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Updates in Anticoagulation Therapy Monitoring

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Last updated:1st Feb 2022
Published:1st Feb 2022

Updates in Anticoagulation Therapy Monitoring

McRae H, Militello L, Refaai M. Biomedicines. 2021;9(3):262.

  • Recommendations for monitoring and reversal of newer anticoagulants such as low molecular weight heparins, factor Xa inhibitors, and direct thrombin inhibitors have evolved in recent years
  • The need for specific monitoring and reversal agents for these newer anticoagulants have created a knowledge and resource gap
  • Based on the publication by McRae et al. (2021), an overview of the currently available anticoagulants is provided, with a focus on the guidelines and available tests for monitoring and reversal

Anticoagulants are categorised according to their mechanism of action and include heparins, vitamin K antagonists, factor Xa inhibitors and direct thrombin inhibitors, as summarised in Table 11.

Clinical indications and monitoring guidelines for each anticoagulant vary due to differences in mechanism of action, clearance and reversal, drug half-life, therapeutic index and risk of adverse events1

Table 1. Anticoagulants categorised by mechanism of action (Adapted1). Creative Commons Attribution 4.0 International License.

* Fondaparinux, while technically a synthetic low molecular weight heparin, is considered an indirect factor Xa inhibitor.
Anticoagulation Category Medication Name Mechanism of Action Route of Administration
Vitamin K Antagonists Warfarin, Acenocoumarol, Phenprocoumon Inhibition of vitamin K epoxy reductase to decrease the synthesis of vitamin K-dependent coagulation factors Oral
Heparin (Unfractionated) Heparin Inhibition of thrombin and several activated coagulation factors (including Xa) by binding to and enhancing the activity of antithrombin III Intravenous or Subcutaneous paretneral injection
(Low Molecular Weight)
Enoxaparin, Dalteparin, Tinxaparin, Nadroparin Binds to antithrombin III and inhibits thrombin to a much lesser extent than unfractionated heparin; primarily inhibits factor Xa Subcutaneous parenteral injection
Factor Xa Inhibitors Fondaparinux *, Rivaroxaban, Apixaban, Edoxaban, Betrixaban Prevents the cleaving of prothrombin by factor Xa to form thrombin Fondaparinux- Subcutaneous parenteral injection

Rivaroxaban, apixban, edoxaban, betrixaban- Oral
Direct Thrombin Inhibitors Dabigatran, Bivalirudin, Argatroban Directly binds to and inhibit thrombin Dabigatran- Oral
Bivalirudin- Intravenous
Argatroban- Intravenous or Subcutaneous parenteral injection

Vitamin K antagonists

Vitamin K antagonists (VKAs) include warfarin, acenocoumarol and phenprocoumon and are the most commonly prescribed anticoagulants worldwide2. VKAs are orally administered, with dose and monitoring frequency being individually adjusted for each patient3.

VKA therapy is affordable, accessible, and easily reversed when compared to other anticoagulants4,5. However, with delayed onset of action (typically requiring 5–7 days to reach peak therapeutic effect) and variable half-life (40 hours on average, ranging from 20–60 hours), this class of drug can be unpredictable and requires close monitoring5,6.

A liver function test is recommended to identify potential issues with metabolism of VKA or baseline haemostatic issues before commencing VKA treatment7. Monitoring of VKA is done through measuring prothrombin time (PT) and international normalised ratio (INR).

To assess INR after VKA therapy has commenced, the baseline PT, activated partial thromboplastin times (aPTT), and INR values should be obtained to ensure proper calculation of the therapeutic target7. The therapeutic index of VKA is narrow, typically within an INR range of 2.0–3.0, though this may be higher with artificial heart valves or conditions such as antiphospholipid syndrome3.

INR measurements should be taken daily in hospitalised patients and 1–3 times a week for outpatients until the therapeutic dose has been attained and stabilised. Once INR has stabilised for at least 1 week, monitoring is required once every 2–4 weeks7.

Reversal of VKA is achieved through VKA discontinuation (or abruption), administration of vitamin K, fresh frozen plasma transfusion or infusion of prothrombin complex concentrates7,8.

Unfractionated heparin

Therapeutic dosing of unfractionated heparin (UFH) is achieved through intravenous (IV) administration of an initial bolus dose, followed by a weight-based or calculated, fixed-dose via continuous IV infusion, modified according to the bleeding risk of the patient7,9.

The historical gold standard for UFH monitoring is through serial aPTT measurements, taken within 2 hours of initiation and every 6 hours thereafter. The therapeutic range is 1.5–2.5 times the patient’s baseline aPTT score10–12.

