Measuring Direct Oral Anticoagulants: Pharmacodynamic vs Pharmacokinetic Assays - A New Pharmacodynamic Assay
Main Article Content
Abstract
Direct oral anticoagulants need no routine monitoring, but measurement of drug levels or activity can be essential in emergent and selected situations. Pharmacokinetic assays measure drug concentration and pharmacodynamic assays measure drug activity on coagulation. However, drug effect on coagulation as measured by a pharmacodynamic assay does not always correlate with drug efficacy as measured by a pharmacokinetic assay. To measure antithrombotic effect, routinely available pharmacodynamic assays are too insensitive to reliably assess low levels of drug concentration where critical decisions need to be made, thus pharmacokinetic assays are used. For emergent situations, however, a readily available and rapid turnaround pharmacokinetic assay is not available. This review discusses the qualities and value of pharmacokinetic and pharmacodynamic assays, summarizes the various assays currently in use, and presents data on a recently developed, whole blood, point of care coagulometer that provides a pharmacodynamic assessment of blood coagulation with sensitivity to the direct oral anticoagulants.
Article Details
How to Cite
KIMMITT, Chad; SIEGAL, Deborah; ANSELL, Jack ,.
Measuring Direct Oral Anticoagulants: Pharmacodynamic vs Pharmacokinetic Assays - A New Pharmacodynamic Assay.
Medical Research Archives, [S.l.], v. 14, n. 1, feb. 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7245>. Date accessed: 03 feb. 2026.
doi: https://doi.org/10.18103/mra.v14i1.7245.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.
5. Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.
6. Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
7. Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory mon¬itor¬ing of non-vita¬min K antag¬onist oral anti¬co¬ag¬u¬lant use in patients with atrial fibril¬lation: a review JAMA Cardiol. 2017;2:566-574.
8. Gendron N, Billoir P, Siguret V, et al. Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants? Thromb Res. 2024;237:171-180.
9. Mithoowani S, Tan CW, Siegal DM. Measuring direct oral anticoagulant (DOAC) levels: Applications, limitations, and future directions. Int J Lab Hematol. 2025;22 Apr 2025. doi: 10.1111/ijlh.14483.
10. Mithoowani S, Bungard T, Castellucci L, et al. Multidisciplinary expert guidance for the management of severe bleeding on oral anticoagulation: An algorithm for practicing clinicians. Thromb Haemost. 2025;125:717-732.
11. Ebner M, Birschmann I, Peter A, et al. Emergency coagulation assessment during treatment with direct oral anticoagulants: Limitations and solutions. Stroke. 2017;48:2457-2463.
12. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–962.
13. Siegal DM, Freedman D, Ansell J. Urgent procedures or surgeries among patients receiving oral anticoagulants: A systematic literature review. J Thromb Thrombolys. 2023;55:197-202.
14. Douketis JD, Li Na, St. John M, et al. Perioperative management of direct oral anticoagulants in patients having a high bleed risk surgery or neuraxial procedure: the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE-2) pilot randomized trial. J Thromb Haemost. 2025;23:2226-2234.
15. McCabe JJ, Cheung Y, Foley M, et al. Residual risk of recurrent stroke despite anticoagulation in patients with atrial fibrillation: A systematic review and meta-analysis. . 2025:82:696-705.
16. Choi Y, Kim JS. Anticoagulation failure in stroke: Causes, risk factors, and treatment. J Stroke. 2025;27:195-206.
17. Probeck K, Elitharp D, Condon C, Casparis A, Labropoulos N. True failures of direct oral anticoagulants at a university medical center. J Vas Surg. 2022;10:561 (abst).
18. Seiffge DJ, De Marchis GM, Koga M, et al. Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation. Ann Neruol. 2020;87:677-687.
19. Meinel TR, Branca M, De Masrchis GM, et al. Prior anticoagulation in patients with ischemic stroke and atrial fibrillation. Ann Neurol. 2021;90:517.
20. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of Andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380:1326-1335.
