Efficacy and tolerance of selective and non-selective factor Xa inhibitors in the prevention of thrombosis in kidney disease in patients with systemic lupus erythematosus and antiphospholipid syndrome

The use of factor Xa inhibitors is justified in the therapy of thrombosis in antiphospholipid syndrome (APS) and active lupus nephritis (LN). To monitor the efficacy and safety of these drugs, plasma anti-Xa (aXa) activity is determined.

Objective: to assess the aXa activity of selective and non-selective factor Xa inhibitors in patients with systemic lupus erythematosus (SLE) and APS depending on how they affect the kidneys.

Patients and methods. Clinical and laboratory findings were prospectively analyzed in SLE and APS patients who long received low molecular weight heparins (LMWHs) and selective Xa inhibitors, such as fondaparinux and rivaroxaban. The investigation enrolled 70 patients (54 females and 16 males) aged 39 years (range, 31 to 43 years) with SLE (n=15 (21%)), primary APS (PAPS) (n=10 (14%)), and SLE + APS (n=45 (65%)).

Results. Kidney disease was diagnosed in 33 (47%) of the 70 patients. LN was detected in 15 (25%) of the 60 patients: 10 and 5 patients with SLE and SLE + APS, respectively. APS nephropathy (APSN) was manifested by elevated creatinine and urea levels with normal urine sediment and no history of glomerulonephritis and was observed in 18 (33%) of the 55 patients: in 16 with SLE + APS and 2 with PAPS. The therapeutic aXa range of 0.1—1.5 IU/ml was found in 43 (61%) of the 70 patients, low and high aXa activities were seen in 14 (20%) and 13 (19%) patients, respectively.

In patients with APSN, the creatinine clearance (CC) depended on aXa levels: the highest CC was noted in patients with aXa >1.5 IU/mL, the lowest CC was in those with aXa <0.9 IU/ mL (p=0.046). The levels of aXa above the therapeutic range were more common in patients taking fondaparinux (9 (31%) out of the 29 patients) than in those using nadroparin (2 (7%) out of the 29 patients) (odds ratio (OR) 1.92; 95% confidence interval (CI), 1.25—2.97; p=0.04). In the fondaparinux group, high aXa was more frequently observed in patients with high SLE activity (7 (47%) out of the 15 patients) than in those with moderate or mild SLE activity (none out of the 7 patients) (OR 1.88; 95% CI, 1.17—3.01; p=0.037) and was unassociated with LN. The highest aXa level with no signs of hemorrhage was 2.08 IU/mL.

Conclusion. The level of aXa is a qualitative laboratory marker for the efficacy and safety of LMWHs and fondaparinux. In patients with APS, the enhanced aXa activity of LMWHs and fondaparinux was associated with elevated CC and was not accompanied by hemorrhage. Fondaparinux is an effective and safe anticoagulant for the treatment and prevention of thrombosis in SLE and APS. The therapeutic window for aXa should be extended in these patients.

1. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x

2. Nasonov EL. Antifosfolipidnyi sindrom [Antiphospholipid syndrome]. Moscow: Litterra; 2004. 440 p.]

3. Bertolaccini ML, Amengual O, Andreoli L, et al. The 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014 Sep;13(9):917-30. doi: 10.1016/j.autrev.2014.05.001. Epub 2014 May 10.

4. Petri M. Update on anti-phospholipid antibodies in SLE: the Hopkins' Lupus Cohort. Lupus. 2010 Apr;19(4):419-23. doi: 10.1177/0961203309360541.

5. Tektonidou MG, Sotsiou F, Nakopoulou L, et al. Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum. 2004 Aug;50(8):2569-79. doi: 10.1002/art.20433

6. Seredavkina NV, Reshetnyak TM. The IX European forum on antiphospholipid antibodies. A Brief review. Nauchno-praktich-eskaya revmatologiya = Rheumatology Science and Practice. 2014;52(1):115-21. (In Russ.). doi: 10.14412/1995-4484-2014-115-121.

7. Решетняк ТМ. Лечение антифосфолипидного синдрома: современные стандарты. Тромбоз, гемостаз и реология. 2016; (1):11-20. [Reshetnyak TM. Тreatment of antiphospholipid syndrome: modern standards. Tromboz, gemostaz i reologiya. 2016; (1):11-20. (In Russ.)].

