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DOI: 10.1055/s-0044-1786990
Pleiotropic Effects of Heparin and its Monitoring in the Clinical Practice
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).![](https://www.thieme-connect.de/media/sth/EFirst/lookinside/thumbnails/10-1055-s-0044-1786990_03230-1.jpg)
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 effectsAuthors' 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
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References
- 1 Bussey H, Francis JL. Heparin Consensus Group. Heparin overview and issues. Pharmacotherapy 2004; 24 (8 Pt 2): 103S-107S
- 2 Ludwig RJ. Therapeutic use of heparin beyond anticoagulation. Curr Drug Discov Technol 2009; 6 (04) 281-289
- 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
- 4 Lee MS, Kong J. Heparin: physiology, pharmacology, and clinical application. Rev Cardiovasc Med 2015; 16 (03) 189-199
- 5 Baytas SN, Linhardt RJ. Advances in the preparation and synthesis of heparin and related products. Drug Discov Today 2020; 25 (12) 2095-2109
- 6 McLEAN J. The discovery of heparin. Circulation 1959; 19 (01) 75-78
- 7 Oduah EI, Linhardt RJ, Sharfstein ST. Heparin: past, present, and future. Pharmaceuticals (Basel) 2016; 9 (03) 38
- 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
- 9 Fan BE, Favaloro EJ. Counting the carbon cost of heparin: an evolving tragedy of the commons?. Lancet Haematol 2022; 9 (07) e469-e471
- 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
- 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
- 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 Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: time for a fresh look. Thromb Haemost 2006; 96 (05) 547-552
- 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
- 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
- 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
- 17 Garon JE. Monitoring low molecular weight heparins. Clin Leadersh Manag Rev 2003; 17 (01) 47-50
- 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
- 19 Signorelli SS, Scuto S, Marino E, Giusti M, Xourafa A, Gaudio A. Anticoagulants and osteoporosis. Int J Mol Sci 2019; 20 (21) 5275
- 20 Hirsh J, Fuster V. American Heart Association. Guide to anticoagulant therapy. Part 1: Heparin. Circulation 1994; 89 (03) 1449-1468
- 21 Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin. Handb Exp Pharmacol 2012; (207) 43-61
- 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
- 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
- 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
- 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
- 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
- 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
- 28 Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res 2008; 122 (06) 743-752
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 62 Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29 (02) 125-130
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 74 Depasse F, Gilbert M, Goret V, Rolland N, Samama MM. Anti-Xa monitoring: inter-assay variability. Thromb Haemost 2000; 84 (06) 1122-1123
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 84 Horton S, Augustin S. Activated clotting time (ACT). Methods Mol Biol 2013; 992: 155-167
- 85 Kase PB, Dearing JP. Factors affecting the activated clotting time. J Extra Corpor Technol 1985; 17: 27-30
- 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
- 87 Arachchillage DJ, Crossette-Thambiah C, Laffan M. Lupus anticoagulant and cardiopulmonary bypass. Semin Thromb Hemost 2022; 48 (05) 628-630
- 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
- 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
- 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
- 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
- 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