Download PDF
CC BY 4.0 · Semin Thromb Hemost 2024; 50(08): 1153-1162
DOI: 10.1055/s-0044-1786990
Review Article

Pleiotropic Effects of Heparin and its Monitoring in the Clinical Practice

Deepa J. Arachchillage
1   Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
2   Department of Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom
,
Steve Kitchen
3   Department of Coagulation, Royal Hallamshire Hospital, Sheffield, United Kingdom
› Author Affiliations Funding This article is not funded by any external sources. However, D.J.A. is funded by Medical Research Council, United Kingdom (MR/V037633/1).
› Further Information
   Permissions and Reprints

Abstract

Unfractionated heparin (UFH) was uncovered in 1916, has been used as an anticoagulant since 1935, and has been listed in the World Health Organization's Model List of Essential Medicines. Despite the availability of many other anticoagulants, the use of heparin (either low molecular weight heparin [LMWH] or UFH) is still substantial. Heparin has pleotropic effects including anticoagulant and several nonanticoagulant properties such as antiproliferative, anti-inflammatory activity, and anticomplement effects. Although UFH has been widely replaced by LMWH, UFH is still the preferred anticoagulant of choice for patients undergoing cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, and patients with high-risk mechanical cardiac valves requiring temporary bridging with a parenteral anticoagulant. UFH is a highly negatively charged molecule and binds many positively charged molecules, hence has unpredictable pharmacokinetics, and variable anticoagulant effect on an individual patient basis. Therefore, anticoagulant effects of UFH may not be proportional to the dose of UFH given to any individual patient. In this review, we discuss the anticoagulant and nonanticoagulant activities of UFH, differences between UFH and LMWH, when to use UFH, different methods of monitoring the anticoagulant effects of UFH (including activated partial thromboplastin time, heparin anti-Xa activity level, and activated clotting time), while discussing pros and cons related to each method and comparison of clinical outcomes in patients treated with UFH monitored with different methods based on available evidence.

Keywords

unfractionated heparin - activated partial thromboplastin time - heparin anti-Xa - activated clotting time - pleotropic effects

Authors' Contributions

D.J.A. designed the manuscript. Both D.J.A. and S.K. wrote, reviewed, and approved the final manuscript.




