Enhanced anticoagulant activity of enoxaparin in patients with ESRD as measured by thrombin generation time (original) (raw)

Abstract

Patients with renal dysfunction who undergo systemic anticoagulation with enoxaparin are at increased risk for bleeding. Although there is decreased renal clearance of enoxaparin in this population, the clinical utility of monitoring antifactor Xa activity is controversial because it is weakly correlated to bleeding. The goal of this study was to investigate the role of other novel anticoagulation markers, such as thrombin generation time, platelet contractile force, and clot elastic modulus, while controlling for antifactor Xa activity in patients with and without renal dysfunction. Thirty anticoagulant- and antiplatelet-naive subjects completed this trial (10 controls, 10 patients with chronic kidney disease, and 10 patients with end-stage renal disease [ESRD]). Blood samples were obtained and spiked ex vivo with increasing concentrations of enoxaparin antifactor Xa activity (0.25, 0.5, 1.0, and 3.0 IU/mL). Thrombin generation time, platelet contractile force, and clot elastic modulus were measured in each group at each antifactor Xa activity concentration. Subjects with ESRD had an approximately 50% greater anticoagulant effect, determined by thrombin generation time prolongation, than controls at antifactor Xa activity concentrations of 0.5 to 3.0 IU/mL. This may explain why subjects with ESRD with seemingly therapeutic antifactor Xa levels still experience adverse bleeding. There were no intergroup differences in platelet function, determined by platelet contractile force and clot elastic modulus. Antifactor Xa poorly predicts the degree of anticoagulation in patients with ESRD administered low-molecular-weight heparin (LMWH). Thrombin generation time may be a clinically useful anticoagulation monitoring tool to monitor LMWH therapy, especially in patients with renal dysfunction. Additional randomized prospective studies are needed to corroborate these findings.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (19)

  1. Spinler SA, Inverso SM, Cohen M, Goodman SG, Stringer KA, Antman EM: Safety and efficacy of unfraction- ated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: Analysis from the ESSENCE and TIMI 11B studies. ESSENCE and TIMI 11B Investigators. Am Heart J 146:33-41, 2003
  2. Gerlach AT, Pickworth KK, Seth SK, Tanna SB, Barnes JF: Enoxaparin and bleeding complications: A re- view in patients with and without renal insufficiency. Phar- macotherapy 20:771-775, 2000
  3. Cestac P, Bagheri H, Lapeyre-Mestre M, et al: Utilisa- tion and safety of low molecular weight heparins: Prospec- tive observational study in medical inpatients. Drug Saf 26:197-207, 2003
  4. Chow SL, Zammit K, West K, Dannenhoffer MA, Lopez-Candales A: Correlation of antifactor Xa concentra- tions with renal function in patients on enoxaparin. J Clin Pharmacol 43:586-590, 2003
  5. Cadroy Y, Pourrat J, Baladre M, et al: Delayed elimina- tion of enoxaparin in patients with chronic renal insuffi- ciency. Thromb Res 63:385-390, 1991
  6. Collett JP, Montalescot G, Choussat R, Lison L, Ankri A: Enoxaparin in unstable angina patients with renal failure. Int J Cardiol 80:81-82, 2001
  7. Sanderink J, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX: Pharmacokinetics and pharma- codynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 105:225-231, 2002
  8. Becker RC, Spencer FA, Gibson M, et al: Influence of patient characteristics and renal function on factor Xa inhibi- tion pharmacokinetics and pharmacodynamics after enoxapa- rin administration in non-ST-segment elevation acute coro- nary syndromes. Am Heart J 143:753-759, 2002
  9. Matthiasson SE, Lindblad B, Stjernquist U, Bergqvist D: The haemorrhagic effect of low molecular weight hepa- rins, dermatan sulphate and hirudin. Haemostasis 25:203- 211, 1995
  10. Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC: College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy. Arch Pathol Lab Med 122:799-807, 1998 11. Greaves M: Limitations of the laboratory monitoring of heparin therapy. Thromb Haemost 87:163-164, 2002 12. Harenberg J: Is laboratory monitoring of low- molecular weight heparin therapy necessary? Yes. J Thromb Haemost 2:547-550, 2004
  11. Bounameaux H, DeMoerloose P: Is laboratory moni- toring of low-molecular weight heparin therapy necessary? No. J Thromb Haemost 2:551-554, 2004
  12. Carr ME, Martin EJ, Kuhn JG, Spiess MD: Onset of force development as a marker of thrombin generation in whole blood: The thrombin generation time (TGT). J Thromb Haemost 1:1977-1983, 2003 15. Aledort LM: Why thrombin generation? From bench to bedside. Pathophysiol Haemost Thromb 33:2-3, 2003 16. Butenas S, van't Veer C, Mann KG: "Normal" throm- bin generation. Blood 94:2169-2178, 1999
  13. Carr ME: Development of platelet contractile force as a research and clinical measure of platelet function. Cell Biochem Biophys 38:55-78, 2003
  14. Krishnaswami A, Carr ME, Jesse RL, et al: Patients with coronary artery disease who present with chest pain have significantly elevated platelet contractile force and clot elastic modulus. Thromb Haemost 88:739-744, 2002
  15. Al-Obaidi MK, Philippou H, Stubbs PJ, et al: Relation- ships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes. Circulation 101:372- 377, 2000
  16. Carr ME, Martin EJ, Kuhn JG, Seremetis SV: Effects of recombinant factor VIIa on platelet function and clot structure in blood with deficient prothrombin conversion. Thromb Haemost 89:803-811, 2003
  17. Carr ME, Krishnaswami A, Martin EJ: Platelet con- tractile force (PCF) and clot elastic modulus (CEM) are elevated in diabetic patients with chest pain. Diabet Med 19:862-866, 2002
  18. Carr ME, Angchaisuksiri P, Carr SL, Martin EJ: Effect of non-heparin thrombin antagonists on thrombin generation, platelet function, and clot structure in whole blood. Cell Biochem Biophys 39:89-99, 2003
  19. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equa- tion. Ann Intern Med 130:461-470, 1999 24. Lovenox package insert. Bridgewater, NJ: Aventis Pharmaceuticals, 2003 25. Brophy DF, Wazny LD, Gehr TWB, Comstock TJ, Venitz J: The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease. Pharmacotherapy 21:169-174, 2001