21. Levy JH, Shaw JR, Castellucci LA, et al. Reversal of direct oral anticoagulant: guidance from the SSC of the ISTH. J Thromb Haemost. 2024;22:2889-2899.
22. Baker RM, Selby R, Moffat KA, et al. Investigating interassay variability between direct oral anticoagulant calibrated anti-factor Xa assays: a substudy of the perioperative anticoagulation use for surgery evaluation (PAUSE). Res Pract Thromb Haemost. 2025:9:e102899.
23. Ansell, J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. The pharmacology and management of the vitamin K antagonists: ACCP evidence-based clinical practice guidelines. . 2008;133:160S-198S.
24. Connors JM. Testing and monitoring direct oral anticoagulants. Blood.2018;132:2009-2015.
25. Testa S, Legnani C, Tripodi A, et al. Poor comparability of coagulation screening test with specific measurement in patients receiving direct oral anticoagulants: results from a multicenter/multiplatform study. J Thromb Haemost. 2016;14:2194-2201.
26. Shaw JR, Li N, Nixon J, et al. Coagulation assays and direct oral anticoagulant levels among patients having an elective surgery or procedure. J Thromb Haemost. 2022;20:2953-2963.
27. Van Edom CJ, Fiorelli F, Balthazar T, et al. Discrepancy between parallel anti-Xa and activated partial thromboplastin time is related to mortality in patients with Impella-supported cardiogenic shock. J Thromb Haemost. 2025;23:1810-1816.
28. Baker P, Platton S, Arachchillage DJ, et al.. Measurement of heparin, direct oral anticoagulants and other non-coumarin anticoagulants and their effects on haemostasis assays: A British Society for Haematology Guideline. Br J Haematol. 2024;205:1302-1318.
29. Kim PY, Yeh CH, Dale BJ, et al.. Mechanistic basis for the differential effects of rivaroxaban and apixaban on global tests of coagulation. TH Open 2018:2:e190-e201.
30. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI; Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14:623-7.
31. 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;151:127-138.
32. 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;118:437-450.
33. Sahli SD, Castellucci C, Roche TR, Rössler J, Spahn DR, Kaserer A. The impact of direct oral anticoagulant on viscoelastic testing – A systematic review. Front Cardiovasc Med. 2022;9:991675.
34. Qiao J, Tran MH. Challenges to laboratory monitoring of direct oral anticoagulants. Clin Appl Thromb/Hemost. 2024;30:1-14.
35. Depasse F, Binder NB, Mueller J, et al. Thrombin generation assays are versatile tools in blood coagulation analysis: A review of technical features, and applications from research to laboratory routine. J Thromb Haemost.2021;19:2907-2917.
36. Dirienzo L, Vitulli A, Mancazzo F, et al. Differential effect of direct oral anticoagulants on thrombin generation and fibrinolysis in patients with atrial fibrillation and venous thromboembolism. Blood Transfus. 2022;20:505-515.
37. Shaw JR, Castellucci LA, Siegal D, Carrier M. DOAC-associated bleeding, hemostatic strategies, and thrombin generation assays-a review of the literature. J Thromb Haemost. 2023;21:433-452.
38. Shaw JR, Li N, Grusse M, et al. Influence of direct oral anticoagulant levels and thrombin generation on postoperative bleeding [SONAR]: A nested case control study. Thromb Haemost. 2025;125:1226-1239.
39. Foulon-Pinto G, Lafuente-Lafuente C, Jourdi G, et al. Assessment of DOAC in Geriatrics (Adage Study): Rivaroxaban/Apixaban concentrations and thrombin generation profiles in NVAF very elderly patients. Thromb Haemost. 2023;123:402-414.
40. Zepeski AE, Faine BA, Merrill AE, Sutamtewagul G, Bhagavathi S. Utilization of anti-factor Xa levels to guide reversal of oral factor Xa inhibitors in the emergency department. Am J Health Syst Pharm. 2022;79:e20-e26.