Publication History

Article published online:
29 May 2024

© 2024. 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/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Bussey H, Francis JL. Heparin Consensus Group. Heparin overview and issues. Pharmacotherapy 2004; 24 (8 Pt 2): 103S-107S
    CrossrefPubMedGoogle Scholar
  • 2 Ludwig RJ. Therapeutic use of heparin beyond anticoagulation. Curr Drug Discov Technol 2009; 6 (04) 281-289
    CrossrefPubMedGoogle Scholar
  • 3 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (1 Suppl) 64S-94S
    CrossrefPubMedGoogle Scholar
  • 4 Lee MS, Kong J. Heparin: physiology, pharmacology, and clinical application. Rev Cardiovasc Med 2015; 16 (03) 189-199
    CrossrefPubMedGoogle Scholar
  • 5 Baytas SN, Linhardt RJ. Advances in the preparation and synthesis of heparin and related products. Drug Discov Today 2020; 25 (12) 2095-2109
    CrossrefPubMedGoogle Scholar
  • 6 McLEAN J. The discovery of heparin. Circulation 1959; 19 (01) 75-78
    CrossrefPubMedGoogle Scholar
  • 7 Oduah EI, Linhardt RJ, Sharfstein ST. Heparin: past, present, and future. Pharmaceuticals (Basel) 2016; 9 (03) 38
    CrossrefPubMedGoogle Scholar
  • 8 World Health Organization. WHO Model List of Essential Medicines—22nd list, 2021. 2021 . Accessed on January 10, 2024 at: https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02
    PubMedGoogle Scholar
  • 9 Fan BE, Favaloro EJ. Counting the carbon cost of heparin: an evolving tragedy of the commons?. Lancet Haematol 2022; 9 (07) e469-e471
    CrossrefPubMedGoogle Scholar
  • 10 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
    CrossrefPubMedGoogle Scholar
  • 11 De Caterina R, Husted S, Wallentin L. et al; European Society of Cardiology Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 109 (05) 769-786
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 13 Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: time for a fresh look. Thromb Haemost 2006; 96 (05) 547-552
    PubMedGoogle Scholar
  • 14 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 (2 Suppl): e24S-e43S
    CrossrefPubMedGoogle Scholar
  • 15 Gouin-Thibaut I, Martin-Toutain I, Peynaud-Debayle E, Marion S, Napol P, Alhenc-Gelas M. AGEPS Hemostasis Group. Monitoring unfractionated heparin with APTT: a French collaborative study comparing sensitivity to heparin of 15 APTT reagents. Thromb Res 2012; 129 (05) 666-667
    CrossrefPubMedGoogle Scholar
  • 16 Davenport A. Review article: Low-molecular-weight heparin as an alternative anticoagulant to unfractionated heparin for routine outpatient haemodialysis treatments. Nephrology (Carlton) 2009; 14 (05) 455-461
    CrossrefPubMedGoogle Scholar
  • 17 Garon JE. Monitoring low molecular weight heparins. Clin Leadersh Manag Rev 2003; 17 (01) 47-50
    PubMedGoogle Scholar
  • 18 Kitchen S, Gray E, Mackie I, Baglin T, Makris M. BCSH committee. Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol 2014; 166 (06) 830-841
    CrossrefPubMedGoogle Scholar
  • 19 Signorelli SS, Scuto S, Marino E, Giusti M, Xourafa A, Gaudio A. Anticoagulants and osteoporosis. Int J Mol Sci 2019; 20 (21) 5275
    CrossrefPubMedGoogle Scholar
  • 20 Hirsh J, Fuster V. American Heart Association. Guide to anticoagulant therapy. Part 1: Heparin. Circulation 1994; 89 (03) 1449-1468
    CrossrefPubMedGoogle Scholar
  • 21 Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin. Handb Exp Pharmacol 2012; (207) 43-61
    CrossrefPubMedGoogle Scholar
  • 22 Khorana AA, Sahni A, Altland OD, Francis CW. Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arterioscler Thromb Vasc Biol 2003; 23 (11) 2110-2115
    CrossrefPubMedGoogle Scholar
  • 23 Marchetti M, Vignoli A, Russo L. et al. Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thromb Res 2008; 121 (05) 637-645
    CrossrefPubMedGoogle Scholar
  • 24 Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 2007; 110 (05) 1149-1161
    CrossrefPubMedGoogle Scholar
  • 25 Rosenberg RD, Bauer KA. The heparin-antithrombin system: a natural anticoagulant mechanism. Hemostasis and Thrombosis : Basic Principles and Clinical Practice. 3rd ed. . Edited by Colman RW, Hirsh J, Marder VJ, Salzman EW. Philadelphia, PA: JB Lippincott Co; 1994: 837-860
    Google Scholar
  • 26 Hirsh J, Anand SS, Halperin JL, Fuster V. American Heart Association. Guide to anticoagulant therapy: Heparin : a statement for healthcare professionals from the American Heart Association. Circulation 2001; 103 (24) 2994-3018
