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Semin Thromb Hemost 2020; 46(04): 419-427
DOI: 10.1055/s-0039-1697950
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Anti-Factor Xa–Based Anticoagulation during Extracorporeal Membrane Oxygenation: Potential Problems and Possible Solutions

Marco Ranucci
1   Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
,
Mauro Cotza
1   Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
,
Giuseppe Isgrò
1   Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
,
Giovanni Carboni
1   Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
,
Andrea Ballotta
1   Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
,
Ekaterina Baryshnikova
1   Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
,
for the Surgical Clinical Outcome REsearch (SCORE) Group › Author Affiliations
Further Information

Publication History

Publication Date:
28 September 2019 (online)

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Abstract

Choices for monitoring of unfractionated heparin (UFH) anticoagulation in extracorporeal membrane oxygenation (ECMO) patients include activated clotting time, activated partial thromboplastin time, reaction times of viscoelastic tests, and anti-factor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the anti-factor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of anti-factor Xa as the sole method of monitoring of UFH effects in ECMO. Anti-factor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the anti-factor Xa assay is a plasma-based test which does not take into account the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and underestimating their role may lead to over-anticoagulation, should only anti-factor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of fibrinogen during the ECMO course. In this case, an UFH monitoring based on anti-factor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, anti-factor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

Keywords

ECMO - anti-factor Xa - unfractionated heparin - viscoelastic tests
 

  • References

  • 1 Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal membrane oxygenation. Semin Thromb Hemost 2018; 44 (01) 20-29
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Menk M, Briem P, Weiss B. , et al. Efficacy and safety of argatroban in patients with acute respiratory distress syndrome and extracorporeal lung support. Ann Intensive Care 2017; 7 (01) 82
    CrossrefPubMedGoogle Scholar
  • 3 Sanfilippo F, Asmussen S, Maybauer DM. , et al. Bivalirudin for alternative anticoagulation in extracorporeal membrane oxygenation: a systematic review. J Intensive Care Med 2017; 32 (05) 312-319
    CrossrefPubMedGoogle Scholar
  • 4 Esper SA, Welsby IJ, Subramaniam K. , et al. Adult extracorporeal membrane oxygenation: an international survey of transfusion and anticoagulation techniques. Vox Sang 2017; 112 (05) 443-452
    CrossrefPubMedGoogle Scholar
  • 5 Ranucci M, Baryshnikova E, Cotza M. , et al; Group for the Surgical and Clinical Outcome Research (SCORE). Coagulation monitoring in postcardiotomy ECMO: conventional tests, point-of-care, or both?. Minerva Anestesiol 2016; 82 (08) 858-866
    PubMedGoogle Scholar
  • 6 Koster A, Ljajikj E, Faraoni D. Traditional and non-traditional anticoagulation management during extracorporeal membrane oxygenation. Ann Cardiothorac Surg 2019; 8 (01) 129-136
    CrossrefPubMedGoogle Scholar
  • 7 Moynihan K, Johnson K, Straney L. , et al. Coagulation monitoring correlation with heparin dose in pediatric extracorporeal life support. Perfusion 2017; 32 (08) 675-685
    CrossrefPubMedGoogle Scholar
  • 8 Panigada M, , E Iapichino G, 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
    CrossrefPubMedGoogle Scholar
  • 9 Bembea MM, Annich G, Rycus P, Oldenburg G, Berkowitz I, Pronovost P. Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med 2013; 14 (02) e77-e84
    CrossrefPubMedGoogle Scholar
