[en] INTRODUCTION: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with the activation of inflammatory mediators that possess prothrombotic activity and could cause postoperative haemostatic disorders. This study was conducted to investigate the effect of cardiac surgery on prothrombotic activity in children undergoing cardiac surgery for complex cardiac defects. METHODS: Eighteen children (ages 3 to 163 months) undergoing univentricular palliation with total cavopulmonary connection (TCPC) (n = 10) or a biventricular repair (n = 8) for complex cardiac defects were studied. Prothrombotic activity was evaluated by measuring plasma levels of prothrombin fragment 1+2 (F1+2), thromboxane B2 (TxB2), and monocyte chemoattractant protein-1 (MCP-1). Anti-thrombotic activity was evaluated by measuring levels of tissue factor pathway inhibitor (TFPI) before, during, and after cardiac surgery. RESULTS: In all patients, cardiac surgery was associated with a significant but transient increase of F1+2, TxB2, TFPI, and MCP-1. Maximal values of F1+2, TxB2, and MCP-1 were found at the end of CPB. In contrast, maximal levels of TFPI were observed at the beginning of CPB. Concentrations of F1+2 at the end of CPB correlated negatively with the minimal oesophageal temperature during CPB. Markers of prothrombotic activity returned to preoperative values from the first postoperative day on. Early postoperative TFPI levels were significantly lower and TxB2 levels significantly higher in patients with TCPC than in those with biventricular repair. Thromboembolic events were not observed. CONCLUSION: Our data suggest that children with complex cardiac defects undergoing cardiac surgery show profound but transient imbalance between pro- and anti-thrombotic activity, which could lead to thromboembolic complications. These alterations are more important after TCPC than after biventricular repair but seem to be determined mainly by low antithrombin III.
Chan AK Leaker M Burrows FA Williams WG Gruenwald CE Whyte L Adams M Brooker LA Adams H Mitchell L Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass Thromb Haemost 1997 77 270-277 9157580
Despotis GJ Joist JH Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: An update J Cardiothorac Vasc Anesth 1999 13 4 Suppl 1 18-29 discussion 36-37 10468245
Jaggers JJ Neal MC Smith PK Ungerleider RM Lawson JH Infant cardiopulmonary bypass: A procoagulant state Ann Thorac Surg 1999 68 513-520 10.1016/S0003-4975(99)00644-X 10475421
Ries M Klinge J Rauch R Age-related reference values for activation markers of the coagulation and fibrinolytic systems in children Thromb Res 1997 85 341-344 10.1016/S0049-3848(97)00019-4 9062957
Mangano DT Multicenter Study of Perioperative Ischemia Research Group Aspirin and mortality from coronary bypass surgery N Engl J Med 2002 347 1309-1317 10.1056/NEJMoa020798 12397188
Pearl JM Manning PB McNamara JL Saucier MM Thomas DW Effect of modified ultrafiltration on plasma thromboxane B2, leukotriene B4, and endothelin-1 in infants undergoing cardiopulmonary bypass Ann Thorac Surg 1999 68 1369-1375 10.1016/S0003-4975(99)00978-9 10543508
Kojima T Gando S Kemmotsu O Mashio H Goda Y Kawahigashi H Watanabe N Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: Role of tissue factor pathway inhibitor J Cardiothorac Vasc Anesth 2001 15 60-64 10.1053/jcan.2001.20278 11254842
Adams MJ Cardigan RA Marchant WA Grocott MP Mythen MG Mutch M Purdy G Mackie IJ Machin SJ Tissue factor pathway inhibitor antigen and activity in 96 patients receiving heparin for cardiopulmonary bypass J Cardiothorac Vasc Anesth 2002 16 59-63 10.1053/jcan.2002.29677 11854880
