Argatroban, Bivalirudin, and Lepirudin do not Decrease Clot Propagation and Strength as Effectively as Heparin-activated Antithrombin In Vitro

Vance G Nielsen, Brad L. Steenwyk, William Q. Gurley, Sara J. Pereira, William A. Lell, James K. Kirklin

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: Heparin-induced thrombocytopenia is a potentially limb- and life-threatening response to heparin exposure. Direct thrombin inhibitors (DTIs) have been reported to provide anti-coagulation for cardiopulmonary bypass; however, clot formation within the cardiopulmonary bypass circuit has been reported after the administration of DTIs. We present a case of thrombosis of the cardiopulmonary bypass circuit and, ultimately, death after argatroban administration. An in vitro thrombelastographic assessment of the effects of DTIs on clot kinetics was consequently performed to determine potential causes for this complication. Methods: Normal human plasma was unmodified or exposed to heparin (1, 2, 3 U/ml), argatroban (5, 10, 50 μg/ml), bivalirudin (12, 20, 120 μg/ml), or lepirudin (3, 6, 10 μg/ml) before activation with tissue factor/kaolin in a thrombelastograph. Clot initiation (R, reaction time), propagation (MTG, maximum thrombus generation), and strength (MG, maximum elastic modulus) were determined. Analysis of variance was performed, with p < 0.05 considered significant. Results: Compared with unmodified plasma, heparin significantly prolonged R and essentially reduced MTG and MG to the limits of detection in an activity-dependent fashion. In general, the DTIs tested prolonged R in a concentration-dependent fashion but did not diminish MTG or MG nearly as well as heparin. The only exception was 10 μg/ml lepirudin, which eliminated coagulation. Conclusions: DTIs demonstrated a significant prolongation of clot initiation but poor attenuation of propagation and strength. Further in vitro and clinical investigations to design a heparin-equivalent regimen to provide anti-coagulation for patients with heparin-induced thrombocytopenia are indicated.

Original languageEnglish (US)
Pages (from-to)653-663
Number of pages11
JournalJournal of Heart and Lung Transplantation
Volume25
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

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Antithrombins
Heparin
Thrombosis
Cardiopulmonary Bypass
Thrombocytopenia
Kaolin
Elastic Modulus
Thromboplastin
bivalirudin
argatroban
lepirudin
In Vitro Techniques
Limit of Detection
Analysis of Variance
Extremities

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Transplantation

Cite this

Argatroban, Bivalirudin, and Lepirudin do not Decrease Clot Propagation and Strength as Effectively as Heparin-activated Antithrombin In Vitro. / Nielsen, Vance G; Steenwyk, Brad L.; Gurley, William Q.; Pereira, Sara J.; Lell, William A.; Kirklin, James K.

In: Journal of Heart and Lung Transplantation, Vol. 25, No. 6, 06.2006, p. 653-663.

Research output: Contribution to journalArticle

Nielsen, Vance G ; Steenwyk, Brad L. ; Gurley, William Q. ; Pereira, Sara J. ; Lell, William A. ; Kirklin, James K. / Argatroban, Bivalirudin, and Lepirudin do not Decrease Clot Propagation and Strength as Effectively as Heparin-activated Antithrombin In Vitro. In: Journal of Heart and Lung Transplantation. 2006 ; Vol. 25, No. 6. pp. 653-663.
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abstract = "Background: Heparin-induced thrombocytopenia is a potentially limb- and life-threatening response to heparin exposure. Direct thrombin inhibitors (DTIs) have been reported to provide anti-coagulation for cardiopulmonary bypass; however, clot formation within the cardiopulmonary bypass circuit has been reported after the administration of DTIs. We present a case of thrombosis of the cardiopulmonary bypass circuit and, ultimately, death after argatroban administration. An in vitro thrombelastographic assessment of the effects of DTIs on clot kinetics was consequently performed to determine potential causes for this complication. Methods: Normal human plasma was unmodified or exposed to heparin (1, 2, 3 U/ml), argatroban (5, 10, 50 μg/ml), bivalirudin (12, 20, 120 μg/ml), or lepirudin (3, 6, 10 μg/ml) before activation with tissue factor/kaolin in a thrombelastograph. Clot initiation (R, reaction time), propagation (MTG, maximum thrombus generation), and strength (MG, maximum elastic modulus) were determined. Analysis of variance was performed, with p < 0.05 considered significant. Results: Compared with unmodified plasma, heparin significantly prolonged R and essentially reduced MTG and MG to the limits of detection in an activity-dependent fashion. In general, the DTIs tested prolonged R in a concentration-dependent fashion but did not diminish MTG or MG nearly as well as heparin. The only exception was 10 μg/ml lepirudin, which eliminated coagulation. Conclusions: DTIs demonstrated a significant prolongation of clot initiation but poor attenuation of propagation and strength. Further in vitro and clinical investigations to design a heparin-equivalent regimen to provide anti-coagulation for patients with heparin-induced thrombocytopenia are indicated.",
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T1 - Argatroban, Bivalirudin, and Lepirudin do not Decrease Clot Propagation and Strength as Effectively as Heparin-activated Antithrombin In Vitro