    CrossrefPubMedGoogle Scholar
  • 27 Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest 1998; 101 (04) 877-889
    CrossrefPubMedGoogle Scholar
  • 28 Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res 2008; 122 (06) 743-752
    CrossrefPubMedGoogle Scholar
  • 29 Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-inflammatory effects of heparin and its derivatives: a systematic review. Adv Pharmacol Sci 2015; 2015: 507151
    PubMedGoogle Scholar
  • 30 Nelson RM, Cecconi O, Roberts WG, Aruffo A, Linhardt RJ, Bevilacqua MP. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood 1993; 82 (11) 3253-3258
    CrossrefPubMedGoogle Scholar
  • 31 Kreimann M, Brandt S, Krauel K. et al. Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4. Blood 2014; 124 (15) 2442-2449
    CrossrefPubMedGoogle Scholar
  • 32 Johnson Z, Kosco-Vilbois MH, Herren S. et al. Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J Immunol 2004; 173 (09) 5776-5785
    CrossrefPubMedGoogle Scholar
  • 33 Young E, Podor TJ, Venner T, Hirsh J. Induction of the acute-phase reaction increases heparin-binding proteins in plasma. Arterioscler Thromb Vasc Biol 1997; 17 (08) 1568-1574
    CrossrefPubMedGoogle Scholar
  • 34 Zaferani A, Talsma D, Richter MKS. et al. Heparin/heparan sulphate interactions with complement–a possible target for reduction of renal function loss?. Nephrol Dial Transplant 2014; 29 (03) 515-522
    CrossrefPubMedGoogle Scholar
  • 35 Litov L, Petkov P, Rangelov M. et al. Molecular mechanism of the anti-inflammatory action of heparin. Int J Mol Sci 2021; 22 (19) 10730
    CrossrefPubMedGoogle Scholar
  • 36 Salas A, Sans M, Soriano A. et al. Heparin attenuates TNF-alpha induced inflammatory response through a CD11b dependent mechanism. Gut 2000; 47 (01) 88-96
    CrossrefPubMedGoogle Scholar
  • 37 Jafri M, Li L, Liang B, Luo M. The effect of heparin and other exogenous glycosaminoglycans (GAGs) in reducing IL-1β-induced pro-inflammatory cytokine IL-8 and IL-6 mRNA expression and the potential role for reducing inflammation. Pharmaceuticals (Basel) 2024; 17 (03) 371
    CrossrefPubMedGoogle Scholar
  • 38 Shi C, Wang C, Wang H. et al. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective cohort study. Clin Transl Sci 2020; 13 (06) 1087-1095
    CrossrefPubMedGoogle Scholar
  • 39 Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10 (11) 1222-1226
    CrossrefPubMedGoogle Scholar
  • 40 Samarkos M, Mylona E, Kapsimali V. The role of complement in the antiphospholipid syndrome: a novel mechanism for pregnancy morbidity. Semin Arthritis Rheum 2012; 42 (01) 66-69
    CrossrefPubMedGoogle Scholar
  • 41 Sanford D, Naidu A, Alizadeh N, Lazo-Langner A. The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. J Thromb Haemost 2014; 12 (07) 1076-1085
    CrossrefPubMedGoogle Scholar
  • 42 Fu S, Yu S, Wang L, Ma X, Li X. Unfractionated heparin improves the clinical efficacy in adult sepsis patients: a systematic review and meta-analysis. BMC Anesthesiol 2022; 22 (01) 28
    CrossrefPubMedGoogle Scholar
  • 43 Monreal M, Lafoz E, Olive A, del Rio L, Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994; 71 (01) 7-11
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Pettilä V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 1999; 96 (04) 275-282
    CrossrefPubMedGoogle Scholar
  • 45 Rajsic S, Breitkopf R, Jadzic D, Popovic Krneta M, Tauber H, Treml B. Anticoagulation strategies during extracorporeal membrane oxygenation: a narrative review. J Clin Med 2022; 11 (17) 5147
    CrossrefPubMedGoogle Scholar
  • 46 Burša F, Sklienka P, Frelich M, Jor O, Ekrtová T, Máca J. Anticoagulation management during extracorporeal membrane oxygenation-a mini-review. Medicina (Kaunas) 2022; 58 (12) 1783
    CrossrefPubMedGoogle Scholar
  • 47 Koopman MM, Prandoni P, Piovella F. et al; The Tasman Study Group. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334 (11) 682-687
    CrossrefPubMedGoogle Scholar
  • 48 Levine M, Gent M, Hirsh J. et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334 (11) 677-681
    CrossrefPubMedGoogle Scholar
  • 49 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996; 100 (03) 269-277
    CrossrefPubMedGoogle Scholar
  • 50 Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995; 155 (06) 601-607