UFH may also be monitored via anti-factor Xa (anti-Xa) activity, with this method demonstrating greater efficiency in achieving the target therapeutic dose. However, there is no evidence to suggest that this is associated with improved clinical outcomes, and aPTT measurements are still considered gold-standard13. Monitoring via anti-Xa is not feasible in patients with recent oral factor Xa inhibitor use, as these patients may have residual anti-Xa activity which can result in an incorrect reading7.

When administered through continuous IV infusion, the half-life of UFH is 30 minutes, compared to 90 minutes when injected subcutaneously. Reversal is achieved through administration of protamine sulphate, or discontinuation of UFH treatment due to its short half-life11.

Low molecular weight heparin

Multiple preparations of low molecular weight heparin (LMWH) are available worldwide, including enoxaparin, dalteparin, tinzaparin, and nadroparin. Each LMWH preparation is pharmacologically distinct, resulting in different efficacy and safety profiles7. LMWH is administered through parenteral subcutaneous injection, once or twice daily7,11.

When therapeutic monitoring is required for LMWH therapy, anti-Xa is the gold standard because aPTT is not significantly affected by LMWH treatment. Anti-Xa levels should be monitored at 4 hours post-administration, when they should be at peak concentration14,15.

LMWH is often preferred over UFH due to greater bioavailability and longer half-life (4 hours), resulting in a stronger anticoagulant response and less need for frequent monitoring7,11. These factors do make urgent reversal more difficult to achieve, and in this instance, protamine sulphate can be administered16.


Fondaparinux is administered through subcutaneous parenteral injection once daily, with dose calculated according to body weight and indication for use. This potent anticoagulant maintains 100% bioavailability after administration, and reaches peak concentration at 1.5–2 hours post-administration17,18 Therapeutic activity remains for 2–5 days in patients with normal renal function. Therapeutic monitoring is generally not required for this drug, however if levels must be acutely determined, anti-Xa measurements can be used19.

No reversal agents have been approved for fondaparinux, with protamine sulphate being ineffective for this purpose. In the instance of fondaparinux-induced haemorrhage, administration of recombinant activated factor VII has been shown to stop bleeding18.

Parenteral direct thrombin inhibitors

Direct thrombin inhibitors (DTIs) include bivalirudin and argatroban. Bivalriudin is frequently used in critically ill patients as an alternative to UFH treatment. DTIs have a half-life of 25–120 minutes depending on the route of administration20.

The most commonly used measurements to monitor DTI concentration are aPTT and activated clotting time (ACT). Alternative measures include thrombin time (TT), dilute thrombin time (dTT), chromogenic anti-IIa, and ecarin clotting time (ECT)21.

For aPTT monitoring in patients with heparin-induced thrombocytopenia, the target aPTT ranges for bivalirudin and argatroban are 1.5–3.0 and 1.5–2.5 times the baseline aPTT, respectively21.

No reversal agents are available for IV DTIs, although emerging evidence has shown administration of recombinant activated factor VII (FVIIa) to be beneficial for treatment of severe bleeding22.

Direct oral anticoagulants

The four direct oral anticoagulants (DOACs) approved for use in the USA and Europe include rivaroxaban, apixaban, edoxaban (all factor Xa inhibitors) and dabigatran (a DTI)23. Betrixaban is an additional factor Xa inhibitor which has only been approved in the USA24,25. DOACs are short-acting, orally administered, and some require twice-daily dosing26.

DOAC therapy usually does not require routine therapeutic monitoring or dose adjustment27. In instances where therapeutic monitoring is necessary, the gold standard for measurement is mass spectrometry calibrated for each individual drug. More rapid, less accurate measures that can be used include PT, aPTT, dTT, ecarin, and anti-Xa assays; however, these must also be calibrated to the individual DOAC being measured28.

Reversal of dabigatran can be achieved through administration of idarucizumab, and reversal of apixaban and rivaroxaban through andexanet alfa26.

-Due to differences in half-life, drug clearance and mechanism of action between anticoagulants, familiarity with the updated guidelines and gold standards of therapeutic monitoring and measurements are necessary.

-The most common tests for anticoagulant therapeutic monitoring include PT, aPTT and anti-Xa. Requirements for therapeutic monitoring vary according to the type of anticoagulant, due to individual drug characteristics such as half-life.

-Reversal is generally more straightforward for anticoagulants with short-half lives when compared to those with long-half lives; and reversal agents include protamine sulphate, prothrombin complex and recombinant activated factor VII.


