 'distances': [973], '45': [975], 'normalized': [978, 1012, 1118, 1126, 1523], 'channel': [980], 'length': [981], '(relative': [982], 'units,': [983], 'RU).': [984], 'D,': [985], 'Turbidimetry.': [986], 'Clotted': [987], '(PAD4': [989], '[peptidyl-arginyl-deiminase-4]-treated': [990], '0/8': [992], 'h,': [993, 1501, 1506], 'their': [995, 1300], '1:1': [996], 'mixture)': [997], 'lysed': [998, 1359], 'plasmin': [1000], '(1': [1001], 'µmol/L).3': [1002, 1356], 'Time': [1003], 'half-maximal': [1005], 'turbidity': [1006], '340': [1008], 'nm': [1009], '(t50)': [1010], 'control': [1014], 't50': [1015], 'reference.': [1017], 'E/F,': [1018], 'Polyacrylamide-gelelectrophoresis,': [1019], 'western': [1020], 'blot.': [1021], '0.05': [1022], 'g/L': [1023], 'applied': [1025, 1262], '3h': [1027], 'where': [1028], 'indicated.': [1029], 'E,': [1030, 1059, 1878, 2176, 2207, 2213], 'upper': [1031], 'row:': [1032, 1061], '≈1': [1033], 'kDa': [1034], 'shift': [1035, 1052], 'apparent': [1038], 'size': [1039], 'Aα': [1041, 1107, 1122], 'chain': [1042], 'upon': [1043, 1289, 1461, 1639], '0.3': [1046], 'μmol/L': [1047], 'fibrinogen,': [1049], 'resembling': [1050], 'previously': [1053], 'lower': [1060, 1090, 1215, 1248, 1964], 'patterns': [1063], 'similar': [1065, 1439], 'hirudin-anticoagulated': [1067], 'recalcified': [1068, 1325], 'vitro,': [1074], 'absent': [1075], 'native': [1077], '(±clotted': [1079], 'Note:': [1082], 'molecular': [1083], 'weights': [1084], 'chains': [1088, 1108], 'than': [1091, 1967, 2044], 'human.': [1092], 'F,': [1093], 'Homogenized': [1094], 'inferior': [1095, 1397, 1454, 1486], 'vena': [1096, 1398, 1455, 1487], 'cava': [1097, 1399, 1456, 1488], '(IVC)': [1098], 'corresponding': [1101, 1470, 1637], '48': [1103], 'h': [1104, 1485], 'postligation.': [1105], 'anticitrullinated': [1111], '(CitFg)/anti-alpha': [1113], 'antibodies': [1114], '(upper/lower).': [1115], 'To': [1116], 'calculate': [1117], 'intensity,': [1120], 'signals': [1123], '(upper)': [1124], 'nonspecific': [1129], 'antibody': [1131], 'signal': [1132, 1469], 'intensity': [1133, 1479, 1525], 'stripped': [1135], 'reblotted': [1137], 'membranes': [1138], '(not': [1139], 'shown).Assuming': [1140], 'nano-thromboelastography': [1143], 'behaves': [1145], 'Hookean': [1148], 'spring,': [1149], 'analogous': [1154], 'elasticity': [1159], 'measured': [1160], 'conventional': [1162], 'thromboelastometry.2': [1163], 'The': [1164, 2287, 2381], '3/0': [1170, 1275], '0.52±0.08': [1175], '(n=3),': [1176], 'reduced': [1178], 'elasticity,2': [1180], 'rheometry3': [1184], 'results': [1185], 'formed': [1188, 1307, 1371, 1969], '(8': [1195], '0.6': [1199], 'PAD4).': [1201], 'At': [1202], 'clotting,': [1206], '(G′,': [1211], 'G″)': [1212], 'stabilized': [1213], 'values': [1216], 'clots,': [1219], 'elastic': [1222, 1965], 'viscous': [1224], 'properties,': [1225], 'respectively,': [1226], 'while': [1227], 'tangent': [1230], '(G″/G′)': [1231], 'increased,': [1232], 'revealing': [1233], 'overall': [1234], 'plastic': [1236], 'stability.': [1237], 'Compared': [1238], 'control,': [1240], 'flow-curves': [1241], 'presented': [1245], 'dynamic': [1249], 'lack': [1253], 'hardening': [1256], '[B]).': [1264], 'Gel/fluid': [1265], 'transition': [1266], '(marking': [1267], 'disassembly3)': [1269], 'occurred': [1270], '41.2±2.5/62.8±5.8': [1272], 'Pa': [1273], '(n=10/11,': [1279], 'P=0.0033,': [1280], 'Kolmogorov-Smirnov': [1281, 1535], 'test),': [1282], 'citrullination.Besides': [1290], 'biomechanics,': [1292], 'persistence': [1294], 'also': [1297], 'depends': [1298], 'susceptibility': [1301], 'plasmin,': [1303], 'serine': [1305], 'protease': [1306], 