Hemodialysis Anticoagulation - Different Protocols / Protocol Selection - Dr. Gawad

1. Hemodialysis Anticoagulation Different Protocols / Protocol Selection Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria – EGY drgawad@gmail.com UNC, Mansoura, International Hemodialysis Course 13-18 Dec 2015

2. To download the full animated lecture please contact me on drgawad@gmail.com Visit www.NephroTubeCNE.com for more lectures

3. Patients on Hemodialysis are at risk of both bleeding tendency & thrombosis • uremia-associated platelet dysfunction • endothelial abnormalities. • anticoagulants on HD • systemic inflammation • diffuse endothelial damage. • ↓proteins C and S, antithrombin III levels & activity. • HD filters and lines • Turbulent blood flow and high shear stress during HD. • leukocytes and platelets coaggregate • high hematocrit • blood transfusions. Bleeding Thrombosis Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

4. Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Bombeli T, Spahn DR. Br J Anaesth. 2004 Aug;93(2):275-87

5. Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Bombeli T, Spahn DR. Br J Anaesth. 2004 Aug;93(2):275-87

6. Talk Outline • Unfractionated Heparin (UFH) • Low Molecular Weight Heparin (LMWH) • Heparin Free Dialysis • Regional anticoagulation with protamine reversal • Heparin Coated Filter • Regional Citrate Anticoagulation (RCA) • Citrasate • Heparinoids • Direct Thrombin Inhibitors • Platelet-inhibiting agents • Anticoagulation Selection Heparin related Citrate related Others

8. UFH Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Bombeli T, Spahn DR. Br J Anaesth. 2004 Aug;93(2):275-87

9. Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Brayan F. etal. Am Fam Physician. 1999 Feb 15;59(4):945-952.

10. Heparin Administration Methods Initial Bolus Followed by Method A Routine heparin constant-infusion method Method B Routine heparin single-dose-only or repeated-bolus method Method C Tight heparin constant-infusion method Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

12. A- Routine heparin, constant-infusion method Initial bolus dose Infusion dose Intermittent HD 2000 IU 1,200 IU/hr 50 IU/kg 800–1500 IU/hr CRRT 2000-5000 IU (30 IU/kg) 500-1000 IU/hr (5-10 IU/kg/hr) Target: aPTT 45 to 60 sec or 1.5 to 2.0 times normal ERBP. NDT, Volume 17 suppl 7 July 2002 ERBP. NDT, Volume 17 suppl 7 July 2002 Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

13. Heparin Monitoring – Clotting Tests A- Routine heparin, constant-infusion method Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

14. Heparin Monitoring – Clotting Tests A- Routine heparin, constant-infusion method Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

15. A- Routine heparin, constant-infusion method Initial bolus dose Infusion dose Intermittent HD 2000 IU 1,200 IU/hr CRRT 2000-5000 IU (30 IU/kg) 500-1000 IU/hr (5-10 IU/kg/hr) Target: aPTT 45 to 60 sec or 1.5 to 2.0 times normal When to stop heparin infusion? Stopping heparin infusion 1 hour prior to the end of dialysis will result in the desired clotting time at termination of the session Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

16. Heparin Monitoring – Clotting Tests A- Routine heparin, constant-infusion method In practice heparin therapy is ordinarily prescribed empirically, without monitoring of coagulation In patients who are at an elevated risk of bleeding, the need to monitor anticoagulation is often circumvented by using heparin-free dialysis. Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

18. B- Routine heparin, single-dose-only or repeated-bolus method Initial bolus dose Subsequent repeated boluses 4000 IU 1000-2000 IU when needed 2000 IU 1000 IU at start of 2nd hr 1000 IU at start of 3rd hr 1000 IU at start of 4th hr 2000 IU No repeated boluses Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

20. C- Tight (Minimum-dose) heparin, constant-infusion method • Recommended for patients who are at SLIGHT RISK for bleeding: –when the risk of bleeding is chronic and prolonged –if the use of heparin-free dialysis has been unsuccessful because of frequent clotting. Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

21. Heparin Monitoring – Clotting Tests C- Tight (Minimum-dose) heparin, constant-infusion method Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

22. C- Tight (Minimum-dose) heparin, constant-infusion method Obtain baseline clotting time Initial bolus dose = 750 IU Recheck Clotting time after 3 minutes Desired clotting time Start dialysis and heparin infusion at a rate of 600 IU/hr Monitor clotting times every 30 minutes Not desired clotting time Administer a supplemental bolus dose Keep clotting time within desired range Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

