Subscribe to RSS
DOI: 10.1055/a-1508-8230
Optimal Tests to Minimise Bleeding and Ischaemic Complications in Patients on Extracorporeal Membrane Oxygenation
Abstract
Patients supported with extracorporeal membrane oxygenation (ECMO) experience a very high frequency of bleeding and ischaemic complications, including stroke and systemic embolism. These patients require systemic anticoagulation, mainly with unfractionated heparin (UFH) to prevent clotting of the circuit and reduce the risk of arterial or venous thrombosis. Monitoring of UFH can be very challenging. While most centres routinely monitor the activated clotting time and activated partial thromboplastin time (aPTT) to assess UFH, measurement of anti-factor Xa (anti-Xa) level best correlates with heparin dose, and appears to be predictive of circuit thrombosis, although aPTT may be a better predictor of bleeding. Although monitoring of prothrombin time, platelet count and fibrinogen is routinely undertaken to assess haemostasis, there is no clear guidance available regarding the optimal test.
Additional tests, including antithrombin level and thromboelastography, can be used for risk stratification of patients to try and predict the risks of thrombosis and bleeding. Each has their specific role, strengths and limitations. Increased thrombin generation may have a role in predicting thrombosis. Acquired von Willebrand syndrome is frequent with ECMO, contributing to bleeding risk and can be detected by assessing the von Willebrand factor activity-to-antigen ratio, while the platelet function analyser can be used in urgent situations to detect this, with a high negative predictive value. Tests of platelet aggregation can aid in the prediction of bleeding.
To personalise management, a selection of complementary tests to collectively assess heparin-effect, coagulation, platelet function and platelet aggregation is proposed, to optimise clinical outcomes in these high-risk patients.
** Joint senior authors.
Author Contributions
D.A.G. and S.P. are responsible for the paper conception and design. C.V. and R.K. performed the literature search and data analysis and prepared the first draft. D.R.J.A. provided the haemostasis management algorithm. D.A.G., C.V., D.R.J.A. and S.P. all critically reviewed and revised the manuscript. All authors have approved the final version of the manuscript.
Publication History
Received: 29 January 2021
Accepted: 12 May 2021
Accepted Manuscript online:
13 May 2021
Article published online:
21 June 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Cheng R, Hachamovitch R, Kittleson M. et al. Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult patients. Ann Thorac Surg 2014; 97 (02) 610-616
- 2 Gorog DA, Price S, Sibbing D. et al. Antithrombotic therapy in patients with acute coronary syndrome complicated by cardiogenic shock or out-of-hospital cardiac arrest: a joint position paper from the European Society of Cardiology (ESC) Working Group on Thrombosis, in association with the Acute Cardiovascular Care Association (ACCA) and European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J Cardiovasc Pharmacother 2021; 7 (02) 125-140
- 3 McMichael ABV, Hornik CP, Hupp SR, Gordon SE, Ozment CP. Correlation among antifactor Xa, activated partial thromboplastin time, and heparin dose and association with pediatric extracorporeal membrane oxygenation complications. ASAIO J 2020; 66 (03) 307-313
- 4 Vandenbriele C, Vanassche T, Price S. Why we need safer anticoagulant strategies for patients on short-term percutaneous mechanical circulatory support. Intensive Care Med 2020; 46 (04) 771-774
- 5 Atallah S, Liebl M, Fitousis K, Bostan F, Masud F. Evaluation of the activated clotting time and activated partial thromboplastin time for the monitoring of heparin in adult extracorporeal membrane oxygenation patients. Perfusion 2014; 29 (05) 456-461
- 6 Irby K, Swearingen C, Byrnes J, Bryant J, Prodhan P, Fiser R. Unfractionated heparin activity measured by anti-factor Xa levels is associated with the need for extracorporeal membrane oxygenation circuit/membrane oxygenator change: a retrospective pediatric study. Pediatr Crit Care Med 2014; 15 (04) e175-e182
- 7 Baird CW, Zurakowski D, Robinson B. et al. Anticoagulation and pediatric extracorporeal membrane oxygenation: impact of activated clotting time and heparin dose on survival. Ann Thorac Surg 2007; 83 (03) 912-919
