Stanislav Bondarenko, Masahiro Hasegawa, Valentyna Maltseva, Olexandr Vysotskyi, Yale Fillingham.
Response/Recommendation: Activated partial thromboplastin time (aPTT) and prothrombin time (PT) can be used to monitor the activity of unfractionated heparin and vitamin K antagonists respectively. Neither the aPTT nor the international normalized ratio (INR) can be reliably used to monitor the activity of factor Xa inhibitors. The application of chromogenic anti-Xa assays is reliable for assessing the activity of factor Xa inhibitors in serum or plasma. No therapeutic ranges of anti-Xa assays are available, either for prevention or for therapy.
Strength of Recommendation: Limited.
Rationale: Rivaroxaban, apixaban, edoxaban, and fondaparinux are direct inhibitors of factor Xa and are recommended for patients after hip or knee arthroplasty (THA or TKA) for the prevention of venous thromboembolism (VTE)1,2. According to International Council for Standardization in Haematology (ICSH) recommendations, the range of peak concentration in blood of each drug is established to achieve a therapeutic effect in the case of VTE prophylaxis3. However, it is necessary to take into account the peculiarities of the dosage in the case of VTE prophylaxis after THA or TKA3. Monitoring of the effectiveness of factor Xa inhibitors is usually not required after administration. However, situations that require an assessment of the blood levels of these drugs may arise. In particular, rivaroxaban and apixaban may cause clinically significant bleeding when given after THA or TKA4,5. The search for the most optimal test for monitoring the effect of factor Xa inhibitors continues.
There is a qualitative and quantitative assessment of factor Xa inhibitors in the blood. However, a qualitative assessment PT; aPPT; thromboelastography, and rotational thromboelastography are not reliable for monitoring rivaroxaban, apixaban, edoxaban due to the complexity of standardization related to the large number of reagent variants used and the variability of results among patients3. This is also demonstrated by studies involving patients after orthopedic interventions6,7.
Several studies have identified a relationship between the concentration of factor Xa inhibitors in the blood and coagulometric measurements. The concentrations of rivaroxaban8,9 and apixaban8 in the blood of patients after THA or TKA directly depend on the results of the thrombin generation test. At the same time, according to research by Samama et al., thrombin generation test results can vary greatly in each patient (n = 106) after THA or TKA and rivaroxaban administration10. Mani et al., found that in 47 patients after major orthopedic surgery 12 hours after administration of rivaroxaban the PT and aPTT values did not differ from those before the administration of the drug, and also they did not reveal the effect of rivaroxaban on thrombin time11. Mueck et al., found a relationship between blood concentration of rivaroxaban and PT (in seconds) in 1,181 patients after THA during treatment12. Rivaroxaban and apixaban have different effects on the coagulometric measurements of patients after THA and TKA. Freyburger et al., found that rivaroxaban resulted in a higher increase of antithrombin levels, aPTT, PT and D-dimer compared to apixaban6. Also, rivaroxaban more pronouncedly reduced the concentration of thrombin (thrombin generation test) than apixaban6,8. Fuji et al., showed the dependence of the blood concentration of edoxaban in 264 patients after THA on PT, INR, and aPTT13. Hasegawa et al., also found the effect of edoxaban on increasing the peak time of aPTT waveform in 99 patients after orthopedic surgery14. Kodato et al., found that in the case of the development of deep venous thrombosis (DVT) in patients with edoxaban administration after TKA (n = 286), the INR is lower on the third postoperative day than in patients without DVT15.
Quantification of the activity of rivaroxaban, apixaban, and edoxaban in the serum or plasma is preferred16,17. This includes liquid chromatography-mass spectrometry/mass spectrometry, drug-calibrated clot-based, and chromogenic anti-Xa assays3. Mass spectrometry is the standard for determining the concentration (ng/ml) of factor Xa inhibitors in the blood, while chromogenic anti-Xa assays are clinically more accessible, although they require calibration for a specific drug3. In the case of low drug levels (<30 ng/ml), the sensitivity of the specifically calibrated chromogenic anti-Xa assays is reduced3,6. At the same time, the ex vivo concentration of rivaroxaban is more accurately determined as compared to apixaban18. Also, the exaggerated result of the chromogenic anti-Xa assay can be influenced by body weight less than 50kg and renal failure, as shown by Delavenne et al., in 809 patients with VTE prophylaxis with fondaparinux after major orthopedic surgeries19.
The use of different types of anti-Xa assay can give different results. Ikejiri et al., measured anti-Xa activities using 3 different chromogenic anti-Xa assays in 200 patients who underwent THA or TKA and were treated with edoxaban for the prophylaxis of DVT. The anti-Xa activities were significantly higher in the patients without DVT than in those with DVT on Day 4. There were no significant differences in the anti-Xa activities between patients with and without massive bleeding on Days 1, 4, 8, and 1520. Ikejiri et al., also found differences in anti-Xa activity when comparing three anti-Xa assays in 99 patients after THA or TKA after taking fondaparinux, but there was a similar increase in anti-Xa activity over 15 days21. No differences were found in anti-Xa activity in patients with and without DVT21. 98 orthopedic patients including those receiving THA or TKA were treated with fondaparinux for prophylaxis of DVT. Anti-Xa activity using chromogenic anti-Xa assay gradually increased from days 1 to 8 and showed no significant differences between patients with and without DVT22. Yukizawa et al., also showed no differences in anti-Xa activity (after 1, 3, 7, and 14 days) in 85 patients with and without DVT taking fondaparinux after THA23. Reinecke et al., found no relationship between blood rivaroxaban levels and the occurrence of VTE in a model for predicting VTE in patients after THA or TKA, based on data from 12,729 patients from phase 3 RECORD1-4 studies24.