23. C- Tight (Minimum-dose) heparin, constant-infusion method When to stop heparin infusion? Continue heparin infusion until the end of the dialysis session Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

24. Clotting inspite of anticoagulation Don’t always blame heparin Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

25. Clotting inspite of anticoagulation Don’t always blame heparin Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

26. Clotting inspite of anticoagulation Recurrent clotting warrants individual reevaluation and adjustments in heparin dosing ERBP. NDT, Volume 17 suppl 7 July 2002

27. Complications of Heparinization 1- Bleeding • Incidence of bleeding ranges from 10 to 50 % • Mortality due to bleeding as high as 15 % • The risk of bleeding is proportional to the aPTT and not to the heparin dose van de Wetering et al. J Am Soc Nephrol. 1996 Jan;7(1):145-50. Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

28. Complications of Heparinization 1- Bleeding Post therapy needle puncture site bleeding Don’t always blame heparin • Re-evaluation of the heparin dose • Vascular access should be evaluated for the presence of outflow stenosis • Evaluation of needle insertion technique ERBP. NDT, Volume 17 suppl 7 July 2002 Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

29. Complications of Heparinization 2- Heparin Induced Thrombocytopenia www.NephroTubeCNE.com www.NephroTubeCNE.com

30. Other Heparin-associated Complications • Lipid: ↑ serum T.G., ↓ HDL • Hyperkalemia (heparin-induced suppression of aldosterone synthesis) • Pruritis • Anaphylactoid reactions (First Use Syndrome) • Osteoporosis • Alopecia ERBP. NDT, Volume 17 suppl 7 July 2002 Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

33. Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012

34. UFH Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Bombeli T, Spahn DR. Br J Anaesth. 2004 Aug;93(2):275-87 LMWH

35. Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Brayan F. etal. Am Fam Physician. 1999 Feb 15;59(4):945-952.

36. LMWH vs UFH • LMWH has: – longer half-life – more rapid onset of action – higher bioavailability – more predictable effects Aggarwal A. Nephrol Dial Transplant. 2004;19:1559–1563. Lai KN, et al. Int J Artif Organs. 2001;24:447.

37. LMWH vs UFH • LMWH has: – less nonspecific binding to the endothelium, plasma proteins, and platelets – less platelet and leukocyte activation and fibrin deposition on dialyzer surfaces – No antidote (not reversible with protamine) Aggarwal A. Nephrol Dial Transplant. 2004;19:1559–1563. Lai KN, et al. Int J Artif Organs. 2001;24:447.

38. LMWH vs UFH • LMWH has: – Less risk of heparin induced osteoporosis – less bleeding and less thrombocytopenia (but HIT occurs, due to cross-reactive Ab) – Less hyperkalemia – Less disturbance of lipid profile – Anaphylactoid first dose syndrome (as UHF) Kishimoto TK, et al. N Engl J Med. 2008;358:2457–2467. Aggarwal A. Nephrol Dial Transplant. 2004;19:1559–1563. Lai KN, et al. Int J Artif Organs. 2001;24:447. ERBP. NDT, Volume 17 suppl 7 July 2002

39. LMWH vs UFH J Am Soc Nephrol. 2004 Dec;15(12):3192-206. Mean differences for bleeding assessed as vascular access compression time

40. J Am Soc Nephrol. 2004 Dec;15(12):3192-206. Relative risks for extracorporeal circuit thrombosis LMWH vs UFH

41. ERBP. NDT, Volume 17 suppl 7 July 2002

42. But as LMWHs are very expensive and have generally not been found to be superior to UFH in terms of dialysis-related bleeding UFH is widely used

43. Commonly Used LMWHs IHD dosing Lower dosages should be used in patients who have a mildly increased risk of hemorrhage. Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

44. Commonly Used LMWHs IHD dosing longer half-life → permits anticoagulation with a single dose at the start of dialysis though split dosing may be better for extended dialysis sessions Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

45. Commonly Used LMWHs CRRT dosing Bolus Infusion Dalteparin 20 U/kg 10 U/kg per hour Sagedal S, Hartmann A. Eur J Med Res. 2004;9:125–130. Oudemans-van Straaten HM, et al. Crit Care Med. 2009;37:545–552. Enoxaparin and Nadroparin may be used, but the experience is limited

46. Commonly Used LMWHs CRRT dosing Joannidis M et al. Intensive Care Med 2007; 33:1571. Ashita J Tolwani, Keith M Wille. UpToDate. Nov 2015. But generally LMWHs are not widely used in CRRT because of a very prolonged half-life and may be associated with a high risk of bleeding No major benefit in terms of reduced bleeding episodes or increased filter survival associated with LMWH.