- 8 De Waele JJ, Van Cauwenberghe S, Hoste E, Benoit D, Colardyn F. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med 2003; 29 (02) 325-328
- 9 Price EA, Jin J, Nguyen HM, Krishnan G, Bowen R, Zehnder JL. Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin. Ann Pharmacother 2013; 47 (02) 151-158
- 10 Oladunjoye OO, Sleeper LA, Nair AG. et al. Partial thromboplastin time is more predictive of bleeding than anti-Xa levels in heparinized pediatric patients after cardiac surgery. J Thorac Cardiovasc Surg 2018; 156 (01) 332.e1-340.e1
- 11 Aubron C, DePuydt J, Belon F. et al. Predictive factors of bleeding events in adults undergoing extracorporeal membrane oxygenation. Ann Intensive Care 2016; 6 (01) 97
- 12 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3, Suppl): 188S-203S
- 13 Anticoagulation Guideline ELSO. 2014 . Accessed April 20, 2021 at: https://www.elso.org/portals/0/files/elsoanticoagulationguideline8-2014-table-contents.pdf
- 14 Ignjatovic V, Summerhayes R, Gan A. et al. Monitoring unfractionated heparin (UFH) therapy: which anti-factor Xa assay is appropriate?. Thromb Res 2007; 120 (03) 347-351
- 15 Schaefer B, Hausfeld A, Martin M. et al. Impact of exogenous antithrombin on low molecular weight heparin anti-Xa activity assays in a pediatric and young adult leukemia and lymphoma cohort with variable antithrombin levels. Pediatr Blood Cancer 2020; 67 (11) e28654
- 16 Bembea MM, Schwartz JM, Shah N. et al. Anticoagulation monitoring during pediatric extracorporeal membrane oxygenation. ASAIO J 2013; 59 (01) 63-68
- 17 Nankervis CA, Preston TJ, Dysart KC. et al. Assessing heparin dosing in neonates on venoarterial extracorporeal membrane oxygenation. ASAIO J 2007; 53 (01) 111-114
- 18 Liveris A, Bello RA, Friedmann P. et al. Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation*. Pediatr Crit Care Med 2014; 15 (02) e72-e79
- 19 Chu DC, Abu-Samra AG, Baird GL. et al. Quantitative measurement of heparin in comparison with conventional anticoagulation monitoring and the risk of thrombotic events in adults on extracorporeal membrane oxygenation. Intensive Care Med 2015; 41 (02) 369-370
- 20 Arnouk S, Altshuler D, Lewis TC. et al. Evaluation of anti-Xa and activated partial thromboplastin time monitoring of heparin in adult patients receiving extracorporeal membrane oxygenation support. ASAIO J 2020; 66 (03) 300-306
- 21 Raghunathan V, Liu P, Kohs TCL. et al. Heparin resistance is common in patients undergoing extracorporeal membrane oxygenation but is not associated with worse clinical outcomes. ASAIO J 2021; 67 (08) 899-906
- 22 Staples MH, Dunton RF, Karlson KJ, Leonardi HK, Berger RL. Heparin resistance after preoperative heparin therapy or intraaortic balloon pumping. Ann Thorac Surg 1994; 57 (05) 1211-1216
- 23 Ranucci M, Isgrò G, Cazzaniga A. et al. Different patterns of heparin resistance: therapeutic implications. Perfusion 2002; 17 (03) 199-204
- 24 Avidan MS, Levy JH, Scholz J. et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology 2005; 102 (02) 276-284
- 25 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 (02) 355-360
- 26 Streng AS, Delnoij TSR, Mulder MMG. et al. Monitoring of unfractionated heparin in severe COVID-19: an observational study of patients on CRRT and ECMO. TH Open 2020; 4 (04) e365-e375
- 27 Chlebowski MM, Baltagi S, Carlson M, Levy JH, Spinella PC. Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO. Crit Care 2020; 24 (01) 19
- 28 Panigada M, Cucino A, Spinelli E. et al. A randomized controlled trial of antithrombin supplementation during extracorporeal membrane oxygenation. Crit Care Med 2020; 48 (11) 1636-1644
- 29 Alexander DC, Butt WW, Best JD, Donath SM, Monagle PT, Shekerdemian LS. Correlation of thromboelastography with standard tests of anticoagulation in paediatric patients receiving extracorporeal life support. Thromb Res 2010; 125 (05) 387-392
- 30 Prakash S, Wiersema UF, Bihari S, Roxby D. Discordance between ROTEM® clotting time and conventional tests during unfractionated heparin-based anticoagulation in intensive care patients on extracorporeal membrane oxygenation. Anaesth Intensive Care 2016; 44 (01) 85-92
- 31 Nair P, Hoechter DJ, Buscher H. et al. Prospective observational study of hemostatic alterations during adult extracorporeal membrane oxygenation (ECMO) using point-of-care thromboelastometry and platelet aggregometry. J Cardiothorac Vasc Anesth 2015; 29 (02) 288-296