41. Maier CL, Asbury WH, Duncan A, et al. Using an old test for new tricks: Measuring direct oral anti-Xa drug levels by conventional heparin-calibrated anti-Xa assay. Am J Hematol. 2019;94:e132-e134.
42. Ahn HS, Chae H, Kim Y, Lee HK, Kim H. Heparin-calibrated anti-Factor Xa assay for the measurement of direct anticoagulants such as apixaban, rivaroxaban, and edoxaban. Clin Lab. 2024;1:70.
43. Meihandoest T, Studt JD, Mendez A, et al. Accuracy of a single, heparin-calibrated anti-Xa assay for the measurement of rivaroxaban, apixaban, and edoxaban drug concentrations: A prospective cross-sectional study. Front Cardiovasc Med. 2022;9:817826.
44. Mithoowani S, Moffat KA, Gupta A, Carlino SA, Crowther MA. Low molecular weight heparin anti-Xa assays can identify patients with clinically important apixaban and rivaroxaban drug levels. Thromb Res. 2022;215:1-4.
45. Gosselin RC, Cuker A. Assessing direct oral anticoagulants in the clinical laboratory. Clin Lab Med. 2024;44:551-562.
46. Harenberg J, Beyer-Westendorf J, Crowther M, et al. Accuracy of a rapid diagnostic test for the presence of direct oral factor Xa or thrombin inhibitors in urine-A multicenter trial. Thromb Haemost. 2020;120:132-140.
47. Harenberg J, Gosselin RC, Cuker A, et al. Algorithm for rapid exclusion of clinically relevant plasma levels of direct oral anticoagulants in patients using the DOAC dipstick: An expert consensus paper. Thromb Haemost. 2024;124:770-777.
48. Kumar S, Lim E, Covic A, et al. Anticoagulation in concomitant chronic kidney disease and atrial fibrillation: JACC review topic of the week. J Am Coll Cardiol. 2019;74:2204-2215.
49. Ansell J, Zappe S, Jiang X, et al. A novel whole blood point-of-care coagulometer to measure the effect of direct oral anticoagulants and heparins. Semin Thromb Hemost. 2019;45:259-263.
50. Lee, R. I. & White, P. D. A clinical study of the coagulation time of blood. Am J Med Sci. 1913;145:496–503.
51. Spector I, Corn M. Control of heparin therapy with activated partial thromboplastin times. JAMA. 1967;201:75.
52. 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;287:324–7.
53. Bakhru SH, Jiang X, Chen L, et al. Validation of a whole blood coagulometer sensitive to the direct oral anticoagulants. Sci Rep. 2025;15:7355.
54. Bakhru SH, Jiang X, Chen L, et al. Measuring anticoagulation effect of DOACs using a novel point of care coagulometer. Euro Soc Emerg Med 2025;September:abstract
2. Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
3. Büller HR, Décousus H, Grosso MA. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415.
4. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.
5. Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.
6. Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
7. Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory mon¬itor¬ing of non-vita¬min K antag¬onist oral anti¬co¬ag¬u¬lant use in patients with atrial fibril¬lation: a review JAMA Cardiol. 2017;2:566-574.
8. Gendron N, Billoir P, Siguret V, et al. Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants? Thromb Res. 2024;237:171-180.
9. Mithoowani S, Tan CW, Siegal DM. Measuring direct oral anticoagulant (DOAC) levels: Applications, limitations, and future directions. Int J Lab Hematol. 2025;22 Apr 2025. doi: 10.1111/ijlh.14483.
10. Mithoowani S, Bungard T, Castellucci L, et al. Multidisciplinary expert guidance for the management of severe bleeding on oral anticoagulation: An algorithm for practicing clinicians. Thromb Haemost. 2025;125:717-732.
11. Ebner M, Birschmann I, Peter A, et al. Emergency coagulation assessment during treatment with direct oral anticoagulants: Limitations and solutions. Stroke. 2017;48:2457-2463.
12. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–962.
13. Siegal DM, Freedman D, Ansell J. Urgent procedures or surgeries among patients receiving oral anticoagulants: A systematic literature review. J Thromb Thrombolys. 2023;55:197-202.
