Thromb Haemost 2007; 98(01): 234-242
DOI: 10.1160/TH06-10-0607
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Monitoring direct thrombin inhibitors with a plasma diluted thrombin time

Jason E. Love
1   Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
,
Chris Ferrell
1   Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
,
Wayne L. Chandler
1   Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
› Author Affiliations
Further Information

Publication History

Received 26 October 2006

Accepted after resubmission 08 April 2007

Publication Date:
29 November 2017 (online)

Summary

Activated partial thromboplastin time (aPTT) monitoring of direct thrombin inhibitors (DTIs) is vulnerable to interference from many sources. If the baseline aPTT is prolonged, as occurs with lupus inhibitors, alternative methods are required to monitor DTI levels. We compared the plasma diluted thrombin time (1:4 dilution of patient plasma with normal plasma) and the aPTT in patient samples spiked with argatroban, bivalirudin, or lepirudin at three concentration levels. Each drug was spiked into five samples with lupus inhibitors, five samples with deficient vitamin K-dependent factors, three samples with elevated D-dimers, and eight samples with normal baseline aPTT values. The aPTT overestimated the spiked DTI concentration in all samples with lupus inhibitors, low levels of vitamin K-dependent factors, and elevated D-dimers. In samples with normal baseline aPTTs, the aPTT failed to correctly estimate the spiked drug concentration in four of 24 samples spiked with argatroban, seven of 24 spiked with lepirudin, and three of 24 spiked with bivalirudin. The plasma diluted thrombin time was not affected by lupus inhibitors, low vitamin K-dependent factor levels or elevated D-dimer levels and correctly estimated the spiked drug level in 63 of 63 samples spiked with argatroban, 63 of 63 samples spiked with bivalirudin, and 62 of 63 samples spiked with lepirudin. In conclusion, the plasma diluted thrombin time appears to be a viable alternative to the aPTT for monitoring DTI levels, especially in patients with lupus inhibitors or low levels of vitamin K-dependent factors.

 
  • References

  • 1 Nutescu ED, Wittkowsky AK. Direct thrombin inhibitors for anticoagulation. Ann Pharmacother 2004; 38: 99-109.
  • 2 Srinivasan AF, Rice L, Bartholomew JR. et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164: 66-70.
  • 3 Dang CH, Durkalski VL, Nappi JM. Evaluation of treatment with direct thrombin inhibitors in patients with heparin-induced thrombocytopenia. Pharmaco-therapy 2006; 26: 461-468.
  • 4 Francis JL, Hursting JM. Effect of argatroban on the activated partial thromboplastin time: a comparison of 21 commercial reagents. Blood Coagul Fibrinolysis 2005; 16: 251-257.
  • 5 Fenyvesi T, Jorg I, Harenberg J. Monitoring of anticoagulant effects of direct thrombinin hibitors. Semin Thromb Hemost 2002; 28: 361-368.
  • 6 de Denus S, Spinler S. Clinical monitoring of direct thrombinin hibitors using the ecarin clottingtime. Pharmacotherapy 2002; 22: 433-435.
  • 7 Pendelton R, Wheeler M, Rodgers G. Argatroban dosing of patients with heparin-induced thrombocytopenia and an elevated aPTT due to antiphospholipid antibodysyndrome. Ann Pharmacother 2006; 40: 972-976.
  • 8 Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003; -2004 173-183.
  • 9 Warkentin TE. Bivalent direct thrombinin hibitors: hirudin and bivalirudin. Best Pract Res Clin Haematol 2004; 17: 105-125.
  • 10 Reid TJ, Alving BM. Aquantitative thrombin time for determining levels of hirudin and hirulog. Thromb Haemost 1993; 70: 608-616.
  • 11 Di Nisio M, Middeldorp S, Buller HR. Direct thrombinin hibitors. N Engl J Med 2005; 353: 1028-1040.
  • 12 Ahmad S, Ahsan A, Hoppensteadt DA. Clinical laboratory monitoring of a synthetic antithrombin agent, argatroban, using high performance liquid chromatography and functional methods. Int Angiol 1999; 18: 198-206.
  • 13 Harenberg J, Jorg I, Fenyvesi T. et al. Treatment of patients with a history of heparin-induced thrombocytopenia and anti-lepirudin antibodies with argatroban. J Thromb Thrombolysis 2005; 19: 65-69.
  • 14 Gosselin RC, King JH, Janatpour KA. et al. Comparing direct thrombin inhibitors using a PTT, ecarin clotting times, and thrombin inhibitor management testing. Ann Pharmacother 2004; 38: 1383-1388.
  • 15 Leo A, Winteroll S. Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring alternative anticoagulants. Clin Diagn Lab Immunol 2003; 10: 731-740.
  • 16 Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids. Semin Thromb Hemost 1996; 10: 197-202.