- 32 Laine A, Niemi T, Suojaranta-Ylinen R. et al. Decreased maximum clot firmness in rotational thromboelastometry (ROTEM®) is associated with bleeding during extracorporeal mechanical circulatory support. Perfusion 2016; 31 (08) 625-633
- 33 Hellmann C, Schmutz A, Kalbhenn J. Bleeding during veno-venous ECMO cannot reliably be predicted by rotational thrombelastometry (ROTEM™). Perfusion 2018; 33 (04) 289-296
- 34 Panigada M, Iapichino GE, Brioni M. et al. Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study. Ann Intensive Care 2018; 8 (01) 7
- 35 Henderson N, Sullivan JE, Myers J. et al. Use of thromboelastography to predict thrombotic complications in pediatric and neonatal extracorporeal membranous oxygenation. J Extra Corpor Technol 2018; 50 (03) 149-154
- 36 Padhya DR, Prutsky GJ, Nemergut ME. et al. Routine laboratory measures of heparin anticoagulation for children on extracorporeal membrane oxygenation: Systematic review and meta-analysis. Thromb Res 2019; 179: 132-139
- 37 Besser M, Baglin C, Luddington R, van Hylckama Vlieg A, Baglin T. High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study. J Thromb Haemost 2008; 6 (10) 1720-1725
- 38 van Hylckama Vlieg A, Christiansen SC, Luddington R, Cannegieter SC, Rosendaal FR, Baglin TP. Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 2007; 138 (06) 769-774
- 39 Wexels F, Dahl OE, Pripp AH, Seljeflot I. Thrombin generation in patients with suspected venous thromboembolism. Clin Appl Thromb Hemost 2017; 23 (05) 416-421
- 40 Mazzeffi M, Strauss E, Meyer M. et al. Coagulation factor levels and underlying thrombin generation patterns in adult extracorporeal membrane oxygenation patients. Anesth Analg 2019; 129 (03) 659-666
- 41 Al Dieri R, de Laat B, Hemker HC. Thrombin generation: what have we learned?. Blood Rev 2012; 26 (05) 197-203
- 42 Bosch YPJ, Al Dieri R, ten Cate H. et al. Measurement of thrombin generation intra-operatively and its association with bleeding tendency after cardiac surgery. Thromb Res 2014; 133 (03) 488-494
- 43 Lubnow M, Philipp A, Dornia C. et al. D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation. J Crit Care 2014; 29 (03) 473.e1-473.e5
- 44 Dornia C, Philipp A, Bauer S. et al. D-dimers are a predictor of clot volume inside membrane oxygenators during extracorporeal membrane oxygenation. Artif Organs 2015; 39 (09) 782-787
- 45 Arachchillage DRJ, Laffan M, Khanna S. et al. Frequency of thrombocytopenia and heparin-induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation compared with cardiopulmonary bypass and the limited sensitivity of pretest probability score. Crit Care Med 2020; 48 (05) e371-e379
- 46 Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4 (04) 759-765
- 47 Ranucci M, Colella D, Baryshnikova E, Di Dedda U. Surgical and Clinical Outcome Research (SCORE) Group. Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery. Br J Anaesth 2014; 113 (06) 970-976
- 48 Van Poucke S, Stevens K, Kicken C, Simons A, Marcus A, Lancé M. Platelet function during hypothermia in experimental mock circulation. Artif Organs 2016; 40 (03) 288-293
- 49 Balle CM, Jeppesen AN, Christensen S, Hvas A-M. Platelet function during extracorporeal membrane oxygenation in adult patients: a systematic review. Front Cardiovasc Med 2018; 5: 157
- 50 Jiritano F, Serraino GF, Ten Cate H. et al. Platelets and extra-corporeal membrane oxygenation in adult patients: a systematic review and meta-analysis. Intensive Care Med 2020; 46 (06) 1154-1169
- 51 Yaw HP, Van Den Helm S, MacLaren G, Linden M, Monagle P, Ignjatovic V. Platelet phenotype and function in the setting of pediatric extracorporeal membrane oxygenation (ECMO): a systematic review. Front Cardiovasc Med 2019; 6: 137
- 52 Balle CM, Jeppesen AN, Christensen S, Hvas A-M. Platelet function during extracorporeal membrane oxygenation in adult patients. Front Cardiovasc Med 2019; 6: 114
- 53 Sniderman J, Monagle P, Annich GM, MacLaren G. Hematologic concerns in extracorporeal membrane oxygenation. Res Pract Thromb Haemost 2020; 4 (04) 455-468
- 54 Uriel N, Pak S-W, Jorde UP. et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010; 56 (15) 1207-1213
- 55 Lukito P, Wong A, Jing J. et al. Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI. J Thromb Haemost 2016; 14 (11) 2253-2260
- 56 Higgins RA, Goodwin AJ. Automated assays for von Willebrand factor activity. Am J Hematol 2019; 94 (04) 496-503