AU - Nielsen, Vance G

AU - Steenwyk, Brad L.

AU - Gurley, William Q.

AU - Pereira, Sara J.

AU - Lell, William A.

AU - Kirklin, James K.

PY - 2006/6

Y1 - 2006/6

N2 - Background: Heparin-induced thrombocytopenia is a potentially limb- and life-threatening response to heparin exposure. Direct thrombin inhibitors (DTIs) have been reported to provide anti-coagulation for cardiopulmonary bypass; however, clot formation within the cardiopulmonary bypass circuit has been reported after the administration of DTIs. We present a case of thrombosis of the cardiopulmonary bypass circuit and, ultimately, death after argatroban administration. An in vitro thrombelastographic assessment of the effects of DTIs on clot kinetics was consequently performed to determine potential causes for this complication. Methods: Normal human plasma was unmodified or exposed to heparin (1, 2, 3 U/ml), argatroban (5, 10, 50 μg/ml), bivalirudin (12, 20, 120 μg/ml), or lepirudin (3, 6, 10 μg/ml) before activation with tissue factor/kaolin in a thrombelastograph. Clot initiation (R, reaction time), propagation (MTG, maximum thrombus generation), and strength (MG, maximum elastic modulus) were determined. Analysis of variance was performed, with p < 0.05 considered significant. Results: Compared with unmodified plasma, heparin significantly prolonged R and essentially reduced MTG and MG to the limits of detection in an activity-dependent fashion. In general, the DTIs tested prolonged R in a concentration-dependent fashion but did not diminish MTG or MG nearly as well as heparin. The only exception was 10 μg/ml lepirudin, which eliminated coagulation. Conclusions: DTIs demonstrated a significant prolongation of clot initiation but poor attenuation of propagation and strength. Further in vitro and clinical investigations to design a heparin-equivalent regimen to provide anti-coagulation for patients with heparin-induced thrombocytopenia are indicated.

AB - Background: Heparin-induced thrombocytopenia is a potentially limb- and life-threatening response to heparin exposure. Direct thrombin inhibitors (DTIs) have been reported to provide anti-coagulation for cardiopulmonary bypass; however, clot formation within the cardiopulmonary bypass circuit has been reported after the administration of DTIs. We present a case of thrombosis of the cardiopulmonary bypass circuit and, ultimately, death after argatroban administration. An in vitro thrombelastographic assessment of the effects of DTIs on clot kinetics was consequently performed to determine potential causes for this complication. Methods: Normal human plasma was unmodified or exposed to heparin (1, 2, 3 U/ml), argatroban (5, 10, 50 μg/ml), bivalirudin (12, 20, 120 μg/ml), or lepirudin (3, 6, 10 μg/ml) before activation with tissue factor/kaolin in a thrombelastograph. Clot initiation (R, reaction time), propagation (MTG, maximum thrombus generation), and strength (MG, maximum elastic modulus) were determined. Analysis of variance was performed, with p < 0.05 considered significant. Results: Compared with unmodified plasma, heparin significantly prolonged R and essentially reduced MTG and MG to the limits of detection in an activity-dependent fashion. In general, the DTIs tested prolonged R in a concentration-dependent fashion but did not diminish MTG or MG nearly as well as heparin. The only exception was 10 μg/ml lepirudin, which eliminated coagulation. Conclusions: DTIs demonstrated a significant prolongation of clot initiation but poor attenuation of propagation and strength. Further in vitro and clinical investigations to design a heparin-equivalent regimen to provide anti-coagulation for patients with heparin-induced thrombocytopenia are indicated.

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