Kawahito K Kawakami M Fujiwara T Adachi H Ino T Interleukin-8 and monocyte chemotactic activating factor responses to cardiopulmonary bypass J Thorac Cardiovasc Surg 1995 110 99-102 10.1016/ S0022-5223(05)80014-5 7609574
Cromme-Dijkhuis AH Hess J Hahlen K Henkens CM Bink-Boelkens MT Eygelaar AA Bos E Specific sequelae after Fontan operation at mid- and long-term follow-up. Arrhythmia, liver dysfunction, and coagulation disorders J Thorac Cardiovasc Surg 1993 106 1126-1132 8246550
Masuda M Kado H Shiokawa Y Fukae K Suzuki M Murakami E Yasui H Clinical results of the staged Fontan procedure in high-risk patients Ann Thorac Surg 1998 65 1721-1725 10.1016/S0003-4975(98)00264-1 9647088
Day RW Boyer RS Tait VF Ruttenberg HD Factors associated with stroke following the Fontan procedure Pediatr Cardiol 1995 16 270-275 10.1007/ BF00798060 8650012
Jahangiri M Kreutzer J Zurakowski D Bacha E Jonas RA Evaluation of hemostatic and coagulation factor abnormalities in patients undergoing the Fontan operation J Thorac Cardiovasc Surg 2000 120 778-782 10.1067/ mtc.2000.108903 11003762
Kaulitz R Luhmer I Bergmann F Rodeck B Hausdorf G Sequelae after modified Fontan operation: Postoperative haemodynamic data and organ function Heart 1997 78 154-159 9326989
Ravn HB Hjortdal VE Stenbog EV Emmertsen K Kromann O Pedersen J Sorensen KE Increased platelet reactivity and significant changes in coagulation markers after cavopulmonary connection Heart 2001 85 61-65 10.1136/ heart.85.1.61 11119465
Odegard KC McGowan FX Jr Zurakowski D DiNardo JA Castro RA del Nido PJ Laussen PC Coagulation factor abnormalities in patients with single-ventricle physiology immediately prior to the Fontan procedure Ann Thorac Surg 2002 73 1770-1777 10.1016/S0003-4975(02)03580-4 12078768
Boisclair MD Lane DA Philippou H Sheikh S Hunt B Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1 + 2 Thromb Haemost 1993 70 253-258 8236130
Knudsen L Hasenkam JM Kure HH Hughes P Bellaiche L Ahlburg P Djurhuus C Monitoring thrombin generation with prothrombin fragment 1.2 assay during cardiopulmonary bypass surgery Thromb Res 1996 84 45-54 10.1016/ 0049-3848(96)00160-0 8885146
Burman JF Chung HI Lane DA Philippou H Adami A Lincoln JC Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass Lancet 1994 344 1192-1193 10.1016/S0140-6736(94)90509-6 7934541
Boldt J Knothe C Welters I Dapper FL Hempelmann G Normothermic versus hypothermic cardiopulmonary bypass: Do changes in coagulation differ? Ann Thorac Surg 1996 62 130-135 10.1016/0003-4975(96)00239-1 8678631
Paparella D Brister SJ Buchanan MR Coagulation disorders of cardiopulmonary bypass: A review Intensive Care Med 2004 30 1873-1881 10.1007/s00134-004-2388-0 15278267
Owings JT Pollock ME Gosselin RC Ireland K Jahr JS Larkin EC Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques Arch Surg 2000 135 1042-1047 10.1001/archsurg.135.9.1042 10982508
Adatia I Barrow SE Stratton PD Miall-Allen VM Ritter JM Haworth SG Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease Circulation 1993 88 5 Pt 1 2117-2122 8222105
Adatia I Barrow SE Stratton P Ritter JM Haworth SG Abnormalities in the biosynthesis of thromboxane A2 and prostacyclin in children with cyanotic congenital heart disease Br Heart J 1993 69 179-182 8435245
Ansley DM Qayumi AK Duncan S Merrick PM Klein R Platelet activating factor and thromboxane B2 production after cardiopulmonary bypass J Invest Surg 1997 10 87-95 9219083
Ernofsson M Thelin S Siegbahn A Monocyte tissue factor expression, cell activation, and thrombin formation during cardiopulmonary bypass: A clinical study J Thorac Cardiovasc Surg 1997 113 576-584 10.1016/ S0022-5223(97)70373-8 9081105