Different factor Xa inhibitors have different effects on coagulometric measurements and different types of anti- Xa assays. As a result, in selected cases in which assessment of their activity is deemed helpful, it is necessary to select a blood test method specific for the Xa inhibitor that the patient is taking. Further research may help standardize the methodology for evaluating the efficacy of factor Xa inhibitors in patients requiring VTE prophylaxis.
1. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in Orthopedic Surgery Patients. Chest. 2012;141(2 Suppl):e278S-e325S. doi:10.1378/chest.11-2404
2. McRae HL, Militello L, Refaai MA. Updates in Anticoagulation Therapy Monitoring. Biomedicines. 2021;9(3). doi:10.3390/biomedicines9030262
3. Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost. 2018;118(3):437-450. doi:10.1055/s-0038-1627480
4. Highcock AJ, As-Sultany M, Finley R, Donnachie NJ. A Prospective Cohort Comparative Study of Rivaroxaban, Dabigatran, and Apixaban Oral Thromboprophylaxis in 2431 Hip and Knee Arthroplasty Patients: Primary Efficacy Outcomes and Safety Profile. J Arthroplasty. 2020;35(11):3093-3098. doi:10.1016/j.arth.2020.06.032
5. van der Veen L, Segers M, van Raay JJ, et al. Bleeding complications of thromboprophylaxis with dabigatran, nadroparin or rivaroxaban for 6 weeks after total knee arthroplasty surgery: a randomised pilot study. BMJ Open. 2021;11(1):e040336. doi:10.1136/bmjopen-2020-040336
6. Freyburger G, Macouillard G, Khennoufa K, Labrouche S, Molimard M, Sztark F. Rivaroxaban and apixaban in orthopaedics: is there a difference in their plasma concentrations and anticoagulant effects? Blood Coagul Fibrinolysis. 2015;26(8):925-933. doi:10.1097/MBC.0000000000000371
7. Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: Two observational studies in patients undergoing total hip or total knee replacement. Thromb Res. 2011;127(5):457-465. doi:10.1016/j.thromres.2011.01.001
8. Helin TA, Virtanen L, Manninen M, et al. Effects of thromboprophylactic doses of apixaban and rivaroxaban on coagulation and thrombin generation in association with total hip replacement. J Thromb Thrombolysis. 2017;43(4):562-569. doi:10.1007/s11239-017-1492-2
9. Green L, Lawrie AS, Patel S, et al. The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation. Br J Haematol. 2010;151(5):469-476. doi:10.1111/j.1365-2141.2010.08433.x
10. Samama MM, Guinet C, Le Flem L, Ninin E, Debue J-M. Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients, who have undergone major orthopedic surgery: an observational study. J Thromb Thrombolysis. 2013;35(2):140-146. doi:10.1007/s11239-012-0803-x
11. Mani H, Hesse C, Stratmann G, Lindhoff-Last E. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Haemost. 2011;106(1):156-164. doi:10.1160/TH10-10-0667
12. Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008;100(3):453-461.
13. Fuji T, Wang C-J, Fujita S, Kawai Y, Kimura T, Tachibana S. Safety and efficacy of edoxaban, an oral factor xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan. J Arthroplasty. 2014;29(12):2439-2446. doi:10.1016/j.arth.2014.05.029
14. Hasegawa M, Wada H, Tone S, et al. Monitoring of hemostatic abnormalities in major orthopedic surgery patients treated with edoxaban by APTT waveform. Int J Lab Hematol. 2018;40(1):49-55. doi:10.1111/ijlh.12727
15. Kodato K, Ishida K, Shibanuma N, et al. Prothrombin time-international normalized ratio is a useful marker for edoxaban efficacy in preventing venous thromboembolism after total knee arthroplasty. Eur J Orthop Surg Traumatol. 2018;28(1):103-108. doi:10.1007/s00590-017-2018-5
16. Douxfils J, Chatelain B, Chatelain C, Dogné J-M, Mullier F. Edoxaban: Impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost. 2016;115(2):368-381. doi:10.1160/TH15-05-0415
17. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review. Chest. 2017;151(1):127-138. doi:10.1016/j.chest.2016.08.1462
18. Ebner M, Birschmann I, Peter A, et al. Limitations of Specific Coagulation Tests for Direct Oral Anticoagulants: A Critical Analysis. J Am Heart Assoc. 2018;7(19):e009807. doi:10.1161/JAHA.118.009807
19. Delavenne X, Zufferey P, Baylot D, et al. Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice. Thromb Haemost. 2010;104(2):252-260. doi:10.1160/TH10-02-0127
20. Ikejiri M, Wada H, Tone S, et al. Comparison of three different anti-Xa assays in major orthopedic surgery patients treated with direct oral anticoagulant. Thromb J. 2017;15:27. doi:10.1186/s12959-017-0150-4
21. Ikejiri M, Wada H, Yamaguchi T, et al. Comparison of three different anti-Xa assays in major orthopedic surgery patients treated with fondaparinux. Int J Hematol. 2016;103(5):554-559. doi:10.1007/s12185-016-1963-9
22. Yoshida K, Wada H, Hasegawa M, et al. Monitoring for anti-Xa activity for prophylactic administration of Fondaparinux in patients with artificial joint replacement. Int J Hematol. 2011;94(4):355-360. doi:10.1007/s12185-011-0933-5
23. Yukizawa Y, Inaba Y, Watanabe S-I, et al. Plasma accumulation of fondaparinux 2.5 mg in patients after total hip arthroplasty. J Thromb Thrombolysis. 2012;34(4):526-532. doi:10.1007/s11239-012-0773-z
24. Reinecke I, Solms A, Willmann S, et al. Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the prevention of venous thromboembolism. J Thromb Thrombolysis. 2020;50(1):12-19. doi:10.1007/s11239-020-02078-8