    CrossrefPubMedGoogle Scholar
  • 51 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106 (08) 2710-2715
    CrossrefPubMedGoogle Scholar
  • 52 Junqueira DR, Zorzela LM, Perini E. Unfractionated heparin versus low molecular weight heparins for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev 2017; 4 (04) CD007557
    PubMedGoogle Scholar
  • 53 van den Besselaar AM, Meeuwisse-Braun J, Jansen-Grüter R, Bertina RM. Monitoring heparin therapy by the activated partial thromboplastin time–the effect of pre-analytical conditions. Thromb Haemost 1987; 57 (02) 226-231
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Gremillet M, Talon L, Lebreton A, Sinegre T. Monitoring heparin therapy: stability of two different anti-Xa assays using blood samples collected in citrate-containing and CTAD tubes. Thromb J 2023; 21 (01) 21
    CrossrefPubMedGoogle Scholar
  • 55 Kitchen S, Adcock DM, Dauer R. et al. International Council for Standardization in Haematology (ICSH) recommendations for processing of blood samples for coagulation testing. Int J Lab Hematol 2021; 43 (06) 1272-1283
    CrossrefPubMedGoogle Scholar
  • 56 Toulon P, Appert-Flory A, Fischer F, Buvat S, Jambou D, Mahagne MH. Monitoring unfractionated heparin therapy. 4 hour-stability of anti-Xa activity in unspun citrated tubes. Thromb Res 2020; 186: 7-12
    CrossrefPubMedGoogle Scholar
  • 57 Ray MJ. An artefact related to the ratio of sample volume to the blood collection vial size which effects the APTTs of specimens taken to monitor heparin therapy. Thromb Haemost 1991; 66 (03) 387-388
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Ray MJ, Carroll PA, Just SJ, Hawson GA. A low volume specimen container suitable for monitoring the aPTT of heparinized patients. Blood Coagul Fibrinolysis 1993; 4 (05) 805-807
    CrossrefPubMedGoogle Scholar
  • 59 Kitchen S, Adcock DM, Dauer R. et al. International Council for Standardisation in Haematology (ICSH) recommendations for collection of blood samples for coagulation testing. Int J Lab Hematol 2021; 43 (04) 571-580
    CrossrefPubMedGoogle Scholar
  • 60 Rasmussen KL, Philips M, Tripodi A, Goetze JP. Unexpected, isolated activated partial thromboplastin time prolongation: A practical mini-review. Eur J Haematol 2020; 104 (06) 519-525
    CrossrefPubMedGoogle Scholar
  • 61 Kamphuisen PW, Eikenboom JC, Vos HL. et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81 (05) 680-683
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29 (02) 125-130
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 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
    CrossrefPubMedGoogle Scholar
  • 64 Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh J. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993; 119 (02) 104-109
    CrossrefPubMedGoogle Scholar
  • 65 Kitchen S, Preston FE. The therapeutic range for heparin therapy: relationship between six activated partial thromboplastin time reagents and two heparin assays. Thromb Haemost 1996; 75 (05) 734-739
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6 Suppl): 141S-159S
    CrossrefPubMedGoogle Scholar
  • 67 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
    CrossrefPubMedGoogle Scholar
  • 68 Byun JH, Jang IS, Kim JW, Koh EH. Establishing the heparin therapeutic range using aPTT and anti-Xa measurements for monitoring unfractionated heparin therapy. Blood Res 2016; 51 (03) 171-174
    CrossrefPubMedGoogle Scholar
  • 69 Rosborough TK. Comparison of anti-factor Xa heparin activity and activated partial thromboplastin time in 2,773 plasma samples from unfractionated heparin-treated patients. Am J Clin Pathol 1997; 108 (06) 662-668
    CrossrefPubMedGoogle Scholar
  • 70 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
    PubMedGoogle Scholar
  • 71 Kitchen S, Jennings I, Woods TA, Preston FE. Wide variability in the sensitivity of APTT reagents for monitoring of heparin dosage. J Clin Pathol 1996; 49 (01) 10-14
    CrossrefPubMedGoogle Scholar
  • 72 Cuker A, Ptashkin B, Konkle BA. et al. Interlaboratory agreement in the monitoring of unfractionated heparin using the anti-factor Xa-correlated activated partial thromboplastin time. J Thromb Haemost 2009; 7 (01) 80-86
    CrossrefPubMedGoogle Scholar
  • 73 Favaloro EJ, Mohammed S, Vong R. et al. Verification of the ACL Top 50 Family (350, 550, and 750) for harmonization of routine coagulation assays in a large network of 60 laboratories. Am J Clin Pathol 2021; 156 (04) 661-678
