Semin Thromb Hemost 2004; 30(6): 683-695
DOI: 10.1055/s-2004-861511
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Monitoring the New Antithrombotic Drugs

Jeanine M. Walenga1 , 2 , Debra A. Hoppensteadt2
  • 1Professor, Loyola University Chicago, Maywood, Illinois
  • 2Departments of Thoracic and Cardiovascular Surgery and Pathology, Loyola University Chicago, Maywood, Illinois
Further Information

Publication History

Publication Date:
04 January 2005 (online)

ABSTRACT

Today there is a diverse group of anticoagulant and antithrombotic drugs available that includes warfarin derivatives, heparin, low-molecular-weight heparins, thrombin inhibitors, factor Xa inhibitors, and various antiplatelet agents. Many of these new drugs do not alter measurable blood coagulation parameters, yet they are effective antithrombotic agents through their actions on vascular endothelial cells and proteins. Thus, these new agents do not affect the traditional clot-based prothrombin time/International Normalized Ratio (PT/INR) and activated partial thromboplastin time (aPTT) tests, and monitoring and standardization require the development of new methods. In addition to clot-based assays, chromogenic assays, enzyme-linked immunosorbent assay (ELISA), high-performance liquid chromatography (HPLC), flow cytometry, and other techniques have been used to monitor these new drugs. On the other hand, some of the new antithrombotic drugs do affect the PT, aPTT, and activated clotting time (ACT); however, they behave differently from the warfarin derivatives and heparin. The traditionally used relationship of target time to clot values and INR to clinical effect cannot necessarily be transferred to the new drugs. Unfortunately, monitoring is not as simple as it was for warfarin and heparin. Although the new antithrombotic drugs have been approved for clinical use, assay systems for monitoring most of them are still in development or have not been clinically validated. This applies to each of the clinical settings targeted for prophylaxis, treatment, or interventional procedures (i.e., high- and low-dosing regimens typically require different monitoring methods). In addition to basic monitoring, other issues such as sensitivity of the drug to different laboratory monitoring reagents and instrumentation, drug combination monitoring, and patient-related factors that contribute to the variability of the results still need to be addressed.

