Anti-coagulants during Hemodialysis

1. Bancha Satirapoj, MD Division of Nephrology Department of Medicine Phramongkutklao Hospital and College of Medicine Anti-coagulants during Hemodialysis

2. Dialysis and Thrombosis • Kidney disease • Inflammation • Endothelial injury • Expression and activity of procoagulant factors • Dialysis process • Needle, blood line, blood flow • Platelet-platelet aggregation • Platelet-erythrocyte aggregation • Extrinsic and Intrinsic pathway activation

3. IXa VIIIa Ca2+ PL Xa Va Ca2+ PL Coagulation cascade Intrinsic pathway Extrinsic pathway 1 Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin** X Xa 50 IIa II Fibrin Fibrinogen *Rosenberg RD, et al. N Engl J Med 1999;340:1555–64. ** Wessler S, et al. ThromboDiathHaemorrh 1974;32:71–8. Clot

4. Intrinsic pathway Extrinsic pathway PKK: HMWK ↓ KK XII XIIa Leukocyte activation Tissue factor Dialyzer surface VIIIaVIII VIIa VII XI XIa IX Ixa X Prothrombin Fibrinogen Fibrin LMWH Ca2+ HEPARIN Xa DTI Ca2+ XIII XIIIa V Va Thrombin Ca2+ Ca2+ Fibrin clot Citrate Adapted from Shen JI, et al. Am J Kidney Dis. 2012; 60(3):473-486

5. ANTICOAGULATION IN HEMODIALYSIS PATIENTS

6. Anticoagulation with RRT • Prevent clotting of the filter and reduction in membrane permeability • Adequate RRT • Blood loss in the clotted filter

7. Unfractionated Heparin

8. Unfractionated Heparin • Sulfate polysaccharide • 45 saccharide units • MW 10-16 kDa • Most common anticoagulant used for long-term hemodialysis potential surface of heparin

9. Heparin action Stop the coagulation cascade and promoting anticoagulation

10. UFH activity • Half-lifeof UFH = 1 hour in patients with kidney failure • Half-life of UFH = 30 minutes in patients with normal kidney function

11. Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

12. Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

13. Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

14. Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

15. Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

16. Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

17. Monitor Anti-coagulations • No routinely measure anticoagulation parameters • Dialyzer clotting • Prolonged bleeding following dialysis • Monitoring with the activated partial thromboplastin time (aPTT)

18. Dialysis-specific factors: clotting • Low blood flow • High hematocrit • High ultrafiltration rate • Vascular access stenosis • Poor needle placement Anti-coagulant treatments

19. STANDARD ANTICOAGULATION • Heparin: pharmacodynamicmodeling • Using an initial bolus followed by a constant fixed infusion of heparin to maintain an activated clotting time (ACT) of 200 to 250 seconds • Normal = 90 to 140 seconds

20. Improved dialyzer reuse after use of a population pharmacodynamicmodel to determine heparin doses • Dialyzer reuse rates increased significantly over time in the treatment group but remained unchanged in the control group (P<0.003) * Number of uses Use of a heparin model can improve dialyzer reuse rates Ouseph R, Brier ME, Ward RA Am J Kidney Dis. 2000;35(1):89.

21. UFH Risks Benefits • Bleeding • Heparin-induced thrombocytopenia • Hypertriglyceridemia • Anaphylaxis • Hyperkalemia • Bone mineral disease • Decreased clotting of the dialysis circuit • Low cost • Widely available • Short half-life • Reversible with protamine

22. Low molecular weight heparin

23. Low molecular weight heparin • MW 4-5 kDa • 18 saccharide units • LMWH inactivate factor Xa • Lesser effect on thrombin (factor IIa)

24. Low molecular weight heparin

25. LMWH VS HEPARIN • More specific binding action >UFH • Easier to dose by weight • Single prefilled syringe injection • Increased half-life 2-4 hr • Prefer IV > SC • No agents for reverse its effects

26. LMWH for Anticoagulation During Long-term Hemodialysis

27. LMWH for Anticoagulation During Long-term Hemodialysis

28. Monitor anticoagulations • No routinely measure anticoagulation parameters • Dialyzer clotting • Prolonged bleeding following dialysis • Monitoring with the activated partial thromboplastin time (aPTT) is not accurate • Measurement of anti-factor Xa levels keep 0.4-0.6 IU/mL or high risk bleeding 0.2-0.4 IU/mL

29. Efficacy and safety

30. Comparison of LMWH (enoxaparin) and standard heparin for HD anticoagulation • 36 chronic HD pts • Randomly assigned to enoxaparin (1 MKD) or standard heparin, followed for 12 wks  Single-dose protocol of enoxaparin is an effective and very convenient alternative to sodium heparin * *+ Frequency of clot formation (%) * * * * + + Grade Saltissi D, et al. Nephrol Dial Transplant 1999;14:2698-703.