47. LMWHs Monitoring • aPTT is not accurate with LMW heparin • Measurement of anti-factor Xa levels provide a better indication • But coagulation tests are not routinely monitored with LMWH treatments (anti-Xa activity assays are not readily available) Polkinghorne KR et al. Am J Kidney Dis. 2002;40(5):990.

50. Heparin-free dialysis - Indications Persons with heparin allergy ERBP. NDT, Volume 17 suppl 7 July 2002 Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

51. Heparin-free dialysis - Procedure Heparin rinse: Rinse extracorporeal circuit with saline containing 2000 to 5000 units of heparin/L Drain the heparin-containing priming fluid by unheparinized saline at the outset of dialysis. Set the blood flow rate to 250-500 mL/min Periodic saline rinse with 50-250 mL of saline every 15-30 minutes Stamatiadis DN et al. Clin Nephrol. 2004;62(1):29.

52. Heparin-free dialysis - Procedure Heparin rinse: Rinse extracorporeal circuit with saline containing 2000 to 5000 units of heparin/L Drain the heparin-containing priming fluid by unheparinized saline at the outset of dialysis. Set the blood flow rate to 250-500 mL/min Periodic saline rinse with 50-250 mL of saline every 15-30 minutes This step is optional. Avoid if HIT Allow inspection of a hollow-fiber dialyzer for evidence of clotting Stamatiadis DN et al. Clin Nephrol. 2004;62(1):29.

53. Heparin-free dialysis - CRRT Predilution mode is preferred (because prefilter fluid replacement reduces the hemoconcentration within the hemofilter when plasma water is removed) Keeping the blood flows at 200 mL/min or higher Joannidis M et al. Crit Care. 2007;11(4):218.

56. Regional anticoagulation with protamine reversal binds to heparin and eliminates its anticoagulant activity van der Voort PH et al. Blood Purif. 2005;23(3):175-80.

57. Regional anticoagulation with protamine reversal binds to heparin and eliminates its anticoagulant activity Technically difficult and rebound bleeding two to four hours after the end of dialysis van der Voort PH et al. Blood Purif. 2005;23(3):175-80.

60. Heparin coated filter Evenepoel P et al. Am J Kidney Dis. 2007 May;49(5):642-9.

61. Heparin coated filter Evenepoel P et al. Am J Kidney Dis. 2007 May;49(5):642-9. The coated membranes were associated with a significantly increased incidence of membrane clotting

66. Regional Citrate Anticoagulation Stucker F et al. Crit Care. 2015;19(1):91. Apsner R et al. Am J Kidney Dis. 2005;45(3):557

67. Regional Citrate Anticoagulation Stucker F et al. Crit Care. 2015;19(1):91. Apsner R et al. Am J Kidney Dis. 2005;45(3):557

68. Regional Citrate Anticoagulation Stucker F et al. Crit Care. 2015;19(1):91. Apsner R et al. Am J Kidney Dis. 2005;45(3):557 • It may cause alkalemia on a long-term basis • Dialysis solution bicarbonate level should be reduced

69. Regional Citrate Anticoagulation The major problems: • hypocalcemia or hypercalcemia • hypernatremia (due to the hypertonic sodium citrate solution) • metabolic alkalosis Stucker F et al. Crit Care. 2015;19(1):91. Apsner R et al. Am J Kidney Dis. 2005;45(3):557

70. Regional Citrate vs Heparin Anticoagulation • RCA may reduce bleeding risk more. • RCA has similar or better efficacy on circuit patency depending. • RCA may also reduce neutrophil and complement activation in the extracorporeal circuit. Wu MY, et al. Am J Kidney Dis. 2012;59:810–818. Monchi M, et al. Intensive Care Med. 2004;30:260–265. Schilder L, et al. BMC Nephrol. 2014;15:19.