Khan MM Gikakis N Miyamoto S Rao AK Cooper SL Edmunds LH Jr Colman RW Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass Ann Thorac Surg 1999 68 473-478 10.1016/ S0003-4975(99)00551-2 10475415
Gessler P Pretre R Burki C Rousson V Frey B Nadal D Monocyte function-associated antigen expression during and after pediatric cardiac surgery J Thorac Cardiovasc Surg 2005 130 54-60 10.1016/ j.jtcvs.2005.01.008 15999041
Weyrich AS Denis MM Kuhlmann-Eyre JR Spencer ED Dixon DA Marathe GK McIntyre TM Zimmerman GA Prescott SM Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates Circulation 2005 111 633-642 10.1161/01.CIR.0000154607.90506.45 15668340
Schecter AD Rollins BJ Zhang YJ Charo IF Fallon JT Rossikhina M Giesen PL Nemerson Y Taubman MB Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells J Biol Chem 1997 272 28568-28573 10.1074/jbc.272.45.28568 9353321
Garlichs CD Kozina S Fateh-Moghadam S Handschu R Tomandl B Stumpf C Eskafi S Raaz D Schmeisser A Yilmaz A Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia Stroke 2003 34 1412-1418 10.1161/01.STR.0000074032.64049.47 12764232
Gessler P Pretre R Hohl V Rousson V Fischer J Dahinden C CXC-chemokine stimulation of neutrophils correlates with plasma levels of myeloperoxidase and lactoferrin and contributes to clinical outcome after pediatric cardiac surgery Shock 2004 22 513-520 10.1097/ 01.shk.0000145939.54838.51 15545821
Szaba FM Smiley ST Roles for thrombin and fibrin(ogen) in cytokine/ chemokine production and macrophage adhesion in vivo Blood 2002 99 1053-1059 10.1182/blood.V99.3.1053 11807012
Qing M Schumacher K Heise R Woltje M Vazquez-Jimenez JF Richter T Arranda-Carrero M Hess J von Bernuth G Seghaye MC Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects J Am Coll Cardiol 2003 41 2266-2274 10.1016/ S0735-1097(03)00477-7 12821258
Levy JH Tanaka KA Inflammatory response to cardiopulmonary bypass Ann Thorac Surg 2003 75 S715-720 10.1016/S0003-4975(02)04701-X 12607717
Hovels-Gurich HH Vazquez-Jimenez JF Silvestri A Schumacher K Minkenberg R Duchateau J Messmer BJ von Bernuth G Seghaye MC Production of proinflammatory cytokines and myocardial dysfunction after arterial switch operation in neonates with transposition of the great arteries J Thorac Cardiovasc Surg 2002 124 811-820 10.1067/mtc.2002.122308 12324741
Cromme-Dijkhuis AH Henkens CM Bijleveld CM Hillege HL Bom VJ van der Meer J Coagulation factor abnormalities as possible thrombotic risk factors after Fontan operations Lancet 1990 336 1087-1090 10.1016/ 0140-6736(90)92568-3 1977979
Jahangiri M Shore D Kakkar V Lincoln C Shinebourne E Coagulation factor abnormalities after the Fontan procedure and its modifications J Thorac Cardiovasc Surg 1997 113 989-992 discussion 992-993 10.1016/ S0022-5223(97)70283-6 9202678
van Nieuwenhuizen RC Peters M Lubbers LJ Trip MD Tijssen JG Mulder BJ Abnormalities in liver function and coagulation profile following the Fontan procedure Heart 1999 82 40-46 10377307
Ranucci M Frigiola A Menicanti L Ditta A Boncilli A Brozzi S Postoperative antithrombin levels and outcome in cardiac operations Crit Care Med 2005 33 355-360 10.1097/01.CCM.0000153409.55645.58 15699839
Hashimoto K Yamagishi M Sasaki T Nakano M Kurosawa H Heparin and antithrombin III levels during cardiopulmonary bypass: Correlation with subclinical plasma coagulation Ann Thorac Surg 1994 58 799-804 discussion 804-805 7944706
Wiedermann CJ Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis Crit Care 2006 10 209 1550851 16542481 10.1186/ cc4822