31. Meta-analysis: LMWH VS HEPARINBleeding: vascular access compression time LMWH and unfractionated heparin are similarly safe in preventing extracorporeal circuit thrombosis Lim W, et al. J Am SocNephrol 2004;15:3192-206.

32. Meta-analysis: LMWH VS HEPARINExtracorporeal circuit thrombosis LMWH and unfractionated heparin are similarly effective in preventing extracorporeal circuit thrombosis Lim W, et al. J Am SocNephrol 2004;15:3192-206.

33. Adverse effects

34. Adverse effects: LMWH VS HEPARIN • Thrombocytopenia • Osteoporosis • Hyperkalemia • Hyperlipidemia

35. HEPARIN-INDUCED THROMBOCYTOPENIA IN HEMODIALYSIS • Frequency of HIT is suggested to be 8.1% of patients exposed to heparin • Significantly lower (1.8%) in patients exposed to LMWH Syed S, Nat Rev Nephrol 2009;5:501-11.

36. HEPARIN-INDUCED THROMBOCYTOPENIA • Type I HIT • Heparin binds, activates, and depletes platelets. • Typically occurs within the first 4 days of starting heparin therapy • Mild thrombocytopenia withaverage 100,000/mm3 • Resolves with time • Heparin therapy does not need to be stopped

37. HEPARIN-INDUCED THROMBOCYTOPENIA • Type II HIT • Usually occurs 5-12 day • Heparin binds to platelets, releasing platelet factor 4 (PF4) • More platelet aggregation • Paradoxical thrombus formation with limb-threatening ischemia

38. HEPARIN-INDUCED THROMBOCYTOPENIA • Extensive cross-reactivity (>90 percent) between the LMWH and standard heparin in terms of antibody recognition

39. HEPARIN-INDUCED THROMBOCYTOPENIA • No heparin hemodialysis • Regional citrate hemodialysis • Change to peritoneal dialysis • Other anti-coagulants

40. Heparin-induced thrombocytopenia (HIT) • In a patient with HIT • All heparin must be stopped • Using direct thrombin inhibitors (argatroban) or Factor Xa inhibitors (danaparoid or fondaparinux) > other or no anticoagulation during RRT (1A) • In a patient with HIT who does not have severe liver failure • Using argatroban rather than other thrombin or Factor Xa inhibitors during RRT (2C) KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

41. Adverse effects: LMWH VS HEPARIN • Thrombocytopenia • Osteoporosis • Hyperkalemia • Hyperlipidemia

42. Effect of LMWH on bone metabolism in patients on maintenance hemodialysis • 40 patients on stable hemodialysis using unfractionated heparin (UFH) for more than 24 months • Tartrate-resistant acid phosphatase (TRACP) reflecting osteoclastic activity was elevated in 35% of patients. • Following LMWH treatment, TRACP was reduced by 13% (p<0.05) LMWH may partially alleviate osteoporosis associated with UFH administration in patients on maintenance hemodialysis. Lai KN, et al. Int J Artif Organs 2001;24:447-55.

43. Bone Mineral Disease • UFH is known to increase the risk of osteoporosis in pregnancy

44. Adverse effects: LMWH VS HEPARIN • Thrombocytopenia • Osteoporosis • Hyperkalemia • Hyperlipidemia

45. Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of LMWH and unfractionated heparin Comparison of unfractionated heparin (UH) and low molecular weight heparin (LMWH) protocols Hottelart C, et al. Artif Organs. 1998;22(7):614-617.

46. Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of LMWH and unfractionated heparin Comparison of unfractionated heparin (UH) and low molecular weight heparin (LMWH) protocols Hottelart C, et al. Artif Organs. 1998;22(7):614-617.

47. Hyperkalemia • Hypoaldosteronism with resultant hyperkalemia is a known side effect of UFH • Predialysispotassium levels decreased from 5.66 mEq/L to 5.15 mEq/L when patients were given LMWH instead of UFH Hottelart C, et al. Artif Organs. 1998;22(7):614-617.

48. Adverse effects: LMWH VS HEPARIN • Thrombocytopenia • Osteoporosis • Hyperkalemia • Hyperlipidemia

49. Reduced lipid concentrations during four years of dialysis with LMWH 500- 400- 300- 200- 100- 0- LMWH Triglycerides, mg/dL Heparin Heparin -20 -10 0 10 20 30 Time, months Triglyceride levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH Deuber HJ, Schulz W. Kidney Int 1991;40:496-500.

50. Reduced lipid concentrations during four years of dialysis with LMWH 350- 300- 250- 200- 150- 100- 50- 0- LMWH Heparin Heparin Cholesterol, mg/dL -20 -10 0 10 20 30 Time, months Cholesterol levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH Deuber HJ, Schulz W. Kidney Int 1991;40:496-500.