    CrossrefPubMedGoogle Scholar
  • 74 Depasse F, Gilbert M, Goret V, Rolland N, Samama MM. Anti-Xa monitoring: inter-assay variability. Thromb Haemost 2000; 84 (06) 1122-1123
    PubMedGoogle Scholar
  • 75 Amiral J, Amiral C, Dunois C. Optimization of heparin monitoring with anti-FXa assays and the impact of dextran sulfate for measuring all drug activity. Biomedicines 2021; 9 (06) 700
    CrossrefPubMedGoogle Scholar
  • 76 Hollestelle MJ, van der Meer FJM, Meijer P. Quality performance for indirect Xa inhibitor monitoring in patients using international external quality data. Clin Chem Lab Med 2020; 58 (11) 1921-1930
    CrossrefPubMedGoogle Scholar
  • 77 Mouton C, Calderon J, Janvier G, Vergnes MC. Dextran sulfate included in factor Xa assay reagent overestimates heparin activity in patients after heparin reversal by protamine. Thromb Res 2003; 111 (4–5): 273-279
    CrossrefPubMedGoogle Scholar
  • 78 Hardy M, Cabo J, Deliège A. et al. Reassessment of dextran sulfate in anti-Xa assay for unfractionated heparin laboratory monitoring. Res Pract Thromb Haemost 2023; 7 (08) 102257
    CrossrefPubMedGoogle Scholar
  • 79 Whitman-Purves E, Coons JC, Miller T. et al. Performance of anti-factor Xa versus activated partial thromboplastin time for heparin monitoring using multiple nomograms. Clin Appl Thromb Hemost 2018; 24 (02) 310-316
    CrossrefPubMedGoogle Scholar
  • 80 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
    CrossrefPubMedGoogle Scholar
  • 81 Belk KW, Laposata M, Craver C. A comparison of red blood cell transfusion utilization between anti-activated factor X and activated partial thromboplastin monitoring in patients receiving unfractionated heparin. J Thromb Haemost 2016; 14 (11) 2148-2157
    CrossrefPubMedGoogle Scholar
  • 82 Swayngim R, Preslaski C, Burlew CC, Beyer J. Comparison of clinical outcomes using activated partial thromboplastin time versus antifactor-Xa for monitoring therapeutic unfractionated heparin: a systematic review and meta-analysis. Thromb Res 2021; 208: 18-25
    CrossrefPubMedGoogle Scholar
  • 83 Ranger A, Gaspar M, Elkhatteb A. et al. The heparin-von Willebrand factor interaction and conventional tests of haemostasis - the challenges in predicting bleeding in cardiopulmonary bypass. Br J Haematol 2021; 192 (06) 1073-1081
    CrossrefPubMedGoogle Scholar
  • 84 Horton S, Augustin S. Activated clotting time (ACT). Methods Mol Biol 2013; 992: 155-167
    CrossrefPubMedGoogle Scholar
  • 85 Kase PB, Dearing JP. Factors affecting the activated clotting time. J Extra Corpor Technol 1985; 17: 27-30
    CrossrefPubMedGoogle Scholar
  • 86 Suárez Cuenca J, Gayoso Diz P, Gude Sampedro F, Gómez Zincke JM, Rey Acuña H, Fontanillo Fontanillo MM. Method to calculate the protamine dose necessary for reversal of heparin as a function of activated clotting time in patients undergoing cardiac surgery. J Extra Corpor Technol 2013; 45 (04) 235-241
    CrossrefPubMedGoogle Scholar
  • 87 Arachchillage DJ, Crossette-Thambiah C, Laffan M. Lupus anticoagulant and cardiopulmonary bypass. Semin Thromb Hemost 2022; 48 (05) 628-630
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Ural K, Owen C. Pro: The Hepcon HMS should be used instead of traditional Activated Clotting Time (ACT) to dose heparin and protamine for cardiac surgery requiring cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2016; 30 (06) 1727-1729
    CrossrefPubMedGoogle Scholar
  • 89 Gilly G, Trusheim J. Con: The Hepcon HMS should not be used instead of traditional activated clotting time to dose heparin and protamine for cardiac surgery requiring cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2016; 30 (06) 1730-1732
    CrossrefPubMedGoogle Scholar
  • 90 Despotis GJ, Summerfield AL, Joist JH. et al. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 1994; 108 (06) 1076-1082
    CrossrefPubMedGoogle Scholar
  • 91 Raymond PD, Ray MJ, Callen SN, Marsh NA. Heparin monitoring during cardiac surgery. Part 1: Validation of whole-blood heparin concentration and activated clotting time. Perfusion 2003; 18 (05) 269-276
    CrossrefPubMedGoogle Scholar
  • 92 Despotis GJ, Joist JH, Hogue Jr CW. et al. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995; 110 (01) 46-54
    CrossrefPubMedGoogle Scholar