Argatroban, bivalirudin, and lepirudin do not decrease clot propagation and strength as effectively as heparin-activated antithrombin in vitro.
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 microg/ml), bivalirudin (12, 20, 120 microg/ml), or lepirudin (3, 6, 10 microg/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 microg/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.
Nielsen
Vance G
VG
Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama 35249-6810, USA. vnielsen@uab.edu
Steenwyk
Brad L
BL
Gurley
William Q
WQ
Pereira
Sara J
SJ
Lell
William A
WA
Kirklin
James K
JK
D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002648:Child; D004305:Dose-Response Relationship, Drug; D017809:Fatal Outcome; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016027:Heart Transplantation; D006493:Heparin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006629:Hirudins / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides; D013916:Thrombelastography / Q000187:drug effects; D013921:Thrombocytopenia / Q000139:chemically induced; D017211:Treatment Failure; D014914:Whole Blood Coagulation Time
D000925:Anticoagulants; D000991:Antithrombins; D005343:Fibrinolytic Agents; D006629:Hirudins; D010446:Peptide Fragments; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; C031942:argatroban; C074619:bivalirudin; C083544:lepirudin