8. Tektonidou M. Renal involvement in the antiphospholipid syndrome (APS)-APS nephropathy. Clin Rev Allergy Immunol. 2009 Jun;36(2-3):131-40. doi: 10.1007/s12016-008- 8112-z.

9. Smythe MA, Priziola J, Dobesh PP, et al. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016 Jan;41(1):165-86. doi: 10.1007/s11239-015-1315-2.

10. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2): 288-91.

11. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5; 150(9):604-12. doi: 10.7326/0003-4819-150-9-200905050-00006

12. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004 Feb;15(2):241-50. doi: 10.1097/01.ASN.0000108969.21691.5D

13. Gerhardsson J, Sundelin B, Zickert A, et al. Histological antiphospholipid-associated nephropathy versus lupus nephritis in patients with systemic lupus erythematosus: an observational cross-sectional study with longitudinal follow-up. Arthritis Res Ther. 2015 Apr 27;17:109. doi: 10.1186/s13075-015-0614-5.

14. Group KDIGOKCW. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;(3):1 —150.

15. Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res. 2007;119(3): 385-8. Epub 2006 May 2. doi: 10.1016/j.thromres.2006.03.008

16. Farooq V, Hegarty J, Chandrasekar T, et al. Serious adverse incidents with the usage of low molecular weight heparins in patients with chronic kidney disease. Am J Kidney Dis. 2004 Mar;43(3):531-7. doi: 10.1053/j.ajkd.2003.11.012

17. Olie RH, Meertens NEL, Henskens YM, et al. Empirically reduced dosages of tinza-parin in patients with moderate-to-severe renal insufficiency lead to inadequate anti-Xa levels. Nephron. 2017;137(2):113-123. doi: 10.1159/000477474. Epub 2017 Jun 30.

18. Damamme A, Urien S, Borgel D, et al. Pharmacokinetics of enoxaparin after renal transplantation in pediatric patients. J Clin Pharmacol. 2018;58(12):1597-603. http://dx.doi.org/10.1002/jcph.1289

19. Green B, Greenwood M, Saltissi D, et al. Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes. Br J Clin Pharmacol. 2005 Mar;59(3):281-90.

20. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol. 2004 Dec;15(12): 3192-206. doi: 10.1097/01.ASN.0000145014.80714.35

21. Bu ller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003 Oct 30;349(18):1695-702. doi: 10.1056/NEJMoa035451

22. Turpie AG, Lensing AW, Fuji T, et al. Pharmacokinetic and clinical data supporting the use of fondaparinux 1.5 mg once daily in the prevention of venous thromboembolism in renally impaired patients. Blood Coagul Fibrinolysis. 2009 Mar;20(2):114-21. doi: 10.1097/MBC.0b013e328323da86.

23. Ageno W, Riva N, Noris P, et al. Safety and efficacy of low-dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study. J Thromb Haemost. 2012 Nov;10(11):2291-7. doi: 10.1111/j.1538-7836.2012.04908.x.

24. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e419S-e496S. doi: 10.1378/chest.11-2301

25. Eriksson BI, Lassen MR, Colwell CW Jr. Efficacy of fondaparinux for thromboprophylaxis in hip fracture patients. J Arthroplasty. 2004 Oct;19(7 Suppl 2):78-81. doi: 10.1016/j.arth.2004.06.012

26. Haase M, Bellomo R, Rocktaeschel J, et al. Use of fondaparinux (ARIXTRA) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II. Nephrol Dial Transplant. 2005 Feb;20(2):444-6. doi: 10.1093/ndt/gfh544

27. Sharathkumar AA, Crandall C, Lin JJ, et al. Treatment of thrombosis with fonda-parinux (Arixtra) in a patient with end-stage renal disease receiving hemodialysis therapy. JPediatrHematol Oncol. 2007 Aug;29(8): 581-4. doi: 10.1097/MPH.0b013e3181256ba5

28. Jain N, Reilly RF. Clinical pharmacology of oral anticoagulants in patients with kidney disease. Clin J Am Soc Nephrol. 2018 May 25. pii: CJN.02170218. doi: 10.2215/CJN.02170218. [Epub ahead of print]

29. Moore TJ. Optimal dosing of rivaroxaban is undefined. BMJ. 2016 Oct 18;355:i5549. doi: 10.1136/bmj.i5549.