Monitoring of Unfractionated Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO

 

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Abstract

Objective Severe cases of coronavirus disease 2019 (COVID-19) can require continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO). Unfractionated heparin (UFH) to prevent circuit clotting is mandatory but monitoring is complicated by (pseudo)-heparin resistance. In this observational study, we compared two different activated partial thromboplastin time (aPTT) assays and a chromogenic anti-Xa assay in COVID-19 patients on CRRT or ECMO in relation to their UFH dosages and acute phase reactants.

Materials and Methods The aPTT (optical [aPTT-CS] and/or mechanical [aPTT-STA] clot detection methods were used), anti-Xa, factor VIII (FVIII), antithrombin III (ATIII), and fibrinogen were measured in 342 samples from 7 COVID-19 patients on CRRT or ECMO during their UFH treatment. Dosage of UFH was primarily based on the aPTT-CS with a heparin therapeutic range (HTR) of 50–80s. Associations between different variables were made using linear regression and Bland–Altman analysis.

Results Dosage of UFH was above 35,000IU/24 hours in all patients. aPTT-CS and aPTT-STA were predominantly within the HTR. Anti-Xa was predominantly above the HTR (0.3–0.7 IU/mL) and ATIII concentration was >70% for all patients; mean FVIII and fibrinogen were 606% and 7.5 g/L, respectively. aPTT-CS correlated with aPTT-STA (r ² = 0.68) with a bias of 39.3%. Correlation between aPTT and anti-Xa was better for aPTT-CS (0.78 ≤ r ² ≤ 0.94) than for aPTT-STA (0.34 ≤ r ² ≤ 0.81). There was no general correlation between the aPTT-CS and ATIII, FVIII, fibrinogen, thrombocytes, C-reactive protein, or ferritin.

Conclusion All included COVID-19 patients on CRRT or ECMO conformed to the definition of heparin resistance. A patient-specific association was found between aPTT and anti-Xa. This association could not be explained by FVIII or fibrinogen.

^* Equal contribution.

Publication History

Received: 09 September 2020

Accepted: 25 September 2020

Article published online:
19 November 2020

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Pravda NS, Pravda MS, Kornowski R, Orvin K. Extracorporeal membrane oxygenation therapy in the COVID-19 pandemic. Future Cardiol 2020
  MissingFormLabel

  Search in Google Scholar
• 2 Smereka J, Puslecki M, Ruetzler K. et al. Extracorporeal membrane oxygenation in COVID-19. Cardiol J 2020; 27 (02) 216-217
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 3 Jacobs JP, Stammers AH, St Louis J. et al. Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in COVID-19: experience with 32 patients. ASAIO J 2020
  MissingFormLabel

  Search in Google Scholar
• 4 Ziats NP, Pankowsky DA, Tierney BP, Ratnoff OD, Anderson JM. Adsorption of Hageman factor (factor XII) and other human plasma proteins to biomedical polymers. J Lab Clin Med 1990; 116 (05) 687-696
  MissingFormLabel

  PubMedSearch in Google Scholar
• 5 Despotis GJ, Avidan MS, Hogue Jr CW. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72 (05) S1821-S1831
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 6 Tsujimoto H, Tsujimoto Y, Nakata Y. et al. Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy. Cochrane Database Syst Rev 2020; 3: CD012467
  MissingFormLabel

  PubMedSearch in Google Scholar
• 7 Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost 2020; 18 (07) 1559-1561
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 8 Ranucci M, Ballotta A, Di Dedda U. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 2020; 18 (07) 1747-1751
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 9 Mulder M, Fawzy I, Lance M. ECMO and anticoagulation: a comprehensive review. Neth J Crit Care 2018; 26 (01) 6-13
  MissingFormLabel

  PubMedSearch in Google Scholar
• 10 Protti A, Iapichino GE, Di Nardo M, Panigada M, Gattinoni L. Anticoagulation management and antithrombin supplementation practice during veno-venous extracorporeal membrane oxygenation: a worldwide survey. Anesthesiology 2020; 132 (03) 562-570
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 11 Smythe MA, Priziola J, Dobesh PP, Wirth D, Cuker A, Wittkowsky AK. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016; 41 (01) 165-186
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 12 Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (02) e24S-e43S
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 13 Baglin T, Barrowcliffe TW, Cohen A, Greaves M. British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133 (01) 19-34
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 14 Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287 (07) 324-327
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 15 Bates SM, Weitz JI, Johnston M, Hirsh J, Ginsberg JS. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001; 161 (03) 385-391
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 16 Marlar RA, Clement B, Gausman J. Activated partial thromboplastin time monitoring of unfractionated heparin therapy: issues and recommendations. Semin Thromb Hemost 2017; 43 (03) 253-260
  MissingFormLabel