- 57 Kalbhenn J, Schlagenhauf A, Rosenfelder S, Schmutz A, Zieger B. Acquired von Willebrand syndrome and impaired platelet function during venovenous extracorporeal membrane oxygenation: rapid onset and fast recovery. J Heart Lung Transplant 2018; 37 (08) 985-991
- 58 Meyer AL, Malehsa D, Budde U, Bara C, Haverich A, Strueber M. Acquired von Willebrand syndrome in patients with a centrifugal or axial continuous flow left ventricular assist device. JACC Heart Fail 2014; 2 (02) 141-145
- 59 Oezpeker C, Zittermann A, Baurichter D. et al. Changes in von Willebrand factor profile predicts clinical outcomes in patients on mechanical circulatory support. J Card Surg 2018; 33 (10) 693-702
- 60 Ki KK, Passmore MR, Chan CHH. et al. Low flow rate alters haemostatic parameters in an ex-vivo extracorporeal membrane oxygenation circuit. Intensive Care Med Exp 2019; 7 (01) 51
- 61 Klaeske K, Dieterlen M-T, Scholz U. et al. Acquired von Willebrand factor deficiency is reduced in HeartMate 3 patients†. Eur J Cardiothorac Surg 2019; 56 (03) 444-450
- 62 Dean JA, Blanchette VS, Carcao MD. et al. von Willebrand disease in a pediatric-based population--comparison of type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay. Thromb Haemost 2000; 84 (03) 401-409
- 63 Favaloro EJ. Utility of the platelet function analyser (PFA-100/200) for exclusion or detection of von Willebrand disease: a study 22 years in the making. Thromb Res 2020; 188: 17-24
- 64 Topf H-G, Weiss D, Lischetzki G, Strasser E, Rascher W, Rauh M. Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease. Thromb Haemost 2011; 105 (06) 1091-1099
- 65 Schmidt DE, Majeed A, Bruzelius M, Odeberg J, Holmström M, Ågren A. A prospective diagnostic accuracy study evaluating rotational thromboelastometry and thromboelastography in 100 patients with von Willebrand disease. Haemophilia 2017; 23 (02) 309-318
- 66 Topf H-G, Strasser ER, Breuer G, Rascher W, Rauh M, Fahlbusch FB. Closing the gap - detection of clinically relevant von Willebrand disease in emergency settings through an improved algorithm based on rotational thromboelastometry. BMC Anesthesiol 2019; 19 (01) 10
- 67 Zhou Y, Qin S, Hilton T. et al. Quantification of von Willebrand factor cleavage by ADAMTS-13 in patients supported by left ventricular assist devices. ASAIO J 2017; 63 (06) 849-853
- 68 Farag M, Spinthakis N, Gue YX. et al. Impaired endogenous fibrinolysis in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention is a predictor of recurrent cardiovascular events: the RISK PPCI study. Eur Heart J 2019; 40 (03) 295-305
- 69 Gorog DA, Lip GYH. Impaired spontaneous/endogenous fibrinolytic status as new cardiovascular risk factor?: JACC review topic of the week. J Am Coll Cardiol 2019; 74 (10) 1366-1375
- 70 Kaikita K, Hosokawa K, Dahlen JR, Tsujita K. Total thrombus-formation analysis system (T-TAS): clinical application of quantitative analysis of thrombus formation in cardiovascular disease. Thromb Haemost 2019; 119 (10) 1554-1562
- 71 Hagström E, James SK, Bertilsson M. et al; PLATO Investigators. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016; 37 (16) 1325-1333
- 72 Wallentin L, Hijazi Z, Andersson U. et al; ARISTOTLE Investigators. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130 (21) 1847-1858
- 73 Lok SI, Winkens B, Goldschmeding R. et al. Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support. Eur J Heart Fail 2012; 14 (11) 1249-1256
- 74 Mackman N, Bergmeier W, Stouffer GA, Weitz JI. Therapeutic strategies for thrombosis: new targets and approaches. Nat Rev Drug Discov 2020; 19 (05) 333-352
- 75 Larsson M, Rayzman V, Nolte MW. et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6 (222) 222ra17
- 76 Matafonov A, Leung PY, Gailani AE. et al. Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 2014; 123 (11) 1739-1746
- 77 Yau JW, Liao P, Fredenburgh JC. et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 2014; 123 (13) 2102-2107
- 78 David T, Kim YC, Ely LK. et al. Factor XIa-specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis. Sci Transl Med 2016; 8 (353) 353ra112
- 79 Büller HR, Bethune C, Bhanot S. et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
- 80 Weitz JI, Bauersachs R, Becker B. et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA 2020; 323 (02) 130-139
- 81 Combes A, Hajage D, Capellier G. et al; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018; 378 (21) 1965-1975