71. Kidney International Supplements (2012) 2, 89–115

72. Kidney International Supplements (2012) 2, 89–115

73. Kidney International Supplements (2012) 2, 89–115 RCA is not widely used for IHD but is more popular for CRRT.

76. Bicarbonate dialysis solution with low-concentration citrate (Citrasate™) A small amount of citric acid is used instead of acetic acid as the acidifying agent. acid and base concentrates are mixed resulting dialysis solution commonly contains 0.8 mmol/L (2.4 mEq/L) citrate. Citrate complexing with calcium → inhibit blood coagulation and platelet activation locally at the dialyzer membrane surface Ahmad S et al. Hemodial Int. 2005;9:264.

77. Bicarbonate dialysis solution with low-concentration citrate (Citrasate™) A small amount of citric acid is used instead of acetic acid as the acidifying agent. acid and base concentrates are mixed resulting dialysis solution commonly contains 0.8 mmol/L (2.4 mEq/L) citrate. Citrate complexing with calcium → inhibit blood coagulation and platelet activation locally at the dialyzer membrane surface Ahmad S et al. Hemodial Int. 2005;9:264. Further studies are needed to delineate the role of citric acid-based dialysates. It is commercially available.

80. Danaparoid Fondaparinux Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Bombeli T, Spahn DR. Br J Anaesth. 2004 Aug;93(2):275-87

81. Their use is primary in management of HIT Davenport. Semin Dial. 2011;24:382-385. Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

84. Argatroban Lepirudin (recombinant hirudin) Bivalirudin Pharmacology, 5th edition. Lippincott Williams & Wilkins. Chapter 20, IV. 2012 Image reference: Bombeli T, Spahn DR. Br J Anaesth. 2004 Aug;93(2):275-87

85. Their use is primary in management of HIT Davenport. Semin Dial. 2011;24:382-385. Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S. Bivalirudin aPPTr of around 1.5–2.0. infusion rate is 1.0–2.5 mg/hour (0.009–0.023 mg/kg/hour) adjusted to

87. Recombinant Hirudin – RB variant

93. Platelet-inhibiting agents • PGI2 and its synthetic derivative, Epoprostenol: – inhibit platelet aggregation and adhesion – PGI2 is a potent vasodilator, the risk of hypotension • Nafamostat mesilate – Synthetic serine protease inhibitor, – It is a prostacyclin analog that does not cause hypotension. – Several side effects (anaphylaxis, agranulocytosis, hyperkalemia) have been reported. Balik M et al. Blood Purif. 2005;23(4):325-9. Epub 2005 Aug 23. Higuchi N et al. Nephron. 2000 Nov;86(3):400-1.

94. Platelet-inhibiting agents • PGI2 and its synthetic derivative, Epoprostenol: – inhibit platelet aggregation and adhesion – PGI2 is a potent vasodilator, the risk of hypotension • Nafamostat mesilate – Synthetic serine protease inhibitor, – It is a prostacyclin analog that does not cause hypotension. – Several side effects (anaphylaxis, agranulocytosis, hyperkalemia) have been reported. There are only limited clinical experience with prostacyclin and few published reports of its safety and efficacy Balik M et al. Blood Purif. 2005;23(4):325-9. Epub 2005 Aug 23. Higuchi N et al. Nephron. 2000 Nov;86(3):400-1.

97. Patients with risk of bleeding ERBP. NDT, Volume 17 suppl 7 July 2002 Daugirdas. Handbook of dialysis. Chapter 14, 5th edition, 2015.

98. IHD CRRT Patient’s bleeding risk Routine UFH, constant infusion √ √ No risk Routine UFH, boluses or no bolus √ --- No risk Tight (Minimum-dose) heparin, constant-infusion method √ √ Slight minimal (if heparin free dialysis failed) LMWH √ √ (but not widely used, limited experience) No risk Heparin free dialysis √ √ Slight, moderate, high Regional anticoagulation with protamine reversal --- --- --- Heparin Coated Filter --- --- --- Regional Citrate Anticoagulation --- √ Slight, moderate, high Citrasate --- --- --- Heparinoids √ √ HIT Direct Thrombin Inhibitors √ √ HIT Platelet-inhibiting agents --- --- ---

99. Gawad Thank You

Hemodialysis Anticoagulation - Different Protocols / Protocol Selection - Dr. Gawad

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