Semin Thromb Hemost 2014; 40(01): 129-134
DOI: 10.1055/s-0033-1363462
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Determination of Direct Oral Anticoagulants from Human Serum Samples

Job Harenberg
1   Department of Clinical Pharmacology Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
,
Sandra Kraemer
1   Department of Clinical Pharmacology Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
,
Shanshan Du
1   Department of Clinical Pharmacology Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
,
Christina Giese
1   Department of Clinical Pharmacology Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
,
Astrid Schulze
2   Department of Orthopedic and Trauma Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
,
Roland Kraemer
3   Inorganic Chemistry Institute, University of Heidelberg, Heidelberg, Germany
,
Christel Weiss
4   Department of Biometry and Statistics, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
31. Dezember 2013 (online)

Abstract

Dabigatran, rivaroxaban, and apixaban are direct oral anticoagulants (DOAC) inhibiting thrombin or factor Xa and effectively preventing thromboembolic complications using fixed doses without need for laboratory-guided dose adjustment. Plasma samples are needed to determine the actual concentration or activity of DOACs, which may be required for special patient populations such as those with acute deterioration of renal function due to any disease, before surgical interventions, during bleeding or thrombotic episodes while on therapy with DOACs, the elderly and youngest populations, unexpected pregnancy, suspicion of overdose and toxication, and to control adherence to therapy. Serum samples have several advantages over plasma samples such as no need of sampling with a specific coagulation tube, reduced pre-analytical errors, and longer storage stability. Determination of rivaroxaban and apixaban from serum samples of patients on treatment performed well and better than samples of patients treated with dabigatran compared with plasma samples. Specific adaption to automated coagulation platforms may improve the performance of the assays from serum samples.