  • 10 Northrop MS, Sidonio RF, Phillips SE. , et al. The use of an extracorporeal membrane oxygenation anticoagulation laboratory protocol is associated with decreased blood product use, decreased hemorrhagic complications, and increased circuit life. Pediatr Crit Care Med 2015; 16 (01) 66-74
    CrossrefPubMedGoogle Scholar
  • 11 O'Meara LC, Alten JA, Goldberg KG. , et al. Anti-Xa directed protocol for anticoagulation management in children supported with extracorporeal membrane oxygenation. ASAIO J 2015; 61 (03) 339-344
    CrossrefPubMedGoogle Scholar
  • 12 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
    CrossrefPubMedGoogle Scholar
  • 13 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
    CrossrefPubMedGoogle Scholar
  • 14 Winter WE, Flax SD, Harris NS. Coagulation testing in the core laboratory. Lab Med 2017; 48 (04) 295-313
    CrossrefPubMedGoogle Scholar
  • 15 Vera-Aguilera J, Yousef H, Beltran-Melgarejo D. , et al. Clinical scenarios for discordant anti-Xa. Adv Hematol 2016; 2016: 4054806
    PubMedGoogle Scholar
  • 16 Iapichino GE, Protti A, Andreis DT. , et al. Antithrombin during extracorporeal membrane oxygenation in adults: national survey and retrospective analysis. ASAIO J 2019; 65 (03) 257-263
    CrossrefPubMedGoogle Scholar
  • 17 Nelson KM, Hansen LA, Steiner ME, Fischer GA, Dehnel J, Gupta S. Continuous antithrombin III administration in pediatric veno-arterial extracorporeal membrane oxygenation. J Pediatr Pharmacol Ther 2017; 22 (04) 266-271
    PubMedGoogle Scholar
  • 18 Stansfield BK, Wise L, Ham III PB. , et al. Outcomes following routine antithrombin III replacement during neonatal extracorporeal membrane oxygenation. J Pediatr Surg 2017; 52 (04) 609-613
    CrossrefPubMedGoogle Scholar
  • 19 Wong TE, Nguyen T, Shah SS, Brogan TV, Witmer CM. Antithrombin concentrate use in pediatric extracorporeal membrane oxygenation: a multicenter cohort study. Pediatr Crit Care Med 2016; 17 (12) 1170-1178
    CrossrefPubMedGoogle Scholar
  • 20 Diaz R, Moffett BS, Karabinas S, Guffrey D, Mahoney Jr DH, Yee DL. Antithrombin concentrate use in children receiving unfractionated heparin for acute thrombosis. J Pediatr 2015; 167 (03) 645-649
    CrossrefPubMedGoogle Scholar
  • 21 Dufour N, Radjou A, Thuong M. Hemolysis and plasma free hemoglobin during extracorporeal membrane oxygenation support: from clinical implications to laboratory details. A review. ASAIO J 2020; 66 (03) 239-246
    CrossrefPubMedGoogle Scholar
  • 22 Pan KC, McKenzie DP, Pellegrino V, Murphy D, Butt W. The meaning of a high plasma free haemoglobin: retrospective review of the prevalence of haemolysis and circuit thrombosis in an adult ECMO centre over 5 years. Perfusion 2016; 31 (03) 223-231
    CrossrefPubMedGoogle Scholar
  • 23 Lyu L, Yao J, Gao G. , et al. Incidence, risk factors, and outcomes of hyperbilirubinemia in adult cardiac patients supported by veno-arterial ECMO. Artif Organs 2018; 42 (02) 148-154
    CrossrefPubMedGoogle Scholar
  • 24 Kostousov V, Nguyen K, Hundalani SG, Teruya J. The influence of free hemoglobin and bilirubin on heparin monitoring by activated partial thromboplastin time and anti-Xa assay. Arch Pathol Lab Med 2014; 138 (11) 1503-1506
    CrossrefPubMedGoogle Scholar
  • 25 Khan J, Chandler WL. Interference in the anti-Xa heparin activity assay due to hemolysis and icterus during pediatric extracorporeal life support. Artif Organs 2019 ; doi: 10.1111/aor.13467 [Epub ahead of print]
    PubMedGoogle Scholar
  • 26 Lippi G, Plebani M, Favaloro EJ. Interference in coagulation testing: focus on spurious hemolysis, icterus, and lipemia. Semin Thromb Hemost 2013; 39 (03) 258-266
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Kon ZN, Dahi S, Evans CF. , et al. Class III obesity is not a contraindication to venovenous extracorporeal membrane oxygenation support. Ann Thorac Surg 2015; 100 (05) 1855-1860
    CrossrefPubMedGoogle Scholar
  • 28 McCaughan GJB, Favaloro EJ, Pasalic L, Curnow J. Anticoagulation at the extremes of body weight: choices and dosing. Expert Rev Hematol 2018; 11 (10) 817-828