14. Douketis JD, Li Na, St. John M, et al. Perioperative management of direct oral anticoagulants in patients having a high bleed risk surgery or neuraxial procedure: the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE-2) pilot randomized trial. J Thromb Haemost. 2025;23:2226-2234.
15. McCabe JJ, Cheung Y, Foley M, et al. Residual risk of recurrent stroke despite anticoagulation in patients with atrial fibrillation: A systematic review and meta-analysis. . 2025:82:696-705.
16. Choi Y, Kim JS. Anticoagulation failure in stroke: Causes, risk factors, and treatment. J Stroke. 2025;27:195-206.
17. Probeck K, Elitharp D, Condon C, Casparis A, Labropoulos N. True failures of direct oral anticoagulants at a university medical center. J Vas Surg. 2022;10:561 (abst).
18. Seiffge DJ, De Marchis GM, Koga M, et al. Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation. Ann Neruol. 2020;87:677-687.
19. Meinel TR, Branca M, De Masrchis GM, et al. Prior anticoagulation in patients with ischemic stroke and atrial fibrillation. Ann Neurol. 2021;90:517.
20. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of Andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380:1326-1335.
21. Levy JH, Shaw JR, Castellucci LA, et al. Reversal of direct oral anticoagulant: guidance from the SSC of the ISTH. J Thromb Haemost. 2024;22:2889-2899.
22. Baker RM, Selby R, Moffat KA, et al. Investigating interassay variability between direct oral anticoagulant calibrated anti-factor Xa assays: a substudy of the perioperative anticoagulation use for surgery evaluation (PAUSE). Res Pract Thromb Haemost. 2025:9:e102899.
23. Ansell, J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. The pharmacology and management of the vitamin K antagonists: ACCP evidence-based clinical practice guidelines. . 2008;133:160S-198S.
24. Connors JM. Testing and monitoring direct oral anticoagulants. Blood.2018;132:2009-2015.
25. Testa S, Legnani C, Tripodi A, et al. Poor comparability of coagulation screening test with specific measurement in patients receiving direct oral anticoagulants: results from a multicenter/multiplatform study. J Thromb Haemost. 2016;14:2194-2201.
26. Shaw JR, Li N, Nixon J, et al. Coagulation assays and direct oral anticoagulant levels among patients having an elective surgery or procedure. J Thromb Haemost. 2022;20:2953-2963.
27. Van Edom CJ, Fiorelli F, Balthazar T, et al. Discrepancy between parallel anti-Xa and activated partial thromboplastin time is related to mortality in patients with Impella-supported cardiogenic shock. J Thromb Haemost. 2025;23:1810-1816.
28. Baker P, Platton S, Arachchillage DJ, et al.. Measurement of heparin, direct oral anticoagulants and other non-coumarin anticoagulants and their effects on haemostasis assays: A British Society for Haematology Guideline. Br J Haematol. 2024;205:1302-1318.
29. Kim PY, Yeh CH, Dale BJ, et al.. Mechanistic basis for the differential effects of rivaroxaban and apixaban on global tests of coagulation. TH Open 2018:2:e190-e201.
30. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI; Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14:623-7.
31. 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;151:127-138.
32. 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;118:437-450.
33. Sahli SD, Castellucci C, Roche TR, Rössler J, Spahn DR, Kaserer A. The impact of direct oral anticoagulant on viscoelastic testing – A systematic review. Front Cardiovasc Med. 2022;9:991675.
34. Qiao J, Tran MH. Challenges to laboratory monitoring of direct oral anticoagulants. Clin Appl Thromb/Hemost. 2024;30:1-14.
35. Depasse F, Binder NB, Mueller J, et al. Thrombin generation assays are versatile tools in blood coagulation analysis: A review of technical features, and applications from research to laboratory routine. J Thromb Haemost.2021;19:2907-2917.