'activators': [1312], '(eg,': [1313], '[tissue-type': [1315], 'activator]).': [1317], 'Therefore,': [1318], '(pretreated': [1333, 1380], '1.15': [1335, 1382], 'hours)': [1340], 'transparent': [1342], 'microfluid': [1343], 'channels.': [1344], 'Fibrin/fluid': [1345], 'interface': [1346], 'migration': [1347], 'followed': [1349], 'photoscanning': [1351], 'applying': [1353], '(0.3': [1355], 'CitFg-supplemented': [1357], 'slower': [1360], '[C]).': [1362], 'Similarly,': [1363], 'turbidimetry': [1364], 'showed': [1365, 1465], 'decelerated': [1366], 'plasmin-mediated': [1367], 'degradation': [1368], '6': [1377], 'PAD4,': [1384], 'Figure': [1385], '[D]).To': [1386], 'stenosis': [1400], '8-': [1403], '10-week': [1405], 'old': [1406], 'wild-type': [1407], 'C57BL/6J': [1408], 'male': [1409], 'mice.': [1410], 'model,': [1413], 'thrombus': [1414, 1544], 'development': [1415], '(under': [1416], 'restricted': [1417], 'flow': [1418], 'without': [1419], 'direct': [1420], 'endothelial': [1421], 'damage)': [1422], 'closely': [1423], 'resembles': [1424], 'thrombi.4': [1428], 'First,': [1429], 'established': [1431], 'shows': [1436], 'pattern': [1438], 'Western': [1446], 'blot': [1447], '[E]).': [1449], 'Next,': [1450], 'blotted': [1452], 'processed': [1453], '(samples': [1458], 'encoded': [1460], 'blinded': [1462], 'harvest),': [1463], 'which': [1464, 2415], 'strong': [1467], 'Aα-chain': [1472], '[E]': [1474], '[F]).': [1476], 'Normalized': [1477], '0.53±0.19': [1481], '(n=6)': [1482], 'within': [1483], '1-3': [1484], 'ligation,': [1489], 'statistically': [1492], 'significant': [1493], 'change': [1494], 'later': [1496], 'timepoints': [1497], '(0.31±0.11': [1498], '6-12': [1500], 'n=9;': [1502], '0.49±0.14': [1503], '24-48': [1505], 'n=7).': [1507], 'thrombus-bearing': [1511], 'mice': [1512, 1935], 'vitro': [1515, 1573], 'generated': [1517], 'thereof,': [1518], 'hardly': [1521], 'detectable:': [1522], '0.04±0.02': [1527], 'plasma;': [1529], '0.04±0.01': [1530], '(n=4,': [1534], 'P<0.05': [1537], 'when': [1538], 'either': [1539], 'compared': [1541], 'any': [1543, 2422], 'age': [1545], 'group).Here,': [1546], 'demonstrate': [1548], 'CitFg—previously': [1550], 'identified': [1551], 'rheumatoid': [1553, 2300], 'arthritis': [1554], 'atherosclerotic': [1556], 'plaques,': [1557], 'not': [1559, 1996, 2015, 2028, 2035], 'clots—(1)': [1562], 'reduces': [1564], 'increases': [1568], 'abundant': [1577], 'Since': [1587], 'microrheological': [1588], 'parameters': [1589], 'associated': [1593], 'thromboembolism': [1595, 1959], 'recurrence,5': [1596], 'our': [1597, 1605], 'findings': [1598, 1629], 'warrant': [1599], 'future': [1600], 'studies': [1601], 'how': [1604], 'proposed': [1606], 'novel': [1607], 'mechanism': [1608], 'regulating': [1609], 'translates': [1612], 'characteristics': [1615], 'thrombi.Nonstandard': [1617], 'Abbreviations': [1618], 'AcronymsCitFgcitrullinated': [1620], 'fibrinogenPADpeptidyl-arginyl-deiminasetPAtissue-type': [1621], 'activatorData': [1623], 'availabilityThe': [1624], 'data': [1625], 'support': [1627], 'available': [1634], 'author': [1638], 'reasonable': [1640], 'request.AcknowledgmentsWe': [1641], 'grateful': [1643], 'Györgyi': [1645], 'Oravecz,': [1646], 'Krisztián': [1647], 'Bálint,': [1648], 'Long': [1649], 'Chu,': [1650], 'Steve': [1652], 'Cifuni': [1653], 'excellent': [1655], 'technical': [1656], 'assistance.Sources': [1657], 'FundingThis': [1659], 'supported': [1662, 1735, 1765], 'Higher': [1665], 'Education': [1666], 'Excellence': [1668, 1726], 'Programme': [1669], 'Ministry': [1672], 'Human': [1674, 2444], 'Capacities': [1675], 'Hungary': [1677], 'thematic': [1682], 'programme': [1683], 'University': [1686], 