    CrossrefPubMedGoogle Scholar
  • 29 Isherwood M, Murphy ML, Bingham AL, Siemianowski LA, Hunter K, Hollands JM. Evaluation of safety and effectiveness of standardized antifactor Xa-based unfractionated heparin protocols in obese versus non-obese patients. J Thromb Thrombolysis 2017; 43 (04) 476-483
    CrossrefPubMedGoogle Scholar
  • 30 Andrew M, Marzinotto V, Massicotte P. , et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35 (01) 78-83
    CrossrefPubMedGoogle Scholar
  • 31 Schechter T, Finkelstein Y, Ali M. , et al. Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti-factor Xa levels. J Thromb Haemost 2012; 10 (03) 368-374
    CrossrefPubMedGoogle Scholar
  • 32 Mazzeffi M, Tanaka K. Platelets and ECMO: should we worry about count, function, or both?. Intensive Care Med 2016; 42 (07) 1199-1200
    CrossrefPubMedGoogle Scholar
  • 33 Mazzeffi M, Greenwood J, Tanaka K. , et al. Bleeding, transfusion, and mortality on extracorporeal life support: ECLS working group on thrombosis and hemostasis. Ann Thorac Surg 2016; 101 (02) 682-689
    CrossrefPubMedGoogle Scholar
  • 34 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
    CrossrefPubMedGoogle Scholar
  • 35 Chung JH, Yeo HJ, Kim D. , et al. Changes in the levels of beta-thromboglobulin and inflammatory mediators during extracorporeal membrane oxygenation support. Int J Artif Organs 2017; 40 (10) 575-580
    CrossrefPubMedGoogle Scholar
  • 36 Tauber H, Streif W, Fritz J. , et al. Predicting transfusion requirements during extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth 2016; 30 (03) 692-701
    CrossrefPubMedGoogle Scholar
  • 37 Mutlak H, Reyher C, Meybohm P. , et al. Multiple electrode aggregometry for the assessment of acquired platelet dysfunctions during extracorporeal circulation. Thorac Cardiovasc Surg 2015; 63 (01) 21-27
    PubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Balle CM, Jeppesen AN, Christensen S, Hvas AM. Platelet function during extracorporeal membrane oxygenation in adult patients: a systematic review. Front Cardiovasc Med 2018; 5: 157
    Google Scholar
  • 40 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
    CrossrefPubMedGoogle Scholar
  • 41 Riley JB, Schears GJ, Nuttall GA, Oliver Jr WC, Ereth MH, Dearani JA. Coagulation parameter thresholds associated with non-bleeding in the eighth hour of adult cardiac surgical post-cardiotomy extracorporeal membrane oxygenation. J Extra Corpor Technol 2016; 48 (02) 71-78
    Google Scholar
  • 42 Acharya P, Jakobleff WA, Forest SJ. , et al. Fibrinogen albumin ratio and ischemic stroke during venoarterial extracorporeal membrane oxygenation. ASAIO J 2020; 66 (03) 277-282
    CrossrefPubMedGoogle Scholar
  • 43 Ranucci M, Baryshnikova E, Crapelli GB, Rahe-Meyer N, Menicanti L, Frigiola A. ; Surgical Clinical Outcome REsearch (SCORE) Group. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc 2015; 4 (06) e002066
    PubMedGoogle Scholar
  • 44 Niebler RA, Parker H, Hoffman GM. Impact of anticoagulation and circuit technology on complications during extracorporeal membrane oxygenation. ASAIO J 2019; 65 (03) 270-276
    CrossrefPubMedGoogle Scholar
  • 45 Delmas C, Jacquemin A, Vardon-Bounes F. , et al. Anticoagulation monitoring under ECMO support: a comparative study between the activated coagulation time and the anti-Xa activity assay. J Intensive Care Med 2018; 1: 885066618776937
    PubMedGoogle Scholar
  • 46 Leuquier L, Annich G, I'Brahim O. , et al. ELSO Anticoagulation Guideline 2014. Ann Arbor, MI: The Extracorporeal Life Support Organization (ELSO); 2014
    Google Scholar
  • 47 Baluwala I, Favaloro EJ, Pasalic L. Therapeutic monitoring of unfractionated heparin - trials and tribulations. Expert Rev Hematol 2017; 10 (07) 595-605
    CrossrefPubMedGoogle Scholar
  • 48 Holbrook A, Schulman S, Witt DM. , et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e152S-e184S
    CrossrefPubMedGoogle Scholar
