FXa Inhibition and Coagulation Changes During DVT Prophylaxis by Enoxaparin Over the Course of a 15-Day Follow-Up in Septic Patients

Abstract

The objective of our study was to examine the changes in coagulation parameters and inflammatory reaction over the course of 15 days in patients with severe sepsis. We tried to identify mechanisms by which sepsis-induced pathophysiological changes may influence the effectiveness of subcutaneously (SC) administered enoxaparin 40 mg once daily.

A total of 16 patients (8 men, 8 women; age 35-83 years) meeting the inclusion criteria of severe sepsis were enrolled in this study. The follow-up was performed on days 1, 2, 3, 6, 9, 12, and 15 of hospitalization at the intensive care unit (ICU). Blood coagulation (activated partial thromboplastin time [aPTT], prothrombin time [PT], fibrinogen, antithrombin (AT), protein C [PC], D-dimer, fragment 1.2 [F1.2], factor Xa [FXa] inhibition) and inflammatory reactants (interleukin 6 [IL-6], C-reactive protein [CRP], orosomucoid, α-1-antitrypsin) were tested.

The mean FXa inhibition was 0.17 (±0.17) IU/mL. The arbitrarily established range of FXa inhibition for prophylaxis, 0.2 to 0.4 IU/mL, was reached in 22 cases (20%), while in 74 cases (68%), it was below and in 13 cases (12%) above the aforementioned range. Factor Xa inhibition positively correlated with AT (r = .42; P < .001) and PC (r = .45; P < .001) activities. A negative correlation was found between the FXa inhibition and α-1-antitrypsin concentrations (r = —.33; P = .01) but only in the subgroup with α-1-antitrypsin concentrations ≥2.2 g/L.

We confirmed that in most patients with sepsis, the prophylaxis with enoxaparin did not lead to the required FXa inhibition. The inhibition of FXa by enoxaparin depends mainly on the AT and PC activities.

Keywords

sepsis hemostasis low-molecular-weight heparin intensive care unit venous thromboembolism

References

Levi M. , ten Cate H. , van der Poll T. Endothelium: interface between coagulation and inflammation. Crit Care Med. 2002; 30(5 suppl):S220-S224.

Esmon CT , Fukudome K. , Mather T. , et al. Inflammation, sepsis, and coagulation. Haematologica . 1999;84(3):254-259.

Samama MM An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med. 2000;160(22):3415-3420.

Dellinger RP , Levy MM , Carlet JM , et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327.

Dorffler-Melly J. , de Jonge E. , Pont AC , et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet. 2002;359(9309):849-850.

Jochberger S. , Mayr V. , Luckner G. , et al. Antifactor Xa activity in critically ill patients receiving antithrombotic prophylaxis with standard dosages of certoparin: a prospective, clinical study. Crit Care. 2005;9(5):R541-R548.

Priglinger U. , Delle Karth G. , Geppert A. , et al. Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill? Crit Care Med. 2003;31(5):1405-1409.

Rommers MK , Van der Lely N. , Egberts TC , van den Bemt PM Anti-Xa activity after subcutaneous administration of dalteparin in ICU patients with and without subcutaneous oedema: a pilot study. Crit Care. 2006;10(3):R93.

Rutherford EJ , Schooler WG , Sredzienski E. , Abrams JE , Skeete DA Optimal dose of enoxaparin in critically ill trauma and surgical patients. J Trauma. 2005 ;58(6):1167-1170.

10.

De Paepe P. , Belpaire FM , Buylaert WA Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet. 2002;41(14):1135.

11.

Rabbat CG , Cook DJ , Crowther MA , et al. Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency. J Crit Care. 2005;20(4):357-363.

12.

Duhl AJ , Paidas MJ , Ural SH , et al, for the Pregnancy and Thrombosis Working Group. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol. 2007;197(5):457.e1-457.e21.

13.

Samama MM , Cohen AT , Darmon JY , et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341(11):793-800.

14.

Gruys E. , Toussaint MJ , Niewold TA , Koopmans SJ Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B. 2005; 6(11):1045-1056.

15.

Levy MM , Fink MP , Marshall JC , et al. 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 ;31(4):1250-1256.

16.

Dellinger RP , Carlet JM , Masur H. , et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3):858-873.

17.

Knaus WA , Draper EA , Wagner DP , Zimmerman JE Apache II : a severity of disease classification system. Crit Care Med . 1985;13(10):818-829.

18.

Clark LC , Thompson HL Determination of creatine and creatinine in urine. Anal Chem . 1949;21(10):1218-1221.

19.

Bland JM , Altman DG Correlation, regression, and repeated data. BMJ. 1994;308(6933):896.

20.

Bland JM , Altman DG Calculating correlation coefficients with repeated observations: part 1-correlation within subjects. BMJ. 1995;310(6977):446.

21.

Taylor FB Jr , Toh CH , Hoots WK , Wada H. , Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation . Thromb Haemost. 2001; 86(5):1327-1330.

22.

Hirsh J. , Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):188S-203S.

23.

Xiao H. , Siddiqui J. , Remick DG Mechanisms of mortality in early and late sepsis. Infect Immun . 2006;74(9):5227-5235.

24.

Kinasewitz GT , Yan SB , Basson B. , et al. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care. 2004;8(2):R82-R90.

25.

Biolo G. , Toigo G. , Ciocchi B. , et al. Metabolic response to injury and sepsis: changes in protein metabolism. Nutrition. 1997; 13(9 suppl):52S-57S.

26.

Briza J. , Kudrna K. , Kvasnicka J. , Busta O. , Trca T. Acute phase reaction in severe injuries [in Czech]. Sb Lek . 2002;103(2): 193-202.

27.

Young E. , Prins M. , Levine MN , Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance . Thromb Haemost. 1992;67(6):639-643.

28.

Desjardins L. , Bara L. , Boutitie F. , et al. Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study. Arch Pathol Lab Med. 2004 ;128(5):519-526.

29.

Freedman MD A bioavailability study in the proposed patient population-with much more needed now. Crit Care Med. 2003;31(5):1588-1589.

30.

Levine MN , Planes A. , Hirsh J. , Goodyear M. , Vochelle N. , Gent M. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost . 1989 ;62(3):940-944.