  1. McRae H, Militello L, Refaai M. Updates in Anticoagulation Therapy Monitoring. Biomedicines. 2021;9(3).
  2. Ho KH, Van Hove M, Leng G. Trends in anticoagulant prescribing: a review of local policies in English primary care. BMC Health Serv Res. 2020;20(1).
  3. Alquwaizani M, Buckley L, Adams C, Fanikos J. Anticoagulants: A Review of the Pharmacology, Dosing, and Complications. Curr Emerg Hosp Med Rep. 2013;1(2):83–97.
  4. Burn J, Pirmohamed M. Direct oral anticoagulants versus warfarin: is new always better than the old? Open Hear. 2018;5(1).
  5. Patel S, Singh R, Preuss C V., Patel N. Warfarin. Hemost Thromb Third Ed. 2021;125–131.
  6. Boulanger L, Kim J, Friedman M, Hauch O, Foster T, Menzin J. Patterns of use of antithrombotic therapy and quality of anticoagulation among patients with non-valvular atrial fibrillation in clinical practice. Int J Clin Pract. 2006;60(3):258–264.
  7. Hull R, David A, Vazquez S, Tirnauer S. Warfarin and other VKAs: Dosing and adverse effects. 2020. Accessed 14 January 2022.
  8. Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257–3291.
  9. Bernardi E, Piccioli A, Zuin R, Girolami A, Prandoni P. Nomograms for the administration of unfractionated heparin in the initial treatment of acute thromboembolism-an overview. Thromb Haemost. 2000;84(1):22–6.
  10. Bussey H, Francis JL. Heparin overview and issues. Pharmacotherapy. 2004;24(8 Pt 2).
  11. Blann AD, Landray MJ, Lip GYH. ABC of antithrombotic therapy: An overview of antithrombotic therapy. BMJ. 2002;325(7367):762.
  12. Appert-Flory A, Fischer F, Jambou D, Buvat S, Mahagne M-H, Toulon P. Monitoring Unfractionated Heparin Treatments. Stability of Plasma Anti-Xa Activity up to 4 Hours in Citrated Tubes. Blood. 2019;134(Supplement_1):3403–3403.
  13. Coons JC, Iasella CJ, Thornberg M, Fitzmaurice MG, Goehring K, Jablonski L, et al. Clinical outcomes with unfractionated heparin monitored by anti-factor Xa vs. activated partial Thromboplastin time. Am J Hematol. 2019;94(9):1015–1019.
  14. Bounameaux H, De Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost. 2004;2(4):551–554.
  15. Egan G, Ensom MHH. Measuring Anti–Factor Xa Activity to Monitor Low-Molecular-Weight Heparin in Obesity: A Critical Review. Can J Hosp Pharm. 2015;68(1):33.
  16. Van Veen JJ, MacLean RM, Hampton KK, Laidlaw S, Kitchen S, Toth P, et al. Protamine reversal of low molecular weight heparin: clinically effective? Blood Coagul Fibrinolysis. 2011;22(7):565–570.
  17. Lassen MR, Bauer KA, Eriksson BI, Turpie AGG. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet (London, England). 2002;359(9319):1715–1720.
  18. Bijsterveld N, Moons A, Boekholdt S, van Aken B, Fennema H, Peters R, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550–2554.
  19. Johnson PN, Benefield EC, Bui P-YN, Gausman JN, Marlar RA, Gessouroun MR. Fondaparinux Monitoring: Need for a Local Fondaparinux-Calibrated Anti-F actor Xa Assay. J Pediatr Pharmacol Ther. 2013;18(4):318–319.
  20. Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011;72(4):581–592.
  21. Van Cott EM, Roberts AJ, Dager WE. Laboratory Monitoring of Parenteral Direct Thrombin Inhibitors. Semin Thromb Hemost. 2017;43(3):270–276.
  22. Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res. 2001;101(3):145–157.
  23. CHMP. Committee for Medicinal Products for Human Use (CHMP) Assessment report. 2020. Accessed 17 January 2022.
  24. Chen A, Stecker E, Warden BA. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. J Am Heart Assoc. 2020;9(13).
  25. Skelley JW, Thomason AR, Nolen JC. Betrixaban (Bevyxxa): A Direct-Acting Oral Anticoagulant Factor Xa Inhibitor. Pharm Ther. 2018;43(2):85.
  26. Gosselin RC, Adcock DM, Douxfils J. An update on laboratory assessment for direct oral anticoagulants (DOACs). Int J Lab Hematol. 2019;41 Suppl 1(S1):33–39.
  27. Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation: A Review. JAMA Cardiol. 2017;2(5):566–574.
  28. Adcock DM, Gosselin R. Direct Oral Anticoagulants (DOACs) in the Laboratory: 2015 Review. Thromb Res. 2015;136(1):7–12.