  • 49 Favaloro EJ, Bonar R, Aboud M. , et al; RCPA QAP in Haematology. How useful is the monitoring of (low molecular weight) heparin therapy by anti-Xa assay? A laboratory perspective. Lab Hematol 2005; 11 (03) 157-162
    CrossrefPubMedGoogle Scholar
  • 50 Brogan TV, Lequier L, Lorusso R, MacLaren G, Peek G. , eds. Extracorporeal Life Support: The ELSO Red Book, 5th ed. ELSO; 2017
    Google Scholar
  • 51 Ryerson LM, Lequier LL. Anticoagulation management and monitoring during pediatric extracorporeal life support: a review of current issues. Front Pediatr 2016; 4: 67
    PubMedGoogle Scholar
  • 52 Kuhle S, Eulmesekian P, Kavanagh B. , et al. Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children. Haematologica 2007; 92 (04) 554-557
    CrossrefPubMedGoogle Scholar
  • 53 Ojito JW, Hannan RL, Burgos MM. , et al. Comparison of point-of-care activated clotting time systems utilized in a single pediatric institution. J Extra Corpor Technol 2012; 44 (01) 15-20
    PubMedGoogle Scholar
  • 54 Sarode K, Hussain SS, Tyroch A, Mukherjee D. A review of the current role of blood clotting analyzers in clinical practice. Cardiovasc Hematol Disord Drug Targets 2017; 17 (03) 167-179
    PubMedGoogle Scholar
  • 55 Ranucci M, Di Dedda U, Baryshnikova E. Platelet contribution to clot strength in thromboelastometry: count, function, or both?. Platelets 2020; 31 (01) 88-93
    CrossrefPubMedGoogle Scholar
  • 56 Anderson L, Quasim I, Steven M. , et al. Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelastography and rotational thromboelastometry. J Cardiothorac Vasc Anesth 2014; 28 (06) 1550-1557
    CrossrefPubMedGoogle Scholar
  • 57 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
    CrossrefPubMedGoogle Scholar
  • 58 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
    CrossrefPubMedGoogle Scholar
  • 59 Henderson N, Sullivan JE, Myers J. , et al. Use of thromboelastography to predict thrombotic complications in pediatric and neonatal extracorporeal membraneous oxygenation. J Extra Corpor Technol 2018; 50 (03) 149-154
    CrossrefPubMedGoogle Scholar
  • 60 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
    CrossrefPubMedGoogle Scholar
  • 61 Kessel AD, Kline M, Zinger M, McLaughlin D, Silver P, Sweberg TM. The impact and statistical analysis of a multifaceted anticoagulation strategy in children supported on ECMO: performance and pitfalls. J Intensive Care Med 2017; 32 (01) 59-67
    CrossrefPubMedGoogle Scholar
  • 62 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
    CrossrefPubMedGoogle Scholar
  • 63 Panigada M, Iapichino G, L'Acqua C. , et al. Prevalence of “flat-line” thromboelastography during extracorporeal membrane oxygenation for respiratory failure in adults. ASAIO J 2016; 62 (03) 302-309
    CrossrefPubMedGoogle Scholar
  • 64 Panigada M, Artoni A, Passamonti SM. , et al. Hemostasis changes during veno-venous extracorporeal membrane oxygenation for respiratory support in adults. Minerva Anestesiol 2016; 82 (02) 170-179
    PubMedGoogle Scholar
  • 65 Gilman EA, Koch CD, Santrach PJ, Schears GJ, Karon BS. Fresh and citrated whole-blood specimens can produce different thromboelastography results in patients on extracorporeal membrane oxygenation. Am J Clin Pathol 2013; 140 (02) 165-169
    CrossrefPubMedGoogle Scholar
  • 66 Bembea MM, Schwartz JM, Shah N. , et al. Anticoagulation monitoring during pediatric extracorporeal membrane oxygenation. ASAIO J 2013; 59 (01) 63-68
    CrossrefPubMedGoogle Scholar
  • 67 Khaja WA, Bilen O, Lukner RB, Edwards R, Teruya J. Evaluation of heparin assay for coagulation management in newborns undergoing ECMO. Am J Clin Pathol 2010; 134 (06) 950-954
    CrossrefPubMedGoogle Scholar
  • 68 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
    CrossrefPubMedGoogle Scholar
  • 69 Stammers AH, Willett L, Fristoe L. , et al. Coagulation monitoring during extracorporeal membrane oxygenation: the role of thrombelastography. J Extra Corpor Technol 1995; 27 (03) 137-145
    PubMedGoogle Scholar