 
  • References

  • 1 Lippi G, Salvagno GL, Montagnana M, Lima-Oliveira G, Guidi GC, Favaloro EJ. Quality standards for sample collection in coagulation testing. Semin Thromb Hemost 2012; 38 (6) 565-575
  • 2 Juenke JM, Brown PI, Urry FM, Johnson-Davis KL, McMillin GA. Simultaneous UPLC-MS/MS assay for the detection of the traditional antipsychotics haloperidol, fluphenazine, perphenazine, and thiothixene in serum and plasma. Clin Chim Acta 2013; 423 (1) 32-34
  • 3 Wu AH, McKay C, Broussard LA , et al; National Academy of Clinical Biochemistry Laboratory Medicine. National academy of clinical biochemistry laboratory medicine practice guidelines: recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clin Chem 2003; 49 (3) 357-379
  • 4 Bush DM. The U.S. Mandatory Guidelines for Federal Workplace Drug Testing Programs: current status and future considerations. Forensic Sci Int 2008; 174 (2-3) 111-119
  • 5 Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin. Handbook Exp Pharmacol 2012; 207 (207) 43-61
  • 6 Fischer BE, Schlokat U, Himmelspach M, Dorner F. Binding of hirudin to meizothrombin. Protein Eng 1998; 11 (8) 715-721
  • 7 Hu ZY, Parker RB, Herring VL, Laizure SC. Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem 2013; 405 (5) 1695-1704
  • 8 Rohde G. Determination of rivaroxaban—a novel, oral, direct Factor Xa inhibitor—in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 872 (1-2): 43-50
  • 9 He K, Luettgen JM, Zhang D , et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet 2011; 36 (3) 129-139
  • 10 Harenberg J, Giese C, Marx S, Krämer R. Determination of dabigatran in human plasma samples. Semin Thromb Hemost 2012; 38 (1) 16-22
  • 11 Harenberg J, Marx S, Weiss C, Krämer R, Samama M, Schulman S ; Subcommittee on Control of Anticoagulation of the ISTH. Report of the Subcommittee of Control of Anticoagulation on the determination of the anticoagulant effects of rivaroxaban. J Thromb Haemost 2012; 10 (7) 1433-1436
  • 12 Harenberg J, Kraemer R. Direct thrombin inhibitors. International patent application No PCT/EP2012/002540. 2012
  • 13 Gray E, Harenberg J ; ISTH Control of Anticoagulation SSC Working Group on Thrombin Inhibitors. Collaborative study on monitoring methods to determine direct thrombin inhibitors lepirudin and argatroban. J Thromb Haemost 2005; 3 (9) 2096-2097
  • 14 Harenberg J, Kraemer R. Direct factor Xa inhibitors. International Patent Application PCT/EP2011/005586. 2011
  • 15 Marin SJ, Roberts M, Wood M, McMillin GA. Sensitive UPLC-MS-MS assay for 21 benzodiazepine drugs and metabolites, zolpidem and zopiclone in serum or plasma. J Anal Toxicol 2012; 36 (7) 472-476
  • 16 Couchman L, Birch M, Ireland R , et al. An automated method for the measurement of a range of tyrosine kinase inhibitors in human plasma or serum using turbulent flow liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 2012; 403 (6) 1685-1695
  • 17 Theurillat R, Sendi P, Thormann W. An MEKC assay for the therapeutic drug monitoring of cefepime. J Sep Sci 2013; 36 (17) 2915-2921
  • 18 Olives AI, González-Ruiz V, Martín MA. Isolation and quantitative methods for analysis of non-steroidal anti-inflammatory drugs. Antiinflamm Antiallergy Agents Med Chem 2012; 11 (1) 65-95
  • 19 Connolly SJ, Ezekowitz MD, Yusuf S , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
  • 20 Patel MR, Mahaffey KW, Garg J , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
  • 21 Granger CB, Alexander JH, McMurray JJ , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
  • 22 Liesenfeld KH, Schäfer HG, Trocóniz IF, Tillmann C, Eriksson BI, Stangier J. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62 (5) 527-537
  • 23 Clemens A, Haertter S, Friedman J , et al. Twice daily dosing of dabigatran for stroke prevention in atrial fibrillation: a pharmacokinetic justification. Curr Med Res Opin 2012; 28 (2) 195-201
  • 24 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
  • 25 Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50 (10) 675-686
  • 26 Tanigawa T, Kaneko M, Hashizume K , et al. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet 2013; 28 (1) 59-70
  • 27 Becker RC, Alexander JH, Newby LK , et al. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome. Thromb Haemost 2010; 104 (5) 976-983
  • 28 Harenberg J, Giese C, Marx S, Krämer R. Determination of dabigatran in human plasma samples. Semin Thromb Hemost 2012; 38 (1) 16-22
  • 29 Samama MM, Guinet C, Le Flem L, Ninin E, Debue JM. 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
  • 30 Hapgood G, Butler J, Malan E, Chunilal S, Tran H. The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the Hemoclot thrombin inhibitor assay in patient plasma samples. Thromb Haemost 2013; 110 (2) 308-315
  • 31 Harenberg J, Erdle S, Marx S, Krämer R. Determination of rivaroxaban in human plasma samples. Semin Thromb Hemost 2012; 38 (2) 178-184
  • 32 Douxfils J, Tamigniau A, Chatelain B , et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 2013; 110 (4) 723-731
  • 33 Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 2013; 11 (1) 10
  • 34 Frost C, Nepal S, Wang J , et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013; 76 (5) 776-786
  • 35 Mismetti P, Laporte S. New oral antithrombotics: a need for laboratory monitoring. For. J Thromb Haemost 2010; 8 (4) 621-626
  • 36 Harenberg J, Marx S, Erdle S, Krämer R. Determination of the anticoagulant effects of new oral anticoagulants: an unmet need. Expert Rev Hematol 2012; 5 (1) 107-113
  • 37 Nagler M, Bachmann LM, Alberio L , et al. Variability between laboratories performing coagulation tests with identical platforms: a nationwide evaluation study. Thromb J 2013; 11 (1) 6