  Thieme ConnectPubMedSearch in Google Scholar
• 17 Marlar RA, Gausman JN. The effect of instrumentation and laboratory site on the accuracy of the APTT-based heparin therapeutic range. Int J Lab Hematol 2012; 34 (06) 614-620
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 18 Levine MN, Hirsh J, Gent M. et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994; 154 (01) 49-56
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 19 Thota R, Ganti AK, Subbiah S. Apparent heparin resistance in a patient with infective endocarditis secondary to elevated factor VIII levels. J Thromb Thrombolysis 2012; 34 (01) 132-134
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 20 Downie I, Liederman Z, Thiyagarajah K, Selby R, Lin Y. Pseudo heparin resistance caused by elevated factor VIII in a critically ill patient. Can J Anaesth 2019; 66 (08) 995-996
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 21 Durrani J, Malik F, Ali N, Jafri SIM. To be or not to be a case of heparin resistance. J Community Hosp Intern Med Perspect 2018; 8 (03) 145-148
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 22 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 23 Tas J, van Gassel RJJ, Heines SJH. et al. Serial measurements in COVID-19-induced acute respiratory disease to unravel heterogeneity of the disease course: design of the Maastricht Intensive Care COVID cohort (MaastrICCht). BMJ Open 2020; 10: e040175
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 24 Wang Y, Kang H, Liu X, Tong Z. Combination of RT-qPCR testing and clinical features for diagnosis of COVID-19 facilitates management of SARS-CoV-2 outbreak. J Med Virol 2020; 92 (06) 538-539
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 25 Thachil J, Tang N, Gando S. et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18 (05) 1023-1026
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 26 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 27 Klok FA, Kruip M, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020
  MissingFormLabel

  Search in Google Scholar
• 28 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res 2020; 191: 148-150
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 29 White D, MacDonald S, Bull T. et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis 2020; 50 (02) 287-291
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 30 Dutt T, Simcox D, Downey C. et al. Thromboprophylaxis in COVID-19: anti-FXa-the missing factor?. Am J Respir Crit Care Med 2020; 202 (03) 455-457
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 31 Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother 2011; 45 (7-8): 861-868
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 32 Samuel S, Allison TA, Sharaf S. et al. Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study. J Clin Pharm Ther 2016; 41 (05) 499-502
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 33 Mitsuguro M, Okamoto A, Shironouchi Y. et al. Effects of factor VIII levels on the APTT and anti-Xa activity under a therapeutic dose of heparin. Int J Hematol 2015; 101 (02) 119-125
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 34 Arachchillage DRJ, Kamani F, Deplano S, Banya W, Laffan M. Should we abandon the APTT for monitoring unfractionated heparin?. Thromb Res 2017; 157: 157-161
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 35 van Roessel S, Middeldorp S, Cheung YW, Zwinderman AH, de Pont AC. Accuracy of aPTT monitoring in critically ill patients treated with unfractionated heparin. Neth J Med 2014; 72 (06) 305-310
  MissingFormLabel

  PubMedSearch in Google Scholar
• 36 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 37 Uprichard J, Manning RA, Laffan MA. Monitoring heparin anticoagulation in the acute phase response. Br J Haematol 2010; 149 (04) 613-619
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 38 Guan WJ, Ni ZY, Hu Y. China Medical Treatment Expert Group for Covid-19. et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 39 Jenkins PV, Rawley O, Smith OP, O'Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157 (06) 653-663
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 40 Payne AB, Miller CH, Hooper WC, Lally C, Austin HD. High factor VIII, von Willebrand factor, and fibrinogen levels and risk of venous thromboembolism in blacks and whites. Ethn Dis 2014; 24 (02) 169-174
  MissingFormLabel

  PubMedSearch in Google Scholar
• 41 Rietveld IM, Lijfering WM, le Cessie S. et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019; 17 (01) 99-109
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 42 Ryan K, O'Donnell JS. Elevated plasma factor VIII levels in patients with venous thrombosis--constitutional risk factor or secondary epiphenomenon?. Thromb Res 2012; 129 (02) 105-106
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 43 Desborough MJR, Doyle AJ, Griffiths A, Retter A, Breen KA, Hunt BJ. Image-proven thromboembolism in patients with severe COVID-19 in a tertiary critical care unit in the United Kingdom. Thromb Res 2020; 193: 1-4
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 44 Barrett TJ, Lee A, Xia Y. et al. Biomarkers of platelet activity and vascular health associate with thrombosis and mortality in patients with COVID-19. Circ Res 2020
  MissingFormLabel

  Search in Google Scholar
• 45 Cassinelli G, Torri G, Naggi A. Non-anticoagulant heparins as heparanase inhibitors. Adv Exp Med Biol 2020; 1221: 493-522
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 46 Sanderson RD, Elkin M, Rapraeger AC, Ilan N, Vlodavsky I. Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy. FEBS J 2017; 284 (01) 42-55
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 47 Toh CH, Samis J, Downey C. et al. Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca(++)-dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel marker of impending disseminated intravascular coagulation. Blood 2002; 100 (07) 2522-2529
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 48 Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol 2020; 42 (Suppl. 01) 19-20
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 49 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
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar
• 50 Panigada M, Bottino N, Tagliabue P. et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020; 18 (07) 1738-1742
  MissingFormLabel

  CrossrefPubMedSearch in Google Scholar