REFERENCES

  • 1 Dalen JE, Hirsh J, Guyatt GH Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001 119(1 suppl): 1S-370S
  • 2 Walenga J M, Fareed J. Automation and quality control in the coagulation laboratory.  Clin Lab Med. 1994;  14 709-728
  • 3 Hirsh J, Dalen J E, Anderson D R et al.. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.  Chest. 2001;  119(1 suppl) 8S-21S
  • 4 Ansell J, Hirsh J, Dalen J et al.. Managing oral anticoagulant therapy.  Chest. 2001;  119(1 Suppl) 22S-38S
  • 5 Fairweather R B, Ansell J. van den Besselaar AMHP, et al. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of oral anticoagulant therapy.  Arch Pathol Lab Med. 1998;  122 768-781
  • 6 Hirsh J, Warkentin T E, Shaughnessy S G et al.. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.  Chest. 2001;  119(1 suppl) 64S-94S
  • 7 Olson J D, Arkin C F, Brandt J T et al.. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy.  Arch Pathol Lab Med. 1998;  122 782-798
  • 8 Laposata M, Green D, Van Cott E M et al.. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban.  Arch Pathol Lab Med. 1998;  122 799-807
  • 9 Walenga J, Fareed J, Messmore H L. Newer avenues in the monitoring of antithrombotic therapy: the role of automation.  Semin Thromb Hemost. 1983;  9 346-354
  • 10 Marmur J D, Anand S X, Bagga R S et al.. The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration.  J Am Coll Cardiol. 2003;  41 394-402
  • 11 Kereiakes D J, Grines C, Fry E et al.. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention.  J Invasive Cardiol. 2001;  13 272-278
  • 12 Walenga J M, Jeske W P, Samama M M et al.. Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent. Expert Opin Investig Drugs.  2002;  11 397-407
  • 13 Walenga J M, Hoppensteadt D A, Koza M et al.. Laboratory assays for the evaluation of recombinant hirudin.  Haemostasis. 1991;  21 49-63
  • 14 Lewis B E, Wallis D E, Berkowitz S D et al.. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation. 2001;  103 1838-1843
  • 15 Greinacher A, Volpel H, Janssens U et al.. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.  Circulation. 1999;  99 73-80
  • 16 Tobu M, Demir M, Iqbal O et al.. The irrelevance of international normalized ratio in the monitoring of anti-IIa and anti-Xa drugs. Thrombosis Haemostasis 2003 (suppl 1)(ISSN 1740-3340) (CD-ROM) 1994:
  • 17 Iqbal O, Ahmad S, Lewis B E et al.. Monitoring of argatroban in ARG310 study: potential recommendations for its use in interventional cardiology.  Clin Appl Thromb Hemost. 2002;  8 217-224
  • 18 Lewis B E, Matthai W H, Cohen M et al.. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia.  Catheter Cardiovasc Interv. 2002;  57 177-184
  • 19 Ahmad S, Ahsan A, Iqbal O et al.. Pharmacokinetics and pharmacodynamics of argatroban as studied by HPLC and functional methods: implications in the monitoring and dosage-optimizations in cardiovascular patients.  Clin Appl Thromb Hemost. 1998;  4 243-249
  • 20 Ahmad S, Ahsan A, George M et al.. Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications.  Clin Appl Thromb Hemost. 1999;  5 252-258
  • 21 Walenga J M, Fasanella A R, Iqbal O et al.. Coagulation laboratory testing in patients treated with argatroban.  Semin Thromb Hemost. 1999;  25(Suppl 1) 61-66
  • 22 Hursting M J, Zehnder J L, Joffrion J L et al.. The international normalized ratio during concurrent warfarin and argatroban anticoagulation: differential contributions of each agent and effects of the choice of thromboplastin used.  Clin Chem. 1999;  45 409-412
  • 23 Hoppensteadt D A, Kahn S, Fareed J. Factor X values as a means to assess the extent of oral anticoagulation in patients receiving antithrombin drugs.  Clin Chem. 1997;  43 1786-1788
  • 24 Sheth S B, DiCicco R A, Hursting M J et al.. Interpreting the international normalized ratio (INR) in individuals receiving argatroban and warfarin.  Thromb Haemost. 2001;  85 435-440
  • 25 Walenga J M, Jeske W P, Hoppensteadt D, Fareed J. Factor Xa inhibitors: today and beyond.  Curr Opin Investig Drugs. 2003;  4 272-281
  • 26 Walenga J M, Jeske W P, Hoppensteadt D, Kaiser B. Factor Xa inhibitors.  Curr Opin Cardiovasc Pulmon Renal Invest Drugs. 1999;  1 13-27
  • 27 Tobu M, Iqbal O, Hoppensteadt D A et al.. Effects of a synthetic factor Xa inhibitor (JTV-803) on various laboratory tests.  Clin Appl Thromb Hemost. 2002;  8 325-336
  • 28 Tobu M, Iqbal O, Ma Q et al.. Global anticoagulant effects of a synthetic anti-factor Xa inhibitor (DX-9065a): implications for interventional use.  Clin Appl Thromb Hemost. 2003;  9 1-17
  • 29 Patrono C, Coller B, Dalen J E et al.. Platelet-active drugs. The relationships among dose, effectiveness, and side effects.  Chest. 2001;  119 39S-63S
  • 30 Rand M L, Leung R. Packham MA. Platelet function assays.  Transfus Apheresis Sci. 2003;  28 307-317
  • 31 Kundu S K, Heilmann E J, Sio R, Garcia C, Ostgaard R A. Characterization of an in vitro platelet function analyzer, PFA-100.  Clin Appl Thromb Hemost. 1996;  2 241-249
  • 32 Wheeler G L, Braden G A, Steinhubl S R et al.. The Ultegra rapid platelet-function assay: comparison to standard platelet function assays in patients undergoing percutaneous coronary intervention with abciximab therapy.  Am Heart J. 2002;  143 602-611

 Dr.
Jeanine M Walenga

Cardiovascular Institute, Loyola University Medical Center

2160 S. First Avenue, Maywood, IL 60153

Email: jwaleng@lumc.edu

    >