'STIA-2020-OTKA/137209': [1688], 'K.': [1690, 1880], 'Heart,': [1693], 'Lung,': [1694], 'Blood': [1696], 'Institutes': [1701], 'Health': [1703], '(grant': [1704], 'R35': [1705], 'HL135765': [1706], 'D.D.': [1708], 'Wagner),': [1709], 'Research,': [1713], 'Development': [1714, 1786], 'Innovation': [1716], 'Office': [1717], '(NKFIH)': [1718], 'PD124451': [1720], 'A.': [1722, 1730], 'BIONANO_GINOP-2.3.2-15-2016-00017': [1728], 'Bóta.': [1731], 'I.': [1732], 'postdoctoral': [1737, 1768], 'fellowships': [1738], 'Fulbright': [1746], 'Commission': [1747], 'Tempus': [1752], 'Foundation,': [1754], 'scholarship': [1757, 1789], 'Rosztoczy': [1760], 'Foundation.': [1761], 'fellowship': [1769], 'German': [1772], 'Foundation': [1774], '(CH': [1775], '1734/1-1).': [1776], 'A.Z.': [1777], 'V.J.': [1780], 'received': [1782], 'EFOP': [1783], '(Human': [1784], 'Resource': [1785], 'Operational': [1787], 'Program)': [1788], '(EFOP-3.6.3-VEKOP-16-2017-00009).Disclosures': [1790], 'None.FootnotesFor': [1791], 'Sources': [1792], 'Funding': [1794], 'Disclosures,': [1796], 'page': [1798], '343.Correspondence': [1799], '[email protected].': [1816], 'Döring': [1817], 'Y,': [1818], 'Libby': [1819], 'P,': [1820, 1866], 'Soehnlein': [1821], 'O.': [1822], 'Neutrophil': [1823, 2148], 'traps': [1825, 2150], 'participate': [1826], 'cardiovascular': [1828, 2341], 'diseases:': [1829, 2342], 'experimental': [1831], 'insights.Circ': [1834], 'Res.': [1835], '2020;': [1836], '126:1228–1241.': [1837], 'doi:': [1838, 1858, 1897, 1942, 1979], '10.1161/CIRCRESAHA.120.315931LinkGoogle': [1839], 'Scholar2.': [1840], 'T,': [1842, 2215], 'MS,': [1844], 'B.': [1846], 'Nano-thrombelastography': [1847], 'blood': [1851], 'clotting.J': [1853], 'Struct': [1854], 'Biol.': [1855], '2014;': [1856], '186:462–471.': [1857], '10.1016/j.jsb.2014.04.002CrossrefMedlineGoogle': [1859], 'Scholar3.': [1860], 'I,': [1864, 1910, 2205], 'Sótonyi': [1865], 'L,': [1868, 2221, 2262, 2264, 2276, 2327], 'Krumrey': [1869], 'M,': [1870, 1912, 1920, 1948, 2139, 2219, 2260, 2268], 'Hoell': [1871], 'Varga': [1875], 'Z,': [1876], 'Mechanical': [1881], 'containing': [1888], 'DNA,': [1890], 'histones.J': [1892], 'Biol': [1893], 'Chem.': [1894], '2013;': [1895], '288:6946–6956.': [1896], '10.1074/jbc.M112.404301CrossrefMedlineGoogle': [1898], 'Scholar4.': [1899], 'von': [1900], 'Brühl': [1901], 'ML,': [1902], 'Stark': [1903], 'K,': [1904, 2272, 2280], 'Steinhart': [1905], 'Chandraratne': [1907], 'S,': [1908, 2178, 2278], 'Konrad': [1909], 'Lorenz': [1911], 'Khandoga': [1913], 'Tirniceriu': [1915], 'Coletti': [1917], 'R,': [1918, 2170, 2270, 2329], 'Köllnberger': [1919], 'et': [1921], 'al.': [1922], 'Monocytes,': [1923], 'neutrophils,': [1924], 'platelets': [1926], 'cooperate': [1927], 'initiate': [1929], 'propagate': [1931], 'venous': [1932, 1958, 2294], 'thrombosis': [1933], 'vivo.J': [1937], 'Exp': [1938], 'Med.': [1939], '2012;': [1940], '209:819–835.': [1941], '10.1084/jem.20112322CrossrefMedlineGoogle': [1943], 'Scholar5.': [1944], 'Baker': [1945], 'SR,': [1946], 'Zabczyk': [1947], 'Macrae': [1949], 'FL,': [1950], 'Duval': [1951], 'Undas': [1953], 'Ariëns': [1955], 'RAS.': [1956], 'Recurrent': [1957], 'patients': [1960, 1971, 2298], 'form': [1961], 'modulus': [1966], 'those': [1968], 'non-recurrent': [1973], 'disease.J': [1974], 'Thromb': [1975], 'Haemost.': [1976], '2019;': [1977], '17:618–626.': [1978], '10.1111/jth.14402CrossrefMedlineGoogle': [1980], 'Scholar': [1981], 'eLetters(0)': [1982], 'eLetters': [1983], 'should': [1984, 2040, 2082], 'relate': [1985], 'an': [1987, 2031, 2402], 'article': [1988, 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