36. Dirienzo L, Vitulli A, Mancazzo F, et al. Differential effect of direct oral anticoagulants on thrombin generation and fibrinolysis in patients with atrial fibrillation and venous thromboembolism. Blood Transfus. 2022;20:505-515.
37. Shaw JR, Castellucci LA, Siegal D, Carrier M. DOAC-associated bleeding, hemostatic strategies, and thrombin generation assays-a review of the literature. J Thromb Haemost. 2023;21:433-452.
38. Shaw JR, Li N, Grusse M, et al. Influence of direct oral anticoagulant levels and thrombin generation on postoperative bleeding [SONAR]: A nested case control study. Thromb Haemost. 2025;125:1226-1239.
39. Foulon-Pinto G, Lafuente-Lafuente C, Jourdi G, et al. Assessment of DOAC in Geriatrics (Adage Study): Rivaroxaban/Apixaban concentrations and thrombin generation profiles in NVAF very elderly patients. Thromb Haemost. 2023;123:402-414.
40. Zepeski AE, Faine BA, Merrill AE, Sutamtewagul G, Bhagavathi S. Utilization of anti-factor Xa levels to guide reversal of oral factor Xa inhibitors in the emergency department. Am J Health Syst Pharm. 2022;79:e20-e26.
41. Maier CL, Asbury WH, Duncan A, et al. Using an old test for new tricks: Measuring direct oral anti-Xa drug levels by conventional heparin-calibrated anti-Xa assay. Am J Hematol. 2019;94:e132-e134.
42. Ahn HS, Chae H, Kim Y, Lee HK, Kim H. Heparin-calibrated anti-Factor Xa assay for the measurement of direct anticoagulants such as apixaban, rivaroxaban, and edoxaban. Clin Lab. 2024;1:70.
43. Meihandoest T, Studt JD, Mendez A, et al. Accuracy of a single, heparin-calibrated anti-Xa assay for the measurement of rivaroxaban, apixaban, and edoxaban drug concentrations: A prospective cross-sectional study. Front Cardiovasc Med. 2022;9:817826.
44. Mithoowani S, Moffat KA, Gupta A, Carlino SA, Crowther MA. Low molecular weight heparin anti-Xa assays can identify patients with clinically important apixaban and rivaroxaban drug levels. Thromb Res. 2022;215:1-4.
45. Gosselin RC, Cuker A. Assessing direct oral anticoagulants in the clinical laboratory. Clin Lab Med. 2024;44:551-562.
46. Harenberg J, Beyer-Westendorf J, Crowther M, et al. Accuracy of a rapid diagnostic test for the presence of direct oral factor Xa or thrombin inhibitors in urine-A multicenter trial. Thromb Haemost. 2020;120:132-140.
47. Harenberg J, Gosselin RC, Cuker A, et al. Algorithm for rapid exclusion of clinically relevant plasma levels of direct oral anticoagulants in patients using the DOAC dipstick: An expert consensus paper. Thromb Haemost. 2024;124:770-777.
48. Kumar S, Lim E, Covic A, et al. Anticoagulation in concomitant chronic kidney disease and atrial fibrillation: JACC review topic of the week. J Am Coll Cardiol. 2019;74:2204-2215.
49. Ansell J, Zappe S, Jiang X, et al. A novel whole blood point-of-care coagulometer to measure the effect of direct oral anticoagulants and heparins. Semin Thromb Hemost. 2019;45:259-263.
50. Lee, R. I. & White, P. D. A clinical study of the coagulation time of blood. Am J Med Sci. 1913;145:496–503.
51. Spector I, Corn M. Control of heparin therapy with activated partial thromboplastin times. JAMA. 1967;201:75.
52. 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;287:324–7.
53. Bakhru SH, Jiang X, Chen L, et al. Validation of a whole blood coagulometer sensitive to the direct oral anticoagulants. Sci Rep. 2025;15:7355.
54. Bakhru SH, Jiang X, Chen L, et al. Measuring anticoagulation effect of DOACs using a novel point of care coagulometer. Euro Soc Emerg Med 2025;September:abstract